Pertussis Surveillance in Sweden, Nineteen

Pertussis surveillance in Sweden

Nineteen-year report

Pertussis surveillance in Sweden

Nineteen-year report Bindningar och jäv För Folkhälsomyndighetens egna experter och utredare som medverkat i rapporter bedöms eventuella intressekonﬂikter och jäv inom ramen för anställningsförhållandet.

När det gäller externa experter och utredare som deltar i Folkhälsomyndighetens arbete med rapporter kräver myndigheten att de lämnar skriftliga jävsdeklarationer för potentiella intressekonflikter eller jäv. Sådana omständigheter kan föreligga om en expert t.ex. fått eller får ekonomisk ersättning från en aktör med intressen i utgången av den fråga som myndigheten behandlar eller om det finns ett tidigare eller pågående ställningstagande eller engagemang i den aktuella frågan på ett sådant sätt att det uppkommer misstanke om att opartiskheten inte kan upprätthållas. Folkhälsomyndigheten tar därefter ställning till om det finns några omständigheter som skulle försvåra en objektiv värdering av det framtagna materialet och därmed inverka på myndighetens möjligheter att agera sakligt och opartiskt. Bedömningen kan mynna ut i att experten kan anlitas för uppdraget alternativt att myndigheten föreslår vissa åtgärder beträffande expertens engagemang eller att experten inte bedöms kunna delta i det aktuella arbetet.

De externa experter som medverkat i framtagandet av denna rapport har inför arbetet i enlighet med Folkhälsomyndighetens krav lämnat en deklaration av eventuella intressekonﬂikter och jäv. Folkhälsomyndigheten har därefter bedömt att det inte föreligger några omständigheter som skulle kunna äventyra myndighetens trovärdighet. Jävsdeklarationerna och eventuella kompletterande dokument utgör allmänna handlingar som normalt är offentliga handlingarna ﬁnns tillgängliga på Folkhälsomyndigheten.

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Folkhälsomyndigheten har en förstärkt övervakning av kikhosta sedan de acellulära vaccinerna mot kikhosta introducerades i det nationella barnvaccinationsprogrammet i Sverige år 1996. Övervakningen innefattar incidens av rapporterade fall av kikhosta per åldersgrupp samt en uppföljning via strukturerade telefonintervjuer av alla rapporterade fall 0-20 år gamla. Denna rapport innehåller resultaten för år 2016 samt analys av studiens uppföljning under de senaste nitton åren.

Kikhosta är en särskilt allvarlig och ibland livshotande sjukdom för ovaccinerade spädbarn under sex månader är. Både sjukdomen kikhosta och vaccination mot kikhosta ger ett bra, men relativt kortvarigt skydd mot sjukdom. De senaste tre årens ökade incidens av kikhosta i Sverige, trots hög vaccinationstäckning, och ökningen av kikhosta i andra länder har aktualiserat vikten av fortsatt förstärkt uppföljning av kikhosta i Sverige.

Syftet med uppföljningen av kikhosta är att ge underlag för ändringar av vaccinationsprogrammet eller andra interventioner som kan skydda spädbarn mot kikhosta. Kunskap från uppföljningen om sjukdomens epidemiologi och allvarliga förlopp, vikten av provtagning och förebyggande antibiotikabehandling för de minsta barnen, sprids regelbundet via vetenskapliga publikationer, på Folkhälsomyndighetens webbplats och i samband med utbildningsdagar och kurser riktade till hälso- och sjukvårdspersonal.

Målgruppen för årsrapporten är hälso- och sjukvårdspersonal, och då särskilt personal inom mödravård, barnhälsovård och barnsjukvård samt primärvård och smittskyddsenheter.

Rapporten har skrivits av Bernice Aronsson (projektledare), Henrik Källberg, Emma Byström och Kerstin Drakes-Jämtberg. I den slutliga utformningen har enhetschef Ann Lindstrand och avdelningschef Anders Tegnell deltagit.

Folkhälsomyndigheten

Johan Carlsson, Generaldirektör Preface

The Public Health Agency of Sweden has conducted enhanced surveillance of pertussis since 1996, when acellular vaccines were introduced in Sweden´s national immunisation programme for children. The surveillance includes the incidence of reported pertussis cases per age group and follow-up of all reported cases of pertussis among those 0-20 years of age through structured telephone interviews. This report includes results for 2016, as well analyses from the past 19 years of surveillance.

Pertussis is particularly serious and sometimes life threatening for unvaccinated infants under the age of 6 months. Both pertussis infection and vaccination provide good, but relatively short-lived protection against the disease. The increased incidence of pertussis in Sweden during the last three years – despite high vaccination coverage – and the increase in pertussis in other countries has accentuated the importance of enhanced follow-up of pertussis cases.

The aim of the surveillance of pertussis is to provide knowledge to make informed changes in the national immunisation programme or other interventions to protect infants. Surveillance data on pertussis epidemiology and on severe disease progression, as well as the importance of laboratory testing and prophylactic antibiotic treatment of infants, are disseminated regularly through scientiﬁc articles, on the website of the Public Health Agency, and at conferences and in courses aimed at health care professionals.

This report is written for health care professionals, particularly those working in maternal and child health care, school health care (elevhälsan), and primary care as well as those working at the counties´ Department of Communicable Disease Control and Prevention.

The report was written by Bernice Aronsson (project leader), Henrik Källberg, Emma Byström, and Kerstin Drakes-Jämtberg. Head of Unit Ann Lindstrand and Anders Tegnell, Head of the Department of Monitoring and Evaluation, participated in the ﬁnal revisions of the report.

The Public Health Agency of Sweden

Johan Carlsson, General Director Table of contents

Förord(preface) ...... 5

Abbreviations ...... 12

Summary ...... 13

Introduction of the Swedish Surveillance study of pertussis 14

1 Material and Methods 15

1.1 Datasources ...... 15 1.1.1 SmiNet - mandatory reporting of pertussis cases in Sweden ...... 15

1.1.2 Enhanced surveillance study of pertussis ...... 15

1.1.3 Gothenburg study area ...... 18

1.1.4 Trial I and Trial II ...... 20 1.1.5 Collection of data in the enhanced surveillance study ofpertussis ...... 21

1.2 Diagnostics ...... 23

1.2.1 Methods of diagnostics ...... 23

1.2.2 Case definition ...... 27

1.3 Vaccination...... 27

1.3.1 Vaccination registration ...... 27 1.3.2 Vaccination schedule included in the National Immunisation Programme since 1953 ...... 27

1.3.3 Vaccines used ...... 30

Vaccines during the first year of life ...... 30 Acellular pertussis containing booster vaccines after the first yearofage ...... 31

Vaccine studies in Sweden in the enhanced surveillance study 31 1.3.4 Vaccination coverage ...... 32 1.4 Sample size considerations and the calculation of incidences ...... 33

2 Results 35

2.1 Incidences and cases of pertussis in all age groups . . . . . 35

2.1.1 Number and incidence of pertussis cases in 2016 . . 35

2.1.2 Incidence and cases over time ...... 35 2.1.3 Incidence and cases of pertussis, distributed by age and time intervals ...... 38 Incidence of pertussis in defined age-groups, before and after the introduction of DTaP vaccination ...... 42 Incidence of pertussis at 1-20 years of age presented in timeintervals ...... 42

Pertussis in fully vaccinated children ...... 45

Incidences and cases of pertussis for -all age groups . . . . 47

2.2 Pertussis in infants ...... 48 2.2.1 Number of pertussis cases in 2016 in infancy by vaccination status ...... 49

2.2.2 Timing of vaccinations ...... 50 2.2.3 Incidence and cases of pertussis among the 0–20 years of age, distribution by age and vaccination status ...... 51 2.2.4 Incidence of pertussis in infancy by date and after changes to the national immunisation programme . . 53 2.2.5 Incidence of pertussis during and after the first year of life presented in time intervals ...... 55 Pertussis in infants in different years and in relation to other agegroups...... 56

2.3 Severity of pertussis in infants ...... 58

2.3.1 Hospitalization ...... 59

The rate of hospital admission for pertussis by age . . . . . 59 Hospital stay by age and vaccination status at the pertussis episode...... 60

2.3.2 Complications due to pertussis ...... 61

The rate of complications due to pertussis and by age . . . . 62 Complication in relation to age and vaccination status at the pertussis episode ...... 63

2.3.3 Spasmodic cough ...... 63

Cases of spasmodic cough due to pertussis ...... 63 Duration of spasmodic cough, age and vaccination status at episodestart...... 64

2.3.4 Deaths ...... 66

In conclusion: Severity of pertussis in infants ...... 66

2.4 Treatment of pertussis ...... 69

2.5 Case contact study of pertussis in infants ...... 70 2.6 Geographic differences in Sweden for laboratory-confirmed pertussiscases ...... 70

2.7 The effects of catch-up and booster vaccination schedules . 71

2.7.1 Immunisations during the 1990s ...... 71 2.7.2 Immunisations during the 1990s in pertussis vaccine trials ...... 72 2.7.3 Booster vaccination in children born from 1995 and from 2002 (see also chapter 1.3) ...... 72

2.7.4 Effectiveness of the preschool booster vaccination . . 72

2.8 Follow up of vaccine studies and immunisation 1996-97 . . 72

2.8.1 TrialsIandII ...... 72 2.8.2 Surveillance of children immunised Jan 1, 1996, to Sep30,1997 ...... 74 2.9 Pertussis incidence in Västra Götaland and the evaluation of severity of pertussis in the Gothenburg study area . . . . . 76

2.9.1 Incidences and cases of pertussis in Västra Götaland 77 2.9.2 Severity of pertussis in the enhanced surveillance study for children in the Gothenburg study area in comparison with rest of Sweden ...... 81

3 Discussion 86

4 Plan for continued work 96

4.1 Scientific publications and presentations ...... 97

4.2 Limitations...... 97

5 Administration 99

6 Reports from published peer-reviewed papers 100

6.1 Published reports based on the enhanced surveillance data . 100

7 References 102

8 Appendix 115

8.1 Information ...... 115

8.2 Tables referring to Chapter 2.1 to 2.9 ...... 115

8.3 Severity of pertussis ...... 135 8.3.1 Severity of pertussis in Sweden including the Gothenburg study area (from 2003) and excluding the Gothenburg study area (from 1997) ...... 135 8.3.2 Cases of hospitalization due to pertussis for all of Sweden ...... 135 8.3.3 The rate of hospital admission for pertussis by age forallofSweden ...... 135 8.3.4 Incidence of hospital admission and age at the onset of pertussis episode for Sweden without Gothenburg studyarea...... 135 8.3.5 Duration of hospital stay by age and vaccination status at the start of the pertussis episode ...... 135

8.4 Complications in the enhanced surveillance study ...... 144 8.4.1 Cases of complications due to pertussis for all of Sweden ...... 144 8.4.2 2 The correlation between the rate of complications due to pertussis and age for all of Sweden ...... 144

8.4.3 Incidence of complications and age for all of Sweden 144 8.4.4 Complications, age, and vaccination status at the start of the pertussis episode for all Sweden . . . . . 145 8.4.5 Spasmodic cough in Sweden with and without Gothenburg studyarea...... 151 8.5 Updated tables with incidence data from the onset of the enhanced studies in Sweden and in the Gothenburg study area, respectively ...... 159 Abbreviations

aP acellular pertussis (vaccine)

CHC Child health care

DTaP Full dose vaccine against diphtheria-, tetanus- and acellular pertussis vaccine

DTap Full dose tetanus toxoid and reduced dose of accelular pertussis antigens and reduced dose of diphtheria toxoid

EPS Enhanced pertussis surveillance

FHA Filamentous haemagglutinin

Hib Haemophilus inﬂuenzae type b

IPV Inactivated polio vaccine

NIP National immunisation programme

PCR Polymerase chain reaction

PHAS Public Health Agency of Sweden

PRN Pertactin

PT Pertussis toxoid

SHC School health care

SMI Smittskyddsinstitutet, in English: Swedish Institute for Communicable Disease Control

SmiNet Computer-linked reporting system for reports of notiﬁable diseases, including pertussis infections

wP whole-cell pertussis (vaccine) Summary

For several decades there has been a 97–98% coverage of the vaccinations recommended in the National Immunisation Programme (NIP) in infancy, delivered through Sweden’s well-established Child Health Clinic (CHC) system. This 19-year enhanced pertussis surveillance (EPS) has reported on the epidemiology of pertussis in Sweden at the population level since acellular pertussis (aP) was introduced in 1996. This report shows that since the introduction of aP vaccine, there has been a dramatic decline in the overall pertussis incidence in the Swedish population. However, after years of low pertussis incidence there has been an increase in the number of reported pertussis cases in almost all age groups during the last three years, which might be an indicator of waning immunity. The increase of pertussis in 2014 was difﬁcult to predict because it was neither preceded by a decrease in vaccination coverage nor by an obvious increase of pertussis in any age group. With the current situation, it is reasonable to believe that Sweden has passed the honeymoon period as described by de Celle‘s (2016). In the present 19-year report, 647 labortory-conﬁrmed cases of pertussis were reported to SmiNet during 2016, of which 87 cases were among infants younger than 1 year of age. As in previous years, infants had the highest incidence (74.1 cases/100,000 person years) out of all age groups in 2016. The high incidence and high rate of hospitalisation among infants was largely in infants who contracted pertussis before they received one or two doses of vaccine. The results in this report suggest that even after one dose of a pertussis vaccine there is some protection against severe pertussis, indicating the importance of timely vaccination in infants. Sweden has had a relatively late resurgence of pertussis, which might be due to the stable and high vaccination coverage since the introduction of aP vaccine in 1996 and to a long period without pertussis vaccine in the NIP, generating cohorts with naturally acquired immunity with longer duration of disease protection. The booster vaccination (4th dose) was administered during 2007–2012 to two birth cohorts, and this might have extended the period with low incidence among children of school age. Other age groups associated with increased and higher incidences in 2016 compared to 2015 were the 11, 13, and 17 year olds. Future EPS reports will provide data on the effectiveness of the booster dose introduced in 2016 for 14–16 year olds. Despite the existing preventive strategies for reducing pertussis cases in infants, many infants still contract the disease. Infants too young for vaccination are at the greatest risk of life-threatening pertussis, and thus effective strategies to protect the youngest infants are needed. In the case of a further increase of pertussis in infants, other preventive interventions, including recommendation of maternal vaccination, will be re-evaluated when more data on safety and interference are available, and complementary strategies might be recommended in the future.

13 Introduction of the Swedish enhanced surveillance study of pertussis

The main aims of the EPS are to evaluate the impact of the NIP against pertussis on the epidemiology of the disease and its severity, to follow up on the long-term protection after vaccinations with acellular pertussis (aP)-containing combination vaccines, and to document potential effects of changes in the NIP. The results and experiences from the annual enhanced follow-up in Sweden have been published in scientific reports by the Public Health Agency of Sweden (PHAS) (formerly the Swedish Institute for Communicable Disease Control (SMI)) and in reviewed papers, among which the following are the most important (Olin 1999, 2003, Trollfors 2001, Gustafsson 2006, Carlsson 2009, Nilsson 2012, and Carlsson 2015). Further scientific papers are described in Chapter 6. The results from the pertussis serology and other laboratory studies have been published in several papers (Advani 2004, 2007, 2009, Hallander 2005, Elomaa 2007, Hallander & Andersson 2009, Hallander & Gustafsson 2009, and Zeddeman 2014) and in pertussis serology reports with analyses from 1997 and 2007 (reports from the SMI). The EPS includes laboratory-confirmed pertussis cases 0–20 years of age born from 1996 onwards in Sweden, excluding the Gothenburg study area until 2003 and whose parents/caregivers have been interviewed on the duration of cough, complications, treatments, etc., from Oct 1, 1997, onwards. One area of Sweden, called the Gothenburg study area, located within the region of Västra Götaland, was excluded from the enhanced follow-up until 2003 because pertussis surveillance was conducted within a clinical trial setting, including a mass vaccination project, in this study area. In the Gothenburg study area different vaccines was used compared to the NIP as described in 1.3.3. The results and experiences from the follow-up in the Gothenburg study area have been published in scientific journals (Trollfors 1995, Taranger 1997, and Taranger 2001) and also as reports published on the PHAS website (reference in report list: 14-year report, Pertussis Surveillance, Pertussis in the Gothenburg study area). Children from the Gothenburg study area have thereby been reported within the EPS from Jan 1, 2003, onwards and are also included in this report. Children from the Gothenburg study area was reported within the EPS from Jan 1 2003, when the vaccination schedule in this area was alligned to the rest of Sweden (according to NIP). The group with the highest incidence of pertussis – infants – is described in separate sections in the current report. The severity of the pertussis disease is described with regard to vaccination status, hospitalisation, complications, spasmodic cough, duration of cough, etc. Tables presenting age-stratified incidences separating data for the Gothenburg study area and the rest of Sweden appear in the appendix.

14 1 Material and Methods

1.1 Data sources

1.1.1 SmiNet - mandatory reporting of pertussis cases in Sweden

Pertussis was included as a notifiable disease in the new Communicable Disease Act in 1997 (Figure 1). Since Oct 1997, all cases of pertussis, including clinically suspected and/or laboratory-confirmed by culture, polymerase chain reaction (PCR), or serology, should be reported to the PHAS (fomer SMI until 2013) through a computer-linked reporting system called SmiNet (see (Rolfhamre 2006) for a description of SmiNet). Although clinically suspected cases are reporterd to Sminet, only laboratory-confirmed cases are presented in this report. The SmiNet database contains information on patients of all ages. During 1980 to 1996, laboratory-confirmed pertussis was voluntarily reported from all bacteriological laboratories with full personal identifiers. Also, there has been a long-standing Swedish tradition of pertussis reporting by county medical officers since early in the 20th century.

1.1.2 Enhanced surveillance study of pertussis

The EPS in Sweden started in Oct 1, 1997, which was 1 year and 9 months after the introduction of aP vaccines at the ages of 3, 5, and 12 months in the NIP. Cases 0-20 yeras of age are included in the EPS based on culture-positive or PCR-positive reports of pertussis, (and from 2008 also including serology-positive cases), in the SmiNet data base. Hence, only laboratory-conﬁrmed cases of pertussis are included in the EPS report. In the EPS, additional information about these cases is then collected through structured telephone interviews with the parents of children diagnosed with pertussis. Complementary information is also collected from medical records (described in Section 1.1.5).

Figure 1: Reporting of pertussis cases to SmiNet and further to the enhanced surveillance study.

The surveillance period is somewhat different depending on the area of

15 residence, with a shorter surveillance period in the Gothenburg study area (Figure 2). The Gothenburg study area differed in relation to the vaccines that were used in this study area during the initial years (Oct 1, 1997–Dec 31, 2002) and the type of vaccination program (there was a catch-up campaign in Gothenburg study area) as further described below.

Inclusion criteria in the EPS are as follows:

1. Being born Jan 1, 1996, or later or being included in the pertussis vaccine trial cohorts (described in more detail below) and followed-up until 20 years of age.

2. Episode start: a) outside the Gothenburg study area and having a pertussis episode starting Oct 1, 1997, or later or b) in the Gothenburg study area (described in more detail below) and having a pertussis episode starting Jan 1, 2003, or later.

For ease of interpretation, the pertussis vaccine trial cohorts (Trial I and Trial II, described in section 1.1.4) have been excluded from most analyses in the current report. Furthermore, persons included in Trial I and Trial II were born in 1992 and 1993-1994 respectively, and are thereby not included in the EPS report that includes pertussis cases born Jan 1, 1996, or later (0-20 years of age).

Oct 1997 Jan 2003 Now Gothenburg study Area Gothenburg study area data according to Vaccine data only the enhanced surveillance study

Sweden excluding Gothenburg study area data according to the enhanced surveillance study

Figure 2: The enhanced surveillance study in Sweden.

16 Time period Length of Type of data Area evaluation Oct 1, 1997, 19 years Prospective Sweden until Dec 31 clinical and excluding 2016 vaccine data Gothenburg

Oct 1, 1997, 5 years Retrospective Gothenburg until Dec 31, vaccine data study area 2002

Jan 1, 2003, 14 years Prospective Gothenburg until Dec 31 clinical and study area 2016 vaccine data

Table 1: Description of the available data. See below for a more detailed description of the surveillance study in the Gothenburg study area.

The situation in Sweden is unique, being a European country without pertussis vaccination in the NIP from 1979 to 1996 and with a well-implemented NIP and a long-standing tradition of quality in the reporting of laboratory-conﬁrmed cases. This long-term EPS study has been ongoing for over 19 years as of Dec 31, 2016 (Table 1). The mandatory case-based reporting system (SmiNet) was used to identify cases conﬁrmed by culture (and later also by PCR in children born from Jan 1, 1996 onwards, and by serology from 2008).

In the present 19-year report, 647 laboratory-conﬁrmed pertussis cases were reported to SmiNet during 2016. For the EPS study, 298 new cases (including 14 in the Gothenburg study area) with disease onset in 2016 were included in the enhanced analysis (pertussis cases among those 0–20 years of age). For the Gothenburg study area, the enhanced surveillance started in Jan 1, 2003. Accumulated data during the EPS from Jan 1, 2003 till Dec 31, 2016, show that there were a total of 3,446 cases (706 from the Gothenburg study area) in cohorts that were followed up for pertussis in Sweden.

Also, previous pertussis trial cohorts of around 10,000 infants in 1992–1995 and 82,000 infants in 1993–1996 (Trial I and Trial II, respectively) have been evaluated (Gustafsson 1996, Olin 1997). In these trials, both the whole cell pertussis (wP) and aP vaccines were used in the era before the aP vaccine was approved and introduced in the NIP. Data from these trials with lengthier investigative protocols and more thorough evaluations and diagnoses of the children have been evaluated in previous surveillance

17 studies and have been followed up and reported on (Gustafsson 1996, Olin 1997). The changes over time in age-speciﬁc rates of pertussis have been considered as the main outcome, and we have also linked clinical outcome to vaccination status.

Total number of cases, data sources, and vaccination status: When including cases from Trials I and II, the total number of pertussis cases followed up is currently at 4,890. The database comprises Sweden excluding the Gothenburg study area, the Gothenburg study area, and vaccine Trial I and Trial II. The number of cases for each sub-cohort is presented in Table 2. In the present 19-year report, 298 new laboratory-conﬁrmed pertussis cases among those 0–20 years of age with vaccination and clinical data were included in the analyses of the EPS data.

Pertussis cases Sweden excluding the Gothenburg study area 3460 Gothenburg study area 706 Trials I and II 724 Total 4890

Table 2: The number of pertussis cases among those 0-20 years of age followed up in the EPS in Sweden excluding the Gothenburg study area, the Gothenburg study area, and Trials I and II. Data are from laboratory-conﬁrmed case reports of pertussis with episodes starting between Oct 1, 1997 and Dec 31, 2016, in Sweden excluding the Gothenburg study area and Trials I and II. For the Gothenburg study area the data are from case reports of pertussis with episodes starting between Jan 1, 2003, and Dec 31, 2016.

1.1.3 Gothenburg study area

Gothenburg was initially not part of the EPS because the vaccination schedule and vaccines used in Gothenburg (monovalent aP (see chapter 1.3.3)) were different from the rest of Sweden. During the years 1996–1999, the Gothenburg mass vaccination project offered free catch-up vaccination with three doses to all children born in the 1990s (Taranger, 2001). There was no free catch-up offered in the rest of the country, but monovalent aP vaccine was available until the year 2000, and many children in the rest of the country were vaccinated at their parents’ expense during these years. Children from the Gothenburg study area have thereby been reported within the EPS only from Jan 1, 2003, onwards, when the vaccination schedule in this

18 Gothenburg study area was aligned to the rest of Sweden (according to NIP). The Gothenburg study area comprised about 10% of the Swedish population.

Previously, a separate report for the Gothenburg study area was published every year (reference report: 14-year report, Pertussis Surveillance in the Gothenburg study area).The differences between the Gothenburg study area and the rest of Sweden have levelled out since 2005, and thus the previous approach with two separate reports is no longer needed. Data on pertussis cases among those 0–20 years of age from the Gothenburg study area are collected and included in the EPS database, and when relevant issues are formulated, separate data from the Gothenburg study area and the rest of Sweden will be reported.

In the SmiNet database on mandatory reporting data, detailed information about area of residence is not available. When using this data set, the Västra Götaland county area is used as an approximation of the Gothenburg study area (see Figure 3, for the size and geographic make-up of the Gothenburg study area).

19 County of Västra Götaland (1,671,783)

Västra Götaland Kungsbacka Gothenburg study area without Gothenburg within Halland within Västra Götaland study area (80,442) (863,231) (808,552)

Gothenburg study area (943,673)

Figure 3: Description of the Gothenburg study area in relation to the two counties Västra Götaland and Halland. The number of inhabitants in 2016 is given in parentheses.

1.1.4 Trial I and Trial II

Children born in 1992 and in 1993–94 who participated in the two nationwide pertussis vaccine trials of 1992–1993 and 1993–96, Trial I and Trial II (Gustafsson 1996, Olin 1997), respectively, have also since then been identiﬁed through the national register of communicable disease reports and entered into a separate study database. The cases of pertussis have also been followed-up in detail by study nurses who documented the vaccination history and clinical course through structured telephone interviews according to the same procedures carried out during Trial II (Olin, 1997). Pertussis Trial I with a 2-4-6 month schedule included 9,829 infants born in 1992. In Trial II with either a 3-5-12 month schedule (72,698 infants) or a 2-4-6 month schedule (10,194 infants), the pertussis vaccine was administered to children born from June 1993 to May–June 1994 (Gustafsson 1996, Olin 1997). Children participating in Trials I and II have been followed up in the EPS database from Oct 1, 1997. As mentioned above, these cohorts have been excluded

20 from most analyses in the current report. Some results are presented in Section 2.8.1, and more detailed analyses have been presented previously (Gustafsson 1996, Olin 1997). Moreover, the EPS only includes pertussis cases among those 0–20 years of age, and thus persons included in Trial I and Trial II are now too old to be included in the enhanced surveillance study report. However, historical data on pertussis cases included in these trials can be analysed and reported on demand. Furthermore, if persons included in these trials were reported as pertussis cases, they were followed up by the SmiNet reporting system and are possible to identify.

1.1.5 Collection of data in the enhanced surveillance study of pertussis

All data in this report encompass information obtained in two ways: A) within the regular Swedish surveillance of communicable diseases (SmiNet 1.1.1) and B) within the EPS study.

A Within the regular Swedish surveillance of communicable diseases: In Sweden, pertussis has been a notifiable disease since 1996, and it is one of the diseases with mandatory contact tracing. Laboratories report laboratory-confirmed cases by notifications both to the PHAS and to the County Medical Officer of Communicable Disease Prevention and Control. A confirmed case is a case with a positive culture, PCR, or serology result (seroconversion or significant increase in IgG against pertussis toxin (PT)). The notifications are immediately available at both the national and regional level through the web-based SmiNet registry based on disease and personal identifiers. There is limited or no information in the reports on vaccination status or clinical details, including case contacts, but age-specific incidence rates can be calculated from the age at the reporting date. In this report, the annual number of cases notified to SmiNet are based on date of notification of the case.

B Within the EPS: The EPS in Sweden was established in Oct 1997. Every case of laboratory-reported pertussis among those 0–20 years of age, born in 1996 or later, is identified in SmiNet for detailed follow-up, except for those occurring from Oct 1, 1997, to Dec 31, 2002, in the Gothenburg study area where a local surveillance project was in place. All identified reports are matched against the population registry for parental contact details and to check that there has been no death notification. A research nurse performs structured telephone interviews with the parents of each case using a standardized questionnaire. The clinical questions include the type and duration of cough, the

21 presence of apnoea and other complications, the number and length of hospital admissions, the timing of antibiotic treatment if given, and the vaccination dates. If medical records are needed for complementary medical information, the parents are contacted to provide consent. The families of deceased children are not contacted, but their Child Health Care (CHC) records provide vaccination status, and information on gestational age is obtained from the medical birth register. The individual vaccination history allows for the calculation of age-specific incidence rates in vaccinated and non-vaccinated children. With access to clinical information, data from the EPS study are based on the age at onset of symptoms, which is important when analysing the age-specific severity of disease in infants. Date of onset is used as basis for analysis in EPS instead of date of notification of case (as in SmiNet registry), in order to improve data quality.

Vaccination history: The detailed vaccination histories of pertussis cases born since 1996 were obtained from the medical records of the CHC or School Health Care (SHC) Centers by a telephone call to the nurse attending the individual child.

Severity of disease: Parameters reﬂecting severity of disease included duration of spasmodic cough and total duration of cough and hospital admissions.

Data on respiratory complications, neurological complications, dehydration with >5% of weight loss, or other serious complications during the pertussis episode were collected and registered in the database.

Antibiotic treatment: Information on antibiotic use was collected in pertussis cases among those 0-20 years of age, born from Jan 1, 1996, with episodes starting between Jan 1, 2003 and Dec 31, 2016. Data on the time between the onset of an episode and the start of antibiotic treatment were collected along with data on the length of treatment and the type of antibiotics.

Source of transmission This has been included in the EPS study since 2009. A structured questionnaire was added to the telephone interview in the enhanced surveillance study with questions concerning the source of transmission. This information was added to the pertussis cases in infants younger than 1 year. All parents/caregivers were asked if someone who had been coughing for more than a week had been in close contact with the infant with conﬁrmed pertussis disease in the month prior to the start of the episode in the infant. Questions were also asked whether it was none, one, two, or up to three contacts who had had a cough for more than a week.

Database: All clinical data and the unique Swedish personal identiﬁcation numbers were entered into a database. Progress reports have summarized

22 the database information for all episodes up to the end of the previous project year, with the present 19-year report updating the information from Oct 1, 1997, until Dec 31, 2016.

The numbers of pertussis cases with cough characteristics available from the whole country and from the cohorts (the Gothenburg study area and Sweden excluding the Gothenburg study area) are described in Figure 7 Appendix and Figure 9 Appendix.

1.2 Diagnostics

1.2.1 Methods of diagnostics

A confirmed case of pertussis is a case with a positive isolation of Bordetella pertussis (culture), positive PCR for pertussis, or positive result by serology (seroconversion or significant increase in IgG against PT) and these are the case definitions used for notification under the Communicable Diseases Act as detailed in Figures 4 and 5, and Table 3. PCR was the most common diagnostic method used in 2016 (82.3% of the cases). During 2016, all new cases included in the EPS were laboratory-confirmed cases (Table 3).

Starting Jan 1, 2014, the PHAS began to collect data from all laboratories in Sweden on the total number of samples that were analysed for B pertussis (PCR, culture and/or serology). During 2016, a total of 14,306 samples were tested for pertussis, 214 samples by culture, 12,898 by PCR-, and 1,194 by serology. A total of 13,358 samples were tested for pertussis in 2014, and 13,167 samples were tested in 2015. There was no signiﬁcant difference between the total number of samples tested in 2015 compared to 2016. The yearly collection and reporting of these data will help us to further analyse the level of awareness and the epidemiology of pertussis.

The diagnostic methods used have changed over time and in the different age groups. Up to 2003, conﬁrmation of B. pertussis by culture was the dominant laboratory method in all age groups. In children, PCR is now the most common method for diagnosing pertussis. In the older age group, the use of serology and PCR testing has increased. Thus, since 2006 serology and PCR have been the most common methods used for diagnosing pertussis in patients older than 10 years of age (Figures 4 and 5).

In 1997 the proportion of PCR-conﬁrmed cases was less than 5% and in 2003 around 20% of all laboratory reports were based on PCR. Nowadays less than 5% of the pertussis reports are based on culture (Table 3). It is well known that PCR has a higher sensitivity in comparison with culture, especially in milder cases and later stage of the disease but at cost of a

23 higher risk of false-positivity. The increasing use of PCR might thus increase the reporting of cases. Serology has the advantage of higher sensitivity in cases where diagnosis is performed late in the disease. However, serology has a lower speciﬁcity than culture and PCR.

Culture PCR 1500 Serology

1000 Cases

500

0 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

Year

Figure 4: Laboratory methods used for veriﬁcation of cases in children aged 0-10 years. Data are based on laboratory-conﬁrmed cases reported to SmiNet, according to the Communicable Disease Act.

24 400

Culture PCR 300 Serology

200 Cases

100

0 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015

Year

Figure 5: Laboratory methods used for veriﬁcation of cases in children and adults aged 11 years or older. Data are based on laboratory-conﬁrmed cases, reported to SmiNet, according to the Communicable Disease Act.

25 Age (years) Method 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 12 13 14 15 16 Age (years) 0-10 Culture 607 959 1553 1699 564 763 255 336 231 78 32 21 19 6 3 5 3 1 1 2 PCR 59 58 76 6 32 27 63 514 242 138 161 102 60 92 52 85 76 200 158 167 Serology 15 0 0 28 10 14 7 12 17 21 42 26 16 11 2 6 8 12 2 3 11- Culture 37 87 201 280 106 196 115 185 158 56 26 9 20 14 3 8 0 3 9 9 PCR 5 2 12 2 3 8 23 148 125 106 103 89 51 67 47 87 89 366 305 364 Serology 7 0 0 6 7 7 6 15 45 72 159 113 82 53 62 78 47 97 105 100

Table 3: Laboratory methods used for veriﬁcation of cases in children 0-10 years and adults aged 11 years or older. Data are from cases, reported to SmiNet, according to the Communicable Disease Act. Data presented on cases with spefciﬁed information on laboratory method used. 26 1.2.2 Case definition

For the cases in SmiNet with a pertussis diagnosis, a pertussis case is defined by detection of B. pertussis by culture or PCR in a sample regardless of symptoms. From 2008 onward, positive serology has been included. Only positive samples that are taken more than 6 months after a previous positive sample are considered to be a new episode of pertussis. By this definition, every pertussis case in persons 0–20 years of age with laboratory-confirmed pertussis is defined as a case and can potentially be included in the EPS study except for those occurring from Oct 1, 1997, to Dec 31, 2002, in the Gothenburg study area.

Clinical data were analysed according to several cough definitions, including 14 days of coughing corresponding to the current case definitions for surveillance from the European Union (EU 2012) and from the World Health Organization (WHO 2016) and 21 days of paroxysmal cough according to a previous WHO definition established for use in efficacy trials (WHO 1991).

1.3 Vaccination

1.3.1 Vaccination registration

Since many years, Sweden has a well-established and internationally renowned CHC system covering >99% of all children in the country from new-borns to 6 years of age. Health care is provided by the SHC system for children from 6 to 18 years of age. CHC and SHC nurses vaccinate children and register the vaccinations in an individual medical record and report the vaccine doses given within the NIP to the regional health authorities. Vaccination coverage is then estimated at a national level by the PHAS. Since Jan 2013, all vaccinations should also be reported to the national immunisation register. This mandatory reporting directly to PHAS will in coming years replace the current reporting system on vaccination coverage from the regions.

1.3.2 Vaccination schedule included in the National Immunisation Programme since 1953

The vaccination schedules used in the NIP are outlined in Figure 6 a-e.

Vaccination with full dose diphtheria-tetanus-acellular pertussis (DTaP) vaccines started in Jan 1996 after a 17-year period of no pertussis vaccine being included in the NIP following the withdrawal of the wP vaccine due to concerns about its safety and efﬁcacy (Romanus 1987) (Figure 6 b-c). The DTaP vaccine was registered in 1995 based on the results of several large aP

27 vaccine trials conducted in Sweden (Gustafsson 1996, Olin 1997, Trollfors 1995, Greco 1996). Due to the delayed start of ordinary vaccination or to catch-up vaccination, many children born in 1995 were vaccinated against pertussis with monovalent pertussis (aP) vaccine.

Children that for some reason had delayed vaccination were until the spring of 2002 vaccinated according to the same principle during the second year of life, i.e. two doses with a 2 month interval, followed by a third dose after 6 months, and from the age of 2 years according to a two-dose schedule (except in Gothenburg, where a three-dose schedule was used regardless of age).

As mentioned above, the Gothenburg mass vaccination project offered free catch-up vaccination with three doses to all children born in the years 1996–1999 (Taranger 2001). There was no free catch-up offered in the rest of the country, but monovalent aP vaccine was available until the year 2000, and many children were vaccinated at their parents´ expense during these years.

Acellular pertussis vaccine was administered to children from 1996 at 3, 5, and 12 months of age (Figure 6 d). Some years after their introduction, data showed that aP vaccines induced protection for a limited time only. Therefore, in 2005 a revision of the national immunisation schedule was initiated. As a first step, a booster dose was recommended to children in school year 4 (age 10 years) from autumn 2005 (Figure 6 d). The first cohort recommended for this fourth dose of DTaP were children born in 1995, i.e. the year before the formal introduction of DTaP in infancy, because this cohort was to a large extent (59%) immunised before 2 years of age. As a decay in antibody levels to non-protective levels was observed 4–5 years after vaccination with aP vaccine, with a corresponding decline in vaccine effectiveness and increase in pertussis incidence (Olin 2003, Gustafsson 2006) a second step was taken in Jan 2007, when the schedule was changed to include a fourth dose at 5–6 years and a fifth dose at 14–16 years in children born from 2002 onwards (Figure 6 e). This means that from 2007, the NIP has included a preschool and a 14–16-year booster dose against diphtheria, tetanus, and pertussis for children born from 2002 onwards (Regulation HSLF-FS 2015:6). The teenage booster dose (dTap) was implemented in 2016 (Figure 6 e).

28 Figure 6: Pertussis vaccinations in childhood for those born from 1953 onwards in Sweden. During the time period from 1953 to 1979, wP vaccines was used in the NIP (a). During the time from 1979 to 1994, the use of pertussis vaccines in NIP was interrupted (b). Large pertussis trials with aP vaccines were conducted in Sweden from 1979 to 1994 (b). After approval of the new vaccines in 1995, children born in 1995 received one dose at 10 years of age (c). In 1996, primary immunisation against pertussis was reintroduced in the NIP, and infants received the aP vaccines (DTaP) at 3 and 5 months of age and an early booster at 12 months followed by a fourth dose (DTaP) at 10 years of age (d). The booster-dose in the NIP was changed in 2007 with the fourth dose moved to preschool age and a ﬁfth dose (dTap) introduced at 14-16-years of age (teenage booster) (e). In children born from 2002 the booster doses are administered at 5 years of age and from 2016 at 14-16 years of age (e).

29 1.3.3 Vaccines used

Acellular pertussis containing vaccines during the first year of life

In the beginning of 1996, when aP vaccine was introduced in the NIP, only one DTaP vaccine (Infanrix®, GlaxoSmithKline (GSK)) was used in all parts of Sweden except in the Gothenburg area. Infanrix®is a three-component aP vaccine containing 25 µg (PT), 25 µg ﬁlamentous haemagglutinin (FHA), and 8 µg Pertactin (PRN), see also chapter 2.8.2. In the Gothenburg study area, a one-component DTaP vaccine containing 40 µg of PT (DiTeKik®, Statens Seruminstitut, Denmark) was used.

Starting in September 1998 and continuing through 1999, some counties in Sweden switched to the ﬁrst licensed combined pentavalent DTaP-Hib-IPV vaccine (Pentavac®, Sanoﬁ Pasteur MSD), a two-component aP vaccine containing 25 µg PT and 25 µg FHA. From the year 2000, another pentavalent combination vaccine (Infanrix-Polio+Hib®, GSK) was licensed and came into use. In Gothenburg and surrounding communities, an area covering 11.4% of Swedish new-borns during the follow-up period, the Di-Te-Kik®vaccine was used (Statens Serum Institut, SSI). In the year 2000 these communities switched to Pentavac®. From 2000-2001, the vaccination programme in Sweden has recommended the use of the pentavalent combination vaccines (DTaP-Hib-polio) for all infants.

Due to county-based procurements of vaccines, the use of the aP-containing vaccines within the NIP has varied over time and county, ranging from the initial use of trivalent vaccines (DTaP) containing one or three pertussis components to the later use of ﬁve or six-valent vaccines containing two or three pertussis components.

In Sweden, vaccination against hepatitis B is recommended for infants and children at risk, but it is not yet included in the NIP for all children. However, all counties have since 2016 offered hepatitis B vaccines to all children. According to information from GSK Sweden, based on the number of sold doses of Infanrix®hexa related to annual birth cohorts (data from Statistics Sweden, http://www.scb.se), 67% of all children are estimated to have received Infanrix®hexa in January 2014 with corresponding rates of 78% and 90% in January 2015 and December 2015, respectively. During 2016, almost all counties used Infanrix®hexa, and more than 90% of the children are estimated to have received Infanrix®hexa.

30 Acellular pertussis containing booster vaccines after the first year of age

The booster dose in the NIP was changed in 2007 with the fourth dose moved to preschool age and a fifth dose introduced at 14-16-years of age (teenage booster). In children born from 2002, the booster doses are administered at 5–6 years of age and from 2016 at 14–16 years of age. Children born from 1995 have received a DTaP vaccine as a booster at 10 years of age. This was changed for children born from 2002 who were offered a DTaP vaccine at 5–6 years of age. The two vaccines available are Infanrix-polio®, from GSK (diphtheria toxoid ≥30 IE, tetanus toxoid ≥40 IE, PT 25 µg, FHA 25 µg, PRN 8 µg and polio vaccine) and Tetravac® from Sanofi (diphtheria toxoid ≥30 IE, tetanus toxoid ≥40 IE, PT 25 µg, FHA 25 µg and polio vaccine). A fifth booster dose with a reduced dose vaccine against diphtheria, and pertussis (dTap-vaccine) at 14–16-years of age, was introduced during 2016 (diTekiBooster®, SSI).

Vaccines used in efficacy studies in Sweden: Trials I and II and the Gothenburg area study.

Children in two randomized double-blind vaccine efﬁcacy trials in Sweden performed in 1992–1995 were vaccinated according to the following:

1. Trial I included 9,829 infants in 1992. They were vaccinated at 2, -4, and -6 months of age with a ﬁve-component DTaP vaccine (Connaught Laboratories Limited (CLL)), a two-component DTaP vaccine (GSK), or a DTwP vaccine (CLL) (Gustafsson 1996).

2. Trial II included 82,892 infants in 1993–1994. They were vaccinated with a ﬁve-component vaccine (CLL), a two-component vaccine (GSK), a three-component vaccine (Chiron), or a DTwP vaccine (Evans) (Olin 1997).

3. In the Gothenburg study area during the 1990s, infants were offered vaccination with a vaccine containing diphtheria, tetanus, and pertussis toxoids (DTP-toxoids) at 3, 5, and 12 months of age. Children aged 1 year were offered three doses of PT alone. Finally, for children who had been incompletely vaccinated with wP vaccine or with other aP vaccines, the vaccination series was completed with PT. Each 0.5-mL dose of pertussis vaccine contained 40 µg of PT inactivated by hydrogen peroxide. Each 0.5-mL dose of DTP-toxoids vaccine contained 40 µg of PT. The PT vaccine was produced by North American Vaccine, and the diphtheria and tetanus toxoids were produced by Statens Seruminstitut (Trollfors 1995, Taranger 1997, Taranger 2001).

31 1.3.4 Vaccination coverage

In the pertussis vaccine studies (Trial I and Trial II) performed in the 1990s, a large proportion of Swedish children were enrolled. The largest study, Trial II, comprised 46.9% of the infants born in 1993, and 42.0% of those born in 1994. The NIP with aP vaccine started in 1996, but 59.3% of the children born in 1995 were vaccinated in a catch-up programe (Table 4).

For several decades there has been a well-established CHC system in Sweden with a 98–99% coverage of the vaccinations recommended in the NIP in infancy. With the introduction of a DTaP vaccine, the three-dose coverage for pertussis vaccination at 3, 5, and 12 months of age rapidly reached this level in 1996 (98.7%). The national vaccination coverage has remained at the same level during the subsequent switch to multivalent combination vaccines, including aP (Årsrapport 2016) (Table 4).

32 Year of birth aP coverage with 3 doses (%) 1993 46.9 1994 42.0 1995 59.3 1996 98.7 1997 98.6 1998 98.7 1999 98.5 2000 98.3 2001 98.4 2002 98.6 2003 98.7 2004 98.6 2005 98.3 2006 98.4 2007 98.0 2008 98.3 2009 98.3 2010 98.4 2011 98.2 2012 98.1 2013 97.5

Table 4: Vaccination coverage of three doses of vaccination with acellular pertussis containing vaccines for children born 1993 to 2013. The children should have had their second birthday before the evaluation of coverage in January each year. At two years of age years 99.3-99.4% of the children were vaccinated with three doses of DT vaccines.

1.4 Sample size considerations and the calculation of incidences

Formal a priori sample size calculations are not meaningful in a post-marketing follow-up of the NIP and the observational studies included in this report. Age-specific incidence rates of pertussis cases per 100,000 person years are based on the number of laboratory-confirmed reported pertussis cases during the study period from Oct 1, 1997, to Dec 31, 2016. In addition, annual overall incidences and age-specific incidences of pertussis in Sweden are based on the number of notified culture-confirmed or PCR-confirmed cases of pertussis, and from 2008 also serology-confirmed cases, in the whole population and in all age groups. Furthermore, annual incidences are based on age at the notification of cases and on the corresponding

33 mid-year populations derived from the mean of population numbers in two consecutive years divided by two http://www.scb.se).

To simplify the calculations of person time of follow-up, we assumed an equal number of new-born infants each month of a calendar year i.e. 7,212 children per month during 1996 and 6,842 children per month during 1997. In addition, it was assumed that all children were born in the middle of the month and that vaccination took place according to the recommended schedule, i.e. at 3, 5, and 12 months of age. Only person time since Oct 1, 1997, was included because the collection of laboratory-conﬁrmed cases of pertussis started from that date. With these simpliﬁcations, we calculated the number of person months for each monthly cohort of new-borns in the following age/vaccination-intervals:

• Person months from birth to 3 months of age (before dose 1).

• Person months between 3 and 5 months of age (between dose 1 and dose 2).

• Person months between 5 and 12 months of age (between dose 2 and dose 3).

• Person months after 12 months of age (after dose 3) until Dec 31, 2016.

34 2 Results

2.1 Incidences and cases of pertussis in all age groups

2.1.1 Number and incidence of pertussis cases in 2016

In the present 19-year report, 647 labortory-conﬁrmed cases of pertussis were reported to SmiNet during 2016, and the greatest number of reported cases was among infants younger than 1 year of age (n = 87).

In 2016, the incidences were still increased in all age groups compared to 2009–2013, although a small decrease was seen in most age groups compared to 2014, except for the 4, 7, 8, 9, 11, 12, 13, 14, 19, 40–44, and 45–49 year age groups. As in previous years, infants had the highest incidence rate (74.1/100,000 person years) out of all age groups in 2016 compared to 105.3/100,000 person years in 2014 and 73.4/100,000 person years in 2015. Other age groups associated with high incidences in 2016 were the 11, 13, and 17-year-old teenagers with incidence rates of 16.0/100,000, 15.6/100,000, and 14.4/100,000 person years, respectively.

2.1.2 Incidence and cases over time

The overall annual incidence of pertussis during the period when no pertussis vaccine was included in the NIP (before 1996) reached more than 100 cases/100,000 person years. Infant vaccination with aP vaccines was thus introduced in an endemic setting. Since the introduction of aP vaccination at 3, 5, and 12 months of age during 1996, there has been a dramatic decline in the overall pertussis incidence in the Swedish population (Figures 7-12 and Tables 5 and 6). There was a rapid drop from 121/100,000 person years in 1995–1997 to an overall annual incidence of 10–27/100,000 person years in 1998–2001, with a further reduction to 6.7/100,000 person years and 2.3/100,000 person years in 2006 and 2013, respectively. The overall incidences have been 2.8, 2.7, 1.8, 2.8, and 2.3/100,000 person years in 2009–2013, respectively (Table 6).These incidences are lower compared to when the Swedish wP vaccine was still effective during the late 1960s and early 1970s (9.4–12.2/100,000 person years). During 2014, 2015, and 2016, incidences were higher as mentioned earlier (7.1/100,000 person years, 5.9/100,000 person years, and 6.5/100,000 person years, respectively). The decline in incidence after 1996 has been more rapid than when DTwP was introduced during the 1950s. One explanation might be that vaccination coverage in those days was only gradually rising over decades until reaching 90% of the infants, whereas the coverage for DT in the 1990s already was more than 98% and remained so after the reintroduction of pertussis vaccination

35 by adding aP to the DT vaccine.

Figure 7: Overall pertussis incidence in Sweden. Case reports from general practitioners until the mid-1980s, from lab-reports since 1980, and according to the Communicable Disease Act from 1997.

The annual incidence of laboratory-conﬁrmed pertussis cases was around 120–150/100,000 person years during 1989–1995, before the introduction of aP vaccines, with a peak in 1994 with 148/100,000 person years (Table 6 and Figure 7). Peaks occurred every third winter: 1987–1988, 1990–1991 (continuing into 1992), and 1993–1994 in the pre-vaccination period. After the reintroduction of DTaP vaccine, the pattern of cyclic peaks every third year changed, and there was a small peak at about 25/100,000 person years in the winter of 1999–2000 and thereafter additional minor peaks in 2002, 2004–2005, and 2012.

After ﬁve years (2009–2013) with low incidence of reported cases of pertussis (2.5/100,000 person years on average), a signiﬁcant three-fold increase in incidence was observed in the general population (7.1/100,000 person years) in 2014 compared to 2013 (2.3/100,000 person years). This increase was partly sustained during both 2015 (5.9/100,000 person years) and 2016 (6.5/100,000 person years).

36 It is important to follow the number of reported cases on a monthly basis in order to detect potential seasonal patterns as well as the potential start of an outbreak. In the ﬁrst 6 months of 2014, about 2-5 infants with pertussis were reported per month, whereas in the last 6 months of 2014, 10—26 infants with pertussis per month were reported. From January to July in 2016, 2—7 cases among infants were reported per month. The monthly cases later increased to 11—16 cases from August to December. The monthly number of reported cases in all ages showed a clear increase starting in August 2014, which lasted until February 2015 (66—156 reported cases each month). Between March and July 2015, the monthly number of reported cases decreased (31—41 reported cases per month). In 2015, the overall number of reported cases increased from August to October (53—69 reported cases per month). Between January and July 2016, the monthly number of reported cases decreased (18—-31 reported cases per month). From August to December 2016, there was a clear increase (60—114 cases per month), with the highest number of reported cases in December (114 cases per month), which might indicate a tendency for a seasonal pattern from August to December that is easier to detect during years with high numbers of pertussis cases (Figure 8).

37 150

100

Number of cases per month 50

2004 2006 2008 2010 2012 2014 2016

Year

Figure 8: Number of pertussis cases each month during 2004-2016 (all ages). Data are based on laboratory-conﬁrmed cases reported to SmiNet, according to the Communicable Disease Act.

2.1.3 Incidence and cases of pertussis, distributed by age and time intervals

The peak age-specific incidence in the pre-1996 era was approximately 1,600 cases/100,000 person years, and this occurred in children aged 2–4 years. Pertussis incidence in the vaccinated cohorts born from 2009 was below 10/100,000 person years (Table 6). However, the reduction of age-specific incidence was least marked in infants (Table 6). In this age group, incidences varied between 104 and 284/100,000 person years during the years 1997–2006. In 2006, the age-specific incidence in infancy was below 100/100,000 person years for the first time since records started to be kept. In 2007, the incidence in infants was 85/100,000 person years, and from 2008 to 2013 the incidence in infants was stable at below 50/100,000 person years. In 2014, the incidence in infants increased by three-fold (105.3/100,000 person years) compared to 2013 (34.3/100,000 person years), and the increased infant incidence continued, although at a slightly lower level, during 2015 (73.4/100,000

38 person years) and 2016 (74.1/100,000). There was no significant difference in infant incidence between 2015 and 2016 (p=0.83), but when comparing 2015 and 2016 to 2014, respectively, the incidence was significant (2014 vs 2015: p=0.004; 2014 vs 2016: p=0.002). The age-specific incidence for all reported cases in pre-school children (1–6 years of age) dropped from >1,000/100,000 person years in the time period before the aP vaccine was introduced to approximately 100/100,000 person years in 1998–2000, to 50/100,000 person years in 2001, to approximately 20/100,000 person years in 2003, and from 2009–2013 to fewer than 10/100,000 person years. In 2014, 2015 and 2016, the incidence in pre-school children slightly increased while still remaining below 10/100,000 person years (9.6/100,000, and 7.4/100,000, 7.6/100,000 person years, respectively) (Table 6) In Figure 9, the incidences of pertussis from 1997 to Dec 31, 2016, are illustrated in the form of a heat map to help visualize the data in Table 6.

15 1500

10 1000 Age Cases per year

5 500

0 0 1990 1995 2000 2005 2010 2015

Figure 9: Illustration of incidences per age (1-year age groups) and calendar year. Cases with episodes starting between 1997, and Dec 31, 2016 were reported to SmiNet, according to the Communicable Disease Act. Data before 1997 are from voluntarily reports from bacteriological laboratories.

39 Age 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

0 1191 907 1007 815 906 548 170 93 165 219 115 217 112 285 154 98 91 47 43 49 37 51 39 121 85 87 1 1679 1488 1725 1785 927 940 160 25 34 76 33 42 19 53 27 15 18 17 10 2 2 5 5 19 9 7 2 1984 1778 2044 2393 1743 635 419 80 32 36 37 53 19 50 14 13 9 7 1 6 3 4 9 13 8 9 3 1872 1633 2047 2141 1843 1324 352 205 96 52 29 37 8 31 23 8 7 4 7 8 2 4 7 12 11 11 4 1531 1336 1726 1960 1754 1415 654 157 294 155 28 46 20 50 20 10 10 7 3 5 4 5 5 5 9 9 5 1061 978 1213 1329 1260 1074 608 244 188 281 47 51 14 67 26 21 10 2 8 6 1 7 5 10 9 10 6 772 699 779 894 836 767 472 297 386 254 122 86 25 77 51 22 25 8 4 5 3 6 5 8 6 8 7 391 337 447 464 432 432 289 175 313 345 98 147 31 83 55 26 27 10 3 7 0 6 3 3 6 8 8 193 176 205 255 231 219 157 105 257 289 105 92 45 105 50 30 19 12 6 6 0 2 3 7 8 8 9 110 106 140 117 142 132 64 57 120 208 79 99 34 87 74 24 28 24 5 9 3 5 2 8 7 10 10 72 74 53 69 81 72 54 24 83 131 43 74 45 86 103 23 13 12 5 7 2 1 4 7 3 5 11 50 33 36 55 38 38 31 22 39 62 32 58 43 78 73 28 10 1 3 3 2 1 3 13 13 18 12 15 28 35 33 25 33 24 19 41 41 24 36 28 64 64 28 15 5 1 4 1 0 2 7 10 14 13 17 10 18 23 19 13 5 12 28 30 14 24 23 51 46 32 22 13 5 1 0 2 1 12 5 17 14 14 10 13 14 7 10 9 6 22 21 9 17 13 44 28 21 25 19 11 2 2 1 0 7 11 15 15 10 7 10 12 11 7 9 10 7 11 6 13 9 12 25 14 19 13 23 10 6 7 7 11 11 10 16 8 5 6 7 9 6 4 6 7 11 2 10 10 16 20 14 14 16 16 8 9 9 6 21 11 14 17 6 2 7 2 5 3 2 4 7 14 1 6 3 9 9 4 13 12 12 10 13 7 3 17 15 15 18 6 6 2 9 3 0 3 4 4 7 0 6 1 9 6 9 7 6 9 4 6 7 7 10 14 7 19 8 3 3 4 5 4 6 0 2 5 2 1 3 2 9 7 4 2 4 3 1 5 5 13 9 12 20-24 40 28 32 51 29 16 10 6 7 14 3 13 8 13 12 10 12 13 12 11 15 18 13 50 34 42 25-29 94 73 95 113 66 49 27 6 16 14 7 8 11 19 16 16 14 14 6 11 5 11 12 40 38 40 30-34 113 94 99 135 75 64 24 12 15 28 11 12 6 24 21 11 8 13 9 11 6 21 11 36 33 37 35-39 52 40 61 90 54 41 23 10 19 29 6 20 10 33 30 25 18 19 12 15 5 10 16 47 40 40 40-44 40 32 35 52 27 21 20 4 8 14 8 11 8 18 33 15 29 19 7 16 5 16 12 45 40 48 45-49 19 15 24 23 28 7 7 3 8 7 1 10 2 7 20 12 18 12 5 8 4 9 7 23 39 36 50-54 26 20 28 21 22 18 12 7 2 4 4 9 3 8 12 13 11 8 6 5 6 9 5 26 23 24 55-59 23 18 25 29 20 17 4 3 6 8 5 7 7 7 5 17 14 6 7 1 9 7 4 21 14 17 60-64 32 18 21 22 28 16 10 2 3 9 2 7 2 4 16 17 14 10 6 8 5 7 5 16 14 14 65+ 39 44 39 71 61 52 21 9 14 14 2 10 14 15 26 24 38 22 11 11 12 26 17 60 47 55 Sum 11468 9998 11975 12988 10687 7973 3650 1607 2223 2389 875 1222 576 1407 1068 607 562 373 260 252 169 269 223 688 582 647

Table 5: Number of laboratory-reported cases of pertussis in deﬁned age-groups from 1991 to Dec 31 2016 For laboratory-conﬁrmed cases reported to SmiNet between 1997 and Dec 31, 2016. Data before 1997 are from voluntarily reports from bacteriological laboratories. 40 Age 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

0 963.0 737.6 839.3 710.7 842.6 553.4 183.6 103.7 185.8 244.6 126.1 231.2 114.7 284.5 152.0 94.3 85.0 43.2 38.8 43.0 32.5 45.2 34.3 105.3 73.4 74.1 1 1390.8 1196.6 1396.7 1484.2 806.5 871.7 161.1 26.9 37.7 84.9 36.5 45.6 20.0 53.7 26.7 14.6 17.1 15.7 9.1 1.8 1.7 4.3 4.4 16.5 7.7 5.9 2 1718.7 1469.0 1639.6 1929.4 1446.1 552.5 388.6 80.5 34.3 39.7 41.1 58.3 20.5 52.4 14.1 12.8 8.7 6.6 0.9 5.4 2.7 3.4 7.7 11.3 6.9 7.6 3 1695.0 1409.1 1684.2 1704.3 1478.0 1098.9 306.5 190.0 96.4 55.5 31.8 40.9 8.7 33.3 24.0 8.0 6.8 3.8 6.5 7.3 1.8 3.5 6.0 10.2 9.4 9.3 4 1443.6 1204.7 1482.6 1599.2 1388.5 1135.3 543.2 136.6 272.1 155.1 29.8 50.2 22.0 54.4 21.4 10.4 9.9 6.8 2.9 4.6 3.6 4.5 4.4 4.2 7.6 7.6 5 1026.0 918.6 1088.7 1131.5 1021.7 849.9 487.9 202.6 163.4 259.3 46.8 54.0 15.2 73.3 28.2 22.4 10.3 2.0 7.7 5.7 0.9 6.3 4.4 8.6 7.5 8.3 6 774.1 672.8 728.0 795.1 707.1 621.5 373.4 238.1 320.0 220.3 112.2 85.3 26.3 83.3 55.6 23.7 26.4 8.2 3.9 4.8 2.8 5.5 4.5 7.0 5.1 6.6 7 404.7 336.4 428.2 429.6 381.7 365.1 234.0 138.3 250.5 285.3 84.7 134.7 30.6 87.1 59.3 28.2 28.9 10.5 3.0 6.8 0.0 5.6 2.7 2.6 5.2 6.7 8 200.9 181.3 203.5 242.0 212.4 193.3 132.5 84.9 202.6 230.8 86.6 79.2 41.1 103.4 52.3 32.2 20.4 12.7 6.2 6.1 0.0 1.9 2.8 6.3 7.0 6.8 9 113.4 109.8 143.4 115.0 133.8 121.3 56.4 48.0 96.8 163.6 62.9 81.3 29.2 79.1 72.6 25.0 29.8 25.6 5.3 9.3 3.0 4.8 1.9 7.3 6.2 8.6 10 72.8 75.9 54.6 70.0 79.1 67.8 49.5 21.1 69.8 105.4 33.7 58.7 36.8 73.5 93.4 22.5 13.4 12.7 5.3 7.3 2.0 1.0 3.8 6.5 2.7 4.4 11 50.2 33.2 36.8 56.2 38.3 37.1 29.1 20.1 34.2 52.0 25.7 45.3 34.0 63.7 62.2 25.2 9.7 1.0 3.1 3.2 2.1 1.0 3.0 12.2 11.8 16.0 12 15.4 28.0 35.1 33.4 25.4 33.2 23.4 17.8 37.4 35.9 20.0 28.8 21.8 50.4 52.1 23.8 13.4 4.8 1.0 4.2 1.0 0.0 2.0 6.8 9.3 12.6 13 17.5 10.2 17.9 22.9 19.1 13.2 5.0 11.7 26.2 27.3 12.2 20.0 18.3 39.6 36.2 25.9 18.6 11.6 4.8 1.0 0.0 2.1 1.0 11.9 4.8 15.6 14 14.0 10.2 13.2 13.8 6.9 10.1 9.1 6.0 21.3 19.6 8.2 14.7 10.8 34.9 21.7 16.4 20.1 15.9 9.7 1.9 2.0 1.0 0.0 7.0 10.8 14.2 15 9.6 7.0 10.2 12.1 10.8 6.9 9.0 10.1 7.0 10.6 5.6 11.7 7.8 9.9 19.8 10.8 14.8 10.4 19.1 8.8 5.6 6.9 7.1 11.1 10.9 9.6 16 7.3 4.8 5.9 7.1 9.0 5.9 3.9 6.0 7.0 11.0 1.9 9.2 9.0 13.8 16.5 11.0 10.7 12.4 12.7 6.6 7.8 8.3 5.8 20.8 10.9 13.5 17 5.3 1.8 6.7 2.0 5.0 3.0 2.0 3.9 7.0 14.0 1.0 5.7 2.8 8.1 7.7 3.3 10.2 9.1 9.2 7.9 10.6 6.0 2.7 16.3 14.5 14.4 18 5.3 5.3 1.8 8.5 2.9 0.0 3.0 3.9 3.9 7.0 0.0 5.9 1.0 8.2 5.3 7.7 5.7 4.6 6.8 3.0 4.7 5.7 5.9 9.0 13.1 6.6 19 6.9 2.6 2.6 3.6 4.7 3.9 6.0 0.0 1.9 4.9 2.0 1.0 2.9 1.9 8.2 6.2 3.4 1.6 3.1 2.2 0.8 3.9 4.0 10.9 8.0 11.1 20-24 6.7 4.8 5.5 8.8 5.0 2.8 1.8 1.1 1.3 2.7 0.6 2.5 1.5 2.5 2.3 1.9 2.2 2.3 2.0 1.8 2.3 2.7 1.9 7.4 5.1 6.5 25-29 15.0 11.4 14.6 17.6 10.5 8.0 4.5 1.0 2.7 2.4 1.2 1.4 2.0 3.4 2.9 2.9 2.5 2.5 1.1 1.9 0.8 1.8 1.9 6.2 5.7 5.7 30-34 19.6 16.3 17.0 22.5 12.1 10.0 3.7 1.8 2.3 4.4 1.8 2.0 1.0 3.9 3.4 1.8 1.3 2.2 1.5 1.9 1.0 3.6 1.8 6.0 5.4 5.9 35-39 8.9 6.8 10.4 15.3 9.2 7.0 3.9 1.7 3.2 4.7 0.9 3.0 1.5 5.0 4.7 3.9 2.9 3.0 1.9 2.4 0.8 1.6 2.6 7.7 6.6 6.5 40-44 6.2 5.1 5.7 8.7 4.6 3.6 3.4 0.7 1.4 2.4 1.4 1.9 1.4 3.0 5.3 2.3 4.4 2.8 1.0 2.4 0.8 2.5 1.9 7.0 6.1 7.4 45-49 3.0 2.3 3.6 3.4 4.3 1.1 1.1 0.5 1.3 1.2 0.2 1.7 0.3 1.2 3.4 2.1 3.1 2.0 0.8 1.3 0.6 1.3 1.0 3.4 5.9 5.4 50-54 5.5 4.1 5.4 3.8 3.8 2.9 1.9 1.1 0.3 0.6 0.6 1.5 0.5 1.4 2.1 2.2 1.9 1.4 1.0 0.9 1.0 1.5 0.8 4.3 3.6 3.7 55-59 5.5 4.3 5.9 6.6 4.4 3.7 0.8 0.6 1.1 1.4 0.8 1.1 1.1 1.1 0.8 2.7 2.3 1.0 1.2 0.2 1.6 1.2 0.7 3.6 2.4 2.9 60-64 7.6 4.3 5.1 5.4 6.9 4.0 2.5 0.5 0.7 2.1 0.4 1.5 0.4 0.8 2.9 2.9 2.3 1.6 1.0 1.3 0.8 1.2 0.9 2.8 2.5 2.5 65+ 2.6 2.9 2.5 4.6 4.0 3.4 1.4 0.6 0.9 0.9 0.1 0.7 0.9 1.0 1.7 1.5 2.4 1.4 0.7 0.6 0.7 1.4 0.9 3.2 2.4 2.8 Total 133.1 115.3 137.4 147.9 121.1 90.2 41.3 18.2 25.1 26.9 9.8 13.7 6.4 15.6 11.8 6.7 6.1 4.0 2.8 2.7 1.8 2.8 2.3 7.1 5.9 6.5

Table 6: Incidence of laboratory-reported cases of pertussis in deﬁned age-groups from 1991 to Dec 31 2016 For laboratory-conﬁrmed cases reported to SmiNet between 1997 and Dec 31, 2016. Data before 1997 are from voluntarily reports from bacteriological laboratories. 41 Incidence of pertussis in defined age-groups before and after the introduction of DTaP vaccination

DTaP vaccine was introduced in 1996 into the NIP, and from 2007 a pre-school booster was introduced. The incidences of pertussis for different age groups during 1997–2006 were much higher than during 2007-2016 for the corresponding age groups with the exception of the age group of 16-34 years (Figure 10).

1997−2006 2007−2016

150

100 Incidence (per 100,000)

0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

Age (in years) 20−2425−2930−3435−39

Figure 10: Mean incidence per 100,000 person years of pertussis in deﬁned age groups during 1997-2006 (blue bars) and during 2007-2016 (red bars). Data are based on laboratory-conﬁrmed cases reported to SmiNet according to the Communicable Disease Act.

Incidence of pertussis at 1-20 years of age presented in time intervals

The incidence of pertussis from 1—20 years of age is presented in this chapter in 6- or 7-year intervals: 1997–2003, 2004–2010, and 2011–2016. Data collection was performed in the EPS, including these three data sets,

42 and presented both for Sweden excluding Gothenburg (Figures 11 A, B, D) and for the Gothenburg study area (Figures 11 C,E). Incidences from Oct 1, 1997, to Dec 2016 show a similar pattern in Sweden in both study areas. The incidence decreased from Oct 1, 1997, to Dec 31, 2003, for the pre-school children, but in the next period of Jan 1, 2004, to Dec 31, 2010, there was a higher incidence in 6-9 year-olds.

During the period of Oct 1, 1997, to 2003, there was a relatively high incidence of pertussis in pre-school aged children (1–6 years of age, 13–21/100,000 person years). During the next period, 2004–2010, a decreasing incidence was seen in this age group (1–6 years of age, 10–16/100,000 person years), but a higher incidence in the ﬁrst years in school (7–10 years of age, 18–28/100,000 person years). During the period 2011-2016, the incidences in children up to 14 years of age were lower than the incidences in those 15-20 years of age (Figures 11 D, E).

43 Incidence Oct 1997−Dec 2003 in children older than one year of age Sweden excl. Gothenburg 50 A 40 30 ● ● 20 ● ● ● 10 ● ● ● ● ●

Cases per 100 000 person years 0 5 10 15 20

Years of age

Incidence Jan 2004−Dec 2010 in children older Incidence Jan 2004−Dec 2010 in children older than one year of age Sweden excl. Gothenburg than one year of age Sweden incl. Gothenburg 50 B 50 C 40 40

30 30 ● ● ● ● ● 20 ● 20 ● ● ● ● ● ● ● ● ● ● ● 10 ● ● ● 10 ● ● ● ● ● ● ● ● ● ●

Cases per 100 000 person years 0 Cases per 100 000 person years 0 5 10 15 20 5 10 15 20

Years of age Years of age

Incidence Jan 2011−Dec 2016 in children older Incidence Jan 2011−Dec 2016 in children older than one year of age Sweden excl. Gothenburg than one year of age Sweden incl. Gothenburg 50 D 50 E 40 40 30 30

20 ● ● 20 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 10 ● ● ● ● ● 10 ● ● ● ● ●

Cases per 100 000 person years 0 Cases per 100 000 person years 0 5 10 15 20 5 10 15 20

Years of age Years of age

Figure 11: Trend in the incidence of pertussis in those 0-20 years of age during 1997-2016 divided into three time intervals: Oct 1, 1997- Dec 31, 2003; Jan 1, 2004- Dec 31, 2010; and Jan 1, 2011 - Dec 31, 2016. Data collection was performed in the EPS with episodes starting between Oct, 1, 1997, and Dec 31, 2016, including these three data sets and presented both for Sweden excluding the Gothenburg study area (Figures 11 A, B, D) and including the Gothenburg study area (Figures 11 C, E). Data are presented on pertussis cases born from Jan 1, 1996 onwards.

44 Pertussis in fully vaccinated children 1-18 years of age

It is well known that immunity wanes after pertussis vaccination, but there is limited information available about pertussis in fully vaccinated children. Therefore, the reported cases in the EPS study were analysed to identify pertussis in fully vaccinated individuals 1–18 years of age between 2007 and 2016. The time period was set from 2007 as this corresponds to the year where the booster dose in children aged 5-6 years was implemented. Fully vaccinated children were deﬁned as children aged 1-5 years who had received at least three doses of aP vaccine and children aged 6-18 years who had received at least four doses of aP vaccine. Children with onset of pertussis less than 4 weeks after the last dose of pertussis vaccine were excluded. During the period 2007-2016, a total of 1,213 pertussis cases were reported in children 1-18 years of age. Of these, 537 (44%) were fully vaccinated. Of the children included, the majority had laboratory-conﬁrmed pertussis (Table 7). The proportion of children who were fully vaccinated in the different age groups varied greatly, especially in the older age groups. In children aged 1-5 years, the proportion of fully vaccinated varied between 60% and 73%, with the highest proportion in the 3 year olds. In the 6-18 year olds, the proportion of fully vaccinated varied between 12% and 55%. The 17-18 year olds had the lowest proportion of fully vaccinated, 12%, but very few cases were reported in this age group. The proportion of fully vaccinated children considerably decreased when comparing the 5-year-old children (60%) to the 6-year-old children (22%) (Table 7).

45 Age/Age Number of Number Percent Median Median of median group cases of fully of fully of disease days with number of vaccinated vaccinated duration paroxysmal hospitalisation cases cases (days) cough days

1 81 51 63 48.5 32 0

2 71 45 63 44 31 0

3 77 56 73 55 45 0

4 69 45 65 56 42 0

5 60 36 60 43 32 0

6 79 17 22 50 42 0

7-9 233 58 25 53 33 0

10-13 230 127 55 59 47 0

14-16 196 88 45 63.5 53.5 0

17-18 117 14 12 60.5 52.5 0

Total 1213 537 44 - - -

Table 7: Number of reported pertussis cases with data on vaccination status collected during the period 2007-2016. Data collection was performed in the EPS. Fully vaccinated children were deﬁned as children aged 1-5 years who had received at least three doses of aP vaccine and children aged 6-18 years who had received at least four doses of aP vaccine.

Corresponding data for 2007-2015 published in the 18-year EPS report showed that out of all children 1-18 years of age, 32.4% were fully vaccinated, and in the 2-year-old age group 87% were fully vaccinated. Due to differences in the proportion of fully vaccinated children, all data for this analysis have been re-evaluated and the methods have been improved. Therefore, data in the present 19-year EPS report are not comparable with the data for fully vaccinated children in the 18-year EPS report. More detailed data on pertussis in fully vaccinated children are described in Table 33 Appendix.

46 Incidences and cases of pertussis for -all age groups

The vaccinated birth cohorts born from 1996 had a lower age-specific incidence of laboratory-confirmed pertussis in pre-school and early school age than the corresponding age groups prior to the implementation of aP vaccination in 1996. The age-specific incidence for preschool children (exclusively 0-–1 years) dropped from >1,000/100,000 person years to approximately 100/100,000 person years in 1998–2000, to 50/100.000 in 2001, to approximately 20/100,000 person years in 2003, and to fewer than 10/100,000 person years in 2009–2013. The incidences in 5–6-year-old children decreased after the introduction of the booster vaccine in 2007 (Figure 11). The effect of the booster at 5–6 years of age introduced in 2007 was described in the Pertussis Surveillance report for 2010 and was reported at the European Society for Paediatric Infectious Diseases (ESPID) meeting in 2010 (Rydevik, abstract 2010) (see also chapter 2.8). The implementation of the booster at preschool age was shown to have a strong effect, and the risk of pertussis decreased in children who had received the booster vaccination. The annual incidences decreased from Oct 1, 1997, to Dec 31, 2003, for the pre-school-aged children, but in the subsequent period of Jan 1, 2004, to Dec 31, 2010, there was a higher incidence in 6–9 year olds. This increase was not seen during the last interval of Jan 1, 2011, to Dec 31, 2016, likely due to the 5–6 year booster that was incorporated in the vaccination schedule from 2007. The results are probably due to both a direct effect and an indirect effect (herd immunity) of the booster. From Jan 1, 2010, to Dec 31, 2015, the incidence of pertussis increased significantly among 15—17 year olds possibly due to waning immunity after the 10-year booster administered in children born from 1995. In 2016, this increase levelled out, but if this is a result from booster vaccination of 14–16 year olds that started during 2016 is too early to say. As in previous years, children who were younger than one year (infants) had the highest incidence in 2016 (74.1 cases/100,000 person years) (Figure 12, Tables 5 and 6). In ages above 1 year, the number of cases is quite stable with the exception of the years 2004, 2005, and 2008.

47 2004 250 2005 2006 2007 2008 2009 200 2010 2011 2012 2013 150 2014 2015 2016

Number of cases 100

0 5 10 15

Age, in years

Figure 12: Number of laboratory-conﬁrmed pertussis cases,n 0-20 years of age between 2004 and 2016 by age in years. Data collection was performed in the EPS

2.2 Pertussis in infants

There were 87 cases of laboratory-confirmed pertussis reported in infants (younger than 1 year of age) in 2016. As in previous years, the incidence of pertussis was greatest among infants (74.1/100,000 person years), and this was a small increase in comparison with 2015 (73.4/100,000 person years) and a decrease compared to 2014 (105.3/100,000 person years). During the first 90 days of life, 37 infants had their first symptoms of pertussis, and another 23 infants had their first symptoms of pertussis before they were 150 days of age, i.e. 60 of 87 (69%) of infants with pertussis contracted the disease before 150 days of age (Figure 13). In 2016, infants had the highest incidence of all age groups, and pertussis remains a serious and life-threatening disease for infants, especially for the youngest. Therefore, the analysis and presentation in this report focus on data from cases of pertussis reported in infants. In infants, markers of severity in relation to age at onset of disease and to individual vaccination history as well as to

48 scheduled ages of the NIP were evaluated.

2.2.1 Number of pertussis cases in 2016 in infancy by vaccination status

In 2016, 43% of the pertussis cases in infants were infected within the ﬁrst 90 days of age, and all of these cases were unvaccinated infants. In 2015, 48% of the cases were infected within the ﬁrst 90 days (p = 0.55 for comparing 2016 and 2015). The number of cases reported in 2016 in unvaccinated and vaccinated infants (one dose or more) for different ages (in days) is displayed in Figure 13. In 2016, 38 (44%) of all infants reported with pertussis had been vaccinated with at least one dose, which is slightly more than the 34 cases (41%) reported in 2015.

20 Not vaccinated Vaccinated

10 Number of cases

0 0−30 days 91−120 days 181−210 days 271−300 days

Age in days

Figure 13: Number of reported pertussis cases in infancy in 2016 by vaccination status (not vaccinated or vaccinated with at least one dose of aP vaccine) and age (days). Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act and controlled for vaccination status in the EPS.

49 2.2.2 Timing of vaccinations

The vaccination schedule according to the NIP is dose 1 at 3 months (90 days), dose 2 at 5 months (150 days), and dose 3 at 12 months (365 days) of age. In 2016, the median time between birth and the first vaccination was 93 days for pertussis cases. The consistency in adhering to the recommended NIP, from laboratory-confirmed case reports of pertussis with episodes starting between Oct 1, 1997, and Dec 31, 2016, is illustrated in Figure 14, and this shows only small deviations from scheduled day (Day 0) for administration of the first three doses of aP vaccine. The median time of actual vaccination was 3, 17, and 7 days after the recommended date for dose 1, 2, and 3, respectively. The timeliness of the first dose of DTaP vaccine administration among infants who became infected with pertussis was similar in 2016 compared to the median timeliness over the entire study period of 1997–2016.

50 1.0 97% 91%

0.8

0.6

0.4 Cumulative proportionCumulative vaccinated 0.2

Dose 1 (n= 3157 ) Dose 2 (n= 2606 ) 0.0 Dose 3 (n= 2198 )

−40 −20 0 20 40

Time difference in days compared with scheduled vaccination date

Figure 14: Cumulative proportion of vaccinated children for the ﬁrst three doses of aP vaccination comparing actual vaccination dates with scheduled vaccination dates. Scheduled dates for doses 1, 2 and 3 are 3, 5, and 12 months of age, respectively. Data are from laboratory-conﬁrmed case reports of pertussis with episodes starting between Oct 1, 1997, and Dec 31, 2016. Data collection was performed in the EPS.

2.2.3 Incidence and cases of pertussis among the 0–20 years of age, distribution by age and vaccination status

A substantial proportion of pertussis cases reported in Sweden in the EPS study are in unvaccinated children who are too young to be fully vaccinated with three doses of aP vaccine at 3, 5, and 12 months of age (90, 120, and 365 days of age) according to the NIP. The median ages of pertussis cases with none, one, or two vaccinations were 97, 129, and 272 days, respectively (Table 8). In contrast, for children who had received three doses of aP vaccine during their ﬁrst year of life, the median age for onset of pertussis was 2161 days (5.9 years of age) (range = 360, 8134 days).

51 Doses before Median age in Cases in the Cases in episode of days at onset of Gothenburg Sweden pertussis pertussis study area (n) excluding the Gothenburg study area (n) 0 97 245 1383 1 129 145 403 2 272 209 201 3 2161 723 1473

Table 8: Median age in days at the onset of pertussis and the number of aP vaccination doses prior to the onset of pertussis. Data collection was performed in the EPS, with episodes starting between Oct 1, 1997, and Dec 31, 2016, and from 2003 in the Gothenburg study area. Data are presented for pertussis cases 0–20 years of age.

The proportion of pertussis cases in unvaccinated children during infancy and in pertussis cases 1-20 years of age in the EPS study is shown in Table 9. Seventy-four per cent of the unvaccinated pertussis cases were less than 1 year of age, and 63% were infants younger than 3 months of age.

Age Number of cases Per cent of cases (by age groups) 0-30 days 267 17.6 31-60 days 360 23.7 61-90 days 322 21.2 91-120 days 101 6.7 121-150 days 28 1.8 151-180 days 13 0.9 180-365 days 39 2.6 >365 days 388 25.6

Table 9: Age (days) at episode start for ,1518 unvaccinated cases with pertussis. Data collection was performed in the EPS, with episodes starting between Oct 1, 1997, and Dec 31, 2016. Data are presented for pertussis cases 0-20 years of age.

52 2.2.4 Incidence of pertussis in infancy by date and after changes to the national immunisation programme

The age-speciﬁc incidence among infants was around 700–800/100,000 person years during the 10-year period prior to 1996 (Figure 15 and corresponding Table 6 and Table 16 Appendix). The incidence decreased rapidly after the introduction of pertussis vaccination and oscillated around 200/100,000 person years from 1996 to 2005, after which time the incidence decreased further. This decrease could be due to the new vaccination schedule that included preschool booster vaccinations for children born in 2002 and a booster vaccination at 10 years of age leading to a higher proportion of vaccinated children in the population during 2007–2012. In 2016, the incidence of pertussis in infants was 74.1/100,000 person years, and this was a decrease in comparison with 2014 (105.3/100,000 person years) and an increase in comparison to 2015 (73.4/100,000 person years), but this increase was not signiﬁcant. In 2015 the incidence was more than threefold greater than the incidence in 2013 (p = 0.002) and slightly higher than the highest incidence in 2005, which was when the vaccine booster in 10 year olds was introduced.

53 1200

1000 Onset of aP−vaccine in infancy Jan 1, 1996

800

Booster at 10 years of age 600 in 2005

Incidence (per 100,000) 400

Booster at 5.5 years of age in 2007

200

0 1986 1989 1992 1995 1998 2001 2004 2007 2010 2013 2016

Year

Figure 15: Incidence of pertussis in infants younger than 1 year of age by year. Changes in the NIP are indicated. Data are from case reports of pertussis reported to SmiNet in 1997-2016 according to the Communicable Disease Act. Data before 1997 are from voluntarily reports from bacteriological laboratories

The decline in the incidence among infants after 1996 is to a large extent explained by decreasing number of infant cases from the age of 5–12 months, i.e. from the scheduled age of the second dose of DTaP. The mean number of infants with laboratory-reported pertussis per age (in months) during infancy is illustrated in Figure 16, and data are shown for the 10 years before and the 20 years after the introduction of aP vaccination in infancy. Most cases were reported in the youngest birth cohort in each calendar period, with a marked decline at about 5 months of age.

54 1400 1986−1995 1997−2016

1200

1000

800

600 Incidence (per 100,000)

400

200

0 0 1 2 3 4 5 6 7 8 9 10 11

Age (in months)

Figure 16: Mean incidence (per 100,000 person years) of pertussis in infants in deﬁned age groups during the 10 calendar years before (1986-1995) and during the 20 years after (1997-2016) the introduction of DTaP in 1996. Before 1997, data are from voluntarily reports from bacteriological laboratories, and after 1997 the data are from case reports of pertussis reported to SmiNet according to the Communicable Disease Act.

2.2.5 Incidence of pertussis during and after the first year of life presented in time intervals

The incidence of pertussis during and after the ﬁrst year of life is presented in this chapter in 6- or 7-year time intervals: 1997–2003, 2004–2010, and 2011–2016 (Figures 17 A-E). Data collection was performed in the EPS study, including these three data sets and presented both for Sweden excluding Gothenburg (Figures 17 A, B, and D) and including the Gothenburg study area (Figures 17 C and E).

In 1997–2003, high incidences of pertussis were observed in infants 0–90 and 91–150 days of age. These levels decreased, however, for the subsequent period (2004–2010). Earlier reports evaluating the time period 2009–2013

55 showed a decrease in this time period, but when including the increased incidences of the three years of 2014, 2015, and 2016 the incidences are at the same levels for the youngest children when comparing the time periods 2004–2010 and 2011–2016.

Incidence Oct 1997−Dec 2003 in Sweden excl. Gothenburg 400 A 300 ● 239 ● 248 200

100 ● 59 0 ● 13

Cases per 100 000 person years 0−90 91−150 151−365 >365

Days of age

Incidence Jan 2004−Dec 2010 Incidence Jan 2004−Dec 2010 in Sweden excl. Gothenburg in Sweden incl. Gothenburg 400 B 400 C 300 300

200 200 ● ● 137 151 ● 100 ● 96 100 110

● ● 31 0 18 ● 10 0 ● 13

Cases per 100 000 person years 0−90 91−150 151−365 >365 Cases per 100 000 person years 0−90 91−150 151−365 >365

Days of age Days of age

Incidence Jan 2011−Dec 2016 Incidence Jan 2011−Dec 2016 in Sweden excl. Gothenburg in Sweden incl. Gothenburg 400 D 400 E 300 300

200 200 ● 169 ● 167 100 ● 113 100 ● 111

● ● 21 ● 22 ● 0 9 0 8

Cases per 100 000 person years 0−90 91−150 151−365 >365 Cases per 100 000 person years 0−90 91−150 151−365 >365

Days of age Days of age

Figure 17: Incidence of pertussis (point estimates and 95% conﬁdence intervals) during and after 1 year of age presented in three time intervals. Data collection was performed in the EPS with episodes starting between Oct 1, 1997, and 2016. Days of age are the age at episode start.

Pertussis in infants in different years and in relation to other age groups

Figure 18 shows the incidence for infants younger than 1 year of age. Compared to 1996 when the aP vaccine was introduced, there has been a decrease in the total number of infant pertussis cases, but the age-speciﬁc pattern remains with most infant cases occurring in the age group 0–5 months.

56 2004 2005 2006 40 2007 2008 2009 2010 2011 30 2012 2013 2014 2015 2016 20 Number of cases

0 2 4 6 8 10 12

Age, in months

Figure 18: Number of laboratory-conﬁrmed pertussis cases in infants between 2004 and 2016 , by age in months. Data collection was performed in the EPS of pertussis.

The relative importance of the ﬁrst year in regard to incidence rates is shown in Figure 19. Pertussis in infancy accounts for 70–80% of all cases during the ﬁrst 4 years of life, as reported to SmiNet according to the Communicable Disease Act.

57 100 0 years old 1 year old 2 years old 3 years old

20 % of the total number of cases in each age group % of the total number

2000 2005 2010 2015

Year

Figure 19: Per cent of cases in ages 0–4 years old (new-born up to the 4th birthday). Data are from case reports of pertussis reported to SmiNet, according to the Communicable Disease Act with episodes starting between 1997 and Dec 31 2016.

2.3 Severity of pertussis in infants

In the following sections (2.3.1–2.3.4), the data are presented for age-specific complication and hospitalisation rates in vaccinated (one dose or more) and unvaccinated infants, with information on length of hospital stay and the relation between early or delayed onset of antibiotic treatment and the duration of cough in infants. In the EPS study, data on the first day with symptoms are collected and described as the age at episode start. In 2016, there were higher numbers of reported infant cases having had complications due to pertussis as compared to 2015 and to 2014. In total, 50 (60%) of the infant cases in 2016 and 29 (35%) of the infant cases in 2015 reported having complications. During the period from Jan 1, 2003, to Dec 31, 2016, the age-specific incidence of any complication due to pertussis was highest in children 0–<3 months of age at 81 and 70/100,000 person years from the Gothenburg study area and the rest of Sweden, respectively

58 (Table 9). The incidence decreased thereafter to 2 and 1/100,000 person years, respectively, for children above 1 year of age at the ﬁrst pertussis episode.

More detailed analyses of the data on the severity of pertussis disease and separately for the geographic study areas and for different time periods are presented in the appendix.

All pertussis cases 21 days of cough Hospital admission Complication Age groups Gothenburg Rest of Gothenburg Rest of Gothenburg Rest of Gothenburg Rest of (month) Sweden Sweden Sweden Sweden

0-<3 265 160 174 142 141 117 81 70 (217-321) (147-174) (135-220) (130-155) (107-183) (106-129) (55-114) (62-80)

3-<5 213 111 110 97 30 46 38 25 (161-276) (98-126) (74-158) (85-111) (13-60) (38-56) (18-70) (19-32)

5-<12 113 20 48 15 2 3 8 3 (93-137) (17-23) (35-64) (13-18) (0-8) (2-5) (3-16) (2-4)

+12 24 10 15 7 0 0 2 1 (22-27) (9-10) (13-17) (7-8) (0-1) (0-0) (1-3) (1-1)

Table 10: Incidence of pertussis in relation to severity and age. Incidence per 100,000 person years (95% CI). Incidences are presented for all reported cases with pertussis, reported cases of pertussis with paroxysmal cough for 21 days or more, hospital admissions due to pertussis and complications due to pertussis. Data collection was performed in the EPS with episodes starting between Jan 01 2003, and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

2.3.1 Hospitalization

In 2016, 44 (51%) infants with pertussis were hospitalized and the corresponding numbers were 43 (51%) in 2015 and 67 (55%) in 2014.

Accumulated data from 2003 on hospitalisation, deﬁned as at least one night in the hospital due to pertussis disease during the episode, were available for 3,248 of 3,446 (94%) children in the EPS from Jan 1, 2003, to Dec 31, 2016 (Figure 20 and Figure 5 Appendix). Altogether 638 of the children (20%) were admitted to the hospital during the pertussis episode (Table 11).

The rate of hospital admission for cases with pertussis by age

In the EPS study (Jan 1, 2003, to Dec 31, 2016), a total of 460 of 654 infants (70%) who were younger than 90 days of age at the start of the pertussis

59 episode were admitted to the hospital. The corresponding admission rates, regardless of vaccination status at the start of the episode, for the 310 children in the age group 91—150 days of age, for the 263 children in the age group 151—365 days of age, and for the 2,021 children older than 365 days of age at episode start were 37%, 11%, and 2%, respectively (Table 11).

Age at episode start (days) Area 0-90 91-150 151-365 >365 Sum

Sweden excluding 404/549 106/254 26/159 30/1580 566/2542 Gothenburg (74%) (42%) (16%) (2%) (22%)

Gothenburg 56/105 8/56 2/104 6/441 72/706 (53%) (14%) (2%) (1%) (10%)

Total 460/654 114/310 28/263 36/2021 638/3248 (70%) (37%) (11%) (2%) (20%)

Table 11: Hospital admissions by age at episode start (number and per cent) in the Gothenburg study area compared with the rest of Sweden. Data collection was performed in the EPS with episodes starting between Jan 01 2003, and Dec 31 2016. Data are presented for pertussis cases 0–20 years of age.

Hospital admission by age and vaccination status

The rate of hospital admission among unvaccinated children aged 0—30 days, 31—60 days, and 61—90 days at the beginning of the pertussis episode was 83%, 71%, and 59% respectively, which dropped to only 2% for fully vaccinated pertussis cases older than 1 year of age. For unvaccinated children 91—150 days of age and 151—365 days of age, the rates of hospital admission were still 46% and 19%, respectively. The hospitalisation rate for vaccinated (one dose or more) children younger than 1 year of age was lower when compared with those for the unvaccinated children (Table 12 and Figure 3 Appendix). The downward trend by age was also observed for vaccinated children, both for children vaccinated with only one dose and for children who had received two or more vaccine doses before the pertussis episode. The majority of unvaccinated infants younger than 30 days of age were hospitalised for more than 7 days (Table 12).

60 Age at episode start (days) Vaccine Duration 0-30 31-60 61-90 91-150 151-365 >365 Sum doses of before hospital episode stay

0 0 32 71 87 36 26 404 656 (16.6%) (29%) (41.4%) (53.7%) (81.2%) (98.3%)

1-7 65 95 82 20 5 6 273 (33.7%) (38.8%) (39%) (29.9%) (15.6%) (1.5%)

>7 96 79 41 11 1 1 229 (49.7%) (32.2%) (19.5%) (16.4%) (3.1%) (0.2%) Sum 193 245 210 67 32 411 1158

1 0 4 159 44 12 219 (66.7%) (65.7%) (89.8%) (92.3%)

1-7 1 64 3 1 69 (16.7%) (26.4%) (6.1%) (7.7%)

>7 1 19 2 0 22 (16.7%) (7.9%) (4.1%) (0%) Sum 6 242 49 13 310

>1 0 1 165 1569 1735 (100%) (90.7%) (98.2%)

1-7 16 24 40 (0%) (8.8%) (1.5%)

>7 1 4 5 (0%) (0.5%) (0.3%) Sum 1 182 1597 1780

Table 12: Number of children admitted to the hospital due to pertussis, stratiﬁed by age and vaccination status at episode start. Data collection was performed in the EPS with episodeS starting between Jan 01 2003, and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

2.3.2 Complications due to pertussis

Data on respiratory complications, neurological complications, dehydration with >5% of weight loss, and other serious complications during the pertussis episode were registered in the EPS study for 3,116 of the 3,248 cases (96%) born Jan 1, 1996, until Dec 31, 2016, with vaccination and follow-up information from Jan 1, 2003, for all of Sweden. For the time period 2003–2016, respiratory complication (with apnoea, n = 224, or without apnoea, n = 217) was reported in 441 (14%) of the children, and dehydration was reported in 94 (3%) of the children. Uncommon complications, ge. neurological and other serious complications, were reported in 12 (0.4%) children (Table 13).

Altogether, almost all of the children with respiratory complications with apnoea were admitted to the hospital. The majority of the children with dehydration were also hospitalised (Table 13). For data from Sweden without the Gothenburg study area and for data from the Gothenburg study area from 2003, see Table 22 Appendix and Table 23 Appendix.

61 Complication type Hospitalised Not hospitalised Total Respiratory, with apnoea 204 (91%) 20 (9%) 224 Respiratory, without apnoea 81 (37%) 136 (63%) 217 Dehydration 58 (62%) 36 (38%) 94 Other severe events 8 (67%) 4 (33%) 12 No complication 285 (11%) 2284 (89%) 2569 Sum 636 (20%) 2480 (80%) 3116

Table 13: Complications and hospitalizations in children with pertussis. Data collection was performed in the EPS with episodes starting between Jan 01 2003 and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

The rate of complications due to pertussis by age

To analyse the association between complications during the pertussis episode and age and/or vaccination status of the child at the start of the episode, the subjects were grouped into those without any complication during the pertussis episode and those with at least one noted complication.

Of the 641 children who were younger than 90 days of age at the beginning of the pertussis episode, 43% (n = 273) had at least one complication. The corresponding rates for the 301 children in the age group of 91–150 days of age, for the 254 children in the age group of 151–365 months, and for the 1,920 children aged 365 days or older at the beginning of the pertussis episode were lower (Table 14).

Age at episode start (days) Area 0-90 91-150 151-365 >365 Total

Sweden excluding 242/537 57/245 20/153 146/1487 465/2422 Gothenburg (45%) (23%) (13%) (10%) (19%)

Gothenburg 32/104 10/56 7/101 33/433 82/694 (31%) (18%) (7%) (8%) (12%)

Total 274/641 67/301 27/254 179/1920 547/3116 (43%) (22%) (11%) (9%) (18%)

Table 14: Numbers and proportions of children with at least one complication due to pertussis, by age at onset of disease. Data collection was performed in the EPS with episodes starting between Jan 01 2003, and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

62 Complications in relation to age and vaccination status at the start of the pertussis episode

The events including "any complication" were studied in relation to age as well as to vaccination status at the beginning of the pertussis episode. Detailed data are given in Table 15 and Figure 6 Appendix.

During the studied period 2003-2016, the overall rate of any complication for unvaccinated children was 31% (320/1,041). For unvaccinated children aged 0–30 days, 31-60 days, and 61–90 days at the beginning of the pertussis episode, the complication rates were 56.4%, 38.2%, and 34.5%, respectively. For unvaccinated children between 91–150 days of age and 151–365 days of age, the rates of any complication were 27.9% and 21.4%, respectively, and dropped to 8.8% for children above 1 year of age (Table 15).

Age at episode start (days) Vaccine Complications 0-30 31-60 61-90 91-150 151-365 >365 Sum doses after episode before episode

0 No 81 149 135 44 22 289 720 (43.1%) (61.8%) (65.5%) (72.1%) (78.6%) (91.2%)

Yes 107 92 71 17 6 28 321 (56.9%) (38.2%) (34.5%) (27.9%) (21.4%) (8.8%) Sum 188 241 206 61 28 317 1041

1 No 2 189 44 11 246 (33.3%) (79.1%) (89.8%) (84.6%)

Yes 4 50 5 2 61 (66.7%) (20.9%) (10.2%) (15.4%) Sum 6 239 49 13 307

>1 No 1 161 1441 1603 (100%) (91%) (90.6%)

Yes 16 149 165 (0%) (9%) (9.4%) Sum 1 177 1590 1768

Table 15: The numbers and proportions of children with no or at least one complication stratiﬁed by age and vaccination status at the start of the pertussis episode. Data collection was performed in the EPS, with episodes starting between Jan 01 2003 and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age

2.3.3 Spasmodic cough

Cases of spasmodic cough due to pertussis

Data on cough and spasmodic cough were available for all 3,248 pertussis cases from Jan 31, 2003, to Dec 31, 2016. Altogether 2,618 (80.6%) of the

63 children had at least one day of spasmodic cough during the pertussis episode. Spasmodic cough for 21 days or more during the pertussis episode was reported for 75% of the children. The rates for different age groups varied between 63% and 85%, with the lowest incidence in children aged 151–365 days. During the study period 2003–2016, the rate for infants with spasmodic cough lasting 21 days or longer was 80% (976/1,227) (Table 16). For just 2016, the rate was 85% (74/87), and the youngest infants had the highest rate of long-lasting spasmodic cough.

Age at episode start (days) Area 0-90 91-150 151-365 >365 Total

Sweden excluding 489/549 222/254 123/159 1188/1580 2022/2542 Gothenburg (89%) (87%) (77%) (75%) (80%)

Gothenburg 69/105 29/56 44/104 272/441 414/706 (66%) (52%) (42%) (62%) (59%)

Total 558/654 251/310 167/263 1460/2021 2436/3248 (85%) (81%) (63%) (72%) (75%)

Table 16: Numbers and proportions of children with spasmodic cough for 21 days or longer, stratiﬁed by age at onset of pertussis disease, in Gothenburg and the rest of Sweden. Data collection was performed in the Swedish enhanced surveillance, with episodes starting between Jan 01 2003 and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

Duration of spasmodic cough by age and vaccination status at episode start

Regardless of age, of those children who were vaccinated but still contracted pertussis the rate of spasmodic cough for 21 days or more among those vaccinated with one dose was 82% (253/310), and among those vaccinated with two or more doses the rate was 71% (1,265/1,780) (Table 17). This reduction in the rate of spasmodic cough by the number of doses of pertussis vaccine before the episode start was statistically signiﬁcant (p < 0.001).

64 Age at episode start (days) Vaccine Duration 0-30 31-60 61-90 91-150 151-365 >365 Total doses of before the spasmodic episode cough start (days)

0 0 21 19 23 10 6 115 194 (10.9%) (7.8%) (11%) (14.9%) (18.8%) (28%)

1-20 8 17 8 6 0 7 46 (4.1%) (6.9%) (3.8%) (9%) (0%) (1.7%)

>20 164 209 179 51 26 289 918 (85%) (85.3%) (85.2%) (76.1%) (81.2%) (70.3%) Sum 193 245 210 67 32 411 1158

1 0 0 25 7 1 33 (0%) (10.3%) (14.3%) (7.7%)

1-20 0 17 7 0 24 (0%) (7%) (14.3%) (0%)

>20 6 200 35 12 253 (100%) (82.6%) (71.4%) (92.3%) Sum 6 242 49 13 310

>1 0 52 351 403 (0%) (28.6%) (22%)

1-20 1 24 87 112 (100%) (13.2%) (5.4%)

>20 106 1159 1265 (0%) (58.2%) (72.6%) Sum 1 182 1597 1780

Table 17: Duration of spasmodic cough, stratiﬁed by age and vaccination status at episode start. Data collection was performed in the EPS with episodes starting between Jan 01 2003 and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

In a complementary analysis, we compared any complication among unvaccinated children with pertussis aged 3 and 12 months at the beginning of the pertussis episode with the same aged children with pertussis but who had been given one dose of a pertussis vaccine before the start of the pertussis episode. The following results are highlighted:

1. The median (mean) age at start of an episode was 114 (149) days for unvaccinated children and 125 (131) days for children vaccinated with one dose before the episode.

2. Overall 30% of the unvaccinated children aged 3-12 months and 20% of the children vaccinated with only one dose had a complication during the pertussis episode. This difference was statistically signiﬁcant (p=0.034).

It can be concluded that in unvaccinated children there was a strong association between age at the beginning of the pertussis episode and the risk of a complication due to the disease. In vaccinated children, there was also an

65 inverse association between vaccination status, i.e. the greater the number of vaccine doses before the episode of pertussis, the lower the risk of any complication.

As could be expected, there was also a strong association between any complication and a hospital stay during the pertussis episode. Altogether, 56% (493 out of 877) of the children with at least one complication also had a hospital admission due to the disease during the pertussis episode. For 3,426 children with pertussis without any complication, the hospitalization rate was 12% (p < 0.001).

2.3.4 Deaths

During the 19-year study period, there were 12 deaths due to pertussis among unvaccinated infants and one death in a vaccinated 2-year-old child with severe underlying disease. The parents of these children were not contacted within the project, and only limited information, which was obtained from medical personnel, is available for these cases. Eight infants were full term and four were born before gestational week 37. Ages at death were from 3 weeks to 3 months for the full term infants and from 3 to 6 months for the premature infants. The one that died at 6 months fell ill with pertussis at about 3–4 months of age.

In conclusion: Severity of pertussis in infants

The data in the EPS showed that the incidences for hospital admissions due to pertussis were highest for the youngest infants (Figure 20 see also Table 10 for the Gothenburg study area and Sweden without the Gothenburg study area).

66 120 ● 119.9

100

● 44.7 40 Cases per 100 000 person years

● 3.2 0 ● 0.2

0−90days 91−150days 151−365days >365days

Days of age

Figure 20: Incidence of hospital admission per 100,000 person years due to pertussis stratiﬁed by age at episode start. Data collection was performed in the EPS of pertussis, with episodes starting between Jan 1, 2003, and Dec 31, 2016. Data are presented pertussis cases among those 0-20 years of age.

The age-speciﬁc incidence rate of hospitalisation due to pertussis was highest for children 0—90 days of age. The incidence decreased with increasing age to less than 1/100,000 person years for children older than 1 year of age at the start of the pertussis episode. Although fewer children were hospitalised in 2016 (n = 44) and in 2015 (n = 43) compared with 2014 (n = 67), the hospitalisation rate did not differ to a large extent at 55% in 2014 vs. 51% in both 2015 and in 2016.

The overall rate of hospital admission for unvaccinated children was 43% for the study period of Jan 1, 2003, to Dec 31, 2016. However, in this group, 91% were younger than 3 months of age and too young to be vaccinated. Regardless of age, the rate of hospitalisation for children vaccinated with one dose was 29%. For children vaccinated with two or more doses before the pertussis episode, 2.5% were hospitalised. This association between rate of hospital admission and vaccination status was confounded by age. For example, for children 12 months of age the rate of hospital admission was

67 low and independent of the vaccination status of the child.

With regard to any complication in unvaccinated children, there was an association between the rate of complication and the age of the child at the beginning of the pertussis episode. Regardless of age, the rate of any complication for children vaccinated with one dose was 20% and for children vaccinated with two or more doses before the pertussis episode the rate was 9% (p = 0.006). This statistically significant difference was confounded by age. For children older than 12 months, the rate of any complication was about 9% for unvaccinated children and 9% for children vaccinated with two or more doses. In the age interval 5–<12 months, the complication rate was 21% for unvaccinated children, 10% for children vaccinated with one dose, and 11% for those vaccinated with two or more doses prior to the episode. This downward "trend" in rate by number of doses prior to the pertussis episode was statistically significant (p < 0.001). These results suggest that there was some protection against "severe" pertussis, which was defined as any complication due to the disease, already after one dose of a pertussis vaccine. This finding was further evaluated in a paper from the PHAS (Nilsson 2012).

In all, 591 of 654 infants (90%) who were younger than 90 days of age at the start of the pertussis episode had spasmodic cough, and for 558/654 (85%) the cough lasted for 21 days or longer. The corresponding rates for the 310 children in the age group of 91–150 days of age, for the 263 children in the age group 151–365 days, and for the 263 children aged 12 months or older were 81%, 63%, and 72%, respectively. The age-speciﬁc incidence rate of pertussis with spasmodic cough for 21 days or more was highest in children 0–90 days of age (356/100,000 person years) and decreased to 44/100,000 person years for children older than 1 year of age at the start of the pertussis episode.

It can be concluded that there was a strong association between age at the beginning of the pertussis episode and the risk of a complication due to the disease for an unvaccinated child. In vaccinated children there was an inverse association between vaccination status, i.e. the number of vaccine doses, before the start of the episode and the risk of any complication.

68 2.4 Treatment of pertussis

The proportions of infants with pertussis who received antibiotic treatment in the age groups <3 months, 3–<5 months, and 5–<12 months during 2003–2016 were 88.7%, 81.8%, and 79.8% respectively. For children 1–10 years of age and for children from 11 years of age and older in the EPS study, antibiotic treatment was administered to similar proportions of children at 44.8% and 36.1%, respectively.

The time between the onset of the pertussis disease and the start of antibiotic treatment is shown in Figure 21. The treatment period tends to start rather late, and there is no clear difference between the youngest infants (0–3 months of age) and the older infants based on the median values. However, there are several extreme values, particularly for children more than 1 year of age. Furthermore, in the youngest age group and in children 5–<12 months, one child in each group had received prophylactic treatment.

150 ●

Md=13 Md=12 Md=13 Md=16

● ● ● 100 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 50 ● ● ● ● ● ● ● ● ● ● ● ●

0 Days between episode start between Days and antibiotic treatment ●

● ●

0−<3Months 3−<5Months 5−<12Months >=12Months

Age at episode start

Figure 21: Number of days between episode start and start of antibiotic treatment. Data collection was performed in the EPS, with episodes starting between Jan 1, 2003, and Dec 31, 2016. Data are presented for pertussis cases among those 0-20 years of age. Md = Median.

69 2.5 Case contact study of pertussis in infants

The ongoing EPS study was extended in January 2009 to also investigate infant pertussis case contact. The aim of this study was to investigate the most common source of pertussis infection for the youngest infants, with a focus on identifying the outcome of severe disease in infant cases stratiﬁed by the contact source of infection.

A total of 345 infants with a mean age of 3.6 months were included in the case-contact study during 2009–2016, and 117 of them were vaccinated. Persons with cough for 7 days or more who had been in contact with the infants were categorized as mothers, fathers, siblings, other persons, and/or as unknown (if the parents had not noticed anyone with cough).

Mothers were the most commonly identiﬁed source, and a manuscript with more detailed analyses regarding the case contact study is currently in preparation.

2.6 Geographic differences in Sweden for laboratory-confirmed pertussis cases

The Swedish reporting system is based on data from counties, and at this level there are variations in the incidence in terms of time and between different areas of the country. Figure 22 illustrates the geographic variations in reported pertussis cases (clinical and laboratory reported) during the years 1997–2016.

During 2016, most of the pertussis cases (27%) were reported from the county of Stockholm followed by the county of Scania (Skåne) (18%) and the county of Västra Götaland (17%). The county of Uppsala had the highest incidence of 17 reported cases per 100,000 person years followed by the counties of Gotland and Södermanland with 16/100,000 and 12/100,000 person years, respectively.

70 1997 1998 1999 2000 2001 2002

2003 2004 2005 2006 2007 2008

2009 2010 2011 2012 2013 2014

2015 2016 20

Figure 22: Incidence of reported pertussis cases (laboratory reports) in different counties of Sweden from 1997-2016 with episodes starting between Oct 1, 1997 and Dec 31, 2016 reported to SmiNet according to the Communicable Disease Act. Colour changes indicate the 25%, 50%, and 75% quartiles. Source: SmiNet.

2.7 The effects of catch-up and booster vaccination schedules

2.7.1 Immunisations during the 1990s

Infants born during the latter part of 1995 were vaccinated against pertussis in most parts of the country, with the start of vaccination taking place in January 1996 when aP vaccines were introduced into the NIP. At the age of 2 years, the overall three-dose coverage for the 1995 cohort was 59%. Since the restart of the NIP, including vaccination against pertussis with the aP vaccines in 1996, the coverage rate has been between 98% and 99%. Free catch-up vaccinations to more than 65,000 children born in the 1990s were offered in the Gothenburg study area from 1997 to 1999 (Taranger 2001). Likewise, children in the rest of the country were also catch-up vaccinated

71 to some degree.

2.7.2 Immunisations during the 1990s in pertussis vaccine trials

Some study children from Trials I and II (Gustafsson 1996, Olin 1997) were boosted in early childhood (almost all children vaccinated with DTwP in Trial I, and almost all children vaccinated with DTPa2 in the two trials). Within other studies, small groups of children were boosted at around 5–6 years of age during the 1990s.

2.7.3 Booster vaccination in children born from 1995 and from 2002 (see also chapter 1.3)

In 2005, a revision of the national vaccination schedule was initiated. As a first step, a booster was recommended for children in school year 4 (age 10 years) from autumn 2005. The first cohort for whom this fourth dose of aP vaccine was recommended was children born in 1995, i.e. the year before the formal introduction of DTaP in infancy, because this cohort was to a large extent (59%) catch-up-vaccinated before 2 years of age. The booster at 10 years of age was valid until 2011–2012. The next schedule revision was completed in Dec 2006 and included a fourth dose at 5–6 years of age and a fifth dose at 14–16 years of age for children born from 2002.

2.7.4 Effectiveness of the preschool booster vaccination

The effectiveness of the booster at 5-–6 years was evaluated and was presented in an international meeting in 2010 (Rydevik 2010). The results have also been brieﬂy presented in Chapter 4 of the 13-year report of the pertussis surveillance in Sweden. The presence of a preschool booster was shown to have a strong effect, with fewer than half the number of pertussis cases prior to the booster vaccination. An update of these results is now ongoing for publication (manuscript in preparation). Also, an effect on herd immunity has been evaluated and the results have been published (Carlsson, 2015).

2.8 Follow up of vaccine studies and immunisation 1996-97

2.8.1 Trials I and II

Two nationwide trials were performed during the 1990s. Pertussis Trial I with a 2-4-6 month schedule was performed in 9,829 infants during 1992–1995 (Gustafsson 1996). In Trial II either a 3-5-12 month (72,698 infants) or a

72 2-4-6 month schedule (10,194 infants) was performed during 1993–1996 (Olin 1997). Based on the study results, an extra dose of aP vaccine was offered in early childhood to children vaccinated with a DTPa2 vaccine (unregistered vaccine). The estimated incidence of pertussis in children vaccinated with the DTPa2 vaccine completed with a booster dose at the end of Trial II was lower than in cohorts vaccinated with three doses of the other study vaccines (DTPa3, DTPa5, or DTwP), all of which were shown to be more efﬁcacious in the trial. Among children vaccinated according to the 3-5-12 month schedule, i.e. including an early booster at 12 months of age, the long-term incidence of pertussis was higher in the DTPa5 group than in the DTwP group, which was in contrast to what was estimated in the trial. These studies have been followed-up in detail by study nurses who documented the vaccination history and clinical course in pertussis cases through structured telephone interviews according to the same procedures carried out during Trial II.

Children participating in Trials I and II have been followed up in the enhanced surveillance database from Oct 1, 1997. However, as mentioned above, these cohorts make up the Gothenburg study area and have been excluded from most analyses in this report. More detailed analyses have been presented previously (Gustafsson 1996, Olin 1997) and in the technical reports. They are also described in Table 2 in chapter 1.1.2, Table 9 in chapter 2.2.3, and below.

Table 18 reports laboratory-conﬁrmed cases of pertussis during the follow-up period from Oct 1, 1997, until Dec 31, 2016, among children vaccinated with three or four doses before the onset of cough. In all, there were 310 cases of laboratory-conﬁrmed pertussis cases among the participants in Trial I and Trial II who had received three trial doses.

The overall incidence of pertussis was 18 cases per 100,000 person years of follow-up (Table 18). The trial participants were between 4 and 18 years of age during the follow-up period, and they had received the primary series of pertussis vaccine before 1 year of age.

Table 18 also shows the incidence ﬁgures during the 19-year follow up for children vaccinated at 3, 5, and 12 months of age in Trials I and II. The overall rate for Trial II children varied from 17/100,000 in the DTwP group to 11–37/100,000 in the DTaP groups who had received three doses of a pertussis vaccine.

Due to poor efﬁcacy shown in Trial I for US DTwP, and in both trials for DTPa2 (unregistered vaccine), the recipients of these vaccines were offered a fourth dose of aP vaccines at 3–4 years of age. As expected, the estimated incidence after four doses in the DTPa2 trial arm (11/100,000 person years) in Trial II was in the lower range of the DTPa3, DTPa5, and DTwP vaccines, all of which were shown to be efﬁcacious in Trial II.

73 The former publications in the Gothenburg study area are mentioned in Chapter 2.9.

Trial Vaccines Enrolled Person years Cases Incidence (95% children conﬁdence interval)

Trial I 3d CLI 2,001 38,436 2 5 (1-19) DTPwc+/- 1d Cll Pa5

3d SKB 2,538 48,751 6 12 (5-27) DTPa2+/- 1d SKPB Pa3

3d CLL 2,551 49,000 12 24 (13-43) DTPa5 I

Trial II 3d Evans 19,971 383,610 65 17 (13-22) DTPwc

3d SKB 6,444 123,778 46 37 (27-50) DTPa2

3d SKB 13,731 263,750 30 11 (8-16) DTPa2, 1d SKB Pa3

3d Chiron 20,239 388,757 62 16 (12-20) DTPa3

3d CLL 20,230 388,585 87 22 (18-28) DTPa5 II

Both trials All 87,705 1,684,667 310 18 (16-21)

Table 18: Number of laboratory-conﬁrmed cases among participants in Trial I and Trial II, the number of fully vaccinated children (three doses at either 2-4-6 or 3-5-12 months of age), estimated person years of follow up, and incidence per 100,000 person years of follow up. Data collection was performed in the EPS with episodes starting between Jan 01 2003 and Dec 31 2016. Data are presented for pertussis cases 0-20 years of age.

2.8.2 Surveillance of children immunised Jan 1, 1996, to Sep 30, 1997

In the beginning of 1996, when a pertussis vaccine was reintroduced in the NIP, only one DTaP vaccine (Infanrix®, GSK) was used in all parts of Sweden except in the Gothenburg study area (see 1.3.3.).

The ﬁrst 21 months (until Sept 30, 1997) cohort was regarded as a "pure" Infanrix®cohort, because that vaccine was the only pertussis vaccine used for this birth cohort in Sweden when the Gothenburg study area is excluded. However, most of these children have received one of the two DTaP vaccine at 10 years of age. Incidences and cases for this group are shown in Table 19.

74 Onset of pertussis relative to Person years Number of cases Incidence 95% conﬁdence vaccination with Infanrix interval

0-90days 2552.00 0 (5) 0 (196) 0-145 (64-457) 91-150days 4537.00 4 (8) 88 (176) 24-226 (76-347) 151-365days 33882.00 17 (19) 50 (56) 29-80 (34-88) After 1 year of age 2790664.00 470 (562) 17 (20) 15-18 (19-22)

Table 19: Incidence of pertussis in the cohort vaccinated with Infanrix®(vaccinated between January 1, 1996 and September 30, 1997). Data are from case reports of pertussis among those 0-20 years of age with episodes starting between Oct 1, 1997, and Dec 31 2016. Data collection was performed in the EPS. The table shows the age groups at the onset of the pertussis episode, the person-years of follow-up, the number of laboratory-conﬁrmed cases, the incidence per 100,000 person years and the 95% conﬁdence interval. The numbers in parentheses include the unvaccinated children of the respective age group (intent to treat).

75 2.9 Pertussis incidence in Västra Götaland and the evaluation of severity of pertussis in the Gothenburg study area

This chapter provides an overview of the Gothenburg study area. However, the Swedish reporting system is county-based and therefore we can only present overall rates from the whole county of Västra Götaland. The Gothenburg study area is only a part of this county and represents about half of the Västra Götaland population. In addition, the study area includes one municipality within another county (Halland), which represents about one quarter of the county population (Figure 3). In other words, the national communicable disease reporting system does not allow comparisons of the Gothenburg study area with the rest of Sweden. Instead, data from the whole county of Västra Götaland are used.

Despite the fact that the county of Västra Götaland is not a reasonable proxy for the ten Västra Götaland municipalities of the Gothenburg study area, we consider it valuable to present the overall number of 3,744 laboratory-conﬁrmed cases from Västra Götaland during the 1997–2016 period compared to the 15,923 laboratory-conﬁrmed cases from the rest of Sweden during the same time interval. We have also made some efforts to check indicators of different levels of awareness and reporting practices in Västra Götaland and in the rest of Sweden. In addition, data on some performance indicators for the vaccination program were collected within the EPS and could be compared between the Gothenburg study area and the rest of Sweden.

Infants born during the latter part of 1995 were vaccinated against pertussis in most parts of the county of Västra Götaland when the aP vaccines were licensed in January 1996. At 2 years of age, the overall three-dose coverage for the 1995 cohort was close to 60%. The catch-up vaccination campaign covered a large proportion of toddlers and school children in the Västra Götaland region, but only covered a smaller proportion in the rest of Sweden. In the Gothenburg study area, free catch-up vaccinations were offered from 1997 to 1999 to more than 65,000 children born in the 1990s. By the spring of 2000, about 56% of children born in the 1990s had been vaccinated with three doses of aP vaccine (Taranger 2001).

The influence of the Gothenburg catch-up vaccination campaign on the long-term circulation of pertussis is not known. The mass vaccination study suggested the presence of herd immunity as reflected by a significant reduction in the number of pertussis cases in vaccinated and unvaccinated individuals in 1997–1999.

76 2.9.1 Incidences and cases of pertussis in Västra Götaland

During the years 2000-2005, it was obvious from the yearly national epidemiological reports that there were more laboratory–conﬁrmed cases of pertussis in the county of Västra Götaland in relation to population size than in the rest of Sweden (Figures 23 and 24). The incidence in this region was clearly in excess of the expected incidences during 2001–2004 compared with the rest of the country, with a marked peak in 2004.

Several reasons for the increased incidences have been evaluated in previous reports. One signiﬁcant difference was the fact that 56% of the children in the area who were born in 1990 through 1995 were vaccinated within the Gothenburg study project during the years 1997–2000 (Taranger 2001) resulting in a large cohort with waning immunity after 4-6 years’ time. Other potential reasons that have been discussed include more pertussis cases being diagnosed (a greater proportion of mild cases in the Gothenburg study area) and the use of the mono-component vaccine (Carlsson 2009).

77 100

60 %

0 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016

Year

Figure 23: Proportion of the laboratory-reported cases in SmiNet from Västra Götaland. Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act. The blue line indicates the expected number of pertussis cases in relation to the incidence in the rest of Sweden.

78 Västra Götaland 80 Sweden excl. Västra Götaland

20 Incidence (per 100,000 person years)

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Year

Figure 24: Incidence of pertussis (cases per 100,000 person years) per month. Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act.

Detailed data on the overall number of pertussis cases in Västra Götaland region are presented in the Appendix. However, an illustration of the yearly pertussis incidence for the period 1986-2016 is shown below (Figure 25). See also Figure 7 and Figure 24 for incidences in the whole of Sweden.

79 2500

15 2000

1500 10 Age Cases per year 1000

500

0 0 1990 1995 2000 2005 2010 2015

Figure 25: Illustration of the incidence per age (1 year age groups) and calendar year in Västra Götaland for cases with episodes starting between 1997, and Dec 31, 2016. Cases were reported to SmiNet according to the Communicable Disease Act. Data before 1997 are from voluntarily reports from bacteriological laboratories.

Pertussis in infancy in the Västra Götaland region and the rest of Sweden

The difference in incidences of pertussis between the Västra Götaland region and the rest of Sweden is especially marked in infants (younger than 12 months of age). Figure 26 provides the age-speciﬁc incidence in infants per calendar year in the Västra Götaland region and the rest of Sweden during the 1986–2016 period.

The incidence rates in infants in the Västra Götaland region during the period 1999–2005 varied between 246 and 872/100,000 person years, i.e. at levels seen in Sweden before the introduction of DTaP in 1996, whereas the corresponding rates in the rest of Sweden during the same time period were 78–185/100,000 (Figure 26). In 2007, the age-speciﬁc incidence in

80 infancy was below 100/100,000 in the Västra Götaland region for the ﬁrst time since 1985.

1400 Västra Götaland Sweden excl. Västra Götaland

1200

1000

800

600 Incidence (per 100,000) 400

200

1985 1990 1995 2000 2005 2010 2015

Year

Figure 26: Age-speciﬁc incidence of laboratory-reported pertussis in infants in the Västra Götaland region and in Sweden excluding Västra Götaland during the 10 calendar years before (1986–1995) and 20 years after (1997-2016) the introduction of the DTaP vaccine in 1996. Data are from case reports of pertussis, with episodes starting between 1997 and Dec 31, 2016, reported to SmiNet according to the Communicable Disease Act or from voluntarily reports from bacteriological laboratories before 1997.

2.9.2 Severity of pertussis in the enhanced surveillance study for children in the Gothenburg study area in comparison with rest of Sweden

In this section we describe cases in the database as of Dec 31, 2016, that have a reported onset of cough in the EPS study and were born from January 1, 1996. For analytical purposes, they are split into two groups: those born in the Gothenburg study area (706 pertussis cases including 414 with 21 or

81 more days of spasmodic cough) from Jan 1, 2003 (Table 20), and those born in the rest of Sweden (3,460 and 2,793 cases, respectively) from Oct 1, 1997 (Table 25 Appendix).

In Table 12 Appendix and Table 13 Appendix, laboratory-conﬁrmed cases from Sweden excluding the Gothenburg study area and from the Gothenburg study area per year and birth cohort are shown.

Among 3,248 children with laboratory-conﬁrmed pertussis, 1,158 (35.7%) had not received a pertussis vaccine prior to the illness, including 146 (20.7%) from the Gothenburg study area and 1,012 (39.8%) from the rest of Sweden. We also present data on all children from October 1997. There were 1,369 unvaccinated children with pertussis from Sweden excluding the Gothenburg study area and 245 unvaccinated children from the Gothenburg study area (Table 14 Appendix and Table 15 Appendix).

The median durations of cough and spasmodic cough in children from January 1, 2003, among the 146 unvaccinated children from the Gothenburg study area were 45 and 32 days, respectively. The corresponding ﬁgures from the rest of Sweden were 53 and 40 days. Spasmodic cough for 21 days or more was reported for 65.1% of the Gothenburg study area children and for 81.3% of the children from the rest of Sweden. No spasmodic cough was reported for 27.4% and 15.2% of the episodes in the Gothenburg study area and the rest of Sweden, respectively. This difference is statistically signiﬁcant (p < 0.001).

The incidences of pertussis with 21 days of cough, hospital admission, and complications by age group and study region with episodes starting between Jan 1, 2003, and Dec 31, 2016, are presented in Table 10 in Chapter 2.3.1. For infants younger than 3 months of age there were higher incidences for all parameters in the Gothenburg study area compared with the rest of Sweden. Likewise, the incidences were also mostly higher for the other age groups included in Table 9.

Altogether 638 of the 3,248 children with pertussis (19.6%) had a hospital admission during the pertussis episode. Seventy-two (10.2%) of the children in the Gothenburg study area were hospitalised during the pertussis episode compared to 566 (22.3%) children in the rest of the country (p < 0.001). Hospitalisation rates for children in the Gothenburg study area were signiﬁcantly lower compared to the rates in the rest of Sweden in all age groups in infancy. Hospital admissions were studied from Jan 1, 2003, to Dec 31, 2016 (see Table 10 in chapter 2.3.1). The incidence of pertussis in children in the Gothenburg study area was higher, and the proportion of hospitalized children was lower before 2007 than in the rest of Sweden, but up to 2012 the percentage of hospitalised cases was similar in the two areas. During 2012–2016, the hospitalisation rate in the Gothenburg study area was higher (Figure 27).

82 50

20 Percentage hospitalized Percentage

Sweden excluding Gothenburg 0 Gothenburg

2004 2006 2008 2010 2012 2014 2016

Year

Figure 27: The rate (%) of hospitalisation among pertussis cases in the Gothenburg study area and in the rest of Sweden. Data collection was performed in the EPS, with episodes starting between Jan 1, 2003, and Dec 31, 2016. Data are presented for pertussis cases 0-20 years of age.

For data on complications of pertussis disease, see Chapter 2.3 and 8.4.

For the whole country since Jan 1, 2003, there was a greater likelihood of a reported pertussis case to come from a child in the Gothenburg study area compared to the rest of Sweden (Table 20), but since 2005 the differences have mostly disappeared. Approximately 17% of new-borns in Sweden during the years 1996–2016 were born in the Gothenburg study area, and in the last column below, called "Index", the percentage of pertussis cases in the Gothenburg study area out of the total number of cases in Sweden is therefore divided by 17.

83 Severity Total Number of Percent Index. number cases in the of total Proportion of cases in Gothenburg number of contributed Sweden study area cases that by occured in Gothenburg Gothenburg study study area. area in relation to proportion of newborn children All reported 3248 706 21.7 1.9 cases

Cough 102 42 41.2 3.6 <14 days - spasmodic or non-spasmodic

No 630 223 35.4 3.1 spasmodic cough

Spasmodic 2436 414 17.0 1.5 cough 21 days

Table 20: Number of pertussis cases of differing severity with regard to spasmodic cough. Comparison between the Gothenburg study area and Sweden excluding Gothenburg. Data are from laboratory-conﬁrmed case reports of pertussis. Data collection was performed in the EPS, with episodes starting between Jan 01 2003, and Dec 31 2016. Data are presented for children 0-20 years of age.

Some differences in incidences of pertussis between the Gothenburg study area and the rest of Sweden are found when comparing the two areas for children with 21 or more days of cough regardless of vaccination status.

84 Gothenburg Rest of Sweden 200

174.1 ●

150 ● 142.1

110.1 ● 100 ● 97.1 Cases per 100 000 person years 50 48 ●

● 15.4 15 ● ● 7.4 0

0−90days 91−150days 151−365days >365days

Days of age

Figure 28: Age speciﬁc incidence of spasmodic cough for 21 days or more (WHO 1991) due to pertussis disease per 100,000 person years of follow up –regardless of vaccination status – in Gothenburg study area and in rest of Sweden. Data collection was performed in the EPS with episodes starting between Jan 1, 2003 and Dec 31, 2016. Data are presented for children 0-20 years of age.

85 3 Discussion

Despite high vaccine coverage globally (86% coverage with three doses of a pertussis-containing vaccine in 2015), pertussis remains endemic in all countries and continues to be a public health concern (WHO position paper, Pertussis vaccines 2015). In Sweden, pertussis is the least controlled of all vaccine-preventable bacterial diseases for which universal childhood immunisation is recommended (Årsrapport 2016) even though vaccination coverage for aP-containing vaccines has been 97–98% for decades. The incidence of pertussis has increased in the last three years after many years of low incidence.

In the present 19-year report, 647 labortory-conﬁrmed cases of pertussis were reported to SmiNet during 2016, of which 87 infants were younger than 1 year of age. As in previous years, infants had the highest incidence out of all age groups in 2016. Pertussis remains a serious and life-threatening disease for infants, especially for the youngest. In 2016, no pertussis-related infant deaths were reported in Sweden, but two infants died in 2014 and one infant died in 2015, and all three were younger than 1 month old and unvaccinated. As in previous years, age-speciﬁc incidence of hospitalisation associated with pertussis was highest for infants younger than 3 months of age in 2016. A majority of infants (72%) had pertussis before the age of 5 months, and 60% were unvaccinated. Consequently, the high incidence of pertussis among infants is mainly represented by infants before they received one or two doses of pertussis vaccine.

Increase of pertussis in Sweden since 2014 after years of low incidence

After a 5-year period with a low incidence of reported pertussis cases (2009 to 2013), a signiﬁcant increase was noticed in the general population in 2014. The incidence increased by threefold to 7.1/100,000 person years in 2014. This increase was partly sustained during both 2015 (5.9/100,000 person years) and 2016 (6.5/100,000 person years). As in previous years, infants had the highest incidence out of all age groups in 2016. Other age groups associated with high incidences in 2016 were the 11, 13, and 17-year-old teenagers with an incidence of 14–16.0/100,000.

In Sweden, the resumption of aP vaccination in 1996, after a 17-year period without any pertussis-containing vaccine, had a positive effect on the incidence of pertussis in infants and provided indirect protection of the unvaccinated population. A dramatic decline in pertussis incidence was seen during the ﬁrst years, with further reductions documented during the long-term follow-up until 2013. The total incidence of pertussis decreased from 90.4/100,000 in 1996 to 4.0/100,000 person years in 2008, with further decreases in the incidence during the time period 2009–2013 to 1.8–2.8/100,000 person years. The decrease started in infants and toddlers, and after the

86 pertussis booster vaccination was introduced at 10 years of age in 2006 and subsequently moved to 5–6 years of age in 2007, the decrease continued in infants and was also evident in early school age.

It has been clear for several years that protective immunity following aP vaccines wanes over time (Misegades 2010, Witt 2012, Klein 2012, Sheridan 2012, Baxter 2013, Koepke 2014). Worldwide surveillance data suggest that the use of aP vaccines will result in a resurgence of pertussis after a number of years and that this resurgence might also lead to an increased risk of death in infants who are too young to be vaccinated (WHO position paper 2014, 89, 337–344). Future surveillance will tell if the increase in pertussis in Sweden is part of a renewed cyclic pattern of epidemic waves or if the incidence will be sustained at a higher level. The increase of pertussis in 2014 was difﬁcult to predict because it was neither preceded by a decrease in vaccination coverage nor by an obvious increase of pertussis in any age group. With the current situation, it is reasonable to believe that Sweden has passed the honeymoon period as described by de Celle‘s (2016).

Pertussis in infants

In 2016, as in previous years, in the EPS study, infants had the highest incidence of pertussis of all age groups (74.1/100,000 person years), and most of the infants had pertussis before they had received one or two doses of pertussis vaccine. Long-term follow up shows high incidence of pertussis in 1997–2003 in infants 0–90 and 91–150 days of age (239/100,000 person years and 248/100,000 person years, respectively). These levels decreased, however, for the subsequent period of 2004-2010 (151/100,000 person years for 0-90 days of age and 110/100,000 person years for 91–150 days of age), and then increased again during the period 2011-2016 (167/100,000 person years for 0-90 days of age and 111/100,000 person years for 91-150 days of age).

In a recently published nationwide study from the US, the overall pertussis incidence rate among infants <12 months of age, born from 2005 to 2010, was 117.7/100,000 person years, with infants 3 months of age having the highest incidence rate (247.7/100,000 person years). The incidence rate in the youngest infants was much higher in the US study compared to corresponding Swedish data for the same time period, but a similar age distribution and a similar steady decrease of incidence from the 4th through the 12th months of life was observed (Masseria 2017). However, this difference in incidence levels might be due to differences in clinical routines and surveillance systems.

All children hospitalised in Sweden for pertussis in 2016 were younger than 12 month of age (n = 44). The hospitalisation rate in pertussis cases among infants did not differ compared with 2015 (52% in 2016 vs. 51% in 2015). In the study period between January 2003 and December 2016, the

87 age-speciﬁc incidence rate of hospitalisation due to pertussis was highest for children 0—90 days of age (70% hospitalisation), and the overall rate of hospital admission for unvaccinated children was 43%. In this group, however, 91% were younger than 3 months of age and too young to be vaccinated.

In 2016, 51 out of 83 infants reported complications due to pertussis, and 36 of these infants were hospitalised. All infants reported with complications in 2016 had respiratory complications; with apnoea (n=21) or without apnoea (n=30). The total rate of any complication was higher in 2016 (61%) compared to 2015 (35%) and 2014 (27%) but this can be explained by a higher number of infants reported in 2016 with respiratory complication without apnoea. The rate of respiratory complication with apnoea in 2016 was 25% and corresponding rate in 2014 and in 2015 was 19% and 27% respectively. The higher number of infants reported with respiratory complications without apnoea in 2016 warrants further close observation and analysis. Other studies have shown high rates of respiratory complications with apnoea (56%, Tanaka 2003; 34%, Sowdhamini 2011). In a previously published study based on the Swedish EPS data for 1998–2012, complications of any kind due to pertussis were reported in about a quarter to a third of the infants with pertussis and were more frequent in unvaccinated infants. Respiratory distress, with or without apnoea, was the most frequent problem (Carlsson 2015). The complication rate in 2016 (57%) was higher than reported in 2014 (27%) and 2015 (35%), but the higher rate of complications in 2016 was not associated with a higher hospitalization rate. In the long-term EPS study, with episodes starting between January 2003 and December 2016, of the 641 children who were younger than 90 days of age at the beginning of the pertussis episode, 43% (n = 273) had at least one complication and 76% of children with any complications were younger than 1 year of age.

The present report shows that the first dose of vaccine given at 3 months of age has reduced the risk of severe illness and thus reduced the rates of hospitalisations and complications compared to unvaccinated infants. Ninety per cent of infants younger than 3 months had paroxysmal cough for 21 days or more, and among those having received one dose or more of pertussis vaccine a significantly reduced period of coughing (p < 0.001) was observed. In addition, this report shows that one dose of pertussis vaccine gives significant protection against other complications (including respiratory complications, neurological complications, dehydration with >5% of weight loss, or other serious complications) related to pertussis (p = 0.034) among infants aged 3–12 months compared with unvaccinated infants. These results suggest that already after one dose of a pertussis vaccine there is some protection against severe pertussis, which was defined here as any complication due to the disease. This was previously shown in a US study (Tanaka 2003) and also further evaluated in an article based on

88 EPS data (Nilsson 2012).

Source of pertussis infection in infants

Pertussis is a highly contagious disease with attack rates reaching as high as 80% in susceptible individuals (Mertsola 1983). Numerous studies have evaluated the source of pertussis transmission to infants, and for more than half of all infant cases an unknown source of infection is reported (Bisgard 2004, Kowalzik 2007, Wendelboe 2007). In studies where a source of transmission is identified, mothers have been the most commonly cited source of infection (Elliott 2004, Bisgard 2004, Wendelboe 2007, Kowalzik 2007). Published data, however, from Canada, Australia, the Netherlands, and the US suggest that siblings have an increasingly important role in the transmission of pertussis to infants (Halperin 1999, Jardine 2009, de Greefff 2010, Bertilone 2014, Skoff 2015). One previous study described infant and maternal characteristics as factors that might be associated with increased pertussis-related death (Haberling 2009). None of the previous studies, however, have stratified age at onset, severity, and time between diagnosis and onset of symptoms by contact source of individuals close to the infant. Therefore, the ongoing EPS study was extended in January 2009 to also investigate infant pertussis case contact. The aim of this study was to investigate the most common source of pertussis infection for the youngest infants and to identify the outcome of severe disease in infant cases stratified by the contact source of infection. The analysis of the EPS data case contact data 2009-2015, showed that mothers were the most commonly identified source, and preliminary data indicate the importance of early diagnosis and treatment of mothers with new-borns and the use of post-exposure antimicrobial prophylaxis in infants in order to decrease the disease burden of pertussis in infants.

Pertussis incidence over time in children older than 1 year

Age groups associated with increased and higher incidences in 2016 in comparison to 2015 were the 11, 13, and 17-year-old teenagers. A booster dose among 14–16 year olds was implemented within the NIP in 2016 in Sweden. The vaccination of teenagers has been shown to reduce the spread of infection among teenagers (Acosta 2015), but the available data imply a limited or no herd immunity effect on pertussis incidence in infants (Quinn 2011, Auger 2013, Kandola 2005). Moreover, recently published data indicate short-term protective effects after booster vaccination in adolescence (Tami 2016). The impact of low dose vaccine against tetanus, diphtheria, and acellular pertussis (dTdTap) vaccine among adolescents in the US seemed promising following the introduction of the vaccine, but extended analysis revealed that the trend in adolescent disease was reversed in 2010 when the reported incidence of pertussis among adolescents began to increase at a faster rate than in any other age group. The beneﬁt from ddTap vaccination was mostly seen in adolescents who, when they

89 were infants, received at least some doses of the wP pertussis vaccine. When those cohorts were replaced by younger ones who had received aP vaccines in infancy, pertussis made a comeback in the US (Tami 2016). Similar results were also shown in another study among a cohort of teenagers in the US who had exclusively received aP vaccines with the booster aP vaccination providing moderate protection one year after vaccination, after which protection waned rapidly (Klein 2016). The 14–16-year-old adolescents who have been offered ddTap since 2016 were, according to the NIP, vaccinated with aP vaccine in infancy in Sweden, and future EPS reports will provide data on the effects of this school-leaving booster dose.

Pertussis in fully vaccinated children

The resurgence of pertussis infections in Sweden and in several countries with high vaccination coverage has raised questions about the nature and durability of vaccine-induced immunity (de Celle‘s 2016, Locht 2016). Epidemiological studies showed that aP vaccines are protective in the ﬁrst years after vaccination (Bisgard 2005), but protection is temporary, with rapidly waning immunity (Plotkin 2014a, Plotkin 2014b). A recent study in the state of Florida in the US suggested that there has been sustained transmission of B. pertussis in an aP-vaccinated cohort (Matthias 2016).

The proportion of children in the EPS data who were fully vaccinated in the different age groups varied greatly, especially in the older age groups. In the age groups 1–5 years of age, the proportion of fully vaccinated varied between 60% and 73%, with the highest proportion in the 3 year olds. Considering a vaccine efﬁcacy of 80% after three doses of aP vaccines, the number of fully vaccinated cases among children 1–5 years old is reasonable in relation to the number of children vaccinated and the size of the vaccinated cohorts in Sweden. In the age groups 6–18 years old, the proportion of fully vaccinated varied between 12% and 55%. The 17–18 year olds had the lowest rate of fully vaccinated at 12%, but very few cases were reported in this age group. The proportions of fully vaccinated decreased when comparing the 5-year-old children (60%) to the 6-year-old children (22%). This might be an effect of the booster vaccine administered at 5 years of age according to the NIP. In a pertussis outbreak in the state of Washington in the US in 2012, a valid vaccination history was available for 1,829 of 2,006 (91.2%) patients aged 3 months to 19 years. Overall, 758 of 1,000 (75.8%) patients aged 3 months to 10 years were up-to-date with the childhood DTaP doses (CDC, 2012). A similar high rate of pertussis cases among children who were fully vaccinated was observed in the California pertussis epidemic in 2010, with 66% of reported cases in fully vaccinated children in the 7–10 year olds who had previously received only aP vaccine, which is suggestive of waning immunity (Winter et al 2012). Furthermore, in the California epidemic in 2014, 87% of pertussis cases in adolescents had previously received the dTap booster vaccine, and the median length of

90 time since the prior dTap dose was 3 years (range = 0–7 years) (Winter 2014).

In comparison to previous studies in the US, the proportion of fully vaccinated pertussis cases in the EPS study are lower. Based on aP vaccine efﬁcacy and the observation that immunity for pertussis appears to wane over time after vaccination, our data might be reasonable because pertussis vaccine uptake is high and timely in Sweden. Nonetheless, the continued occurrence of pertussis cases among fully vaccinated children warrants further close observation and analysis.

91 Strategies to protect infants from pertussis in other countries

Over the past few years, several countries have reported an increase in pertussis cases and pertussis-related deaths among infants. In most countries, infants receive their ﬁrst pertussis vaccine between 6 weeks and 2 months of age, followed by additional immunisations given at 1- or 2-month intervals (WHO position paper, Pertussis vaccines 2015). Therefore, the most vulnerable age group is not sufﬁciently protected against the disease (Juretzko 2002).

Cocooning

To decrease the burden of disease among infants, recommendations vary and might include vaccination of children and adults surrounding the new-born baby (known as “cocooning”), vaccination of the mother during the last trimester of pregnancy, and vaccination of health care workers. Moreover, some countries recommend regular vaccination with pertussis-containing vaccines of all adults every 10 years. The cocooning strategy, which was first canvassed by the Global Pertussis Initiative in 2001 (Forsyth 2001), has been recommended in the US since 2006 and at differing times in Germany, France, and Australia (Libster 2012, National Health and Medical Research 2003). Implementation of the cocooning strategy was difficult in the US and other countries, with low uptake due to problems in both delivery and funding of the vaccine (Amirthalingam 2013). The cocooning strategy is estimated to have an impact on disease prevention in some settings if high coverage can be achieved (WHO 2016). However, in periods with low incidence of pertussis in infants, e.g. 30–40/100,000 person years, it has been estimated that the cocooning strategy would need large resources for a limited effect (Skowronski 2012). In addition, a recent US study (Winter 2017) did not find evidence supporting the effectiveness of maternal postpartum cocooning with the dTap vaccine (Baxter 2017). Moreover, current aP vaccines are estimated to have an inherent limitation because the effectiveness of the cocooning strategy relies on herd immunity, which is not sufficiently induced by the aP vaccines (Locht 2016).

Maternal Tdap immunisation

Immunising during pregnancy aims to sufﬁciently boost immunity to optimise transplacental transfer of maternal antibodies to the babies, and thus mothers vaccinated during pregnancy are less likely to be a source of infection for their babies.

In 2015, the WHO stated that vaccination of pregnant women is likely to be the most cost-effective additional strategy for preventing disease in infants too young to be vaccinated and to be more effective and favourable than cocooning (WHO position paper, Pertussis vaccines 2015). Maternal pertussis immunisation is currently recommended in Australia, Belgium, Spain, Ireland, Brazil, Columbia, Argentina, Portugal, the UK, and the

92 US in response to increased incidence. In the UK, a maternal pertussis immunisation programme was introduced in October 2012 as a response to an outbreak in which a large number of adult cases was seen among the population, and immunisation was extended to all age groups, including infants aged <3 months in whom there was an incidence of 240 cases per 100,000 person years. In 2012, there were 14 deaths among 429 infant cases infected with pertussis, compared with 7 deaths among 178 infant cases during 2008 (Cherry 2012, Amirthalingam 2013, Pinto 2013, Amirthalingam 2014). Data from UK studies have shown that maternal pertussis immunisation gives a good immune response in the mother and in the child (Amirthalingam 2014, Dabrera 2015), and the evidence of the effectiveness of maternal immunisation programmes is growing. A retrospective cohort study in California (Winter 2017) concluded that dTap vaccination at 27–36 weeks during pregnancy was 85% more effective than post-partum dTap vaccination at preventing infant disease prior to 8 weeks of age. In addition to the finding of high vaccine effectiveness in the first 2 months of life (91%), maternal dTap vaccination has also been demonstrated to confer a significant amount of protection against pertussis over the entire first year of life (69%), even after infants are vaccinated with DTaP (Baxter 2017). In addition, infants born to vaccinated mothers had lower risk of hospitalisation and intensive care unit admission and shorter hospital stays. The adjusted vaccine effectiveness for preventing hospitalisation among infants was 58% (Winter 2017).

Safety studies have not identiﬁed any serious adverse effects of maternal vaccination (Amirthalingam 2014, Donegan 2014, Dabrera 2015, Moro 2016). Whether vaccination during pregnancy leads to any clinically relevant impairment of infant responses (such as blunting or interference) to primary and booster vaccination in the NIP have been studied (Hardy-Fairbanks 2013, Ladhani 2015, Maertens 2016(Vaccine), Maertens 2016(Clin Infect Dis), Hoang 2016, Voysey 2017), but the subsequent long-term epidemiological effect remains the subject of debate (Munoz 2014, Bento 2016, Maertens 2016, Bento 2017).

Strategies to protect infants from pertussis in Sweden

Due to the remaining cases of pertussis disease among infants in Sweden and the increase of pertussis reported during the last two years, the PHAS issued recommendations in August 2016 to improve pertussis disease control among infants (Link to PHAS). The recommendations were based on the EPS data, conclusions from a systematic literature review (Link to review), and a health economic analysis performed by the PHAS in 2015. The strategies evaluated in the review were discussed by Swedish experts in the ﬁeld and relevant stakeholders, including clinicians and communicable disease ofﬁcers. The proposed interventions are aimed at strengthening the current recommendations in Sweden, that is, to increase

93 the timeliness of the ﬁrst vaccine dose, to increase the awareness of pertussis among caregivers, and to increase testing for pertussis in infants and the use of early post-exposure antibiotic prophylaxis.

It is important to be observant of coughing among close family members during a child’s ﬁrst months of life. Generous use of testing, rapid diagnostics, and treatment can prevent infant deaths, and early post-exposure antibiotic prophylaxis provides good protection against clinical pertussis in infants. The yearly collection and reporting of such data will help us to further analyse if there is any difference in the awareness before and after the publication of the recommendations in August 2016.

The Swedish National Board of Health and Welfare has since 1982 recommended early post-exposure prophylaxis with antibiotics to infants younger than 6 months of age and treatment with antibiotics at ﬁrst symptoms to infants 6–12 months old. Prophylactic treatment, especially for the youngest children, should be started as quickly as possible. The data in the present 19-year report indicate no difference in time between episode start and start of antibiotic treatment for the youngest infants compared with older age groups. Furthermore, there is no obvious difference in the present 19-year report , compared with previous reports, regarding the time between the onset of disease and the start of antibiotic treatment (with a median of 13 days for infants 0–3 months of age). The total number of samples tested for pertussis in the general population was not signiﬁcantly greater in 2016 compared with 2015 or 2014. This information, along with the delay between the onset of disease and the start of treatment, indicates that the awareness of pertussis among health-care workers is low and still needs to be improved. Several years of low incidence of pertussis in Sweden (2008–2013) might have decreased the knowledge of pertussis disease among health-care workers. The time period since the recommendations were published (August 2016) is, however, short (6 months), and we are thus not yet able to evaluate if these recommendations have improved the awareness of pertussis.

Another parameter that can also can be used to evaluate the awareness of pertussis among health-care workers is to analyse the number of times parents have sought medical care for their sick child before pertussis was diagnosed. Since January 2016, data regarding the number of medical care instances have been collected in the structured telephone interviews of the EPS. In 2016, 45 out of 80 infants with pertussis had more than one visit to a doctor. Eighteen of these had two visits, 18 had three visits, six had four visits and three infants had ﬁve visits before a pertussis diagnosis was established. Comparing these data on a yearly basis might lead to a better understanding of whether there are any improvements in the knowledge and awareness of infant pertussis among healthcare workers.

At the moment, neither maternal vaccination nor cocooning immunisation

94 strategies are recommended in Sweden. The cocooning strategy is not recommended due to the cost-effectiveness analysis and presumed difﬁculties of vaccine up-take in combination with the need for high vaccination coverage before a signiﬁcant effect on infants is seen. Maternal vaccination is not recommended due to the lack of robust safety data and data on infant response to the primary immunisation schedule (including blunting and interference) (Link to recomendations). Furthermore, this report shows that the pertussis incidence and hospitalisation incidence in infants are still at lower levels compared to corresponding data in those countries that have decided to recommend maternal vaccination.

Conclusion

In conclusion, the surveillance of pertussis in Sweden provides a reporting methodology that is stable over time and offers a unique opportunity to conduct an enhanced follow-up after the introduction of aP vaccines in an endemic setting with high vaccination coverage. The long-term surveillance provides insights into the overall impact of an aP vaccination programme, including estimates of the duration of vaccine-induced protection after vaccination in infancy and after the introduction of a preschool booster and – with the continuation of the project – after the introduction of a "school-leaving" booster. The unique data on date of onset of disease provided through the surveillance allows for detailed evaluations of the effects of vaccination strategies and the severity of disease in infants.

Despite the existing preventive strategies for reducing pertussis cases in infants, many infants still contract the disease, and infants too young for vaccination are at greatest risk of life-threatening pertussis. Thus effective strategies to protect the youngest infants are needed. In the case of a further increase of pertussis in infants, recommendation of maternal vaccination will be re-evaluated when more data on safety and interference of maternal vaccination are available, and complementary strategies might be recommended in the future.

95 4 Plan for continued work

In accordance with the overall objective of the study, the plan for 2017 is:

• To monitor epidemiological trends over time for pertussis in Sweden (at the broader population level and speciﬁcally in vaccinated cohorts)

• To monitor the impact of any changes in the NIP

• To provide insight into the ability of the timing/dosing schedule to control pertussis

• To provide particular insight into the disease burden in infants

The analyses are primarily descriptive/qualitative and are designed to monitor epidemiological trends for pertussis and to provide insight into how they might be changing with time and vaccination schedule.

Age-specific incidence will be studied in order to monitor the impact of the preschool booster and the adolescent booster on the incidence of pertussis in infants, to monitor the trends of pertussis and the impact of the entire schedule of vaccinations, and to evaluate the effect of booster doses on pertussis epidemiology. Specifically, we will measure the incidence of pertussis during and after first year of life (presented in time intervals according to changes in the NIP), the incidence and cases of pertussis in children by age and by vaccination status, and the incidence of pertussis in infancy by time and by changes to the NIP.

• Antibiotic treatment. The use and the effect of antibiotic treatment in all children will be studied, including the time interval between the onset of disease and the start of antibiotic treatment and the relation between the timing of antibiotic treatment and disease severity.

• Timing of vaccinations and the impact of vaccination status. Due to regional vaccine procurements, exposure to different pertussis vaccines varies with birth cohort and geographical area. Therefore, comparison between vaccines will not be possible, and the outcome of the analyses will instead include the following:

– We will determine the number of pertussis cases and severity of pertussis in infancy by vaccination status. – – In fully vaccinated children (according to the NIP and Summaries of Product Characteristics) with laboratory-conﬁrmed pertussis from 2007 and onwards, we will study the time from last vaccine dose administered until the episode start of pertussis disease. The data will be analysed and reported by age group.

96 • Severity of pertussis disease will be studied with special focus on infants and will include the duration of disease, the rate of hospital admission, the duration of hospital stay, the duration of cough, and the rate of severe complications. Markers of severity will be studied and related to the age at onset of disease and to individual vaccination histories as well as to the scheduled ages of the NIP.

• Case-contact information for infants will be used to study the source of infection and will be related to severity of disease, to age at onset of disease, and to individual vaccination histories.

Additional analyses might be added to the project as decided at the annual review meetings. Annual progress reports will, as previously, summarise the overall number and age-speciﬁc incidence of laboratory-conﬁrmed cases with detailed analyses in vaccinated cohorts.

4.1 Scientific publications and presentations

Papers being prepared for publication include:

1. An evaluation of the preschool booster effect on pertussis incidence

2. The analysis of the case-contacts data, which has recently been presented as a poster at the Nordic Vaccine Meeting 2016.

3. In collaboration with Public Health Agencies in the Netherlands, Norway, Denmark and in the UK prepearing comparative study of hospitalisation incidence in infants.

4.2 Limitations

While it is likely that the mandatory reporting system is reasonably reliable in reporting diagnosed cases, there is substantial risk that infected individuals are not diagnosed in the ﬁrst place. One reason for not being diagnosed is because infected persons can have no, mild, or atypical symptoms. While mild symptoms reduce the probability that the disease will be diagnosed, these cases might still be relevant in the circulation of the disease. Also, there appears to be a conception among both medical professionals and the public that pertussis disease does not infect vaccinated individuals. It is therefore likely that even patients with typical symptoms are not tested for pertussis if they have already been vaccinated. Because there are no data on the true incidence of pertussis, we cannot quantify the magnitude of such under diagnosis, but it is likely that failure to obtain a diagnosis is more common in adults than in children and that it might be increasing

97 with time as the awareness of pertussis has decreased because a large proportion of the population has been vaccinated. Possible consequences of under-diagnosis include overly optimistic conclusions about pertussis incidence, vaccine effectiveness, and the duration of vaccine immunity. Adverse events in vaccinated children are reported directly to the Medical Product Agency in Sweden by the child’s nurse or doctor. These reported data are conﬁdential, and the surveillance team at PHAS has no access to these data. The study on pertussis in fully vaccinated children can be reported on a group level (by age), but not on an individual level. If a parent reports an adverse event (any symptoms), the team at PHAS will contact the reporting doctor or nurse for proper action.

98 5 Administration

The EPS in Sweden started on Oct 1, 1997, and is ongoing with annual reconsideration of continuation. Financial support has been obtained from the vaccine manufacturers Sanoﬁ of France and GlaxoSmithKline Bio of Rixensart, Belgium. Contracts for the project “Pertussis surveillance in Sweden” have been agreed upon for the continued follow-up of clinical epidemiology since 1997 by the manufacturers above. Major policy decisions relating to the conduct of the study are made by the team at PHAS, including the Internal Steering Committee at PHAS, and are discussed with representatives from the supporting manufacturers at annual review meetings. Study staff at PHAS team: Bernice Aronsson (principal investigator, project leader), Kerstin Drakes Jämtberg (study nurse), Emma Byström (research assistant), Henrik Källberg (statistician), and Bo Östlund (administrative coordinator).

Annual reports are published every September on the PHAS website, (http://www.folkhalsomyndigheten.se/).

99 6 Reports from published peer-reviewed papers

6.1 Published reports based on the enhanced surveillance data

The ﬁve-component aP vaccine is recommended for general use: Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a ﬁve-component acellular and awhole cell pertussis vaccine. N Engl J Med 1996; 334:349-55.

Similar efficacy of the UK whole-cell vaccine and the five-component and three-component vaccines Olin, Rasmussen F, Gustafsson L, Hallander HO, Heijbel H. Randomised controlled trial of two-component, three-component, and five-component acellular pertussis vaccines compared with whole-cell pertussis vaccine. Ad Hoc Group for the Study of Pertussis Vaccines. Lancet. 1997 350:1569-77.

First signs of waning immunity at 6-7 years of age Olin P, Gustafsson L,Barreto L, Hessel L, Mast C, Van Rie A, Bogaerts H, Storsaeter J. Declining pertussis incidence in Sweden following the introduction of acellular pertussis vaccine. Vaccine 2003;21:2015-21

Pertussis toxoid causes a small but signiﬁcant reduction of the immunogenicity of diphtheria toxoid and tetanus toxoid. Trollfors B, Taranger J, Lagergård T, Sundh V. Reduced immunogenicity of diphtheria and tetanus toxoids when combined with pertussis toxoid. Pediatr Infect Dis J. 2005 Jan;24(1):85-6.

A booster dose of acellular pertussis vaccine is warranted from 5 to 7 years of age Gustafsson L, Hessel L, Storsaeter J, Olin P. Long term follow-up of Swedish children vaccinated with acellular pertussis vaccines at 3, 5, and 12 months of age indicates the need for a booster dose at 5 to 7 years of age. Pediatrics September 2006; 118:3 978-984

Complementary strategies are needed to achieve further reduction in morbidity from circulation of Bordetella pertussis Carlsson RM1, Trollfors B. Control of pertussis-lessons learnt from a 10-year surveillance programme in Sweden. Vaccine. 2009; 27:5709-18.

A universal adolescent booster vaccination will reduce the incidence of pertussis in the target group but the duration of immunity is uncertain. Hallander HO, Nilsson L, Gustafsson L. Is adolescent pertussis vaccination preferable to natural booster infections? Expert Rev Clin Pharmacol. 2011 Nov;4(6):705-11

The first dose of vaccine has a significant effect on the incidence and associated complications of pertussis, and we find 38% fewer hospitalised infants in the 3-<9 month age group Nilsson L, Lepp T, von Segebaden K, Hallander H, Gustafsson L. Pertussis vaccination in infancy lowers the incidence of pertussis disease and the rate of hospitalisation after one and two doses:

100 analyses of 10 years of pertussis surveillance. Vaccine. 2012 May 2;30(21):3239-47

Age-speciﬁc contact patterns alone can explain shifts in prevalence and age-stratiﬁed incidence Rohani P, Zhong X, King AA. Contact network structure explains the changing epidemiology of pertussis. Science. 2010 Nov 12;330(6006):982-5

Pertussis among infants could be further reduced by increasing awareness of pertussis in adults and adolescents and by strictly following the recommended vaccination schedule Nilsson L, von Segebaden K, Blennow M, Linde A, Uhnoo I. Review Läkartidningen 2013; 110.

Pertussis immunization in infancy does not increase the risk of asthma medication use in adolescents. Vogt H, Bråbäck L, Kling A-M, Grunewald M, Nilsson L. Pertussis immunization in infancy and adolescent asthma medication. Pediatrics 134; 2014: 721 -728

The probability of infection upon contact is age-independent, and we ﬁnd elevated probabilities among children, adolescents and young adults whose contacts might be more intimate than others. Feng Z, Glasser JW, Hill AN, Franko MA, Carlsson RM, Hallander H, Tull P, Olin P. Modeling rates of infection with transient maternal antibodies and waning active immunity: application to Bordetella pertussis in Sweden. Theor Biol. 2014 Sep 7; 356:123-32.

Surveillance of infant pertussis in Sweden 1998-2012: the severity of disease in relation to the national vaccination programme. Carlsson R-M, von Segebaden K, Bergström J, Kling AM, Nilsson L. Euro Surveill. 2015;20(6):pii=21032. 12 February 2015

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113 2014. Article number: ISBN 978-91-7603-445-3 (available at www.folkhalsomyndigheten. se)

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114 8 Appendix

8.1 Information

Below are the contents of the tables and ﬁgures mentioned in Chapter 2 and those included in the Appendix.

8.2 Tables referring to Chapter 2.1 to 2.9

Tables 1 to 3 Appendix to Figure 8 in the main report and show case reports in numbers for:

Table 1 Appendix: Linked to Figure 8. All of Sweden per month from 2004 to 2016 Table 2 Appendix: Linked to Figure 8. Sweden excluding Västra Götaland Table 3 Appendix: Linked to Figure 8. Västra Götaland.

Table 4 Appendix: Number of pertussis cases in Västra Götaland, 1986 2016 Table 5 Appendix: Incidence of pertussis in Västra Götaland, 1986 2016

Table 6 Appendix: Linked to Figure 10 in the main report

Table 7 Appendix: Linked to Figure 11 A-E in the main report Table 8 Appendix: Linked to Figure 12 in the main report

Table 9 Appendix: Linked to Figure 18 A-E in the main report

115 Table 10 Appendix: Spasmodic cough, Gothenburg study area

Table 11 Appendix: Spasmodic cough, Sweden excluding the Gothenburg study area

Table 12 Appendix: Pertussis cases, Sweden excluding the Gothenburg study area

Table 13 Appendix: Pertussis cases, Gothenburg study area

Table 14 Appendix: unvaccinated children, Sweden excluding the Gothenburg study area

Table 15 Appendix: unvaccinated children, Gothenburg study area

Table 16 Appendix: Incidence in infants from case report data (SmiNet)

Table 17 Appendix: Mean incidence in 10-year intervals from case report data (SmiNet)

116 Table 1 Appendix, see Chapter 2.1.2, Figure 8.

Year Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2004 71 67 75 71 161 130 130 166 119 122 143 152 2005 155 90 48 46 83 63 61 87 105 93 125 112 2006 83 68 45 28 49 29 26 60 50 46 75 48 2007 79 92 58 31 58 37 45 36 37 42 29 18 2008 38 23 22 50 26 27 10 22 59 45 21 30 2009 27 24 27 23 13 22 15 23 29 22 10 25 2010 30 18 20 21 14 24 12 21 11 26 27 28 2011 15 9 17 15 10 7 13 20 20 24 7 12 2012 15 10 13 13 10 3 14 29 30 38 48 46 2013 36 18 8 10 8 9 18 43 23 13 20 17 2014 16 8 9 13 20 27 49 88 154 113 92 99 2015 70 68 42 47 39 28 38 62 65 47 35 41 2016 24 29 20 20 19 24 27 94 70 93 128 99

Table 1 Appendix: Number of cases diagnosed with pertussis, per month. Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act.

117 Table 2 Appendix, see Chapter 2.1.2, related to Figure 8.

Year Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2004 48 44 47 31 73 72 80 72 73 54 86 94 2005 108 58 41 31 61 46 42 72 95 80 107 97 2006 67 63 38 25 41 26 26 45 36 38 56 41 2007 64 88 54 27 51 33 43 30 28 39 26 17 2008 25 18 20 25 14 16 4 17 53 32 11 22 2009 21 16 25 18 12 17 12 17 23 20 10 22 2010 21 14 16 21 10 16 9 21 11 24 26 21 2011 13 8 17 13 8 7 11 17 18 23 7 12 2012 14 9 12 13 10 2 11 23 23 30 46 39 2013 35 18 8 7 7 8 16 36 18 11 18 15 2014 15 8 9 13 19 26 42 79 137 107 82 88 2015 59 58 31 42 38 25 33 52 55 36 30 37 2016 23 27 20 16 16 22 25 72 51 77 108 86

Table 2 Appendix: Number of cases diagnosed with pertussis per month in Sweden excluding Västra Götaland Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act.

118 Table 3 Appendix, see Chapter 2.1.2, related to Figure 8.

Year Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec 2004 23 23 28 40 88 58 50 94 46 68 57 58 2005 47 32 7 15 22 17 19 15 10 13 18 15 2006 16 5 7 3 8 3 0 15 14 8 19 7 2007 15 4 4 4 7 4 2 6 9 3 3 1 2008 13 5 2 25 12 11 6 5 6 13 10 8 2009 6 8 2 5 1 5 3 6 6 2 0 3 2010 9 4 4 0 4 8 3 0 0 2 1 7 2011 2 1 0 2 2 0 2 3 2 1 0 0 2012 1 1 1 0 0 1 3 6 7 8 2 7 2013 1 0 0 3 1 1 2 7 5 2 2 2 2014 1 0 0 0 1 1 7 9 17 6 10 11 2015 11 10 11 5 1 3 5 10 10 11 5 4 2016 1 2 0 4 3 2 2 22 19 16 20 13

Table 3 Appendix: Number of cases diagnosed with pertussis per month in Västra Götaland. Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act.

119 Age 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

0 210 131 206 211 199 73 26 17 58 82 51 106 48 147 42 29 16 14 10 11 6 13 10 9 14 23 1 280 226 372 358 303 97 19 8 18 59 20 34 10 41 14 5 2 7 2 2 0 1 1 2 3 2 2 342 277 331 409 373 110 38 6 8 22 26 30 10 33 6 4 2 1 1 1 1 1 3 4 3 1 3 315 220 358 404 309 132 40 17 14 25 18 21 3 18 10 5 1 2 2 1 0 0 2 2 3 4 4 219 189 313 313 347 134 53 21 26 25 17 19 8 30 3 2 3 3 1 1 1 2 0 0 2 1 5 153 140 242 198 206 101 37 16 24 46 12 24 6 44 6 4 3 0 1 0 0 1 0 0 4 3 6 123 105 128 114 167 89 29 19 57 44 33 25 9 51 15 2 4 4 0 2 0 0 0 0 1 1 7 39 46 79 86 97 44 22 16 41 50 30 28 12 43 13 4 5 6 0 3 0 1 0 1 0 1 8 41 18 29 49 44 18 14 8 32 42 28 21 11 38 11 5 0 7 0 1 0 0 1 0 1 1 9 15 12 24 20 32 15 3 7 11 30 18 20 12 30 9 2 1 15 3 4 1 0 0 0 1 1 10 12 6 12 5 16 9 2 3 16 23 7 12 3 23 15 8 2 7 0 0 0 0 0 1 0 2 11 6 2 6 18 8 1 1 1 10 15 11 7 8 17 8 1 2 1 1 0 1 0 1 1 3 1 12 4 3 8 3 4 2 2 2 6 8 9 8 6 19 16 5 1 2 0 1 0 0 0 0 0 2 13 4 1 4 4 0 0 0 1 4 9 2 6 7 15 10 3 3 5 1 0 0 0 0 0 0 2 144 0340100332419512341000011 150 1121001312213533662010100 161 0132111171214510611112311 170 1300110000002113201110211 181 1010000020103021101000130 191 0110100120011211010000301 20-24 5 5 6 14 3 2 1 1 3 1 1 2 0 8 2 0 2 1 2 1 2 1 1 5 3 8 25-29 15 16 16 18 12 5 3 1 3 2 2 2 2 8 3 3 0 5 1 1 0 0 0 5 9 6 30-34 17 22 16 29 16 7 0 1 1 5 3 5 1 13 6 2 0 2 1 1 0 2 0 5 7 9 35-39 8 1 9 14 13 8 0 3 0 8 2 5 4 8 8 0 0 4 2 5 0 1 4 2 4 11 40-44 4 8 5 9 3 0 0 0 0 1 2 4 2 11 4 3 0 7 0 0 0 3 0 6 4 6 45-49 1 1 4 8 3 2 1 1 0 0 0 2 1 4 2 1 1 2 1 0 0 1 0 0 5 4 50-54 6 6 6 3 4 1 2 0 1 0 1 2 0 2 3 2 1 0 2 0 1 1 0 1 3 3 55-59 1 4 10 6 2 2 0 0 0 2 0 1 2 4 1 2 0 0 1 0 0 2 0 1 1 2 60-64 10 7 4 3 3 2 1 0 0 1 0 0 1 2 4 2 1 2 1 0 0 1 0 1 2 0 65+ 8 12 10 11 10 4 2 1 2 3 2 2 2 2 1 2 2 1 2 1 0 3 1 7 7 6 Total 1845 1461 2207 2318 2177 862 298 152 343 518 300 395 172 633 230 105 62 116 47 42 15 37 26 63 86 104

Table 4 Appendix: Number of laboratory-reported cases of pertussis in deﬁned age-groups from 1991 to Dec 31 2016 For laboratory-conﬁrmed cases reported to SmiNet between 1997 and Dec 31, 2016. Data before 1997 are from voluntarily reports from bacteriological laboratories. 120 Age 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

0 986.4 619.7 997.1 1067.3 1079.6 433.8 164.4 110.2 379.2 534.1 327.9 667.7 292.4 871.5 246.0 164.9 87.5 75.6 52.9 56.1 30.8 68.0 51.9 46.3 71.7 116.0 1 1356.1 1061.9 1759.9 1735.2 1531.3 525.6 112.8 50.4 115.9 383.1 129.2 217.2 62.7 248.5 82.5 29.1 11.3 38.1 10.8 10.5 0.0 5.1 5.2 10.3 15.2 10.1 2 1741.4 1345.9 1559.7 1934.3 1806.0 557.2 206.7 35.7 50.4 141.4 168.1 192.8 63.7 206.4 36.3 23.5 11.6 5.6 5.4 5.4 5.3 5.1 15.2 20.6 15.3 5.0 3 1686.9 1119.6 1735.9 1891.3 1452.2 639.5 202.8 92.4 83.2 157.0 115.1 135.0 19.2 114.3 62.4 30.1 5.9 11.5 11.2 5.4 0.0 0.0 10.1 10.1 15.3 20.1 4 1231.1 1010.9 1588.0 1506.2 1615.3 630.0 257.1 106.7 141.2 148.0 106.5 121.0 51.2 191.2 19.0 12.5 18.0 17.5 5.8 5.6 5.4 10.7 0.0 0.0 10.0 5.0 5 881.2 787.0 1289.2 994.9 983.9 469.7 174.1 77.7 121.9 249.2 70.7 149.6 38.1 280.7 38.2 25.3 18.6 0.0 5.8 0.0 0.0 5.4 0.0 0.0 19.8 14.9 6 726.4 602.1 715.9 601.2 832.6 425.2 135.2 89.6 276.8 222.9 178.1 146.5 55.9 322.9 95.3 12.7 25.1 24.7 0.0 11.6 0.0 0.0 0.0 0.0 5.1 4.9 7 239.7 270.9 451.1 476.0 507.5 219.2 105.1 74.5 192.8 241.8 151.4 150.4 70.0 266.4 82.2 25.3 31.5 37.5 0.0 17.8 0.0 5.7 0.0 5.3 0.0 5.1 8 253.8 110.2 169.9 276.6 241.1 94.0 69.6 38.1 148.8 197.0 134.8 105.5 59.0 221.5 68.1 31.5 0.0 43.9 0.0 6.1 0.0 0.0 5.6 0.0 5.2 5.1 9 92.1 73.9 146.0 115.8 179.2 82.1 15.6 34.7 52.4 139.1 84.1 95.9 60.1 160.2 52.3 12.3 6.3 94.1 18.7 24.8 6.1 0.0 0.0 0.0 5.4 5.2 10 73.8 36.7 73.5 30.1 91.9 50.3 10.9 15.6 79.3 109.0 32.3 55.8 14.3 114.8 79.9 46.3 12.2 43.6 0.0 0.0 0.0 0.0 0.0 5.6 0.0 10.6 11 36.9 12.2 36.5 109.1 47.7 5.7 5.6 5.5 52.0 74.1 51.9 32.2 37.1 81.1 39.9 5.3 11.5 6.1 6.2 0.0 6.2 0.0 6.0 5.7 16.6 5.4 12 25.2 18.4 48.7 18.1 24.0 11.9 11.4 11.1 32.7 41.4 44.2 37.6 27.5 88.0 76.2 24.8 5.3 11.4 0.0 6.2 0.0 0.0 0.0 0.0 0.0 10.9 13 25.1 6.3 24.4 24.1 0.0 0.0 0.0 5.7 22.2 48.8 10.3 29.4 32.8 68.5 46.1 14.2 14.9 26.3 5.7 0.0 0.0 0.0 0.0 0.0 0.0 11.2 14 24.6 0.0 18.7 24.2 0.0 6.0 0.0 0.0 17.1 16.6 10.8 20.5 4.9 42.0 22.8 4.6 9.4 14.8 20.9 5.7 0.0 0.0 0.0 0.0 5.9 5.7 15 0.0 6.1 6.2 12.4 6.0 0.0 0.0 6.0 17.7 5.7 11.0 10.7 5.1 14.6 23.3 13.6 13.8 28.2 29.4 10.4 0.0 5.9 0.0 6.0 0.0 0.0 16 5.5 0.0 6.1 18.5 12.3 6.0 5.9 5.9 5.9 41.2 5.6 10.9 5.3 20.3 24.2 4.6 0.0 27.3 4.7 4.9 5.2 5.6 11.7 17.7 5.8 5.8 17 0.0 5.5 17.5 0.0 0.0 6.1 6.0 0.0 0.0 0.0 0.0 0.0 0.0 10.6 5.1 4.8 13.8 9.0 0.0 4.6 4.8 5.1 0.0 11.4 5.8 5.7 18 5.3 5.3 0.0 5.8 0.0 0.0 0.0 0.0 0.0 11.7 0.0 5.8 0.0 16.2 0.0 10.1 4.8 4.6 0.0 4.5 0.0 0.0 0.0 5.4 16.8 0.0 19 5.2 0.0 5.3 5.4 0.0 5.9 0.0 0.0 5.9 11.7 0.0 0.0 5.8 5.5 10.8 5.3 5.0 0.0 4.5 0.0 0.0 0.0 0.0 14.9 0.0 5.5 20-24 4.9 5.0 6.1 14.2 3.1 2.1 1.1 1.1 3.4 1.1 1.1 2.3 0.0 8.8 2.2 0.0 2.1 1.0 1.9 0.9 1.8 0.9 0.9 4.3 2.6 7.2 25-29 13.8 14.3 14.2 16.2 11.0 4.7 2.9 1.0 2.9 1.9 2.0 2.0 2.0 8.2 3.1 3.1 0.0 5.0 1.0 1.0 0.0 0.0 0.0 4.4 7.7 4.9 30-34 17.2 22.4 16.1 28.3 15.1 6.4 0.0 0.9 0.9 4.6 2.8 4.7 1.0 12.4 5.7 1.9 0.0 2.0 1.0 1.0 0.0 2.0 0.0 4.8 6.6 8.3 35-39 8.2 1.0 9.1 14.1 13.1 8.1 0.0 3.0 0.0 7.6 1.8 4.5 3.5 7.1 7.3 0.0 0.0 3.8 1.9 4.7 0.0 1.0 3.9 2.0 3.9 10.7 40-44 3.8 7.7 4.9 9.1 3.1 0.0 0.0 0.0 0.0 1.0 2.0 4.0 2.0 10.7 3.8 2.7 0.0 6.2 0.0 0.0 0.0 2.8 0.0 5.6 3.7 5.6 45-49 1.0 0.9 3.7 7.4 2.8 1.9 1.0 1.0 0.0 0.0 0.0 2.0 1.0 4.0 2.0 1.0 1.0 2.0 1.0 0.0 0.0 0.9 0.0 0.0 4.5 3.6 50-54 7.7 7.5 7.1 3.4 4.2 1.0 1.9 0.0 0.9 0.0 1.0 2.0 0.0 2.0 3.1 2.1 1.0 0.0 2.0 0.0 1.0 1.0 0.0 1.0 2.8 2.7 55-59 1.4 5.8 14.3 8.3 2.7 2.6 0.0 0.0 0.0 2.2 0.0 1.0 1.9 3.8 1.0 2.0 0.0 0.0 1.0 0.0 0.0 2.1 0.0 1.0 1.0 2.1 60-64 14.3 10.1 5.8 4.4 4.5 3.0 1.5 0.0 0.0 1.4 0.0 0.0 1.3 2.4 4.5 2.1 1.0 2.0 1.0 0.0 0.0 1.0 0.0 1.1 2.2 0.0 65+ 3.1 4.6 3.9 4.2 3.8 1.5 0.8 0.4 0.8 1.2 0.8 0.8 0.8 0.8 0.4 0.8 0.8 0.4 0.7 0.4 0.0 1.0 0.3 2.3 2.2 1.9 Total 127.7 100.6 151.2 157.6 147.1 58.1 20.1 10.2 23.1 34.7 20.0 26.3 11.4 41.7 15.1 6.8 4.0 7.5 3.0 2.7 0.9 2.3 1.6 3.9 5.2 6.3

Table 5 Appendix: Incidence of laboratory-reported cases of pertussis in deﬁned age-groups from 1991 to Dec 31 2016 For laboratory-conﬁrmed cases reported to SmiNet between 1997 and Dec 31, 2016. Data before 1997 are from voluntarily reports from bacteriological laboratories. 121 Table 6 Appendix, see Chapter 2.1.3, Figure 10 in the main report.

Age 1986-1995 1997-2016 0 842.5 109.6 1 1290.6 27.7 2 1578.3 39.4 3 1531.0 43.6 4 1346.2 70.8 5 988.0 75.8 6 705.0 87.0 7 382.1 75.6 8 203.8 60.0 9 114.7 43.4 10 65.5 33.1 11 37.9 24.3 12 25.0 19.5 13 17.2 15.6 14 10.5 12.8 15 8.9 10.5 16 6.2 10.1 17 5.1 7.8 18 4.7 5.6 19 5.1 4.2 20-24 6.3 2.7 25-29 14.2 2.8 30-34 16.0 2.9 35-39 9.6 3.4 40-44 5.4 3.0 45-49 3.2 1.9 50-54 4.2 1.6 55-59 4.4 1.4 60-64 4.8 1.6 65+ 2.6 1.3

Table 6 Appendix: Mean incidence (per 100,000 person years) of pertussis in deﬁned age groups during the 10 calendar years before (1986–1995) and during the 20 years after the (1997-2016) introduction of DTaP in 1996. Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act. Age at date for the positive sample.

122 Table 7 Appendix, see Chapter 2.1.3, Figure 11 A-E in the main report.

123 Time period Gothenburg Included Onset of pertussis Person years Number of cases Incidence 95% C.I. Time period

Oct 1997 - Dec 2002 No During 1 year of age 434,346 71 16 13-21 Oct 1997 - Dec 2002 No During 2years of age 424,062 81 19 15-24 Oct 1997 - Dec 2002 No During 3years of age 413,982 79 19 15-24 Oct 1997 - Dec 2002 No During 4years of age 407,196 67 16 13-21 Oct 1997 - Dec 2002 No During 5years of age 406,920 38 9 7-13 Oct 1997 - Dec 2002 No During 6years of age 368,184 23 6 4-9 Oct 1997 - Dec 2002 No During 7years of age 287,742 0 0 0-1 Oct 1997 - Dec 2002 No During 8years of age 207,930 0 0 0-2 Oct 1997 - Dec 2002 No During 9years of age 127,002 0 0 0-3 Oct 1997 - Dec 2002 No During 10years of age 43,086 0 0 0-9 Jan 2003 - Dec 2008 No During 1 year of age 838,602 59 7 5-9 Jan 2003 - Dec 2008 No During 2years of age 818,808 63 8 6-10 Jan 2003 - Dec 2008 No During 3years of age 800,322 63 8 6-10 Jan 2003 - Dec 2008 No During 4years of age 783,042 72 9 7-12 Jan 2003 - Dec 2008 No During 5years of age 768,414 87 11 9-14 Jan 2003 - Dec 2008 No During 6years of age 759,444 122 16 13-19 Jan 2003 - Dec 2008 No During 7years of age 711,804 144 20 17-24 Jan 2003 - Dec 2008 No During 8years of age 621,912 118 19 16-23 Jan 2003 - Dec 2008 No During 9years of age 534,198 90 17 14-21 Jan 2003 - Dec 2008 No During 10years of age 450,006 37 8 6-11 Jan 2003 - Dec 2008 No During 11years of age 368,184 13 4 2-6 Jan 2003 - Dec 2008 No During 12years of age 287,742 8 3 1-5 Jan 2003 - Dec 2008 No During 13years of age 207,930 2 1 0-3 Jan 2003 - Dec 2008 No During 14years of age 127,002 0 0 0-3 Jan 2003 - Dec 2008 No During 15years of age 43,086 0 0 0-9 Jan 2003 - Dec 2008 Yes During 1 year of age 935,238 123 13 11-16 Jan 2003 - Dec 2008 Yes During 2years of age 912,474 106 12 10-14 Jan 2003 - Dec 2008 Yes During 3years of age 891,234 91 10 8-13 Jan 2003 - Dec 2008 Yes During 4years of age 871,470 119 14 11-16 Jan 2003 - Dec 2008 Yes During 5years of age 854,568 136 16 13-19 Jan 2003 - Dec 2008 Yes During 6years of age 843,834 190 23 19-26 Jan 2003 - Dec 2008 Yes During 7years of age 790,338 206 26 23-30 Jan 2003 - Dec 2008 Yes During 8years of age 690,294 142 21 17-24 Jan 2003 - Dec 2008 Yes During 9years of age 592,806 100 17 14-21 Jan 2003 - Dec 2008 Yes During 10years of age 499,164 44 9 6-12 Jan 2003 - Dec 2008 Yes During 11years of age 408,210 13 3 2-5 Jan 2003 - Dec 2008 Yes During 12years of age 318,906 9 3 1-5 Jan 2003 - Dec 2008 Yes During 13years of age 230,310 2 1 0-3 Jan 2003 - Dec 2008 Yes During 14years of age 140,544 0 0 0-3 Jan 2003 - Dec 2008 Yes During 15years of age 47,646 0 0 0-8 Jan 2009 - Dec 2013 No During 1 year of age 510,072 47 9 7-12 Jan 2009 - Dec 2013 No During 2years of age 508,452 36 7 5-10 Jan 2009 - Dec 2013 No During 3years of age 504,816 46 9 7-12 Jan 2009 - Dec 2013 No During 4years of age 500,256 36 7 5-10 Jan 2009 - Dec 2013 No During 5years of age 494,988 35 7 5-10 Jan 2009 - Dec 2013 No During 6years of age 486,078 31 6 4-9 Jan 2009 - Dec 2013 No During 7years of age 475,188 26 5 4-8 Jan 2009 - Dec 2013 No During 8years of age 466,152 27 6 4-8 Jan 2009 - Dec 2013 No During 9years of age 456,774 29 6 4-9 Jan 2009 - Dec 2013 No During 10years of age 445,410 25 6 4-8 Jan 2009 - Dec 2013 No During 11years of age 434,346 44 10 7-14 Jan 2009 - Dec 2013 No During 12years of age 424,062 38 9 6-12 Jan 2009 - Dec 2013 No During 13years of age 413,982 39 9 7-13 Jan 2009 - Dec 2013 No During 14years of age 407,196 36 9 6-12 Jan 2009 - Dec 2013 No During 15years of age 406,920 50 12 9-16 Jan 2009 - Dec 2013 No During 16years of age 368,184 57 15 12-20 Jan 2009 - Dec 2013 No During 17years of age 287,742 46 16 12-21 Jan 2009 - Dec 2013 Yes During 1 year of age 568,710 50 9 7-12 Jan 2009 - Dec 2013 Yes During 2years of age 567,540 43 8 5-10 Jan 2009 - Dec 2013 Yes During 3years of age 563,832 49 9 6-11 Jan 2009 - Dec 2013 Yes During 4years of age 558,804 40 7 5-10 Jan 2009 - Dec 2013 Yes During 5years of age 552,996 39 7 5-10 Jan 2009 - Dec 2013 Yes During 6years of age 542,922 32 6 4-8 Jan 2009 - Dec 2013 Yes During 7years of age 530,346 26 5 3-7 Jan 2009 - Dec 2013 Yes During 8years of age 519,846 30 6 4-8 Jan 2009 - Dec 2013 Yes During 9years of age 508,974 29 6 4-8 Jan 2009 - Dec 2013 Yes During 10years of age 495,948 25 5 3-7 Jan 2009 - Dec 2013 Yes During 11years of age 483,270 49 10 8-13 Jan 2009 - Dec 2013 Yes During 12years of age 471,432 38 8 6-11 Jan 2009 - Dec 2013 Yes During 13years of age 459,984 39 8 6-12 Jan 2009 - Dec 2013 Yes During 14years of age 452,262 37 8 6-11 Jan 2009 - Dec 2013 Yes During 15years of age 451,518 50 11 8-15 Jan 2009 - Dec 2013 Yes During 16years of age 408,210 58 14 11-18 Jan 2009 - Dec 2013 Yes During 17years of age 318,906 47 15 11-20

Table 7 Appendix: Pertussis incidence for children of different ages at different time periods in Sweden including or excluding the Gothenburg area.

124 Table 8 Appendix. Incidence numbers for Figure 12 in the main report.

Age (years) 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

0 263 138 89 76 50 44 49 39 49 41 121 84 84 1 47 23 10 5 13 9 2 2 7 4 20 10 7 2 44 11 11 7 6 4 6 3 5 7 12 7 9 3 28 20 7 8 8 6 5 1 6 5 12 12 13 4 50 17 11 8 5 5 5 4 7 6 6 9 8 5 62 23 19 4 2 7 4 1 6 4 10 8 10 6 70 41 18 19 7 7 5 2 6 5 6 5 8 7 77 52 25 20 14 3 7 1 4 2 5 7 7 8 36 20 12 17 6 5 1 5 2 7 6 9 9 18 15 26 6 9 2 2 2 8 5 10 10 8 17 3 5 3 1 4 8 2 7 11 7 1 3 2 1 3 13 13 17 12 1 4 1 1 2 11 8 16 13 1 0 2 1 11 6 20 14 2 1 0 5 14 13 15 8 6 16 10 8 16 5 19 11 16 17 19 11 14 18 15 6 19 9

Table 8 Appendix: Number of laboratory veriﬁed cases between 2004 and 2016 by age.Data collection was performed in the Swedish enhanced surveillance study of pertussis.

125 Table 9 Appendix, linked to Figure 18 A-E in the main report

Time period Gothenburg Included Onset of pertussis Person years Number of cases Incidence 95% C.I.

Oct 1997 - Dec 2002 No 0-90days 112,542 228 203 177-231 Oct 1997 - Dec 2002 No 91-150days 74,587 165 221 189-258 Oct 1997 - Dec 2002 No 151-365days 258,281 147 57 48-67 Oct 1997 - Dec 2002 No After 365 days of age 3,120,450 359 12 10-13 Jan 2003 - Dec 2008 No 0-90days 215,371 355 165 148-183 Jan 2003 - Dec 2008 No 91-150days 143,092 167 117 100-136 Jan 2003 - Dec 2008 No 151-365days 497,743 99 20 16-24 Jan 2003 - Dec 2008 No After 365 days of age 8,120,496 902 11 10-12 Jan 2003 - Dec 2008 Yes 0-90days 240,321 439 183 166-201 Jan 2003 - Dec 2008 Yes 91-150days 159,660 214 134 117-153 Jan 2003 - Dec 2008 Yes 151-365days 555,321 195 35 30-40 Jan 2003 - Dec 2008 Yes After 365 days of age 9,027,036 1308 14 14-15 Jan 2009 - Dec 2013 No 0-90days 128,638 194 151 130-174 Jan 2009 - Dec 2013 No 91-150days 85,580 87 102 81-125 Jan 2009 - Dec 2013 No 151-365days 298,404 60 20 15-26 Jan 2009 - Dec 2013 No After 365 days of age 7,968,636 668 8 8-9 Jan 2009 - Dec 2013 Yes 0-90days 143,319 215 150 131-171 Jan 2009 - Dec 2013 Yes 91-150days 95,349 96 101 82-123 Jan 2009 - Dec 2013 Yes 151-365days 332,484 68 20 16-26 Jan 2009 - Dec 2013 Yes After 365 days of age 8,874,000 699 8 7-8

Table 9 Appendix: Pertussis incidence in 5-year spans for children younger than 1-year of age at different time periods in Sweden including or excluding the Gothenburg study area.

126 Table 10 Appendix, see Chapter 2.9.2 in the main report.

Doses before episode Birth Cohort 0 1 2 3 2003 24 (9) 12 (5) 40 (9) 28 (16) 2004 42 (20) 26 (14) 21 (10) 11 (7) 2005 9 (6) 3 (2) 6 (1) 4 (3) 2006 10 (10) 3 (1) 2 (1) 3 (0) 2007 5 (4) 2 (2) 4 (3) 6 (3) 2008 5 (4) 3 (3) 1 (1) 1 (0) 2009 3 (2) 2 (1) 2 (1) 2 (2) 2010 9 (4) 0 (0) 0 (0) 4 (2) 2011 2 (2) 1 (1) 0 (0) 3 (2) 2012 7 (6) 1 (0) 5 (4) 1 (1) 2013 5 (4) 0 (0) 0 (0) 1 (1) 2014 4 (3) 2 (1) 2 (2) 1 (0) 2015 5 (4) 1 (1) 1 (1) 0 (0) 2016 4 (3) 3 (3) 0 (0) 0 (0) Subtotal 134 (81) 59 (34) 84 (33) 65 (37)

Table 10 Appendix: Laboratory-conﬁrmed pertussis cases in the Gothenburg study area divided by birth cohort and number of vaccine doses before the start of the episode. The number of cases with 21 or more days of spasmodic cough is shown in parenthese. Data collection was performed in the Swedish enhanced surveillance study of pertussis.

127 Table 11 Appendix, see Chapter 2.9.2 in the main report.

Doses before episode Birth Cohort 0 1 2 3 1997.10-12 13 (10) 4 (4) 5 (4) 37 (33) 1998 73 (56) 28 (22) 21 (15) 210 (166) 1999 121 (106) 45 (42) 26 (19) 140 (108) 2000 114 (104) 33 (27) 9 (7) 122 (92) 2001 51 (41) 15 (13) 11 (7) 87 (68) 2002 99 (87) 36 (30) 4 (4) 69 (54) 2003 79 (63) 18 (15) 14 (11) 64 (54) 2004 110 (95) 47 (42) 19 (14) 53 (37) 2005 83 (72) 18 (16) 4 (2) 29 (19) 2006 79 (66) 20 (18) 9 (5) 30 (17) 2007 58 (54) 11 (10) 11 (9) 26 (15) 2008 38 (32) 7 (6) 5 (3) 23 (15) 2009 40 (29) 13 (10) 2 (2) 18 (12) 2010 40 (30) 12 (10) 3 (2) 27 (17) 2011 34 (27) 8 (6) 1 (1) 20 (16) 2012 36 (26) 13 (13) 1 (1) 31 (25) 2013 35 (30) 6 (6) 9 (8) 19 (10) 2014 92 (77) 30 (25) 14 (11) 3 (1) 2015 39 (36) 16 (16) 7 (7) 2 (2) 2016 46 (41) 14 (12) 7 (5) 0 (0) Subtotal 1280 (1082) 394 (343) 182 (137) 1010 (761)

Table 11 Appendix: Laboratory-conﬁrmed pertussis cases in Sweden, excluding the Gothenburg study area divided by birth-cohort and number of vaccine doses before the start of the episode. The number of cases with 21 or more days of spasmodic cough is shown in parenthese. Data collection was performed in the Swedish enhanced surveillance study of pertussis.

128 Table 12 Appendix, see Chapter 2.9.2 in the main report.

Year of Pertussis episode Birth 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Total cohort

1996 5 17 40 41 20 39 14 60 41 14 3 6 2 0 2 10 4 14 10 14 356 (3) (14) (35) (35) (16) (39) (14) (55) (38) (13) (3) (5) (2) (0) (2) (9) (2) (7) (2) (6) (300) 1997 23 29 19 25 17 32 7 25 26 16 14 8 0 5 2 7 5 20 14 3 297 (6) (15) (19) (22) (14) (29) (4) (20) (25) (14) (13) (7) (0) (5) (2) (6) (5) (11) (5) (2) (224) 1998 61 36 14 7 17 12 34 40 21 13 25 3 1 0 1 4 23 11 9 332 (7) (20) (12) (4) (15) (11) (33) (40) (19) (12) (23) (3) (1) (0) (0) (3) (18) (4) (6) (231) 1999 96 65 9 19 8 18 25 12 18 20 3 5 2 2 1 7 9 13 332 (6) (23) (6) (14) (4) (13) (24) (11) (18) (19) (3) (4) (2) (2) (0) (4) (5) (8) (166) 2000 88 31 16 7 21 14 24 18 15 4 7 0 1 0 6 12 14 278 (5) (6) (9) (6) (14) (11) (17) (17) (12) (4) (6) (0) (1) (0) (6) (10) (7) (131) 2001 33 21 8 16 13 10 10 12 5 3 4 0 2 10 8 9 164 (3) (10) (7) (11) (10) (8) (9) (10) (5) (2) (1) (0) (2) (7) (7) (6) (98) 2002 98 15 15 10 8 3 2 6 6 2 1 5 13 7 17 208 (3) (3) (10) (9) (7) (3) (2) (3) (2) (1) (1) (3) (11) (5) (10) (73) 2003 52 40 11 6 7 4 7 3 0 4 4 10 10 17 175 (2) (17) (10) (6) (7) (4) (4) (0) (0) (0) (2) (8) (4) (14) (78) 2004 116 40 12 7 5 5 5 2 5 1 9 6 16 229 (4) (16) (11) (6) (5) (5) (2) (0) (0) (1) (7) (5) (10) (72) 2005 74 14 4 4 3 3 2 3 0 8 2 17 134 (0) (5) (4) (2) (2) (0) (0) (1) (0) (7) (2) (10) (33) 2006 64 22 9 5 7 0 7 6 7 6 5 138 (4) (6) (7) (5) (2) (0) (3) (1) (6) (2) (3) (39) 2007 46 17 4 4 3 8 2 3 8 11 106 (0) (12) (3) (1) (2) (3) (0) (2) (6) (8) (37) 2008 26 16 3 2 4 6 8 3 5 73 (1) (8) (2) (0) (2) (3) (7) (2) (3) (28) 2009 29 11 2 5 3 9 5 9 73 (0) (2) (2) (1) (2) (5) (4) (4) (20) 2010 31 10 9 5 9 9 9 82 (1) (3) (3) (3) (7) (6) (7) (30) 2011 28 7 3 10 7 8 63 (0) (1) (2) (8) (3) (7) (21) 2012 34 11 15 11 10 81 (0) (2) (15) (8) (7) (32) 2013 25 24 8 12 69 (1) (15) (4) (8) (28) 2014 104 29 6 139 (3) (12) (2) (17) 2015 51 13 64 (1) (8) (9) 2016 67 67 (7) (7) Total 28 107 191 233 117 242 123 345 294 201 165 153 92 94 61 108 87 309 226 284 3460 (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0) (0)

Table 12 Appendix: Laboratory conﬁrmed pertussis cases in Sweden, excluding the Gothenburg study area. Cases are presented per calendar year and birth cohort. In parentheses is the number of children with two or more doses of a pertussis vaccine prior to the start of the episode. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Data are presented for children born from Jan 1 1996.

129 Table 13 Appendix, see Chapter 2.9.2 in the main report.

Year of Pertussis episode Birth 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Total cohort

1996 3 3 7 21 9 21 7 38 3 6 0 1 0 0 0 1 0 0 0 0 120 (3) (3) (7) (21) (8) (19) (6) (37) (3) (6) (0) (1) (0) (0) (0) (1) (0) (0) (0) (0) (115) 1997 2 6 7 17 10 14 8 37 15 2 1 0 0 0 0 0 0 0 1 1 121 (2) (6) (7) (17) (9) (12) (8) (35) (15) (2) (1) (0) (0) (0) (0) (0) (0) (0) (0) (1) (115) 1998 12 24 39 26 21 4 44 11 3 0 1 0 0 0 0 0 0 0 0 185 (5) (18) (36) (25) (20) (4) (42) (9) (3) (0) (1) (0) (0) (0) (0) (0) (0) (0) (0) (163) 1999 25 63 21 20 9 39 10 6 1 2 2 0 0 0 0 0 0 0 198 (8) (45) (21) (18) (9) (36) (9) (6) (1) (2) (2) (0) (0) (0) (0) (0) (0) (0) (157) 2000 32 26 32 6 13 4 2 0 0 0 4 1 0 0 0 1 0 121 (13) (17) (30) (6) (11) (4) (2) (0) (0) (0) (4) (0) (0) (0) (0) (1) (0) (88) 2001 30 50 8 30 5 1 0 1 0 1 0 0 0 0 0 0 126 (8) (33) (8) (28) (5) (1) (0) (1) (0) (1) (0) (0) (0) (0) (0) (0) (85) 2002 50 18 32 5 1 3 0 0 0 0 0 0 0 0 0 109 (8) (12) (32) (5) (0) (3) (0) (0) (0) (0) (0) (0) (0) (0) (0) (60) 2003 28 58 11 1 1 1 1 1 0 0 0 1 1 0 104 (4) (47) (10) (1) (1) (1) (1) (1) (0) (0) (0) (1) (1) (0) (68) 2004 75 18 0 2 2 1 0 0 0 0 0 2 0 100 (17) (9) (0) (2) (2) (1) (0) (0) (0) (0) (0) (1) (0) (32) 2005 14 6 0 0 0 1 0 0 1 0 0 0 22 (3) (6) (0) (0) (0) (1) (0) (0) (0) (0) (0) (0) (10) 2006 10 5 2 0 0 1 0 0 0 0 0 18 (0) (2) (2) (0) (0) (1) (0) (0) (0) (0) (0) (5) 2007 6 6 2 1 0 1 0 0 1 0 17 (1) (5) (2) (0) (0) (1) (0) (0) (1) (0) (10) 2008 7 1 1 0 0 0 0 0 1 10 (0) (0) (1) (0) (0) (0) (0) (0) (1) (2) 2009 4 2 1 0 1 0 1 0 9 (1) (1) (1) (0) (1) (0) (0) (0) (4) 2010 5 0 0 4 0 3 1 13 (0) (0) (0) (3) (0) (1) (0) (4) 2011 2 1 1 1 1 0 6 (0) (0) (1) (1) (1) (0) (3) 2012 9 3 1 0 1 14 (2) (3) (0) (0) (1) (6) 2013 4 1 1 0 6 (0) (1) (0) (0) (1) 2014 5 3 1 9 (1) (1) (1) (3) 2015 5 2 7 (0) (1) (1) 2016 7 7 (0) (0) Total 5 21 63 172 122 208 88 366 96 38 19 23 11 16 5 12 14 9 20 14 1322 (5) (14) (40) (132) (88) (140) (57) (285) (72) (27) (11) (15) (7) (9) (2) (4) (8) (4) (7) (5) (932)

Table 13 Appendix: Laboratory conﬁrmed pertussis cases in the Gothenburg study area. Cases are presented per calendar year and birth cohort. In parentheses is the number of children with two or more doses of a pertussis vaccine prior to the start of the episode. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Data are presented for children born from Jan 1 1996.

130 Table 14 Appendix, see Chapter 2.9.2 in the main report.

Year of Pertussis episode Birth 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Total cohort

1996 2 3 5 6 3 0 0 5 2 1 0 1 0 0 0 1 2 7 8 8 54 1997 12 8 0 3 3 3 3 5 1 2 1 1 0 0 0 1 0 9 9 1 62 1998 38 7 2 3 1 1 1 0 2 1 2 0 0 0 1 0 4 7 3 73 1999 61 26 3 5 4 5 1 1 0 1 0 1 0 0 1 3 4 5 121 2000 58 19 7 1 6 3 7 1 3 0 0 0 0 0 0 2 7 114 2001 22 5 1 4 3 2 1 2 0 1 3 0 0 3 1 3 51 2002 66 5 5 1 1 0 0 3 4 1 0 2 2 2 7 99 2003 41 16 1 0 0 0 3 3 0 3 2 1 6 3 79 2004 77 13 1 1 0 0 3 2 5 0 1 1 6 110 2005 60 5 0 2 1 3 2 2 0 1 0 7 83 2006 44 12 2 0 5 0 4 5 1 4 2 79 2007 35 5 1 3 1 5 2 1 2 3 58 2008 21 5 1 2 2 3 1 1 2 38 2009 19 6 0 4 1 4 1 5 40 2010 23 2 6 2 2 3 2 40 2011 24 3 1 2 4 0 34 2012 24 6 0 3 3 36 2013 21 6 4 4 35 2014 76 12 4 92 2015 35 4 39 2016 46 46 Total 14 49 73 95 53 87 56 124 85 66 52 40 32 53 37 61 48 124 109 125 1383

Table 14 Appendix: Unimmunised children (i.e. children who have not received any pertussis vaccine before onset of cough) per birth-cohort. Cases are deﬁned as conﬁrmed pertussis with PCR or culture and from 2008 also with serology. Data collection was performed in the EPS. Cases are from Sweden excluding the Gothenburg study area.

131 Table 15 Appendix, see Chapter 2.9.2 in the main report.

Year of Pertussis episode Birth 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Total cohort

1996 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 4 1997 0 0 0 1 2 0 0 0 0 0 0 0 0 0 0 0 0 1 0 4 1998 4 0 3 1 1 0 2 1 0 0 0 0 0 0 0 0 0 0 0 12 1999 8 4 0 2 0 2 1 0 0 0 0 0 0 0 0 0 0 0 17 2000 9 7 1 0 2 0 0 0 0 0 0 1 0 0 0 0 0 20 2001 15 6 0 2 0 0 0 0 0 0 0 0 0 0 0 0 23 2002 26 4 0 0 1 0 0 0 0 0 0 0 0 0 0 31 2003 17 6 1 0 0 0 0 0 0 0 0 0 0 0 24 2004 35 6 0 0 0 0 0 0 0 0 0 1 0 42 2005 8 0 0 0 0 0 0 0 1 0 0 0 9 2006 8 2 0 0 0 0 0 0 0 0 0 10 2007 3 1 0 1 0 0 0 0 0 0 5 2008 5 0 0 0 0 0 0 0 0 5 2009 2 0 0 0 0 0 1 0 3 2010 5 0 0 1 0 2 1 9 2011 2 0 0 0 0 0 2 2012 6 0 1 0 0 7 2013 4 0 1 0 5 2014 2 2 0 4 2015 4 1 5 2016 4 4 Total 4 8 16 25 39 22 50 17 9 5 6 2 6 3 6 6 3 12 6 245

Table 15 Appendix: Unimmunised children (i.e. children who have not received any pertussis vaccine before onset of cough) per birth-cohort. Cases are deﬁned as conﬁrmed pertussis with PCR or culture and from 2008 also with serology.Data collection was performed in the Swedish enhanced surveillance study of pertussis. Cases are from the Gothenburg study area

132 Table 16 Appendix

Year Number of cases Incidence 1986 782 783 1987 850 825 1988 1253 1158 1989 1025 900 1990 816 680 1991 1191 963 1992 907 738 1993 1007 839 1994 815 711 1995 906 843 1996 548 553 1997 170 184 1998 93 104 1999 165 186 2000 219 245 2001 115 126 2002 217 231 2003 112 115 2004 285 285 2005 154 152 2006 98 94 2007 91 85 2008 47 43 2009 43 39 2010 49 43 2011 37 32 2012 51 45 2013 39 34 2014 121 105 2015 85 73 2016 87 74

Table 16 Appendix: Incidence (per 100,000 person years) of pertussis in infants younger than 1 year of age Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act..

133 Table 17 Appendix

Age (in months) Incidence 1986-1995 1997-2016 0 120.7 41.6 1 429.7 227.5 2 456.2 224.6 3 608.6 215.4 4 821.3 187.1 5 930.3 109.7 6 1035.1 94.1 7 1094.4 47.3 8 1154.7 41.0 9 1200.2 42.7 10 1117.7 38.1 11 1140.9 46.2

Table 17 Appendix: Mean incidence (per 100,000 person years) of pertussis in infants during the 10 calendar years before (1986–1995) and during the20 years after the (1997-2016) introduction of DTaP in 1996. Data are from case reports of pertussis, reported to SmiNet, according to the Communicable Disease Act..

134 8.3 Severity of pertussis

8.3.1 Severity of pertussis in Sweden including the Gothenburg study area (from 2003) and excluding the Gothenburg study area (from 1997)

8.3.2 Cases of hospitalization due to pertussis for all of Sweden

Data on hospitalizations, deﬁned as at least one night in the hospital due to pertussis disease, were available for 4166 of 4166 children born from Jan 1, 1996 to December 31, 2016 (see Table 18 Appendix). Altogether 887 (21.3 %) of the children had a hospital admission during the pertussis episode. The cases include 72 cases from the Gothenburg study area and 815 cases from rest of the Sweden.

8.3.3 The rate of hospital admission for pertussis by age for all of Sweden

In all, 621 of 887 infants (70 %) who were younger than 3 months of age at the start of the pertussis episode were hospitalised. The corresponding rates, regardless of vaccination status at the episode, for the 476 children in the agegroup of 3 <5 months and for the 411 children in age-group 5-<12 months and for the 2392 children from 12 months or older were 36 %, 12 % and 2 %, respectively (Table 18 Appendix).

8.3.4 Incidence of hospital admission and age at the onset of pertussis episode for Sweden without Gothenburg study area

Hospitalization data for Sweden from Oct 1, 1997, excluding the Gothenburg study area is shown in Figure 1 Appendix, Table 19 Appendix, Figure 2 Appendix and Figure 3 Appendix. The age-speciﬁc incidence rate of hospitalization due to pertussis is highest at 128.3 per 100.000 person years of follow-up for children 0-<3 Months of age and decreases by increasing age, to 0.2 per 100.000 person years for children »=12 Months of age at the start of the pertussis episode (Figure 2 Appendix).

8.3.5 Duration of hospital stay by age and vaccination status at the start of the pertussis episode

Hospital admissions were also studied by age, duration of hospital stay and vaccination status at the start of the pertussis episode. Detailed data

135 are given in Table 19 Appendix and in Figure 3 Appendix. Comparing hospitalizations among unvaccinated children with those who had been given one dose of a pertussis vaccine before the episode in the age interval between 3 and 12 months of age at beginning of the pertussis episode led to the following observations:

1. The median (mean) age at the start of the episode was 114 (149) days for unvaccinated children versus 125 (131) days for children vaccinated with one dose before the start of the episode. Thus, the two groups are "comparable" in age.

2. When comparing the groups described above - a higher rate of hospital admission was seen in the unvaccinated group compared to the vaccinated group (39% vs 30 %). This differences is statistically signiﬁcant, p=0.031).

3. Of those hospitalized due to pertussis at 3-<12 months of age, 41 % of the hospitalizations had a duration longer than a week for unvaccinated and 24 % were longer than a week among children with one dose. This difference was statistically signiﬁcant (p=0.021). These results suggest that there might be some protection against "severe" pertussis, which is deﬁned as requiring hospitalization, already after one dose of a pertussis vaccine.

In summary: There was a strong association between the age of the child at the onset of the pertussis episode and the need for hospitalization as well as between the vaccination status of the child before the start of the episode and the risk of a hospitalization due to the disease. The same conclusion holds for the duration of the hospital stay and age.

136 Table 18 Appendix: Duration of hospital stay for all Sweden from 1997 and for Gothenburg from 2003 in 4166 hospitalized children.

Age at episode start (days) Doses Duration of 0-30 31-60 61-90 91-150 151-365 >365 Sum before hospital stay episode

0 0 45 96 121 68 38 463 831 (17.9%) (28.6%) (41.3%) (56.2%) (71.7%) (97.7%)

1-7 79 130 114 30 10 8 371 (31.3%) (38.7%) (38.9%) (24.8%) (18.9%) (1.7%)

>7 128 110 58 23 5 3 327 (50.8%) (32.7%) (19.8%) (19%) (9.4%) (0.6%) Sum 252 336 293 121 53 474 1529

1 0 4 234 79 15 332 (66.7%) (66.1%) (86.8%) (93.8%)

1-7 1 90 10 1 102 (16.7%) (25.4%) (11%) (6.2%)

>7 1 30 2 0 33 (16.7%) (8.5%) (2.2%) (0%) Sum 6 354 91 16 467

>1 0 1 246 1869 2116 (100%) (92.1%) (98.3%)

1-7 19 29 48 (0%) (7.1%) (1.5%)

>7 2 4 6 (0%) (0.7%) (0.2%) Sum 1 267 1902 2170

Table 18 Appendix: Hospitalisation due to pertussis stratiﬁed by age and vaccination status. Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31 2016. For the Gothenburg study area the data are from case reports of pertussis with episodes starting between Jan 1, 2003, and Dec 31 2016. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Data are here presented for children born from Jan 1, 1996.

137 Table 18 Appendix: Duration of hospital stay for all Sweden excluding the Gothenburg study area from 1997 for 3460 children hospitalized with pertussis.

Age at episode start (days) Doses Duration of 0-30 31-60 61-90 91-150 151-365 >365 Sum before hospital stay episode

0 0 35 79 99 60 35 435 743 (15.4%) (27.1%) (38.4%) (54.1%) (70%) (97.8%)

1-7 71 113 104 29 10 7 334 (31.1%) (38.8%) (40.3%) (26.1%) (20%) (1.6%)

>7 122 99 55 22 5 3 306 (53.5%) (34%) (21.3%) (19.8%) (10%) (0.7%) Sum 228 291 258 111 50 445 1383

1 0 4 194 65 12 275 (80%) (63%) (84.4%) (92.3%)

1-7 1 85 10 1 97 (20%) (27.6%) (13%) (7.7%)

>7 0 29 2 0 31 (0%) (9.4%) (2.6%) (0%) Sum 5 308 77 13 403

>1 0 1 161 1465 1627 (100%) (89.4%) (98.1%)

1-7 17 25 42 (0%) (9.4%) (1.7%)

>7 2 3 5 (0%) (1.1%) (0.2%) Sum 1 180 1493 1674

Table 19 Appendix: Hospitalisation due to pertussis stratiﬁed by age and vaccination status in Sweden excluding the Gothenburg study area. Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997, and Dec 31 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1, 1996.

138 Figure 1 Appendix

Hospitalization data

3321 cases with data on cough characteristics 1

3335 cases with data on complications and hospitalizations 1

1273 Unimmunized cases 2062 Immunized cases

1 1

638 Hospitalized 175 Hospitalized cases (50.12%) cases (8.49%)

Figure 1 Appendix: Hospitalised cases in a ﬂow chart of 3321 cases of pertussis from Sweden excluding the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the EPS. Data are presented for children born from Jan 1 1996.

139 Figure 2 Appendix, Hospitalization in Sweden excluding the Gothenburg study area

Hospital admission due to pertussis with 95% CI

140

● 125.2 120

100

60 ● 55

40 Cases per 100 000 person years

● 4.4 0 ● 0.2

0−90days 91−150days 151−365days >365days

Days of age

Figure 2 Appendix: Incidence of pertussis (per 100,000 person years) in Sweden. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the EPS in children born from January 1, 1996.

140 Figure 3 Appendix, Hospitalizations in Sweden excluding the Gothenburg study area.

Observed duration of hospital stay among cases born 1996 or later, stratified by age and vaccination status at episode start 0 doses 400 300 200 100 0 0−30days 31−60days 61−90days91−150days151−365days>365days 1 dose 200 150 100 50 0 Days at hospital 0−30days 31−60days 61−90days91−150days151−365days>365days 0 days 1−7 days 2 or more doses >7 days 1500

Number of cases 1000

500

0 0−30days 31−60days 61−90days91−150days151−365days>365days Regardless of vaccination status 2000 1500 1000 500 0 0−30days 31−60days 61−90days91−150days151−365days>365days Age at episode start

Figure 3 Appendix: Hospitalised cases, stratiﬁed by age and vaccination status at pertussis episode start in Sweden excluding the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31, 2016. Data collection was performed in the EPS. Data are presented for children born from Jan 1 1996.

141 Figure 4 Appendix

Hospitalization data

3090 cases with data on cough characteristics 1

3084 cases with data on complications and hospitalizations 1

1031 Unimmunized cases 2053 Immunized cases

1 1

494 Hospitalized 136 Hospitalized cases (47.91%) cases (6.62%)

Figure 4 Appendix: Hospitalised cases with cough of at least one day in a ﬂow chart of 3090 cases of pertussis. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Jan 1, 2003 and Dec 31, 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1, 1996.

142 Figure 5 Appendix

Hospitalization data

686 cases with data on cough characteristics 1

683 cases with data on complications and hospitalizations 1

134 Unimmunized cases 549 Immunized cases

1 1

56 Hospitalized 14 Hospitalized cases (41.79%) cases (2.55%)

Figure 5 Appendix: Hospitalised cases with cough of at least one day in a ﬂow chart of 686 cases of pertussis.Cases are from the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Jan 1, 2003 and Dec 31, 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1, 1996.

143 8.4 Complications in the enhanced surveillance study

8.4.1 Cases of complications due to pertussis for all of Sweden

Data on respiratory complications, neurological complications, dehydration with >5 % of weight loss or other serious complications during the pertussis episode were registered in the database for 4029 of the 4166 children born from January 1, 1996 to December 31, 2016, with both vaccination and follow-up information. A respiratory complication (with apnoea, n= 289 or without apnoea, n= 312) was reported for 601 (15 %) of the children, and a dehydration event was reported for 128 (3 %) of the children. Uncommon complications, i.e. neurological and other serious complications, were reported for 12 (0.3 %) of the children.

8.4.2 2 The correlation between the rate of complications due to pertussis and age for all of Sweden

To analyse the association between complications during the pertussis episode and the age and vaccination status of the child at the start of the episode, children were grouped into two groups; children with at least one noted complication and children without any complication during the pertussis episode. Altogether 741 children (18 %) had at least one complication due to pertussis during their pertussis episode and 3288 children (82 %) had no complication at all, information was missing in 137 cases. In the 887 children who were younger than 3 months of age at the beginning of the pertussis episode, 44 % (389) had at least one complication. The corresponding rates for the 476 children in the age group of 3-<5 months, for 411 the children in the age-group of 5-<12 months and for the 2392 children aged 12 months and older at the beginning of the pertussis episode were 22 %, 14 % and 14 %, respectively (Figure 6 Appendix and Table 20 Appendix.

8.4.3 Incidence of complications and age for all of Sweden

The age speciﬁc incidence rate of any complication due to pertussis was highest at 76 per 100,000 person years of follow-up, for children 0-<3 months of age and decreased, by increasing age, to 1 per 100,000 person years for children >=12 months of age or older at the start of the pertussis episode.

144 8.4.4 Complications, age, and vaccination status at the start of the pertussis episode for all Sweden

The events "any complication" were studied in relation to age and vaccination status at the beginning of the pertussis episode. Detailed data are given in Figure 6 Appendix and Table 20 Appendix. For unvaccinated children aged 0-30, 31-60 and 61-90 days at the beginning of the pertussis episode the complication rates were 57 %, 39 % and 35 % respectively, and dropped to 9 % for children above one year of age. For unvaccinated children between 3-<5 and 5-<12 months of age, the rates of any complication were 26 % and 31 %, respectively. Thus, for the unvaccinated children there was a strong association between the rate of any complication due to the disease and age of the child at the beginning of the pertussis episode. The overall rate of any complication for unvaccinated children was 32 %. Regardless of age, the rate of any complication for children vaccinated with one dose was 18 %, and the rate for children vaccinated with two or more doses before the pertussis episode was 9 % (p<0.001). This statistically signiﬁcant difference was confounded by age. For children more than 12 months, the rate of any complication was at about 9 % for unvaccinated children and 10 % for children vaccinated with two or more doses. In the age interval of 5-<12 months at the start of the episode, the complication rate was 31 % for unvaccinated children, 11 % for children vaccinated with one dose and 9 % for those vaccinated with two or more doses prior to the start of the episode. This downward "trend" in rate by the number of doses prior to the pertussis episode was statistically signiﬁcant (p<0.001).

Table 21 Appendix describes the same data as Table 20 Appendix but for Sweden without the Gothenburg study area.

Table 22 Appendix and Table 23 Appendix describe complications in relation to hospitalization for Sweden without the Gothenburg study area and for the Gothenburg study area, respectively. These tables are supplements to Table 13 with all the data but only from 2003 onwards.

145 Table 20 Appendix: Sweden from 1997 and Gothenburg from 2003.

Age at episode start (days) Doses Complications 0-30 31-60 61-90 91-150 151-365 >365 Sum before after episode episode

0 No 107 201 188 85 34 344 959 (43.3%) (60.7%) (65.1%) (73.9%) (69.4%) (90.5%)

Yes 140 130 101 30 15 36 452 (56.7%) (39.3%) (34.9%) (26.1%) (30.6%) (9.5%)

Sum 247 331 289 115 49 380 1411

1 No 2 283 81 13 379 (33.3%) (80.6%) (89%) (81.2%)

Yes 4 68 10 3 85 (66.7%) (19.4%) (11%) (18.8%)

Sum 6 351 91 16 464

>1 No 1 238 1711 1950 (100%) (91.2%) (90.4%)

Yes 23 181 204 (0%) (8.8%) (9.6%)

Sum 1 261 1892 2154

Table 20 Appendix: Any complication due to the pertussis disease and stratiﬁed by age and vaccination status. Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997, and Dec 31 2016. For the Gothenburg study area the data are from case reports of pertussis with episodes starting between Jan 1, 2003 and Dec 31 2016. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Data are here presented for children born from Jan 1, 1996.

146 Table 21 Appendix: Complications since 1997 in Sweden excluding the Gothenburg study area.

Age at episode start (days) Doses Complications 0-30 31-60 61-90 91-150 151-365 >365 Sum before after episode episode

0 No 90 173 161 77 32 327 860 (40.4%) (60.3%) (63.4%) (73.3%) (69.6%) (91.3%)

Yes 133 114 93 28 14 31 413 (59.6%) (39.7%) (36.6%) (26.7%) (30.4%) (8.7%)

Sum 223 287 254 105 46 358 1273

1 No 2 245 68 12 327 (40%) (80.3%) (88.3%) (92.3%)

Yes 3 60 9 1 73 (60%) (19.7%) (11.7%) (7.7%)

Sum 5 305 77 13 400

>1 No 1 159 1329 1489 (100%) (89.8%) (89.6%)

Yes 18 155 173 (0%) (10.2%) (10.4%)

Sum 1 177 1484 1662

Table 21 Appendix: Any complication due to the pertussis disease and stratiﬁed by age and vaccination status in Sweden excl. the Gothenburg study area. Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1, 1996.

147 Figure 6 Appendix: Sweden excluding Gothenburg.

Cases with complications, stratified by age and vaccination status at episode start 0 doses 300

200

100

0 0−30days 31−60days 61−90days 91−150days151−365days >365days 1 dose 250 200 150 100 50 0 Had complication 0−30days 31−60days 61−90days 91−150days151−365days >365days No 2 or more doses Yes

1000 Number of cases

500

0 0−30days 31−60days 61−90days 91−150days151−365days >365days Regardless of vaccination status 1500 1000 500 0 0−30days 31−60days 61−90days 91−150days151−365days >365days Age at episode start

Figure 6 Appendix: Cases with complications, stratiﬁed by age and vaccination status at pertussis episode start in Sweden excluding the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31. 2016. Data collection was performed in the EPS. Data are presented for children born from Jan 1 1996.

148 Table 22 Appendix: Complications, Sweden from 1997.

Complication type Hospitalized Not hospitalized Sum Respiratory, with apnoea 225 (88%) 32 (12%) 257 Respiratory, without apnoea 142 (51%) 135 (49%) 277 Dehydration 76 (68%) 36 (32%) 112 Other severe events 4 (50%) 4 (50%) 8 No complication 361 (13%) 2315 (87%) 2676 Sum 808 (24%) 2522 (76%) 3330

Table 22 Appendix: Type of complications in children with laboratory conﬁrmed pertussis in Sweden excl. the Gothenburg study area. Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1, 1996.

149 Table 23 Appendix: Complications, Sweden from 1997 and Gothenburg from 2003.

Complication type Hospitalized Not hospitalized Sum Respiratory, with apnoea 255 (88%) 34 (12%) 289 Respiratory, without apnoea 150 (48%) 162 (52%) 312 Dehydration 79 (62%) 49 (38%) 128 Other severe events 8 (67%) 4 (33%) 12 No complication 393 (12%) 2895 (88%) 3288 Sum 885 (22%) 3144 (78%) 4029

Table 23 Appendix: Type of complications in children with laboratory conﬁrmed pertussis in Sweden including the Gothenburg study area. Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Data are here presented for children born from Jan 1 1996.

150 8.4.5 Spasmodic cough in Sweden with and without Gothenburg study area

Table 21 Appendix and 24 Appendix present data for spasmodic cough and are constructed in the same way as the previous tables describing complications and hospitalizations.

Figure 7 Appendix: Flowchart of cough characteristics in Sweden from 1997 and Gothenburg from 2003.

Pertussis cases

4,007 cases with data on cough characteristics1

3,992 cases with cough (99.63%) 1

3,885 cases fulfilling the EU case definition (96.96%) 1

3,207 cases fulfilling the WHO case definition (80.03%)

Figure 7 Appendix: Cough characteristics in a ﬂow chart of 4007 cases of pertussis in Sweden. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 01 1997 and Dec 31 2016. For the Gothenburg study area the data are from case reports of pertussis with episodes starting between Jan 01 2003 and Dec 31 2016. Data collection was performed in the EPS of pertussis. Data are here presented for children born from Jan 01 1996.

151 Figure 9 Appendix: Flowchart of cough characteristics in Sweden from 1997.

Sweden excluding the Gothenburg study area

3,321 cases with data on cough characteristics1

3,308 cases with cough (99.61%) 1

3,241 cases fulfilling the EU case definition (97.59%) 1

2,793 cases fulfilling the WHO case definition (84.1%)

Figure 8 Appendix: Cough characteristics in a ﬂow chart of 3090 cases of pertussis in Sweden excluding the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 01 1997 and Dec 31 2016. Data collection was performed in the EPS of pertussis. Data are here presented for children born from Jan 01 1996.

152 Figure 9 Appendix: Flowchart of cough characteristics in Gothenburg from 2003.

Gothenburg study area

686 cases with data on cough characteristics1

684 cases with cough (99.71%) 1

644 cases fulfilling the EU case definition (93.88%) 1

414 cases fulfilling the WHO case definition (60.35%)

Figure 9 Appendix: Cough characteristics in a ﬂow chart of 686 cases of pertussis in the Gothenburg study area. For the Gothenburg study area the data are from case reports of pertussis with episodes starting between Jan 01 2003 and Dec 31 2016. Data collection was performed in the EPS of pertussis. Data are here presented for children born from Jan 01 1996.

153 Table 24 Appendix: Spasmodic cough, enhanced Sweden study from 1997 and Gothenburg from 2003.

Age at episode start (days) Vaccine Duration of 0-30 31-60 61-90 91-150 151-365 >365 Sum doses spasmodic before cough episode

0 0 21 21 26 11 6 117 202 (8.3%) (6.2%) (8.9%) (9.1%) (11.3%) (24.7%)

1-20 10 29 11 11 2 8 71 (4%) (8.6%) (3.8%) (9.1%) (3.8%) (1.7%)

>20 221 286 256 99 45 349 1256 (87.7%) (85.1%) (87.4%) (81.8%) (84.9%) (73.6%)

Sum 252 336 293 121 53 474 1529

1 0 0 32 9 1 42 (0%) (9%) (9.9%) (6.2%)

1-20 0 30 9 0 39 (0%) (8.5%) (9.9%) (0%)

>20 6 292 73 15 386 (100%) (82.5%) (80.2%) (93.8%)

Sum 6 354 91 16 467

>1 0 63 387 450 (0%) (23.6%) (20.3%)

1-20 1 39 115 155 (100%) (14.6%) (6%)

>20 165 1400 1565 (0%) (61.8%) (73.6%)

Sum 1 267 1902 2170

Table 24 Appendix: Spasmodic cough due to the pertussis disease and stratiﬁed by age and vaccination status Data are from laboratory conﬁrmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. For the Gothenburg study area the data are from case reports of pertussis with episodes starting between Jan 1 2003 and Dec 31 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1 1996.

154 Table 25 Appendix: Spasmodic cough, enhanced Sweden study from 1997 excluding Gothenburg study area.

Age at episode start (days) Vaccine Duration of 0-30 31-60 61-90 91-150 151-365 >365 Sum doses spasmodic before cough episode

0 0 13 12 15 8 6 108 162 (5.7%) (4.1%) (5.8%) (7.2%) (12%) (24.3%)

1-20 7 25 10 8 2 8 60 (3.1%) (8.6%) (3.9%) (7.2%) (4%) (1.8%)

>20 208 254 233 95 42 329 1161 (91.2%) (87.3%) (90.3%) (85.6%) (84%) (73.9%)

Sum 228 291 258 111 50 445 1383

1 0 0 16 7 0 23 (0%) (5.2%) (9.1%) (0%)

1-20 0 25 5 0 30 (0%) (8.1%) (6.5%) (0%)

>20 5 267 65 13 350 (100%) (86.7%) (84.4%) (100%)

Sum 5 308 77 13 403

>1 0 28 258 286 (0%) (15.6%) (17.3%)

1-20 1 20 85 106 (100%) (11.1%) (5.7%)

>20 132 1150 1282 (0%) (73.3%) (77%)

Sum 1 180 1493 1674

Table 25 Appendix: Spasmodic cough due to the pertussis disease and stratiﬁed by age and vaccination status in Sweden excl. the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31 2016. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Data are presented for children born from Jan 1 1996.

155 Figure 10 Appendix: Sweden excluding Gothenburg.

Duration of spasmodic cough, stratified by age and vaccination status at episode start 0 doses 300

200

100

0 0−30days 31−60days 61−90days91−150days151−365days>365days 1 dose 250 200 150 100 50 Days of spasmodic 0 cough 0−30days 31−60days 61−90days91−150days151−365days>365days 2 or more doses 0 days 1200 1−20 days 1000 21+ days

Number of cases 800 600 400 200 0 0−30days 31−60days 61−90days91−150days151−365days>365days Regardless of vaccination status 1500

1000

500

0 0−30days 31−60days 61−90days91−150days151−365days>365days Age at episode start

Figure 10 Appendix: Duration of spasmodic cough, stratiﬁed by age and vaccination status at pertussis episode start in Sweden excluding the Gothenburg study area. Data are from laboratory-conﬁrmed case reports of pertussis, with episodes starting between Oct 1, 1997 and Dec 31, 2016. Data collection was performed in the EPS. Data are presented for children born from Jan 1 1996.

156 Table 26 Appendix:

Onset of pertussis Person years of Number of laboratory Incidence(per 100 000 95% conﬁdence episode occurred (in follow-up conﬁrmed cases person-years) interval for age group) incidence per 100,000 person-years

0-90days 51,523 178 (178) 345 (345) 297-400 (297-400) 91-150days 34,238 89 (111) 260 (324) 209-320 (267-390) 151-365days 119,150 233 (237) 196 (199) 171-222 (174-226) After 365 days of age 1,967,584 754 (796) 38 (40) 36-41 (38-43) During 1 year of age 201,867 191 (196) 95 (97) 82-109 (84-112) During 2years of age 192,780 119 (128) 62 (66) 51-74 (55-79) During 3years of age 181,092 91 (94) 50 (52) 40-62 (42-64) During 4years of age 169,356 83 (90) 49 (53) 39-61 (43-65) During 5years of age 157,704 77 (84) 49 (53) 39-61 (42-66) During 6years of age 145,794 72 (78) 49 (54) 39-62 (42-67) During 7years of age 133,692 66 (66) 49 (49) 38-63 (38-63) During 8years of age 122,076 31 (33) 25 (27) 17-36 (19-38) During 9years of age 110,808 10 (10) 9 (9) 4-17 (4-17) During 10years of age 99,696 7 (7) 7 (7) 3-14 (3-14) During 11years of age 88,950 3 (5) 3 (6) 1-10 (2-13) During 12years of age 78,534 1 (1) 1 (1) 0-7 (0-7) During 13years of age 68,382 0 (0) 0 (0) 0-5 (0-5) During 14years of age 58,608 1 (1) 2 (2) 0-10 (0-10) During 15years of age 49,158 0 (0) 0 (0) 0-8 (0-8) During 16years of age 40,026 1 (1) 2 (2) 0-14 (0-14) During 17years of age 31,164 0 (1) 0 (3) 0-12 (0-18) During 18years of age 22,380 1 (1) 4 (4) 0-25 (0-25) During 19years of age 13,542 0 (0) 0 (0) 0-27 (0-27)

Table 26 Appendix: From the enhanced surveillance study. Incidence of reported culture- or PCR-confirmed B. pertussis is described and from 2008 al so serology-diagnosed cases of pertussis among children in the Gothenburg study area. Data are from laboratory confirmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1 1996. We present person years of follow-up, number of laboratory confirmed cases, incidence per 100,000 person years and 95% confidence interval in the following age groups at onset of the pertussis episode; 0-<3 months of age 2; 3-<5 months of age ; 5-<12 months of age ; and after 12 months of age in one-year age intervals3 in vaccinated children. In brackets total figures, regardless of vaccination status, in respective age group, are given.

157 Table 27 Appendix

0-90days 451,337 782 (782) 173 (173) 161-186 (161-186) 91-150days 300,066 309 (420) 103 (140) 92-115 (127-154) 151-365days 1,045,176 257 (307) 25 (29) 22-28 (26-33) After 365 days of age 17,525,318 1506 (1951) 9 (11) 8-9 (11-12) During 1 year of age 1,774,444 124 (178) 7 (10) 6-8 (9-12) During 2years of age 1,695,444 140 (183) 8 (11) 7-10 (9-12) During 3years of age 1,592,880 155 (191) 10 (12) 8-11 (10-14) During 4years of age 1,491,228 134 (177) 9 (12) 8-11 (10-14) During 5years of age 1,390,404 128 (162) 9 (12) 8-11 (10-14) During 6years of age 1,288,608 147 (177) 11 (14) 10-13 (12-16) During 7years of age 1,186,992 138 (170) 12 (14) 10-14 (12-17) During 8years of age 1,088,064 125 (148) 11 (14) 10-14 (11-16) During 9years of age 990,972 108 (121) 11 (12) 9-13 (10-15) During 10years of age 895,416 54 (62) 6 (7) 5-8 (5-9) During 11years of age 802,530 40 (57) 5 (7) 4-7 (5-9) During 12years of age 711,804 36 (46) 5 (6) 4-7 (5-9) During 13years of age 621,912 28 (41) 5 (7) 3-7 (5-9) During 14years of age 534,198 28 (36) 5 (7) 3-8 (5-9) During 15years of age 450,006 40 (50) 9 (11) 6-12 (8-15) During 16years of age 368,184 39 (58) 11 (16) 8-14 (12-20) During 17years of age 287,742 23 (46) 8 (16) 5-12 (12-21) During 18years of age 207,930 11 (28) 5 (13) 3-9 (9-19) During 19years of age 127,002 8 (20) 6 (16) 3-12 (10-24)

Table 27 Appendix: From the enhanced surveillance study. Incidence of reported culture- or PCR-confirmed B. pertussis is described and from 2008 also serology-diagnosed cases of pertussis1 among children outside the Gothenburg study area. Data are from laboratory confirmed case reports of pertussis, with episodes starting between Oct 1 1997 and Dec 31 2016. Data collection was performed in the EPS. Data are here presented for children born from Jan 1 1996. We present person years of follow-up, number of laboratory confirmed cases, incidence per 100,000 person years and 95% confidence interval in the following age groups at onset of the pertussis episode; 0-<3 months of age 2; 3-<5 months of age ; 5-<12 months of age ; and after 12 months of age in one-year age intervals3 in vaccinated children. In brackets total figures, regardless of vaccination status, in respective age group, are given.

158 8.5 Updated tables with incidence data from the onset of the enhanced studies in Sweden and in the Gothenburg study area, respectively

Tables 28 Appendix, 29 Appendix, 30 Appendix, 31 Appendix and 32 Appendix are data up to Dec 31, 2016 comparing incidence ﬁgures and relative risks in the Gothenburg study area with the rest of Sweden.

• Table 28 Appendix shows the person years of follow up for pertussis incidences and conﬁdence intervals in 19 age intervals in the enhanced study since 2003

• Table 29 Appendix shows the person years of follow up for pertussis incidences and conﬁdence intervals in 17 age intervals for children vaccinated with two or more doses of a pertussis vaccine in the enhanced study since 2003

• Table 30 Appendix shows the person years of follow up for pertussis incidences and conﬁdence intervals in 17 age intervals with the WHO criterion (21 or more days of spasmodic cough) in the enhanced study since 2003.

• Table 31 Appendix describes person years of follow up for pertussis incidences and conﬁdence intervals in 19 age intervals within the enhanced study since 1997

• Table 32 Appendix shows the person years of follow up for pertussis incidences and conﬁdence intervals in 17 age intervals for children vaccinated with two or more doses of a pertussis vaccine in the enhanced study since 1997

159 Table 28 Appendix: The Gothenburg study area from 2003.

160 Age at onset of Person years of No of laboratory Incidence 95% conﬁdence Relative risk pertussis; vaccine- follow up conﬁrmed cases per 100,000 interval in Gothenburg or age group person-years compared with Sweden except Gothenburg

Before Dose 1 39,630 (344,009) 104 (544) 262 (158) 214-318 (145-172) 1.66 (1.33-2.05) (0-90days) Between 1 26,337 (228,672) 74 (303) 281 (133) 221-353 (118-148) 2.12 (1.62-2.74) and 2 doses (91-150days) Between 2 91,658 (796,147) 97 (137) 106 (17) 86-129 (14-20) 6.15 (4.69-8.04) and 3 doses (151-365days) After Dose 3 155,274 (1,348,674) 64 (98) 41 (7) 32-53 (6-9) 5.67 (4.07-7.85) and/or during 1 year of age During 2 years of 152,754 (1,327,260) 49 (99) 32 (7) 24-42 (6-9) 4.3 (2.99-6.12) age During 3 years of 149,928 (1,305,138) 30 (108) 20 (8) 14-29 (7-10) 2.42 (1.56-3.65) age During 4 years of 146,976 (1,283,298) 51 (107) 35 (8) 26-46 (7-10) 4.16 (2.92-5.86) age During 5 years of 144,162 (1,263,402) 51 (121) 35 (10) 26-47 (8-11) 3.69 (2.61-5.16) age During 6 years of 141,234 (1,245,522) 67 (153) 47 (12) 37-60 (10-14) 3.86 (2.85-5.18) age During 7 years of 133,692 (1,186,992) 61 (169) 46 (14) 35-59 (12-17) 3.2 (2.35-4.32) age During 8 years of 122,076 (1,088,064) 31 (148) 25 (14) 17-36 (11-16) 1.87 (1.22-2.76) age During 9 years of 110,808 (990,972) 10 (116) 9 (12) 4-17 (10-14) 0.77 (0.36-1.47) age During 10 years of 99,696 (895,416) 7 (62) 7 (7) 3-14 (5-9) 1.01 (0.39-2.22) age During 11 years of 88,950 (802,530) 5 (55) 6 (7) 2-13 (5-9) 0.82 (0.26-2.03) age During 12 years of 78,534 (711,804) 1 (46) 1 (6) 0-7 (5-9) 0.2 (0-1.15) age During 13 years of 68,382 (621,912) 0 (41) 0 (7) 0-5 (5-9) 0 (0-0.86) age During 14 years of 58,608 (534,198) 1 (36) 2 (7) 0-10 (5-9) 0.25 (0.01-1.5) age During 15 years of 49,158 (450,006) 0 (48) 0 (11) 0-8 (8-14) 0 (0-0.73) age During 16 years of 40,026 (368,184) 1 (58) 2 (16) 0-14 (12-20) 0.16 (0-0.92) age During 17 years of 31,164 (287,742) 1 (45) 3 (16) 0-18 (11-21) 0.21 (0.01-1.2) age During 18 years of 22,380 (207,930) 1 (28) 4 (13) 0-25 (9-19) 0.33 (0.01-2.01) age During 19 years of 13,542 (127,002) 0 (20) 0 (16) 0-27 (10-24) 0 (0-1.9) age

Table 28 Appendix: Incidence of pertussis among children, comparing the Gothenburg area (primary numbers) with the rest of Sweden (in brackets). The children are born from January 1, 1996 until Dec 31 2016 and followed from January 1, 2003 until Dec 31 2016 with culture-, or PCR-confirmed B.pertussis with positive serology from 2008. Data collection was performed in the EPS. Person-years of follow-up, number of laboratory confirmed cases, incidence per 100,000 person-years of follow-up and relative risk of having a laboratory-verified episode of B.pertussis in age-/vaccine-groups at onset of the pertussis episode is analysed; 0-<3 months of age (before Dose 1); 3-<5 months of age (between Dose 1 and 2); 5-<12 months of age (between Dose 2 and 3); and after 12 months of age (after Dose 3) in thirteen age intervals. Age is calculated at the date for onset of cough during the episode (for cases without cough the date for the positive sample is used). Age interval in the heading classifies unimmunised children.

161 Table 29 Appendix: Sweden from 1997 and the Gothenburg study area from 2003.

162 Age at onset Person years of No of laboratory Incidence 95% conﬁdence Relative risk of pertussis; follow up conﬁrmed cases per 100,000 interval in Gothenburg vaccine-or age person-years compared with group. Sweden except Gothenburg

Between 2 91,658 (796,147) 94 (108) 103 (14) 83-126 (11-16) 7.56 (5.67-10.06) and 3 doses (151-365days) After Dose 3 155,274 (1,348,674) 61 (68) 39 (5) 30-50 (4-6) 7.79 (5.42-11.17) and/or during 1 year of age During 2 years of 152,754 (1,327,260) 44 (71) 29 (5) 21-39 (4-7) 5.38 (3.61-7.95) age During 3 years of 149,928 (1,305,138) 28 (84) 19 (6) 12-27 (5-8) 2.9 (1.82-4.5) age During 4 years of 146,976 (1,283,298) 46 (72) 31 (6) 23-42 (4-7) 5.58 (3.77-8.19) age During 5 years of 144,162 (1,263,402) 47 (91) 33 (7) 24-43 (6-9) 4.53 (3.11-6.51) age During 6 years of 141,234 (1,245,522) 62 (123) 44 (10) 34-56 (8-12) 4.45 (3.22-6.08) age During 7 years of 133,692 (1,186,992) 61 (137) 46 (12) 35-59 (10-14) 3.95 (2.87-5.38) age During 8 years of 122,076 (1,088,064) 29 (125) 24 (11) 16-34 (10-14) 2.07 (1.33-3.12) age During 9 years of 110,808 (990,972) 10 (103) 9 (10) 4-17 (8-13) 0.87 (0.4-1.66) age During 10 years of 99,696 (895,416) 7 (54) 7 (6) 3-14 (5-8) 1.16 (0.45-2.57) age During 11 years of 88,950 (802,530) 3 (38) 3 (5) 1-10 (3-6) 0.71 (0.14-2.24) age During 12 years of 78,534 (711,804) 1 (36) 1 (5) 0-7 (4-7) 0.25 (0.01-1.5) age During 13 years of 68,382 (621,912) 0 (28) 0 (5) 0-5 (3-7) 0 (0-1.28) age During 14 years of 58,608 (534,198) 1 (28) 2 (5) 0-10 (3-8) 0.33 (0.01-1.97) age During 15 years of 49,158 (450,006) 0 (38) 0 (8) 0-8 (6-12) 0 (0-0.93) age During 16 years of 40,026 (368,184) 1 (39) 2 (11) 0-14 (8-14) 0.24 (0.01-1.39) age During 17 years of 31,164 (287,742) 0 (22) 0 (8) 0-12 (5-12) 0 (0-1.69) age During 18 years of 22,380 (207,930) 1 (11) 4 (5) 0-25 (3-9) 0.84 (0.02-5.81) age During 19 years of 13,542 (127,002) 0 (8) 0 (6) 0-27 (3-12) 0 (0-5.49) age

Table 29 Appendix: Incidence of pertussis among children vaccinated with 2 or more doses prior to episode onset, comparing the Gothenburg area (primary numbers) with the rest of Sweden (in brackets). The children are born from January 1, 1996 until Dec 31 2016 and followed from January 1, 2003 until Dec 31 2016 with culture-, or PCR-confirmed B.pertussis with positive serology from 2008. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Approximate person-years of follow-up (assuming all children are vaccinated on schedule), number of laboratory confirmed cases, incidence per 100,000 person-years of follow-up and relative risk of having a laboratory-verified episode of B.pertussis in age-/vaccine-groups at onset of the pertussis episode is analysed; 0-<3 months of age (before Dose 1); 3-<5 months of age (between Dose 1 and 2); 5-<12 months of age (between Dose 2 and 3); and after 12 months of age (after Dose 3) in thirteen age intervals. Age is calculated at the date for onset of cough during the episode (for cases without cough the date for the positive sample is used). Age interval in the heading classifies unimmunised children

163 Table 30 Appendix: WHO-criterion, Sweden from 1997 and the Gothenburg study area from 2003.

164 Age at onset of Person years of No of laboratory Incidence 95% conﬁdence Relative risk pertussis; vaccine- follow up conﬁrmed cases per 100,000 interval in Gothenburg or age group. person-years compared with Sweden except Gothenburg

Between 2 91,658 (796,147) 39 (83) 43 (10) 30-58 (8-13) 4.08 (2.72-6.04) and 3 doses (151-365days) After Dose 3 155,274 (1,348,674) 28 (43) 18 (3) 12-26 (2-4) 5.66 (3.38-9.32) and/or during 1 year of age During 2 years of 152,754 (1,327,260) 18 (52) 12 (4) 7-19 (3-5) 3.01 (1.66-5.23) age During 3 years of 149,928 (1,305,138) 14 (66) 9 (5) 5-16 (4-6) 1.85 (0.96-3.32) age During 4 years of 146,976 (1,283,298) 28 (51) 19 (4) 13-28 (3-5) 4.79 (2.91-7.75) age During 5 years of 144,162 (1,263,402) 32 (65) 22 (5) 15-31 (4-7) 4.31 (2.73-6.69) age During 6 years of 141,234 (1,245,522) 45 (95) 32 (8) 23-43 (6-9) 4.18 (2.86-6.02) age During 7 years of 133,692 (1,186,992) 39 (104) 29 (9) 21-40 (7-11) 3.33 (2.24-4.85) age During 8 years of 122,076 (1,088,064) 19 (95) 16 (9) 9-24 (7-11) 1.78 (1.03-2.94) age During 9 years of 110,808 (990,972) 9 (78) 8 (8) 4-15 (6-10) 1.03 (0.45-2.06) age During 10 years of 99,696 (895,416) 7 (40) 7 (4) 3-14 (3-6) 1.57 (0.59-3.55) age During 11 years of 88,950 (802,530) 3 (28) 3 (3) 1-10 (2-5) 0.97 (0.19-3.13) age During 12 years of 78,534 (711,804) 0 (31) 0 (4) 0-5 (3-6) 0 (0-1.15) age During 13 years of 68,382 (621,912) 0 (22) 0 (4) 0-5 (2-5) 0 (0-1.66) age During 14 years of 58,608 (534,198) 0 (22) 0 (4) 0-6 (3-6) 0 (0-1.66) age During 15 years of 49,158 (450,006) 0 (35) 0 (8) 0-8 (5-11) 0 (0-1.02) age During 16 years of 40,026 (368,184) 1 (35) 2 (10) 0-14 (7-13) 0.26 (0.01-1.56) age During 17 years of 31,164 (287,742) 0 (20) 0 (7) 0-12 (4-11) 0 (0-1.87) age During 18 years of 22,380 (207,930) 1 (10) 4 (5) 0-25 (2-9) 0.93 (0.02-6.53) age During 19 years of 13,542 (127,002) 0 (7) 0 (6) 0-27 (2-11) 0 (0-6.51) age

Table 30 Appendix: Incidence of pertussis fulfilling the WHO critera (21 or more days of spasmodic cough), among children vaccinated with 2 or more doses prior to episode onset, comparing the Gothenburg area (primary numbers) with the rest of Sweden (in brackets). The children are born from January 1, 1996 until Dec 31 2016 and followed from January 1, 2003 until December 31, 2013 with culture-, or PCR-confirmed B.pertussis with positive serology from 2008. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Approximate person-years of follow-up (assuming all children are vaccinated on schedule), number of laboratory confirmed cases, incidence per 100,000 person-years of follow-up and relative risk of having a laboratory-verified episode of B.pertussis in age-/vaccine-groups at onset of the pertussis episode is analysed; 0-<3 months of age (before Dose 1); 3-<5 months of age (between Dose 1 and 2); 5-<12 months of age (between Dose 2 and 3); and after 12 months of age (after Dose 3) in thirteen age intervals. Age is calculated at the date for onset of cough during the episode (for cases without cough the date for the positive sample is used). Age interval in the heading classifies unimmunised children.

165 Table 31 Appendix: Sweden from 1997 and the Gothenburg study area from 2003.

Age at onset of Person years of No of laboratory Incidence 95% conﬁdence Relative risk follow up follow up conﬁrmed cases per 100,000 interval in Gothenburg person-years compared with Sweden except Gothenburg

0-<3Months 51,523 (451,337) 176 (700) 342 (155) 293-396 (144-167) 2.2 (1.86-2.6) 3-<5Months 34,238 (300,066) 115 (507) 336 (169) 277-403 (155-184) 1.99 (1.61-2.44) 5-<12Months 119,150 (1,045,176) 248 (355) 208 (34) 183-236 (31-38) 6.13 (5.19-7.23) During 1 years of 201,867 (1,774,444) 204 (193) 101 (11) 88-116 (9-13) 9.29 (7.59-11.37) age During 2 years of 192,780 (1,695,444) 134 (196) 70 (12) 58-82 (10-13) 6.01 (4.79-7.53) age During 3 years of 181,092 (1,592,880) 98 (187) 54 (12) 44-66 (10-14) 4.61 (3.57-5.92) age During 4 years of 169,356 (1,491,228) 90 (179) 53 (12) 43-65 (10-14) 4.43 (3.4-5.73) age During 5 years of 157,704 (1,390,404) 87 (165) 55 (12) 44-68 (10-14) 4.65 (3.54-6.06) age During 6 years of 145,794 (1,288,608) 82 (186) 56 (14) 45-70 (12-17) 3.9 (2.97-5.08) age During 7 years of 133,692 (1,186,992) 66 (169) 49 (14) 38-63 (12-17) 3.47 (2.57-4.63) age During 8 years of 122,076 (1,088,064) 34 (154) 28 (14) 19-39 (12-17) 1.97 (1.32-2.87) age During 9 years of 110,808 (990,972) 10 (129) 9 (13) 4-17 (11-15) 0.69 (0.32-1.32) age During 10 years of 99,696 (895,416) 7 (63) 7 (7) 3-14 (5-9) 1 (0.39-2.18) age During 11 years of 88,950 (802,530) 5 (56) 6 (7) 2-13 (5-9) 0.81 (0.25-1.99) age During 12 years of 78,534 (711,804) 1 (45) 1 (6) 0-7 (5-8) 0.2 (0-1.18) age During 13 years of 68,382 (621,912) 0 (40) 0 (6) 0-5 (5-9) 0 (0-0.88) age During 14 years of 58,608 (534,198) 1 (33) 2 (6) 0-10 (4-9) 0.28 (0.01-1.65) age During 15 years of 49,158 (450,006) 0 (49) 0 (11) 0-8 (8-14) 0 (0-0.72) age During 16 years of 40,026 (368,184) 1 (57) 2 (15) 0-14 (12-20) 0.16 (0-0.94) age During 17 years of 31,164 (287,742) 1 (48) 3 (17) 0-18 (12-22) 0.19 (0-1.12) age During 18 years of 22,380 (207,930) 0 (26) 0 (13) 0-16 (8-18) 0 (0-1.42) age During 19 years of 13,542 (127,002) 1 (23) 7 (18) 0-41 (11-27) 0.41 (0.01-2.51) age

Table 31 Appendix: Incidence of pertussis, comparing the Gothenburg area (primary numbers) with the rest of Sweden (in brackets). The children are born from January 1, 1996 until Dec 31 2016 and followed from October 1, 1997 until Dec 31 2016 with culture-, or PCR-confirmed B.pertussis with positive serology from 2008. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Person-years of follow-up, number of laboratory confirmed cases, incidence per 100,000 person-years of follow-up and relative risk of having a laboratory-verified episode of B.pertussis in age-/vaccine-groups at onset of the pertussis episode is analysed; 0-<3 months of age (before Dose 1); 3-<5 months of age (between Dose 1 and 2); 5-<12 months of age (between Dose 2 and 3); and after 12 months of age (after Dose 3) in thirteen age intervals. Age is calculated at the date for onset of cough during the episode (for cases without cough the date for the positive sample is used). Age interval in the heading classifies unimmunised children.

166 Table 32 Appendix: Sweden from 1997 and the Gothenburg study area from 2003.

167 Age at onset of Person years of No of laboratory Incidence 95% conﬁdence Relative risk pertussis; vaccine- follow up conﬁrmed cases per 100,000 interval in Gothenburg or age group. person-years compared with Sweden except Gothenburg

Between 2 and 3 119,150 (1,045,176) 209 (206) 175 (20) 152-201 (17-23) 8.9 (7.31-10.84) doses After Dose 3 and 201,867 (1,774,444) 172 (107) 85 (6) 73-99 (5-7) 14.13 (11.04-18.16) during 1 year of age During 2 years of 192,780 (1,695,444) 118 (147) 61 (9) 51-73 (7-10) 7.06 (5.49-9.06) age During 3 years of 181,092 (1,592,880) 89 (148) 49 (9) 39-60 (8-11) 5.29 (4.02-6.93) age During 4 years of 169,356 (1,491,228) 80 (133) 47 (9) 37-59 (7-11) 5.3 (3.96-7.04) age During 5 years of 157,704 (1,390,404) 77 (128) 49 (9) 39-61 (8-11) 5.3 (3.94-7.09) age During 6 years of 145,794 (1,288,608) 68 (153) 47 (12) 36-59 (10-14) 3.93 (2.91-5.26) age During 7 years of 133,692 (1,186,992) 63 (134) 47 (11) 36-60 (9-13) 4.17 (3.04-5.67) age During 8 years of 122,076 (1,088,064) 32 (128) 26 (12) 18-37 (10-14) 2.23 (1.46-3.3) age During 9 years of 110,808 (990,972) 10 (110) 9 (11) 4-17 (9-13) 0.81 (0.38-1.55) age During 10 years of 99,696 (895,416) 7 (55) 7 (6) 3-14 (5-8) 1.14 (0.44-2.52) age During 11 years of 88,950 (802,530) 3 (40) 3 (5) 1-10 (4-7) 0.68 (0.13-2.12) age During 12 years of 78,534 (711,804) 1 (33) 1 (5) 0-7 (3-7) 0.27 (0.01-1.64) age During 13 years of 68,382 (621,912) 0 (27) 0 (4) 0-5 (3-6) 0 (0-1.33) age During 14 years of 58,608 (534,198) 1 (24) 2 (4) 0-10 (3-7) 0.38 (0.01-2.33) age During 15 years of 49,158 (450,006) 0 (37) 0 (8) 0-8 (6-11) 0 (0-0.96) age During 16 years of 40,026 (368,184) 1 (32) 2 (9) 0-14 (6-12) 0.29 (0.01-1.72) age During 17 years of 31,164 (287,742) 0 (20) 0 (7) 0-12 (4-11) 0 (0-1.87) age During 18 years of 22,380 (207,930) 0 (10) 0 (5) 0-16 (2-9) 0 (0-4.14) age During 19 years of 13,542 (127,002) 0 (9) 0 (7) 0-27 (3-13) 0 (0-4.75) age Overall inc. in 1,965,609 722 (1,475) 37 (8) 34-40 (8-9) 4.36 (3.98-4.77) non-infants (17,505,760)

Table 32 Appendix: Incidence of pertussis among children vaccinated with 2 or more doses prior to episode onset, comparing the Gothenburg area (primary numbers) with the rest of Sweden (in brackets). The children are born from January 1, 1996 until Dec 31 2016 and followed from October 1, 1997 until Dec 31 2016 with culture-, or PCR-confirmed B.pertussis with positive serology from 2008. Data collection was performed in the Swedish enhanced surveillance study of pertussis. Approximate person-years of follow-up (assuming all children are vaccinated on schedule), number of laboratory confirmed cases, incidence per 100,000 person-years of follow-up and relative risk of having a laboratory-verified episode of B.pertussis in age-/vaccine-groups at onset of the pertussis episode is analysed; 0-<3 months of age (before Dose 1); 3-<5 months of age (between Dose 1 and 2); 5-<12 months of age (between Dose 2 and 3); and after 12 months of age (after Dose 3) in thirteen age intervals. Age is calculated at the date for onset of cough during the episode (for cases without cough the date for the positive sample is used). Age interval in the heading classifies unimmunised children.

168 Year Number Number Number Number of Number of Number of Number of Number of of fully of female male cases cases with cases with cases with of cases cases vaccinated cases positive Serology isolation with other cases PCR of diagnostic Bordatella method Perussis by culture

2007 124 38 63 61 0 6 0 118

2008 163 48 84 79 82 58 17 8

2009 74 31 43 31 33 29 12 0

2010 72 16 41 31 49 16 4 3

2011 39 14 22 17 26 9 2 2

2012 91 31 50 41 62 19 7 3

2013 75 30 34 41 55 12 1 7

2014 208 133 101 107 170 26 2 12

2015 162 84 77 85 138 13 5 6

2016 205 112 111 94 178 19 4 7

Total 1213 537 626 587 793 207 54 166

Table 33 Appendix: Number of reported pertussis cases with data on vaccination status collected during the period 2007 to 2016. Data collection was performed in the EPS. Fully vaccinated children were deﬁned as children aged between one to ﬁve years, who had recieved at least three doses of aP vaccin and chlidren aged between six to 18 years who had recieved at least four doses of aP vaccin. 169 Årsrapporten för övervakningen av kikhosta (pertussis) beskriver utfallet av antal rapporterade fall av kikhosta för alla åldersgrupper med förstärkt övervakning av kikhosta hos barn och ungdomar som pågått i Sverige under arton års tid. Rapporten beskriver i detalj förekomst av kikhosta utifrån ålder, vaccinationsstatus och sjukdomsbörda med särskilt fokus på barn yngre än ett år. Rapporten är avsedd som kunskapsstöd för forskare och vårdgivare. Målgruppen för årsrapporten är hälso- och sjukvårdspersonal, och då särskilt personal inom mödravård, barnhälsovård och barnsjukvård samt primärvård och smittskyddsenheter. ————————————————-

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