2012 Review for the New Zealand National Immunisation Schedule:

Auckland UniServices Limited A wholly owned company of The University of Auckland

Prepared for: New Zealand Ministry of Health

Prepared by a scientific team incorporating the Immunisation Advisory Centre, The University of Auckland Institute of Environmental Science and Research Ltd.

February 2013 Contact details: Helen Petousis-Harris Immunisation Advisory Centre Tāmaki Innovation Campus The University of Auckland

Private Bag 92019, Auckland 1142, New Zealand

Phone: +64 9 923 2078 Fax: +64 9 373 7030 Mobile: +64 27 471 6749 Email: [email protected]

2 Antigen Review–2012: Diphtheria Executive summary As a result of the introduction of against diphtheria, the disease is now rare in developed countries. Evidence suggests that the Diphtheria, , acellular Pertussis (DTaP) is safe and well tolerated in infants, toddlers, adolescents and adults. The adult reduced antigen concentration tetanus-diphtheria (Td) is not associated with any safety concerns in 10-64 year olds or in 65+ year olds. Administration of tetanus, diphtheria, acellular (Tdap) to pregnant women is not associated with any unexpected safety patterns in maternal, infant, or fetal outcomes.

DTaP vaccines have been proven to be highly immunogenic as primary and booster . When the primary series is given during the first few years of life, the antibody levels decrease over time with a being recommended around pre-school/early school and adolescence age. Adults who have received a primary course also require a booster dose at some time during their adulthood. For people who have never had a primary series of diphtheria vaccines as a child, three doses of the adult formulation vaccine has been found to induce an adequate immune response. The reduced-antigen-content Tdap-IPV vaccine has been found to be non-inferior to full-strength DTaP-IPV vaccine with respect to immunogenicity when administered to preschool children. The duration of protection from an adult booster dose of diphtheria containing vaccine is unknown as data is limited.

Co-administration studies suggest that Tdap vaccine could be co-administered, without compromise to either the or immunogenicity profiles, with pneumococcal containing from 7 pneumococcal serotypes (PVC7), pneumococcal conjugate vaccine containing antigens from 10 pneumococcal serotypes (PCV10), pneumococcal conjugate vaccine containing antigens from 13 pneumococcal serotypes (PCV13), HPV16/18, MenACWY and influenza vaccines.

New multivalent combination DTaP vaccines are being developed, including two fully liquid hexavalent vaccines combining diphtheria (D), tetanus (T), acellular pertussis (aP), inactivated (IPV), virus (HBV) and type b (Hib) vaccines; and hexavalent and heptavalent vaccines based around three component aP. Early trials with transcutaneous patches also appear promising.

In developed countries, the primary series of immunisations usually consists of three doses of DTaP vaccine, given at intervals of four or more weeks, beginning at two or three months of age, and reinforced by a fourth dose sometime in the second year of life. The policy of using booster doses of vaccines containing diphtheria varies considerably. Diphtheria vaccines are well embedded in the immunisation schedule for children and adolescents around the world. Adult booster doses are generally recommended, but not always funded, and awareness of adult booster vaccines may be low amongst the adult population. Travellers may not be aware of the recommendations for them to have a booster vaccine before travelling to regions where diphtheria is endemic. With respect to diphtheria, the NZ immunisation schedule is in line with international policy and practice.

Antigen Review–2012: Diphtheria iii 2012 Antigen Review for the New Zealand National Immunisation Schedule: Diphtheria

Prepared as part of a Ministry of Health contract by Dr Phil Carter, ESR (Lead Author) Dr Lynn Taylor, Conectus Research and Innovation (Lead author) Dr Helen Petousis-Harris, Immunisation Advisory Centre (PI ) Tracey Poole, Immunisation Advisory Centre Dr Mary Nowlan, Immunisation Advisory Centre (Editor)

This review is one of a series of 18 antigen reviews presented in 15 individual reports. February 2013 (edited December 2014)

iv Antigen Review–2012: Diphtheria Contents Executive summary...... iii Contents Figures...... vii Tables ...... vii Abbreviations...... viii 1. Background...... 1 2. Methodology for review...... 2 2.1 Objectives...... 2 2.2 New Zealand ...... 2 2.3 Literature search strategy...... 2 2.3.1 Medline search terms and strategy...... 2 2.3.2 Cochrane Library search terms and strategy...... 3 2.3.3 Scopus search terms and strategy...... 3 2.3.4 Grey literature...... 3 2.3.5 Additional searches...... 3 2.3.6 Final library ...... 3 3. Recent epidemiology...... 4 3.1 Global epidemiology...... 4 3.1.1 Recent published examples of outbreaks in developed countries...... 4 3.1.2 Serological memory...... 5 3.2 NZ epidemiology...... 5 3.3 Summary of epidemiology...... 5 4. Safety...... 6 4.1 Objective...... 6 4.2 Outcomes...... 6 4.3 Review...... 6 4.3.1 Overview...... 6 4.3.2 Review articles and meta-analyses...... 6 4.3.3 Review of vaccine data bases...... 7 4.3.4 Pregnancy...... 7 4.3.5 Healthcare workers...... 7 4.3.6 Recent studies...... 8 4.4 Summary vaccine safety...... 8

Antigen Review–2012: Diphtheria v 5. Immunogenicity, efficacy, effectiveness and vaccine impact...... 9 5.1 Objective...... 9 5.2 Outcomes...... 9 5.3 Review...... 9 5.3.1 Overview...... 9 5.4 Children...... 10 5.4.1 Immunogenicity of Infanrix®–hexa...... 10 5.4.2 Concomitant administration with ...... 10 5.4.3 Concomitant administration with MMR vaccine...... 10 5.4.4 Combination versus separate administration...... 10 5.4.5 DTaP-IPV//PRP-T (Pentaxim®) as a booster ...... 11 5.4.6 D or d as booster dose ...... 11 5.4.7 Single dose of tetanus- among non/partially immune ...... 11 5.5 Adolescents...... 12 5.5.1 Immunogenicity of diphtheria- ...... 12 5.5.2 Second dose of Tdap ...... 12 5.6 Adults and special groups...... 12 5.6.1 Immunogenicity of Tdap (Boostrix®) in adults 19-64 years of age...... 12 5.6.2 Vaccination of adults with unknown vaccination history...... 12 5.6.3 Duration of antibodies in adults after Tdap...... 12 5.6.4 Decennial boosters ...... 13 5.6.5 Immunogenicity and safety of diphtheria-tetanus vaccine in adults...... 13 5.6.6 Immunogenicity in patients with chronic and recurrent rhinosinusitis...... 13 5.6.7 Pregnancy...... 13 5.6.8 Immunocompromised...... 14 5.7 Co-administration of diphtheria antigen with other vaccines...... 15 5.7.1 Co-administration in children...... 15 5.7.2 Concomitant administration in adults...... 15 5.8 Summary of effectiveness ...... 16 6. Age-specific issues – duration of immunity and booster doses...... 17 6.1 Objective...... 17 6.2 Review...... 17 7. Vaccine options...... 18 7.1 Objective...... 18 7.2 Currently available vaccines...... 18 7.3 Vaccines on the horizon...... 19 7.4 Summary for vaccine options...... 19

vi Antigen Review–2012: Diphtheria 8. Options for scheduling...... 20 8.1 Objective...... 20 8.2 Outcomes...... 20 8.3 Review...... 20 8.4 Recent changes to vaccine recommendations...... 23 8.5 Summary of schedule options...... 23 9. Implementation issues...... 24 9.1 Objective...... 24 9.2 Review...... 24 9.3 Summary for implementation issues...... 24 10. International policy and practice...... 25 10.1 Objective...... 25 10.2 Review...... 25 10.3 Summary of international policy and practice...... 25 References...... 26

Figures Figure 1. Flow of selection of articles for review...... 3

Tables Table 1. Countries with endemic diphtheria in 2012 (US CDC) (9)...... 4 Table 2 Seroprotection and seroconversion rates pre and post-booster vaccination, adapted from (42)...... 11 Table 3 Seroprotection and serconversion rates at 1 month post-primary, pre and post-booster vaccination, adapted from (43)...... 11 Table 4. Seroprotection rate against Diphtheria for 10 years after vaccination and 1 month after receipt of a booster dose of dTap vaccine, with permission (54)...... 13 Table 5. Newborn antibody levels stratified whether mothers received Tdap (59)...... 14 Table 6 List of diphtheria-containing vaccines licensed for immunisation and distribution in the US (US FDA)...... 18 Table 7. Immunisation schedules for Europe, USA, Australia and Canada as of 2012...... 20

Antigen Review–2012: Diphtheria vii Abbreviations ACIP Advisory Committee on Immunisation Practices AEFI Adverse Event Following Immunisation C. diphtheriae Corynebacterium diphtheriae CDC Centers for Disease Control and Prevention DTaP Diphtheria, Tetanus, acellular Pertussis vaccine dTap (or Tdap) Diphtheria, Tetanus, acellular Pertussis vaccine. The lower case “d” and “p”, the concentration of diphtheria and pertussis has been reduced DTwP Diphtheria, Tetanus, whole cell Pertussis vaccine EPI Expanded Program on (WHO) ESR Institute of Environmental Science and Research GBS Guillain-Barré syndrome Hib Haemophilus influenza type b HSCT Haematopoietic stem cell transplant NZ New Zealand PCV13 Pneumococcal conjugate vaccine containing antigens from 13 pneumococcal serotypes PCV7 Pneumococcal conjugate vaccine containing antigens from 7 pneumococcal serotypes SAE Serious Adverse Event Tdap (or dTap) Diphtheria, Tetanus, acellular Pertussis vaccine. The lower case “d” and “p”, the concentration of diphtheria and pertussis toxoids has been reduced UK United Kingdom US / USA United States VAERS Vaccine Adverse Events Reporting System WHO World Health Organization

Acknowledgements The Immunisation Advisory Centre (IMAC) and the University of Auckland appreciates the opportunity to undertake literature reviews of the specific vaccines under consideration for, or currently in use for the NZ national immunisation programme. This work was commissioned by the Ministry of Health, to inform decision-making for changes to the schedule and to enable up-to-date clinical guidelines to be incorporated into the NZ Immunisation Handbook 2014. These documents were prepared by IMAC, in collaboration with Environmental Science and Research (ESR), under contract to the Ministry of Health, and were reviewed by members of the Prescription and Therapeutics Advisory Committee (PTAC) immunisation subcommittee 2013 to Pharmac. The authors would also like to acknowledge Val Grey, Graphic Designer, Faculty of Medical and Health Sciences, The University of Auckland, for her assistance with design and layout of these documents.

viii Antigen Review–2012: Diphtheria 1. Background

Diphtheria is a serious acute infectious disease The first vaccination, which included a preparation of caused by the Corynebacterium diphtheriae. toxin and antitoxin, was widely used in the US from Diphtheria spreads by respiratory tract droplets around 1914, offering approximately 85% protection. through close contact with a case or a carrier, by Treatment of the diphtheria toxin with formalin in the physical contact with skin lesions or by contact with 1920s led to the replacement of the earlier preparation contaminated objects or foods. in favour of the toxoid vaccine. By the mid-1940s, diphtheria toxoid was combined with tetanus toxoid Most commonly, the is in the respiratory and whole cell pertussis to give the DTP vaccine. The tract, but it can also infect the skin. Infection of the widespread and routine childhood DTP immunisations, throat causes a grey to black, tough, fibre-like covering, has led to the decline of these diseases; diphtheria is which can block the airways and can cause respiratory now rare in many parts of the world, although small obstruction. Cutaneous infection can cause a painful outbreaks can occur (1). scaling rash and blisters. Risk factors include crowded environments, such as When infected with a bacteriophage, the bacillus military barracks and prisons, poor hygiene and low produces an as it integrates the toxin- levels or no immunisation. encoding genetic elements into the bacteria. This is known as the ‘toxigenic’ strain. Other strains are non-toxigenic, but they can become toxigenic if infected with the bacteriophage containing the diphtheria toxin gene. The toxin can affect the myocardium, leading to myocarditis and heart failure, the peripheral nervous system and cause demyelination and paralysis, and the kidneys, resulting in necrosis. The exotoxin may also cause severe swelling in the neck, “bull neck”. It is the toxigenic disease that is most serious. Mortality can be between 2-10%, even with treatment.

Antigen Review–2012: Diphtheria 1 2. Methodology for review 2.1 Objectives 2.3 Literature search strategy The objectives for this review have been informed The points below have formed the focus of the by the general specifications for the 2012 NZ literature search: antigen review. These are listed below. The dates for publication are between 2009 and 2012 as per the • Safety brief. This is not a systematic review or a critique of • Effectiveness in disease control the literature. The choice of articles reviewed is based on the purposeful selection of recent reviews and • Effect on studies that may best inform policy discussions around i Indirect effects/ diphtheria vaccines for New Zealand. ii Duration of protection • General specifications • Immunogenicity • Safety • Implementation issues (practicality of and possible • Effectiveness impact on uptake)

• Implementation issues (practicality and possible • Differences that need to be considered for each age impact on uptake) group, and groups with particular needs

• The differences that need to be considered for • Age each age group such as the variable severity of • High-risk groups — definition of which groups diseases and issues for vaccination most likely to benefit and which vaccine/s • Different options of placement on the schedule, • Different options for placement on the schedule, based on international findings and best practice based on international findings and best practice • Different vaccine options and comparisons • Different vaccine options and comparison between between the options the options

• Current international research and evidence 2.2 New Zealand around use of vaccines Epidemiology 2.3.1 Medline search terms and strategy The NZ Epidemiology has been sourced from the 2011 and 2012 Disease Surveillance Reports prepared by MeSH term: Diphtheria AND Vaccin* ESR. At the time of this report the 2012 annual data 6965 was not available. Limit to Humans, English, 2009 – current

722

NOT Cost*, Attitud*

659

NOT Survey, Interview, Qualitative, Parents, Physician, Self-reported

569

199 Remove duplicates

184 (keep and view)

2 Antigen Review–2012: Diphtheria 2.3.2 Cochrane Library search terms and 2.3.5 Additional searches strategy Where questions arose, additional searches were Search term Diphtheria Vaccin* undertaken to ensure there was no further available data. Limit to Cochrane Reviews, Other Reviews, Trials 2009-present 2.3.6 Final library 2 results (keep and view) The final library includes 204 references. Where systematic reviews and/or meta-analysis were 2.3.3 Scopus search terms and strategy available, the preceding literature has been excluded from the review. Diphtheria Vaccin* Published 2011 – present

1225

Limit to: Medicine, humans, English

892

Exclude Letter, Short survey, editorial and erratum

804 Figure 1. Flow of selection of articles for review Reject Veterinary, Arts and Humanities, Social Science articles. Delete duplicates

600 (keep and view)

Final Endnote Library 198 Articles

2.3.4 Grey literature Conference abstracts were sought to include data that has not yet been published, particularly from the key infectious diseases conferences for 2011 and 2012. No abstracts or posters were accessed. Four reports and two data sheets were accessed.

Antigen Review–2012: Diphtheria 3 3. Recent epidemiology 3.1 Global epidemiology In Sweden in 2011, there was an isolated case of C. diphtheriae in a child who had arrived from Somalia; Four biotypes of C. diphtheriae are recognised; gravis, this was the second case since only since 2001, both belfanti, intermedius and mitis. All strains produce an in migrants (5). Following this, after returning from a identical toxin, but the virulence and severity of disease trip to West Africa in 2012, a 68-year-old woman was they cause in humans can be explained by their diagnosed with laryngeal diphtheria in a hospital in different generation times and the rate and quantity Sweden and her 76-year-old husband was diagnosed of the toxin they produce. However, the severity of with cutaneous diphtheria. Despite being regular disease caused by different biotypes has not been travellers to countries outside Europe and North found to be consistently different (1). Different strains America, and visiting several travel medicine clinics, may explain the cyclical nature of epidemics prior to the female was incompletely vaccinated and the male the introduction of diphtheria containing vaccines. was completely unvaccinated against diphtheria (6). Humans appear to be the only host for C. diphtheriae. Between 1986 and 2008, 102 patients with Before the widespread introduction of diphtheria caused by toxigenic corynebacteria reported in the UK toxoid for childhood vaccination beginning in the (an average of four per year). There were five fatalities, 1930s and 1940s, diphtheria was a highly endemic all in unvaccinated individuals (7). childhood disease found in temperate climates. Immunisation programmes led to a rapid reduction in A case of a toxigenic strain of C. diphtheriae gravis diphtheria incidence in the United States, Canada and was recently diagnosed in a partially vaccinated many countries in Western Europe. teenager born in the UK with no recent history of travel or known contact with a case of diphtheria or a Since the introduction of vaccination programmes, carrier (8). outbreaks have occurred in some countries, but these have generally been small and controlled. The Table 1 shows the US Center for Disease Control Soviet Union experienced an outbreak in the 1990s. and Protection (CDC)’s list of the countries still with Factors contributing to the epidemic included a large endemic diphtheria as of 2012. population of susceptible adults, decreased childhood Table 1. Countries with endemic diphtheria in 2012 (US immunisation, suboptimal socioeconomic conditions CDC) (9) and high population movement (2). Region Countries 3.1.1 Recent published examples of Africa Algeria, Angola, Egypt, Eritrea, Ethiopia, outbreaks in developed countries Guinea, Niger, Nigeria, Sudan, Zambia, and other sub- Saharan countries In 2008, Norway had three laboratory confirmed cases Americas Bolivia, Brazil, Colombia, Dominican of diphtheria (usually caused by toxigenic strains of C. Republic, Ecuador, Haiti, and Paraguay diphtheriae), the first since 1962. The three cases were Asia/South Bangladesh, Bhutan, Burma (Myanmar), all members of the same family, which started with Pacific Cambodia, China, India, Indonesia, Laos, an unvaccinated five year old boy who had recently Malaysia, Mongolia, Nepal, Pakistan, Papua travelled to Latvia; his sister developed symptoms and New Guinea, Philippines, Thailand, and Vietnam their mother was also diagnosed with C. diphtheriae. Middle Afghanistan, Iran, Iraq, Saudi Arabia, Syria, The father, who was vaccinated as a child, was found East Turkey, and Yemen to be an asymptomatic carrier. Another 41 samples Europe Albania, Armenia, Azerbaijan, Belarus, were taken from contacts, but none were positive (3). Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Russia, Tajikistan, An isolated case occurred in France in 2011 in a Turkmenistan, Ukraine, and Uzbekistan 40 year old male with no history of travelling to an endemic area. After testing 53 contacts, only his asymptomatic partner proved positive. Testing 13 contacts of the partner also showed negative results. These two cases of toxigenic C. diphtheria were the first since 1989 (4).

4 Antigen Review–2012: Diphtheria 3.1.2 Serological memory 3.3 Summary of epidemiology Serological surveys for diphtheria in six European Diphtheria continues to circulate in some countries countries (Czech Republic, Hungary, Ireland, Latvia, and cases are imported into countries who have Luxembourg, Slovakia) and Israel showed that eradicated endemic diphtheria. There was a case increasing age is related to a gradual increase in imported to NZ in 2012 which resulted in a secondary seronegative subjects (<0·01 IU/ml of diphtheria case in a fully immunised contact. antitoxin antibodies), with some variances being related to the different vaccination schedules used in the participating countries. Differences in seronegativity were also observed between males and females in Hungary, Ireland and Luxembourg, with more unprotected females. Booster doses given at the time of military service could explain the higher seropositive rates in males in Luxembourg and in both males and females in young adults in Israel (10).

3.2 NZ epidemiology Whilst diphtheria is caused by toxin-producing strains of C. diphtheriae, diphtheria-like illness may also result from infection with toxigenic Corynebacterium ulcerans, although this is rare. In NZ, all isolates of C. diphtheriae and C. ulcerans are notifiable until toxigenicity is determined, including cutaneous isolates (11).

The laboratory based surveillance of diphtheria in NZ is conducted by the Institute of Environmental Science and Research (ESR), and the toxin testing and biotyping is performed by the Special Bacteriology Laboratory.

The NZ Pubic Health Surveillance Report covering Oct-Dec 2008 reports the last reported cases of C. diphtheriae. Four isolates of C. diphtheriae were received for toxigenicity testing, typing and surveillance purposes; all isolates were from cutaneous sources and were gravis strains; all the patients were from Auckland, and all the isolates were determined to be non-toxigenic by PCR examination for the toxin gene. One isolate of C. ulcerans was received from cutaneous source in a 46 year old male in Auckland - it was determined by PCR testing to be harbouring the diphtheria toxin gene (12).

In 2012, a case was reported of an adult male who developed a cutaneous infection after being tattooed in Samoa and a secondary case of toxigenic cutaneous diphtheria subsequently identified in a fully immunised 11-year-old household contact (13).

Antigen Review–2012: Diphtheria 5 4. Safety 4.1 Objective 4.3.2 Review articles and meta-analyses The objective of this section is to review the most 4.3.2.1 Combination vaccines: DTaP-IPV recent safety data for currently licenced diphtheria- (Kinrix®) and DTaP-IPV/Hib (Pentacel®) containing vaccines. A 2010 review of articles from 1966 to 2009 compared the immunogenicity and safety of DTaP-IPV (Kinrix®) 4.2 Outcomes and DTaP-IPV/Hib (Pentacel®) vaccines to separate component vaccines. It concluded that combination Outcomes are vaccine safety including adverse events vaccines were immunogenic and safe in infants and following immunisation (AEFI) and serious adverse children. When co-administered with PCV-7 or hepatitis events (SAE). Reactogenicity (injection site reactions B vaccine, immunogenicity was unaffected (14). and minor systemic reactions) have not been included as these have been thoroughly considered in the pivotal licensure studies. The safety of the diphtheria 4.3.2.2DTPa-HBV-IPV/ (Infanrix- ® vaccines has been reviewed according to the following: hexa ) In 2010, a spotlight review of 10 years of clinical • Review articles, meta-analyses data on Infanrix-hexa® (diphtheria, tetanus, acellular • Vaccine safety databases pertussis, hepatitis B (HBV), inactivated poliomyelitis and Hib conjugate vaccine) was published. The • Recent studies combination vaccine was considered “safe and well tolerated in infants under two years of age” with the • Pregnancy incidences of local and general symptoms in Infanrix- • Healthcare workers hexa® recipients being similar to infants receiving comparator vaccines (DTPa-IPV/Hib plus HBV) (15). • Case reports 4.3.2.3 Tdap (Boostrix®) a review of its 4.3 Review properties and use as a single-dose booster immunisation 4.3.1 Overview Tdap (Boostrix®, GlaxoSmithKline) was developed The diphtheria-containing combination vaccines have as a tetanus toxoid, reduced diphtheria toxoid, and been used in immunisation programmes throughout acellular pertussis vaccine designed to avoid the the world for decades. Combination vaccines of the increased reactogenicity observed with the fourth and DTP (diphtheria, tetanus and pertussis) core antigens fifth doses of the infant formulation. It is indicated plus additional other antigens, including polio, from the age of four years in Europe and 10 years hepatitis B and/or Haemophilus influenza (Hib), are in the USA and New Zealand, and can be used as a now in widespread use throughout the developed and booster dose for children, adolescents and adults. A developing world. This review focuses on the most recent review of its properties as a single dose booster recent reviews and also present recent individual case immunisation described this Tdap vaccine as being reports published during 2009-2012. safe, highly immunogenic with low reactogenicity in all age groups. The trials confirm that a single booster dose of Tdap induces seroprotective levels of antibodies to diphtheria and tetanus toxoids in virtually all children and adolescents, and in a high proportion of adults and elderly individuals at approximately one month post-vaccination irrespective of their vaccination history (16).

6 Antigen Review–2012: Diphtheria 4.3.3 Review of vaccine data bases 4.3.3.4 Tdap and Guillain-Barré syndrome Since the (VSD) has 4.3.3.1 US Vaccine Safety Datalink accumulated data on over two million doses of Tdap, A large retrospective cohort study, conducted over six there is about 80% power to detect a relative risk of years, assessed records for adolescents and young 2–3 and a risk difference of 3–6 per million doses adults in the Vaccine Safety Datalink database from for any outcome. Cases of Guillain-Barré syndrome seven managed care organisations in the US from (GBS) occurring in patients aged 10-64 years, up to 1999 to 2004. Of the 436,828 persons aged 9-25 42 days after receiving Tdap vaccine were reviewed. years receiving Td vaccines, the overall estimated The rate ratio of GBS in the exposed compared to risk of a medically attended local reaction was 3.6 the unexposed was 1.21 (95% CI: 0.82, 1.79). This events per 10,000 Td vaccinations. The 11-15 year indicates that Tdap is not associated with an increased old age group showed the lowest risk with 2.8 events risk of GBS within 6 weeks of vaccination (20). per 10,000 vaccinations. The risk of a local reaction was significantly higher in persons who had received 4.3.4 Pregnancy another tetanus and diphtheria toxoid containing vaccine in the previous five years (incidence rate ratio, A search of reports to the 2.9; 95% CI, 1.2 to 7.2) (17). Reporting System (VAERS) identified 132 pregnant women who had received Tdap vaccine. The review of these reports did not identify any concerning patterns 4.3.3.2 Safety of adolescent and adult in maternal, infant or fetal outcomes (21). tetanus-diphtheria-acellular pertussis (Tdap) vaccine The effect on neurodevelopment of infants exposed to in tetanus-diphtheria (Td) vaccines The safety of approximately 660,000 Tdap vaccines, during pregnancy was studied in Brazil. Pregnant administered to subjects aged 10-64 years during mothers aged 15 - 45 years participated through their 2005-2008, was assessed using active surveillance for attendance at prenatal hospital clinics. Hair samples adverse events from the Vaccine Safety Datalink in the were taken from infants who were exclusive breastfed US. The data indicated that Tdap is similar in safety infants at six months and from their mothers. The profile to Td regarding the outcomes studied and mothers had received 0, 1, 2 or 3 doses of Td vaccine supports the viability of sequential analysis for post- containing thiomersal during pregnancy. Regression licensure vaccine safety monitoring (18). analysis showed measures of neurodevelopment of the infants at six months was significantly associated 4.3.3.3 Safety of tetanus toxoid, reduced with total mercury concentration of neonate’s hair, diphtheria toxoid and acellular pertussis but was not sensitive to the number of vaccines taken (Tdap) vaccine administered to adults 65 by the mother. Other factors such as maternal fish consumption were considered important contributing years of age and older factors (22). The Vaccine Adverse Event Reporting System (VAERS) was searched for adverse events (AE) in individuals 4.3.5 Healthcare workers aged ≥65 years who had received Tdap vaccine from 2005-2010. Of the 243 reports received for this ‘off- An adverse event survey was completed by 207 label’ use of Tdap vaccine, only the term ‘Cough’ was healthcare workers after receiving an adult booster associated with disproportionately higher reporting dose of Tdap vaccine. One-hundred and sixty-seven after Tdap compared with Td, but most of these people reported at least one event (81%). Females events were mild. No unusual or unexpected clusters were three times more likely than males to experience of adverse events were identified. This review of the local reactions following the administration of Tdap ‘off-label’ use of Tdap vaccine in adults ≥65 years did vaccine. Also, those who had received the Tdap less not find any safety concerns that warrant further study than five years after their previous Td were more (19). likely to report local reactions than those with a time interval of 10 years or greater since their previous Td (odds ratio 3.06; 95% CI 1.25–7.52). Participants aged 30 years or less were significantly associated with higher rates of systemic events (odds ratio 4.15; 95% CI 1.94–8.86) (23).

Antigen Review–2012: Diphtheria 7 4.3.6 Recent studies 4.3.6.4 Safety of Tdap-IPV given one month after Td-IPV 4.3.6.1 Concomitant administration with A randomised, double-blind, multicentre study MMR vaccines assessed the safety of Tdap-IPV administered one Local reactions were assessed in 1,250 healthy nine month after vaccination Td-IPV in healthy adults year old children who received MMR and Td-IPV vaccinated according to the French vaccination vaccination as per the schedule in the Netherlands. calendar (seven tetanus-diphtheria vaccinations by age Parental reports indicated that local reactions 18 years). Participants received either Td-IPV (n = 249) occurred in 86.5% of the children within seven days or placebo (n = 251) followed by Tdap-IPV one month after vaccination, more often at the Td-IPV (83.4%) later. At seven days, 85.1% versus 93.4% participants than at the MMR site (32.7%). All symptoms were reported at least one reaction at the injection site, transient (24). mainly pain (82.6% versus 92.1%); 40.5% versus 45.0% reported at least one systemic AE (mainly headache: 26.4% versus 26.0%); fever concerned 4.3.6.2 Risk of febrile seizures and epilepsy 1.7% of both groups. No serious vaccine-related AE after DTaP-IPV-Hib were reported. Both safety profiles corresponded to A population-based study of 378,834 children in documented product characteristics. No problems Denmark who had received DTaP-IPV-Hib vaccination were identified with administering Tdap-IPV one month given at three, five and 12 months was conducted after Td-IPV (27). to evaluate the risk of febrile seizures and epilepsy. Nine children were diagnosed with febrile seizures on 4.3.6.5 Safety of Tdap in six to seven year- the day of the first dose of vaccine (5.5 per 100 000 old children person-days), 12 children after the second (5.7 per 100 000 person-days), and 27 children after the third Adverse events were evaluated in 243 healthy six and (13.1 per 100 000 person-days). A higher risk of febrile seven year-old children who were immunized with Tdap seizures was found on the day of the first and second vaccine and were found to be mild and resolved within doses (hazard ratio [HR] 6.02; 95% CI 2.86-12.65 seven days (28). and HR 3.94; 95% CI 2.18-7.10, respectively), but not on the day of the third vaccination (HR 1.07; 95% CI 0.73-1.57) when compared with the reference cohort. 4.4 Summary vaccine safety With respect to epilepsy, children had a lower risk of There have been several publications relating to epilepsy between 3 and 15 months (HR 0.63; 95% multivalent combination vaccines that contain DTaP, CI 0.50-0.79) and a similar risk for epilepsy later in all of which have concluded that the vaccines are safe life (HR 1.01; 95% CI, 0.66-1.56) versus unvaccinated and well tolerated in infants, toddlers, adolescents and children. DTaP-IPV-Hib vaccination was associated with adults. The adult reduced concentration Td has also an increased risk of febrile seizures on the day of the been found to have no safety concerns in adolescents first two vaccinations given at three and five months, and adults aged 10-64 years and in the elderly aged although the absolute risk was small. Vaccination with over 65 years. DTaP-IPV-Hib was not associated with an increased risk of epilepsy (25). Administration of Tdap to pregnant women did not identify any concerning patterns in maternal, infant or fetal outcomes. 4.3.6.3 Post-marketing safety in adolescents In healthcare workers, Tdap given less than five years after their previous Td were more likely to report local A prospective, observational study was carried out adverse events than those with a time interval of 10 in Kaiser Permanente, a US Health Maintenance years or greater since their previous Td. Organization, to estimate the incidence of medically attended neurologic events during the 30 days following vaccination with Tdap (Boostrix®, GlaxoSmithKline). The study population was 13,427 adolescents aged 10 – 18 years. No increased risk for medically-attended neurologic, medically-attended haematological events nor allergic reactions was observed following Tdap vaccination (26).

8 Antigen Review–2012: Diphtheria 5. Immunogenicity, efficacy, effectiveness and vaccine impact 5.1 Objective from circulating disease and antitoxin levels declining with increasing age may result in a susceptible adult The objective of this section is to review the most population (29). recent performance data for currently licenced diphtheria vaccines. Consideration is given to relevant Individuals with circulating antitoxin levels <0.01 IU/ml immunogenicity data, efficacy and effectiveness are generally considered susceptible, with less severe studies that contribute to the current understanding of symptoms being associated with levels above this. The the effectiveness of diphtheria vaccines and evidence protective level is generally considered to be 0.1 IU/ml their impact in populations. and an antitoxin level of >1.0 IU/ml is associated with long-term protection.

Vaccines combining pertussis antigens with diphtheria 5.2 Outcomes and tetanus toxoids have been gradually introduced The outcomes considered for this review are: into immunisation schedules throughout the world. An expert review of 16 years’ experience with the • Children DTaP–IPV/PRP-T Hib combined vaccine, marketed as ® ® • Adolescents Pentaxim /Pentavac ( Pasteur) was published in 2011. First licensed in 1997 in Sweden, the • Adults experience with Pentaxim® now stretches to over 100 countries where over 87 million doses have been • Pregnant women distributed. The findings of this review of clinical trials • Healthcare workers in many countries concluded that good diphtheria immunogenicity has been demonstrated after • Immunocompromised primary vaccination with Pentaxim®, regardless of the population ethnicity and primary . • Co-administration A booster vaccination in the second year of life also results in high levels of immunogenicity for each 5.3 Review antigen (30). There are a number of different vaccine manufacturers 5.3.1 Overview producing vaccines with the core diphtheria, tetanus and pertussis components. Clinical data Immunity against diphtheria is an antibody-mediated in a study of 97 Korean children indicates that the response to the diphtheria toxin and is primarily of the interchangeability of DTaP vaccines results in a non- IgG type. Antitoxin antibodies can pass through the inferior response in the primary series (31). However, placenta to provide passive immunity to the newborn. a prospective phase III randomised multicentre trial Before the widespread use of vaccination, newborn of 253 infants in Canada concluded that, for the babies would have acquired passive immunity from primary series, it was better to complete the primary maternal antitoxin offering protection for the first six- infant three-dose vaccine series with the same vaccine. 12 months of life. Throughout childhood, they would Immunogenicity and reactogenicity were different have been exposed to the diphtheria organism and for mixed two, four, six- month pentavalent infant have developed antibodies. By the age of about 15-20, vaccine schedules. The percentage of children with most people would have developed acquired immunity PRP antibody ≥0.15 g/mL after completion of the to diphtheria. 3-dose infant immunization schedule was higher in the Infanrix™, Pediacel, Pediacel (IPP) group than in the Antitoxin levels decline over time in children after Pediacel, Pediacel, Infanrix™ (PPI). The anti-diphtheria they have received a primary series of vaccines and a toxin response was not assessed in this study, although booster dose is given. In countries where diphtheria Infanrix contains more diphtheria toxin than Pediacel immunisation is common practice and high coverage (25Lf, 15Lf, respectively) (32). rates are achieved, there will be no natural boosting

Antigen Review–2012: Diphtheria 9 5.4 Children 5.4.2 Concomitant administration with hepatitis B vaccine 5.4.1 Immunogenicity of Infanrix®–hexa The immunogenicity of Infanrix®-IPV /Hib co- administered with hepatitis B vaccine was assessed The 2010 ADIS review of 10 years clinician data on in an open-labelled randomised study of 62 healthy Infanrix®-hexa found it to be highly immunogenic, as Taiwanese infants. The DTPa-IPV/Hib was given at 1.5, primary and booster vaccination, for all its component 3.5, 6 and 15–18 months, and hepatitis B vaccine at toxoids/antigens in infants aged <2 years, regardless birth, 1.5, 6 and 15–18 months of age. One month of vaccination schedules. In large clinical studies, after the three-dose primary series, 100% of infants Infanrix® -hexa was found to elicit a strong immune had seroprotective levels of antibodies for diphtheria. response against vaccine toxoids/antigens which The DTPa-IPV/Hib primary and booster vaccination persisted for up to a mean of approximately 6 years were immunogenic, and well tolerated, when co- after booster vaccination (15, 33, 34). administered with HBV vaccine (38). A review article from Germany reviewed published clinical trials and post-marketing surveillance data 5.4.3 Concomitant administration with in relation to immunogenicity, efficacy and safety MMR vaccine profile of Infanrix®-hexa. The data supported the immunogenicity of this across a range of different Immunity to diphtheria and tetanus was analysed in primary and booster vaccination schedules, as well as 338 Austrian children aged four - eight years. Most when administered concomitantly with other licensed of the children (323) had received the schedules vaccines (35). four doses of DTaP–HBV–IPV/Hib (according to the schedule of 2, 3, 4 months and a booster in the second The immunogenicity of two DTaP-HBV-IPV/Hib year of life) and 15 children had received three doses vaccines administered at 3, 5 and 11-12 months of as well as 1 or 2 doses of MMR. When measured ® age (Infanrix -hexa and Hexavac) was studied in 494 between the ages of 4-8 years, 81% of children were infants enrolled in 10 centres throughout Finland, Italy seroprotected for diphtheria. Antibodies levels against and Sweden. The anti-diphtheria concentrations after diphtheria, tetanus and pertussis were dependent on three doses were similar in the two dose primary series the interval since last vaccination while HBs-antibodies ® but the three-dose primary series of Infanrix -hexa were not. The seroprotective rates for diphtheria and induced higher anti-diphtheria concentrations than pertussis at this age indicate that a booster dose at Hexavac™ (36). the age of about six - eight years is required, preferably with a vaccine containing the higher dose of diphtheria 5.4.1.1 Immunogenicity with different toxoid (39). primary schedules Most immunisation schedules in Europe use a three- 5.4.4 Combination versus separate dose primary schedules (2, 3, 4 months or 2, 4, 6 administration months), each with a booster dose in the second A randomised, parallel controlled, single centre year of life. Denmark, Iceland, Sweden, Finland, Italy, was conducted in China in 720 infants, Norway and Austria have implemented a two-dose aged 3, 4 and 5 months old and 18 months old for primary schedule at three and five months of age, with both primary and booster immunisation, to compare booster at 11-12 months. A pooled analysis of data the administration of DTaP/Hib combination vaccine from four European studies, in which Infanrix®-hexa developed by a Chinese manufacturer with the was administered to 702 healthy infants at three, five and 11-12 months of age, found that 96.3% and administration of separate DTaP and Hib vaccines. The 100% of infants had seroprotective antibodies against immunogenicity profile of the DTaP/Hib combination diphtheria, tetanus, hepatitis B and poliovirus one vaccine was equivalent to that of separately month after dose 2 and 98.9% -100% of subjects were administered China-licensed DTaP vaccine and Hib seropositive for all vaccine antigens one month after conjugate vaccine (40). the booster dose 3. For each vaccine antigen from pre- vaccination to one month post dose two, there was at least a 7.5-fold increase in geometric mean antibody titres. Infanrix®-hexa induced an adequate immune response after a two-dose primary plus booster dose when administered according to a three, five and 11-month schedule (37).

10 Antigen Review–2012: Diphtheria 5.4.5 DTaP-IPV//PRP-T (Pentaxim®) as a booster The immunogenicity and safety of a pentavalent combination DTaP-IPV//PRP-T (Pentaxim®) as a booster at 18-19 months of age was assessed in 480 Thai infants who received doses of the same vaccine at two, four and six months of age. Anti-diphtheria antibody titres > 0.01 IU/ml were observed in the majority of children pre-booster. One month after the booster, seroprotection rates were 95% for diphtheria (> 0.10 IU/ml) (41).

An almost identical study of 123 Thai children also found that vaccination at two, four, six months and a booster at 18-19 months of age with the DTaP-IPV//PRP-T vaccine induced antibody persistence at four-six years of age. A second booster with DTaP-IPV induced a strong immune response with seroprotection rates increasing from pre- booster rate 60.2 % to 100 % for diphtheria (> 0.10 IU/ml) (42). See Table 3.

Table 2. Seroprotection and seroconversion rates pre and post-booster vaccination, adapted from (42)

Pre-booster Post-booster % (95%CI) % (95% CI) Anti-Diphtheria ≥0.01 IU/ml 92.7 (86.6-96.6) 100.00 (97.0-100) Anti-Diphtheria ≥0.1 IU/ml 60.2 (50.9-68.9) 100.00 (97.0-100)

A similar study in 207 healthy children in Delhi, India also concluded that the DTaP-IPV//PRP-T vaccine booster at 18- 19 months of age induced strong antibody responses 98% > 0.10 IU/ml. As shown in Table 4 (43).

Table 3 Seroprotection and serconversion rates at 1 month post-primary, pre and post-booster vaccination, adapted from (43)

Post-Primary Pre-booster Post-booster % (95%CI) % (95%CI) % (95% CI) Anti-Diphtheria ≥0.01 IU/ml 99.0 (96.5-99.9) 82.3 (76.3-87.4) 100.00 (98.2-100) Anti-Diphtheria ≥0.1 IU/ml 18.3 (13.2-24.4) 14.1 (9.6-19.8) 98.00 (95.0-99.5)

5.4.6 D or d as booster dose Booster doses or diphtheria are generally given as either standard (≥30 IU) or low (≥2 IU). To ascertain if the seroprotection generated after a dose of low-dose diphtheria vaccine was non-inferior to that induced following a high-dose vaccine given as a booster in children six years of age, 760 children were randomised to receive one of two vaccines. The seroprotective threshold of 0.1 IU/mL was reached by 98.6% and 99.3% of children for diphtheria [as measured by sero-neutralisation (SN)]. The confidence intervals overlapped for immunogenicity, but rates were slightly higher in the high-dose group. This supports the use low-dose diphtheria as a booster in children who have previously received a primary course of diphtheria (44).

Booster vaccination for pre-school children has been recommended in Italy since 1999. The immunogenicity of a booster dose of reduced-antigen content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine (Tdap- IPV; GSK Biologicals Boostrix™-Polio; 3-component pertussis) was compared with full-strength DTPa-IPV vaccine (sanofi-pasteur-MSD Tetravac; 2-component pertussis) in 303 pre-school Italian children. One month post-booster, all subjects were seropositive for anti-diphtheria antibodies. The reduced-antigen-content Tdap-IPV vaccine was found to be non-inferior to full-strength DTPa-IPV vaccine with respect to immunogenicity (45).

5.4.7 Single dose of tetanus-diphtheria vaccine among non/partially immune A single dose booster vaccine has been demonstrated to boost previously acquired immunity in , India where diphtheria is common among children aged five-19 years. A single dose of (Td) vaccine was given to 483 school children aged seven-17 years who were susceptible/partially immune to diphtheria and/or tetanus. Serological testing, six weeks after vaccination, indicated that the vaccine was highly immunogenic with >96% seroprotected against both antigens (46).

Antigen Review–2012: Diphtheria 11 5.5 Adolescents 5.6.2 Vaccination of adults with unknown vaccination history 5.5.1 Immunogenicity of diphtheria-tetanus A study in 18-50 year old adults with unknown vaccine vaccination history reported that one dose of Repevax® Tdap-IPV administered one month after one dose of A multicentre, non-randomised, open label phase Revaxis® Td-IPV induced a high humoral response (51). IV study was conducted in South Korea to compare the immunogenicity and safety of Td vaccine in 132 pre-adolescents aged 11–12 years with 145 5.6.3 Duration of antibodies in adults after adolescents aged 13–18 years. Immunogenicity was Tdap demonstrated in both the 11-12 year and 13-18 year An open-labelled, controlled, serological follow- age groups. Prior to vaccination, 11 (8.3%) of the pre- up study was conducted in 36 centres in the US. adolescent and 6 (4.1%) of the adolescents had anti-D Antibodies to Tdap antigens were measured three antibody concentrations of <0.1 IU/mL. A month years after vaccination in 1386 adults aged 19–64 after vaccination, 100% in both groups achieved years. At three years post-vaccination, the antibody anti-D antibody levels of ≥0.1 IU/mL, indicative of levels were lower than at one year post vaccination, seroprotection (47). but remained higher than pre-vaccination levels. Seroprotection rates for diphtheria were 96.9% for 5.5.2 Second dose of Tdap Boostrix® (GlaxoSmithKline Biologicals) and 97.8% for Adacel® () (52). The immunogenicity of a second dose of an adult formulation Tdap was evaluated in 545 Canadian The long-term persistence of antibodies among adolescents and adults aged 15 - 69 years, five adults was assessed in New South Wales, Australia. years after a first dose. Post-vaccination, 100% of Participants were vaccinated with Tdap vaccine or Td participants had a tetanus antibody level ≥0.1 IU/mL. +monovalent acellular pertussis (pa) vaccines, At 60 A second dose of Tdap vaccine, five years after the months post-vaccination, 94.4% of Tdap vaccinees had initial dose, was well tolerated and immunogenic in anti-diphtheria antibody concentrations consistent with adolescents and adults (48). seroprotection, compared with 93.7% of Td recipients (53). The immunogenicity of a booster dose of Tdap-IPV was evaluated in 415 German adolescents aged 9-13 years, In Finland, a follow-up study was conducted in young who had previously received Tdap-IPV or Tdap +IPV adults, 10 years post-vaccination with single dose of at four to eight years of age. One month after the Tdap vaccine at the age of 10-14 years, to assess the Tdap-IPV booster dose, 100% of subjects had antibody immunogenicity and safety of a second booster dose concentrations/titres associated with seroprotection of dTap vaccine. At ten years, of the 74 participants, against diphtheria, as compared with 98.2% before 82.4% had anti-diphtheria antibody concentrations the booster dose (49). prior to the dTap booster dose and 98.6% had seroprotective antibody levels against diphtheria one 5.6 Adults and special groups month after the booster, as shown in Table 5 (54).

5.6.1 Immunogenicity of Tdap (Boostrix®) in adults 19-64 years of age A randomised study was conducted in the US to assess the immunogenicity of Boostrix® (Tdap3) in adults 19–64 years of age. A total of 2284 healthy adults received either Adacel® (Tdap5) or Boostrix®. Seroprotective levels of antibodies to diphtheria and tetanus toxoids (≥0.1 IU/mL) were observed in >98% of subjects. Boostrix® was shown to be comparable to Adacel® vaccine in providing seroprotection against diphtheria and tetanus, and produced immune responses to pertussis antigens consistent with protection against disease (50).

12 Antigen Review–2012: Diphtheria Table 4. Seroprotection rate against Diphtheria for 10 years after vaccination and 1 month after receipt of a booster dose of dTap vaccine, with permission (54)

5.6.4 Decennial boosters Booster doses of Tdap vaccines are recommended every 10 years in many countries. A recent study evaluated the immunogenicity of a second dose of Tdap (Boostrix®) in 164 adults vaccinated with Tdap 10 years previously. Before the decennial booster, 89.4% were seroprotected (antibodies ≥0.1 IU/mL) for diphtheria. One month post-booster, all participants were seropositive against all vaccine antigens (55).

A Canadian study compared the immunogenicity of a first dose of Tdap with a repeat dose in adults who had received Tdap 10 years earlier. A total of 769 adults aged 20-72 years were enrolled. Post-vaccination antibody levels ≥0.1 IU/mL were achieved by 96.1% of the naïve group and 98.5% of the repeat-dose group for diphtheria (56).

5.6.5 Immunogenicity and safety of diphtheria-tetanus vaccine in adults The immunogenicity and safety of three doses of diphtheria-tetanus (Td) vaccine was studied in Korea, in 242 adults over 40 years old who had never received a diphtheria-tetanus-pertussis containing vaccination. Before vaccination, 33.9% participants showed antibody levels of diphtheria below protective level (<0.1 U/mL). Following the first dose of Td vaccine, 92.6% of subjects achieved protective antibody concentrations (≥0.1 U/mL) for diphtheria, which increased to 99.6% after the third dose (57).

5.6.6 Immunogenicity in patients with chronic and recurrent rhinosinusitis Responses to diphtheria and tetanus vaccine were measured in 25 adult patients (mean age 46 years) with chronic or recurrent sinusitis and in 30 healthy individuals (mean age 43 years). On average, the 25 patients with recurrent sinusitis had a 4.08-fold lower responses to diphtheria toxoid (and 2.2-fold lower responses to tetanus) than the controls. Nearly half (14 of the 25 patients) had antibody levels that did not reach the 95% normal distribution range of healthy controls after either diphtheria or tetanus vaccination. A significant proportion of patients with persisting symptoms of rhinosinusitis may have impaired responses to protein vaccines (58).

5.6.7 Pregnancy A study in the US matched 52 pregnant women attending the University of Louisville Obstetrical Clinic, who were given Tdap vaccine (Sanofi Pasteur), with 52 pregnant women not given the vaccine. The study demonstrated that pregnant women who receive Tdap during pregnancy had significantly higher antibody levels in their serum at delivery to all six antigens in the vaccine than the women who were not vaccinated during pregnancy, as seen in Table 2 (59).

Antigen Review–2012: Diphtheria 13 Table 5. Newborn antibody levels stratified whether mothers received Tdap (59)

5.6.8 Immunocompromised Antibody levels were assessed in 61 children after treatment with chemotherapy for acute lymphoblastic 5.6.8.1 Chemotherapy leukaemia. The patients had protective median antibody levels for diphtheria at diagnosis, but during A Korean study measured diphtheria, tetanus and maintenance and after cessation of chemotherapy, pertussis antibody titres after ‘antineoplastic’ antibody levels to diphtheria were significantly treatment in 146 children aged one to 17 years diminished. Proportion of the patients with complete with haematological conditions (leukaemias and protective antibody levels decreased from 80% at lymphomas). All the children had been fully immunised diagnosis to 11.1% after cessation of chemotherapy. for age prior to treatment. Protective serum antibody The authors concluded by recommending re- titres for diphtheria were decreased by 31.5% vaccination after 3 months of cessation of compared to age-matched healthy populations. The chemotherapy (62). study found no significant correlation for levels of serum antibody titres with the severity of the illness, treatment or age of the patient. The re-immunised 5.6.8.2 Post-transplant group displayed significantly higher protective Persistence of humoral immunity was evaluated in 82 immunity for diphtheria (72.9%) than those who haematopoietic stem cell transplant (HSCT) recipients were not re-immunised (46%, p = 0.001). The authors up to 12.5 years after post-transplant immunization stressed the importance of re-immunisation after against tetanus and diphtheria. Full post-transplant completion of treatment (60). revaccination resulted in long-term persistence of humoral immunity against tetanus and diphtheria in A Hong Kong based study assessed 56 children, HSCT recipients, for an average of 8.6 and 9.0 years, aged one-18 years old who were treated successfully respectively (63). for paediatric haematological malignancy and solid tumours, for evaluation of humoral immunity against vaccine-preventable diseases (hepatitis B, diphtheria, 5.6.8.3 Haemodialysis tetanus, pertussis, measles, mumps, and rubella) and In an Iranian cross-sectional study, consisting of 52 their responses to booster DTP vaccine. At baseline patients who were on haemodialysis and 52 age- (six months after stopping chemotherapy treatment), and sex-matched healthy individuals, the duration of 83.6% children had protective antibody levels against haemodialysis was found to have a significant effect diphtheria. After three doses of DTP, all vaccinees on anti-diphtheria immunity (64). demonstrated an increase in antibody titre which was significantly greater than the placebo group. The authors concluded that post-chemotherapy booster vaccinations produced a strong and sustained effect in humoral immunity against vaccine-preventable infectious diseases (61).

14 Antigen Review–2012: Diphtheria 5.7 Co-administration of The immunogenicity of 10-valent PHiD-CV vaccine co-administered with DTPa-HBV-IPV/Hib vaccine was diphtheria antigen with other assessed in 229 Taiwanese children. Infants were given three doses of the vaccines within the first six vaccines months of life. One month after the third vaccine dose, all participants were seroprotected against the 5.7.1 Co-administration in children diphtheria and the other antigens contained in the co-administered DTPa-HBV-IPV/Hib vaccine. Strong In the US, 487 children aged four-six years were immune responses were also observed against all 10 randomised to receive DTaP-IPV vaccine (Kinrix®, of the vaccine serotypes in PHiD-CV (69). GlaxoSmithKline) + MMR+V on day 0 or Kinrix + MMR on day 0, followed by after German (n=605) and Spanish (n=619) phase III trials, one month. One month post-vaccination, immune compared the administration of Infanrix™ -hexa responses in the group receiving DTaP-IPV+MMR+V on with PCV7 versus PCV13. Each participant received the same day were non-inferior to the group receiving one dose of either PCV13 or PCV7 and a dose of V one month after DTaP-IPV+MMR for responses to Infanrix™-hexa at 2, 3, and 4 months (infant series) DTaP-IPV antigens (65). and 11–12 months of age (toddler dose) in the German study and at 2, 4, 6, months (infant series) and 15 A study compared the safety and immunogenicity months (toddler dose of Infanrix®-IPV + Hib) in the of DTaP -IPV-Hib vaccine (followed by monovalent 5 Spanish study. There was no impact on the immune hepatitis B vaccine [HBV]) with DTaP -HBV-IPV/Hib 3 responses to concomitantly administered antigens in vaccine, both co-administered with PCV7, as a fourth- the Infanrix™-hexa or Infanrix™-IPV + Hib combination dose booster in toddlers aged 11-18 months who had a vaccines (70). primary series. Results showed that

DTaP5-IPV-Hib induced a marked immune response, Tdap-IPV has been evaluated for co-administration and had a similar safety and immunogenicity profile with ASO4-adjuvanted human papillomavirus (HPV) compared with DTaP3-HBV-IPV/Hib (66). vaccine in an open-label, randomised, multicentre study in Spain among healthy females aged 10–18 DTaP-IPV/Hib co-administered with PCV-7 was years randomised to three parallel groups: HPV x 3, assessed in a phase III trial. A group of 586 children Tdap-IPV x 1 or HPV x 3 plus Tdap-IPV co-administered were administered DTaP -IPV/Hib and PCV-7 at the 5 with the first dose. Seroprotection rates for anti-D were same visits at 2, 4, and 6months of age (Stage I) 100% in the Tdap-IPV group and 99.2% in the HPV + and a booster vaccination at 15–16 months of age Tdap-IPV group (71). (Stage II). In a staggered group, 581 children received

DTaP5-IPV/Hib on an identical schedule, but PVC7 was administered to participants ≥15 days after DTaP5-IPV/ 5.7.2 Concomitant administration in adults Hib, at approximately 3, 5, 7, and 16–17 months of The immunogenicity of Tdap co-administered with age. Seroprotection rates to diphtheria and tetanus was assessed in an open-label, toxoids were high in both groups (>99.7%), and thus randomised, controlled study conducted in 12 centres noninferiority was demonstrated. In a descriptive, non- in the United States with 1409 adults aged 19-64 hypothesis-driven comparison, anti-diphtheria GMT years. Participants were randomised to receive Tdap were higher in participants who received the staggered (Boostrix®) and trivalent inactivated influenza vaccine immunisation schedule (7.4 IU/mL compared with 4.1 (TIV), administered either concomitantly or one month IU/mL) (67). apart (TIV followed by Tdap). Seroprotection rates for diphtheria antigen were over 94.1% for both vaccine The immunogenicity of DTaP5-IPV-Hib vs DTaP3-IPV/Hib co-administered with PCV7 was assessed in France and regimens, and immune responses to these antigens Poland. A total of 600 participants received doses at in the concomitant group were non-inferior to those 2, 3, and 4 months (primary series) and a fourth-dose observed in the sequential group (72). booster at 12–18 months of age. Seroprotection rates Similar results were reported in a study of 1104 for DTaP -IPV-Hib were high, and noninferior to DTaP - 5 3 healthy adults >65 years old, who received single IPV/Hib for the primary series, for antigens common to doses of Tdap and seasonal influenza vaccine either both vaccines and PCV7 antigens. For diphtheria, after co-administered or given one month apart. The authors the primary series, ≥99.2% of infants in both groups concluded that Tdap was found to be immunogenic achieved the threshold of ≥0.01 IU/mL (68). in participants aged ≥65 years, with a safety profile comparable to US-licensed Td vaccine, and that

Antigen Review–2012: Diphtheria 15 Tdap and influenza vaccine may be co-administered 5.8 Summary of effectiveness without compromise to either the reactogenicity or immunogenicity profiles of the two vaccines (73). DTaP vaccines have been proven to be highly immunogenic, as primary and when used with lower Co-administration of MenACWY-CRM with Tdap was diphtheria antigen doses in booster vaccinations. assessed in a phase III, observer-blind, multicentre, When the primary series is given during the first few randomised, controlled study conducted in the US. The years of life, the antibody levels decrease over time trial randomised 1054 adolescents and adults, aged leading to a booster dose being required around the 11-25 years, to three study groups: receiving either ages of pre-school/early school and adolescence. MenACWY-CRM +Tdap; MenACWY-CRM + saline Adults who have received a primary course also placebo; or Tdap + saline placebo. The proportion of require a booster dose at some time in their subjects with seroprotective anti-diphtheria antibody adulthood. For people who have never had a primary concentrations (1.0 IU/ml) at one month post- series of vaccines as a child, three doses of the adult vaccination was significantly higher when Tdap was formulation vaccine have been found to induce an administered concomitantly with MenACWY-CRM than adequate immune response. The reduced-antigen- when Tdap was administered with saline placebo (94% content Tdap-IPV vaccine has been found to be non- versus 85%; LL of 95% CI >0%) and was associated inferior to full-strength DTPa-IPV vaccine with respect with higher geometric mean concentrations (GMC) of to immunogenicity when administered to pre-school anti-diphtheria antibodies (74). children.

Immunocompromised patients receiving chemotherapy have been found to have decreased antibodies to diphtheria but that these are restored with diphtheria vaccination post chemotherapy.

Co-administration studies suggest that Tdap vaccine is co-administered without compromise of either the reactogenicity or immunogenicity profiles with PCV7, PCV10, PCV13, HPV16/18, MenACWY and influenza vaccines.

16 Antigen Review–2012: Diphtheria 6. Age-specific issues – duration of immunity and booster doses 6.1 Objective The objective of this section is to consider the evidence for offering the diphtheria vaccine to different age groups, in particular older age groups.

6.2 Review Evidence from recent publications suggests that the currently accepted international vaccine schedules of a primary series of diphtheria containing vaccines for infants followed by a booster around preschool/early school and adolescent ages seems to confer sufficient immunity to protect young persons.

As reported in previous sections, antibodies are known to decrease with increasing age and, in the absence of circulating diphtheria disease, a booster dose in adulthood is recommended.

There were no recent publications on vaccine uptake in adults, coverage or factors affecting uptake.

The duration of protection from an adult booster dose of diphtheria containing vaccine is unknown as data is limited.

Antigen Review–2012: Diphtheria 17 7. Vaccine options 7.1 Objective The objectives for this section are to consider the different vaccine options available to NZ in terms of available diphtheria vaccines and schedules.

7.2 Currently available vaccines No diphtheria-only vaccine is available. The diphtheria vaccine is available as:

DTaP (Diphtheria, Tetanus, acellular Pertussis vaccine)

DTaP in combination with Haemophilus influenzae type b (Hib) vaccine

DTaP in combination with hepatitis B and inactivated polio vaccines

DTaP in combination with Hib, hepatitis B and inactivated polio vaccines

DT or Td (in combination with tetanus vaccine)

Tdap (Tetanus, reduced diphtheria, acellular Pertussis)

Vaccines containing the whole cell pertussis component (DTwP) are no longer recommended for use in New Zealand and so are not listed here.

Table 6 List of diphtheria-containing vaccines licensed for immunisation and distribution in the US (US FDA)

Product Name Trade Name Sponsor Diphtheria & Tetanus Toxoids Adsorbed No Trade Name Sanofi Pasteur, Inc Diphtheria & Tetanus Toxoids Adsorbed No Trade Name Sanofi Pasteur, Ltd Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed Tripedia Sanofi Pasteur, Inc Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed Infanrix GlaxoSmithKline Biologicals Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed Daptacel Sanofi Pasteur, Ltd Diphtheria & Tetanus Toxoids & Acellular Pertussis Vaccine Adsorbed, Pediarix GlaxoSmithKline Biologicals Hepatitis B (recombinant) and Inactivated Poliovirus Vaccine Combined Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed and KINRIX GlaxoSmithKline Biologicals Inactivated Poliovirus Vaccine Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Pentacel Sanofi Pasteur Limited Conjugate) Vaccine Tetanus & Diphtheria Toxoids Adsorbed for Adult Use No Trade Name MassBiologics Tetanus & Diphtheria Toxoids Adsorbed for Adult Use DECAVAC Sanofi Pasteur, Inc Sanofi Pasteur, Ltd Tetanus & Diphtheria Toxoids Adsorbed for Adult Use TENIVAC

Tetanus Toxoid No Trade Name Sanofi Pasteur, Inc Tetanus Toxoid Adsorbed No Trade Name Sanofi Pasteur, Inc Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Adacel Sanofi Pasteur, Ltd Vaccine, Adsorbed Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Boostrix GlaxoSmithKline Biologicals Vaccine, Adsorbed

18 Antigen Review–2012: Diphtheria 7.3 Vaccines on the horizon 7.4 Summary for vaccine A web search of major pharmaceutical companies (as options of Nov 2010) has been reported in an 11-page review. A summary of diphtheria-containing vaccines is below. Multivalent combination DTaP vaccines are now available for up to six different antigens (combined • Two fully liquid hexavalent vaccines combining Diphtheria-Tetanus-acellular Pertussis (DTPa), Hepatitis diphtheria (D), tetanus (T), acellular pertussis (aP), B, Poliovirus and Haemophilus influenzae type b inactivated polio (IPV), hepatitis B virus (HBV) and vaccine). As of early 2013, the Hib component is a Haemophilus influenzae type b (Hib) vaccines, in powder which requires reconstitution prior to injection. development. Two fully liquid hexavalent vaccines combining • Hexavalent and heptavalent vaccines based around diphtheria (D), tetanus (T), acellular pertussis (aP), three component aP, in phase II development. These inactivated polio (IPV), hepatitis B virus (HBV) and combine DTaP, IPV, Hib and meningococcal group Haemophilus influenzae type b (Hib) vaccines are C tetanus-conjugate vaccines, with or without HBV in development, as are hexavalent and heptavalent vaccine. vaccines based around three component aP.

• A broad variety of DTP combinations of varying Results from early trials with transcutaneous complexity produced by developing country vaccination patches are positive. manufacturers are also in development (75).

Novartis has developed a mercury-free formulation of the monovalent diphtheria toxoid vaccine (76).

A new diphtheria–tetanus toxoid (Td) vaccine, GC1107, has been developed by Green Cross Corporation, Korea. In an active comparator-controlled study, GC1107 has been reported to be non-inferior and well tolerated in Korean males aged >20 years (77).

Early trials with transcutaneous vaccination patches, using a hydrogel, for tetanus and diphtheria has been shown to induce an immune response without severe adverse reactions in humans (78).

Antigen Review–2012: Diphtheria 19 8. Options for scheduling 8.1 Objective 8.2 Outcomes This section reviews the evidence for different options A summary of diphtheria-containing immunisation for placement of diphtheria vaccine on the childhood schedules for the US, UK, Australia, NZ and European immunisation schedule and for special groups. countries are summarised. 8.3 Review Table 7. Immunisation schedules for Europe, USA, Australia and Canada as of 2012

Country D antigen – Lower concentration (d) antigen – Primary series & pre-school booster doses adolescent & adult booster doses European Union Austria DTaP at 2 months, 4 months, 6 months and 12 Td-IPV at 6 - 9 years - 14 months as DTaP-Hib-IPV-HepB TdaP at 13 - 16 years Belgium DTaP at 8 weeks, 12 weeks, 16 weeks and 15 Tdap at 14 - 16 years months recommended as the combined DTaP- HBV-IPV- Hib hexavalent vaccine, plus DTaP at 5 - 7 years recommended as the combined DTaP-IPV quadrivalent vaccine Bulgaria DTaP at 2 months, 3 months, 4 months, 16 Td at 12 years months and 6 years Td vaccination recommended at 25 years of age and every 10 years thereafter Croatia DTaP at 2 months, 4 months, 6 months, Td at 7 years, 14 years and 18 years 12-18 months as a pentavalent DTaP-IPV-Hib combination vaccine and DTaP at 3 years Cyprus DTaP at 2 months, 4 months, 6 months 15-18 Td at 14-16 years and Td, adult type- months and 4-6 years booster dose is then given every 10 years. Czech Republic First dose of DTaP-Hib-HepB-IPV given as No d booster on schedule hexavalent vaccine at 13 weeks of age, Second dose of DTaP-Hib-HepB-IPV given as hexavalent vaccine at least one month after the first dose within the first year of life, Third dose of DTaP-Hib-HepB-IPV given as hexavalent vaccine at least one month after the second dose within the first year of life, Fourth dose of DTaP-Hib-HepB-IPV given as hexavalent vaccine 6 months after the third dose and by the end of 18 months of age, 5th dose at 5 years of age. Denmark DTaP and IPV are given with Hib in one TdaP at 5 years (Tdap and IPV are given in injection at 3 months, 5 months and 12 one injection) months Estonia DTaP at 3 months, 4½ months, 6 months, 2 Td at 15-16 years. A seventh vaccine years and 6-7 years dose against diphtheria and tetanus is recommended to children at the age 17 years to children born in the period 1990- 1995 and previously vaccinated at age 12 years with sixth vaccine dose. A Td booster dose is recommended every 10 years starting from the age of 25 years Finland DTaP at 3 months, 5 months, 12 months and 4 tdap at 14-15 years. years. DTaP, IPV and Hib are given as a single . DTaP and IPV are given as a single tetravalent vaccine.

20 Antigen Review–2012: Diphtheria Country D antigen – Lower concentration (d) antigen – Primary series & pre-school booster doses adolescent & adult booster doses France DT at 2 months, 3 months, 4 months, 16-18 Td A booster dose of Td is recommended months, 6 years, 11-13 years. DTaP and IPV at 16-18 years of age, and later on, every are given as a single tetravalent vaccine. 10 years, together with IPV either as Td- Booster doses are mandatory before 18 Polio or as Tdap-Polio for the booster at months for diphtheria. 26-28 years of age for those who had not received a pertussis booster in the previous 10 years Germany DTaP at 2 months, 3 months, 4 months and Tdap at 5-6 years and 9-17 years 11-14 months. Greece DTaP at 2 months, 4 months, 6 months, 15-18 Td at 11-18 years and >18 years. months and 4-6 years Recommended after the age of 11-12 years if at least 5 years have passed since the last dose of DTaP/DTP. Thereafter, recommended every 10 years until the age of 65 years. Hungary DTaP at 2 months, 3 months, 4 months and Tdap at 11 years 18 months (DTaP, IPV and Hib are given as a combined vaccine) and 6 years (DTaP and IPV are given as a combined vaccine) Iceland DTaP at 3 months, 5 months and 18 months. TdaP at 4 years and 14 years. TdaP and IPV DTaP, IPV and Hib are given as a single are given as a single vaccine pentavalent vaccine Ireland DTaP at 2 months, 4 months and 6 months. Td at 11-14 years (DTaP, Hib, IPV and HepB are given as a single hexavalent vaccine) and 4-5 years Italy DTaP at 2-3 months, 4-5 months, 10-12 Tdap at 11-15 years and Td vaccination is months and 5-6 years recommended every ten years thereafter Latvia DTaP at 2 months, 4 months, 6 months, 12-15 Td at 14 years (Given as a combined Td-IPV months (given as a combined DTaP-Hib-IPV- vaccination) HepB vaccination) and 7 years (given as a combined DTaP-IPV vaccination). Lithuania DTaP at 2 months, 4 months, 6 months, 18 Td at 15-16 years months (Given as a combined DTaP-Hib-IPV vaccination) and 6-7 years Luxembourg DTaP at 2 months, 3 months, 4 months, 12 TdaP at 16 years. TdaP and IPV months (Given as a combined hexavalent recommended every 10 years after the age vaccine) and 5-6 years of 16 years Malta DTaP at 6 weeks, 3 months, 4 months. 18 Td at 16 years (Given as a combined Td- months (Given in as a combined DTaP- IPV- IPV) Hib) The Netherlands DTaP at 2 months, 3 months, 4 months, 11 Td at 9 years (IPV and Td are given in a months (DTaP, IPV and Hib are given in a combined vaccine) combined vaccine) and 4 years (DTaP and IPV are given in a combined vaccine) Norway DTaP at 3 months, 5 months and 12 months, Td at 11-12 years (For children born before plus at 7 years For children born in 1998 or 1998) or 15- 16 years (For children born in later 1998 or later) Poland DTwP at 6-8 weeks, 3-4 months, 5-6 months Td at 14 years and recommended at and 16-18 months the age of 19 years or the last year of education at school Portugal DTaP at 2 months, 4 months, 6 months Td at 10-13 years and Td is given every 10 (DTaP, IPV and Hib are given in one injection), years thereafter 18 months (DTaP and Hib are given in one injection) and 5-6 years (DTaP and IPV are given in one injection) Romania DTaP at 2 months, 4 months, 6 months, 12 Td at 14 years. Subsequent doses of Td are months and 4 years offered at 24 years of age and every 10 years thereafter

Antigen Review–2012: Diphtheria 21 Country D antigen – Lower concentration (d) antigen – Primary series & pre-school booster doses adolescent & adult booster doses Slovakia DTaP at 2 months, 4 months, 10 months Td at 12 years Given to adults as a booster (Given in a combined form as DTaP-IPV-Hib- dose every 15 years after the previous HepB hexavalent vaccine), 5 years (Given in vaccination a combined form as DTaP-IPV) and 12 years (Given in a combined form as Td-IPV trivalent vaccine) Slovenia DTaP at 3 months, 4-5 months, 6 months Tdap at 8 years and 12-24 months (Delivered as pentavalent vaccine DTaP-Hib-IPV) Spain DTaP at 2 months, 4 months, 6 months, 15-18 Td at 14-16 years months and 4-6 years Sweden DTaP at 3 months, 5 months, 12 months Tdap at 14-16 years Recommended to (DTaP, IPV and Hib are given as a children born in 2002 and later single pentavalent vaccine), 5-6 years (Recommended to children born in 2002 and later) and 10 years (Recommended to children born before 2002). Switzerland DTaP at 2 months, 4 months, 6 months, 15-24 Td at 11-15 years months (DTaP, IPV and Hib are usually given as a single pentavalent vaccine) and 4-7 years Turkey DTaP at 2 months, 4 months, 6 months, 18-24 Td at 13 years months and 6 years United Kingdom DTaP at 2 months, 3 months, 4 months (DTaP, Td at 13-18 years (Td and IPV are given as IPV and Hib are given as a combined vaccine) a combined vaccine) and 3 years 4 months – 5 years (DTaP (or TdaP) and IPV are given as a combined vaccine)

Australia DTaP-IPV-HepB-Hib at 2 months, 4 months, 6 Tdap at 10-15 years months and 4 years

USA DTaP at 2 months, 4 months, 6 months, 15-18 Td is a tetanus-diphtheria vaccine given to months and 4-6 years. (The fourth dose may adolescents and adults as a booster shot be administered as early as age 12 months, every 10 years provided at least 6 months have elapsed since the third dose) Canada DTaP at 2 months, 4 months, 6 months, 18 Td every 10 years; 1 dose should be given months and 4-6 years as Tdap if not previously given in adulthood

22 Antigen Review–2012: Diphtheria 8.4 Recent changes to vaccine 8.5 Summary of schedule recommendations options Since 2005, the US Advisory Committee on In developed countries, the primary series of Immunization Practices (ACIP) has recommended a immunisations usually consists of three doses of Tdap vaccine booster dose for all adolescents aged DPT vaccine, given at intervals of four or more 11-18 years (preferred at 11-12 years) and for those weeks, beginning at two or three months of age, adults aged 19 through 64 years who have not yet and reinforced by a fourth dose sometime in the received a dose. In October 2010, ACIP recommended second year of life. The policy of using booster doses that unvaccinated adults aged 65 years and older of vaccines containing diphtheria toxoid varies receive Tdap if in close contact with an infant. In considerably. July 2011, the Food and Drug Administration (FDA) approved expanding the age indication for Boostrix® (GlaxoSmithKline Biologicals) to aged 65 years and older. In February 2012, ACIP recommended Tdap for all adults aged 65 years and older (79).

The American Academy of Pediatrics and the Centres for Disease Control and Prevention reviewed the results from clinical trials and in 2011, the recommendation for caution regarding Tdap use within any interval after a tetanus- or diphtheria- containing toxoid product was removed. Tdap should be given when it is indicated and when no contraindication exists. A single dose of Tdap is recommended for children 7-10 years of age who were under-immunised with diphtheria-tetanus-acellular pertussis (DTaP) (80).

In the USA, the Society for Adolescent Medicine (SAM) supports the use of Tdap among all adolescents and young adults aged 10-25 years (81).

In 2011, the Centres for Disease Control and Prevention’s Advisory Committee on Immunization Practices approved recommendations for the use of Tdap vaccine for pregnant women (82).

In 2011, the Food and Drug Administration (FDA) approved an expanded age indication for the tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Tdap; Boostrix®, GlaxoSmithKline Biologicals) to include persons aged 65 years and older. Boostrix® was originally licensed in 2005 for 10- 18 year olds, and in 2008, this was expanded to 19-64 year olds.

Antigen Review–2012: Diphtheria 23 9. Implementation issues 9.1 Objective 9.3 Summary for The objective of this section is to consider the issues implementation issues around implementation. Diphtheria vaccines are well embedded in immunisation schedules for children and adolescents 9.2 Review around the world. Adult booster doses are generally recommended, but not always funded, and awareness There were no specific publications which addressed of adult booster vaccines may be low amongst the implementation issues. adult population.

Due to widespread vaccination programmes, Travellers may not be aware of the recommendations diphtheria is no longer present in many countries. for travellers to have a booster vaccine before Although no animal reservoir exists for C. diphtheriae, travelling the regions where diphtheria is endemic. an animal reservoir does exist for C. ulcerans and this organism may carry the corynebacteriophage that encodes diphtheria toxin. Therefore, continuing active immunisation with diphtheria toxoid is important in the on-going control of diphtheria worldwide.

24 Antigen Review–2012: Diphtheria 10. International policy and practice 10.1 Objective 10.3 Summary of international The objective to this section is to summarise policy and practice international practice with regard to the use of diphtheria vaccines. With respect to diphtheria, the NZ immunisation schedule is in line with international policy and practice. 10.2 Review Diphtheria containing vaccines are well established in the immunisation schedules of developed countries.

A summary of international practices around diphtheria immunisation is provided in Table 7.

Antigen Review–2012: Diphtheria 25 References

1. Tiwari TSP, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines 6th Edition. Elsevier; 2013. p. 154-66. 2. Vitke C, Wharton M. Diphtheria in the Former Soviet Union: Reemergence of a Pandemic Disease. Emerg Infect Dis [Internet]. 1998 [cited 2013 January];4(4). Epub December 1998. Available from: http://wwwnc.cdc. gov/eid/article/4/4/98-0404.htm 3. Rasmussen I, Wallace S, Mengshoel AT, Hoiby EA, Brandtzaeg P. Diphtheria outbreak in Norway: lessons learned. Scand J Infect Dis. 2011;43(11-12):986-9. 4. Rousseau C, Belchior E, Broche B, Badell E, Guiso N, Laharie I, et al. Diphtheria in the south of France, March 2011. Euro Surveill. 2011;16(19). 5. Fredlund H, Noren T, Lepp T, Morfeldt E, Henriques Normark B. A case of diphtheria in Sweden, October 2011. Euro Surveill. 2011;16(50):20038. 6. Lindhusen-Lindhe E, Dotevall L, Berglund M. Imported laryngeal and cutaneous diphtheria in tourists returning from western Africa to Sweden, March 2012. Euro Surveill. 2012;17(23). 7. Wagner KS, White JM, Crowcroft NS, De Martin S, Mann G, Efstratiou A. Diphtheria in the United Kingdom, 1986-2008: the increasing role of Corynebacterium ulcerans. Epidemiol Infect. 2010;138(11):1519-30. 8. Perkins S, Cordery R, Nixon G, Abrahams A, Andrews J, White J, et al. Investigations and control measures following a non-travel-associated case of toxigenic Cornyebacterium diphtheriae, London, United Kingdom, December 2009-January 2010. Euro Surveill. 2010;15(16):22. 9. Tiwari TSP. Chapter 3 Infectious Diseases Related To Travel: Diphtheria CDC Health Information for International Travel (the Yellow Book); 2013 [cited 2013 January]. Available from: http://wwwnc.cdc.gov/ travel/yellowbook/2014/chapter-3-infectious-diseases-related-to-travel/diphtheria 10. di Giovine P, Kafatos G, Nardone A, Andrews N, Olander RM, Alfarone G, et al. Comparative seroepidemiology of diphtheria in six European countries and Israel. Epidemiol Infect. 2013;141(1):132-42. 11. Ministry of Health 2012. Communicable Disease Control Manual 2012. Wellington: Ministry of Heath. 12. The Institute of Environmental Science and Research Ltd New Zealand Public Health Surveillance Report. 2009. 13. McGouran DCR, Ng SKF, Jones MR, Hingston D. A case of cutaneous diptheria in New Zealand. New Zealand Medical Journal. 2012;125(1350). 14. Johns TL, Hutter GE. New combination vaccines: DTaP-IPV (Kinrix) and DTaP-IPV/Hib (Pentacel). Ann Pharmacother. 2010;44(3):515-23. 15. Dhillon S. Spotlight on DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa). BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2010;24(5):299-302. 16. McCormack PL. Reduced-antigen, combined diphtheria, tetanus and acellular pertussis vaccine, adsorbed (Boostrix(R)): a review of its properties and use as a single-dose booster immunization. Drugs. 2012;72(13):1765-91. 17. Jackson LA, Yu O, Belongia EA, Hambidge SJ, Nelson J, Baxter R, et al. Frequency of medically attended adverse events following tetanus and diphtheria toxoid vaccine in adolescents and young adults: a Vaccine Safety Datalink study. BMC Infect Dis. 2009;9:165. 18. Yih WK, Nordin JD, Kulldorff M, Lewis E, Lieu TA, Shi P, et al. An assessment of the safety of adolescent and adult tetanus-diphtheria-acellular pertussis (Tdap) vaccine, using active surveillance for adverse events in the Vaccine Safety Datalink. Vaccine. 2009;27(32):4257-62. 19. Moro PL, Yue X, Lewis P, Haber P, Broder K. Adverse events after tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine administered to adults 65 years of age and older reported to the Vaccine Adverse Event Reporting System (VAERS), 2005-2010. Vaccine. 2011;29(50):9404-8. 20. Nordin JD, Yih WK, Kulldorff M, Weintraub E. Tdap and GBS letter. Vaccine. 2011;29(6):1122. 21. Zheteyeva YA, Moro PL, Tepper NK, Rasmussen SA, Barash FE, Revzina NV, et al. Adverse event reports after tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccines in pregnant women. Am J Obstet Gynecol. 2012;207(1):59 e1-7.

26 Antigen Review–2012: Diphtheria 22. Marques RC, Dorea JG, Bernardi JV. Thimerosal exposure (from tetanus-diphtheria vaccine) during pregnancy and neurodevelopment of breastfed infants at 6 months. Acta Paediatr. 2010;99(6):934-9. 23. Sandora TJ, Pfoh E, Lee GM. Adverse events after administration of tetanus-diphtheria-acellular pertussis vaccine to healthcare workers. Infect Control Hosp Epidemiol. 2009;30(4):389-91. 24. Kennerknecht N, Riffelmann M, Schmetz J, Wirsing von Konig CH. Comparison of commercially available immunoblot assays measuring IgG and IgA antibodies to antigens. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2011;30(12):1531-5. 25. Sun Y, Christensen J, Hviid A, Li J, Vedsted P, Olsen J, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type B. JAMA : the journal of the American Medical Association. 2012;307(8):823-31. 26. Klein NP, Hansen J, Lewis E, Lyon L, Nguyen B, Black S, et al. Post-marketing safety evaluation of a tetanus toxoid, reduced diphtheria toxoid and 3-component acellular pertussis vaccine administered to a cohort of adolescents in a United States health maintenance organization. Pediatr Infect Dis J. 2010;29(7):613-7. 27. Beytout J, Launay O, Guiso N, Fiquet A, Baudin M, Richard P, et al. Safety of Tdap-IPV given one month after Td-IPV booster in healthy young adults: a placebo-controlled trial. Hum Vaccin. 2009;5(5):315-21. 28. Wei SH, Chao YN, Huang SE, Lee TF, Chang LY. Adverse effects of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in 6- to 7-year-old children. Pediatr neonatol. 2011;52(1):38-41. 29. Galazka AM. Diphtheria The Immunological Basis for Immunization Series; 1993. Available from: http://www. who.ch/programmes/gpv/gEnglish/avail/gpvcatalog/catlog1.htm 30. Plotkin SA, Liese J, Madhi SA, Ortiz E. A DTaP-IPV//PRP approximately T vaccine (Pentaxim): a review of 16 years’ clinical experience. Expert Rev Vaccines. 2011;10(7):981-1005. 31. Kwak GY, Kwon HJ, Kim JH, Kim HM, Park JS, Ma SH, et al. The immunogenicity and safety of DTaP interchangeable immunization among Korean children. Vaccine. 2012;30(31):4644-7. 32. Langley JM, Halperin SA, Rubin E, White C, McNeil S, Mutch J, et al. Safety and immunogenicity of 2 mixed primary infant immunization schedules of pentavalent diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, and Haemophilus influenzae Type B vaccines at 2, 4, and 6 months of age: a randomized controlled trial. Pediatr Infect Dis J. 2012;31(2):189-92. 33. Dhillon S. DTPa-HBV-IPV/Hib Vaccine (Infanrix hexa): A Review of its Use as Primary and Booster Vaccination. Drugs. 2010;70(8):1021-58. 34. Lyseng-Williamson KA, Dhillon S. DTPa-HBV-IPV/Hib vaccine (Infanrix hexa): a guide to its use in infants. Paediatr Drugs. 2012;14(5):337-43. 35. Zepp F, Schmitt HJ, Cleerbout J, Verstraeten T, Schuerman L, Jacquet JM. Review of 8 years of experience with Infanrix hexa (DTPa-HBV-IPV/Hib hexavalent vaccine). Expert Rev Vaccines. 2009;8(6):663-78. 36. Kilpi TM, Silfverdal SA, Nilsson L, Syrjanen R, Belloni C, Desole M, et al. Immunogenicity and reactogenicity of two diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccines administered at 3, 5 and 11-12 months of age. Hum Vaccin. 2009;5(1):18-25. 37. Van Der Meeren O, Kuriyakose S, Kolhe D, Hardt K. Immunogenicity of Infanrix hexa administered at 3, 5 and 11 months of age. Vaccine. 2012;30(17):2710-4. 38. Shao PL, Lu CY, Hsieh YC, Bock HL, Huang LM, Taiwan Infanrix-069 Study G. Immunogenicity and reactogenicity of DTPa-IPV/Hib vaccine co-administered with hepatitis B vaccine for primary and booster vaccination of Taiwanese infants. Journal of the Formosan Medical Association = Taiwan yi zhi. 2011;110(6):415-22. 39. Paulke-Korinek M, Fischmeister G, Grac A, Rendi-Wagner P, Kundi M, Mohsenzadeh-Rabbani A, et al. Persistence of antibodies in 4-8 year old Austrian children after vaccination with hexavalent DTaP-HBV-IPV/ Hib and MMR vaccines. Vaccine. 2011;29(32):5130-6. 40. Li G, Zhang H, Zhou W, Ye Q, Li F, Wang H, et al. Safety and immunogenicity of a diphtheria, tetanus, acellular pertussis and Haemophilus influenzae Type b combination vaccine compared with separate administration of licensed equivalent vaccines in Chinese infants and toddlers for primary and booster immunization. Vaccine. 2010;28(25):4215-23.

Antigen Review–2012: Diphtheria 27 41. Chotpitayasunondh T, Thisyakorn U, Pancharoen C, Chuenkitmongkol S, Ortiz E. Antibody persistence after primary and booster doses of a pentavalent vaccine against diphtheria, tetanus, acellular pertussis, inactivated poliovirus, haemophilus influenzae type B vaccine among Thai children at 18-19 months of age. Southeast Asian J Trop Med Public Health. 2012;43(2):442-54. 42. Pancharoen C, Chotpitayasunondh T, Chuenkitmongkol S, Ortiz E. Long-Term Immunogenicity Assessment of a Dtap-Ipv//Prp-T Vaccine Given at 2, 4, 6 and 18-19 Months of Age, and Immunogenicity and Safety of a Dtap-Ipv Vaccine Given as a Booster Dose at 4 to 6 Years of Age in Thai Children. Se Asian J Trop Med. 2012;43(3):687-98. 43. Dutta AK, Verghese VP, Pemde H, Mathew LG, Ortiz E. Immunogenicity and safety of a DTaP-IPV//PRP~T vaccine (Pentaxim) booster dose during the second year of life in Indian children primed with the same vaccine. Indian Pediatr. 2012;49(10):793-8. 44. Gajdos V, Soubeyrand B, Vidor E, Richard P, Boyer J, Sadorge C, et al. Immunogenicity and safety of combined adsorbed low-dose diphtheria, tetanus and inactivated poliovirus vaccine (REVAXIS ((R))) versus combined diphtheria, tetanus and inactivated poliovirus vaccine (DT Polio ((R))) given as a booster dose at 6 years of age. Hum Vaccin. 2011;7(5):549-56. 45. Ferrera G, Cuccia M, Mereu G, Icardi G, Bona G, Esposito S, et al. Booster vaccination of pre-school children with reduced-antigen-content diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine co- administered with measles-mumps-rubella-varicella vaccine: a randomized, controlled trial in children primed according to a 2 + 1 schedule in infancy. Hum Vaccin Immunother. 2012;8(3):355-62. 46. Bitragunta S, Murhekar MV, Chakravarti A, Verma V, Namjoshi GS, Parekh SS, et al. Safety and immunogenicity of single dose of tetanus-diphtheria (Td) vaccine among non/partially immune children against diphtheria and/or tetanus, Hyderabad, India, 2007. Vaccine. 2010;28(37):5934-8. 47. Lee SY, Kwak GY, Nam CH, Kim JH, Hur JK, Lee KY, et al. Immunogenicity and safety of diphtheria-tetanus vaccine in pre-adolescent and adolescent South Koreans. Vaccine. 2009;27(24):3209-12. 48. Halperin SA, McNeil S, Langley J, Blatter M, Dionne M, Embree J, et al. Tolerability and antibody response in adolescents and adults revaccinated with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed (Tdap) 4-5 years after a previous dose. Vaccine. 2011;29(46):8459-65. 49. Knuf M, Vetter V, Celzo F, Ramakrishnan G, Van Der Meeren O, Jacquet JM. Repeated administration of a reduced-antigen-content diphtheria-tetanus-acellular pertussis and poliomyelitis vaccine (dTpa-IPV; Boostrix IPV). Hum Vaccin. 2010;6(7):554-61. 50. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19-64 years of age. Vaccine. 2009;27(5):765-72. 51. Larnaudie S, Guiso N, Baptiste C, Desaint C, Desforges L, Lebon P, et al. Humoral immunity of dTap-IPV vaccine (REPEVAX(R)) administered one month after dT-IPV vaccine (REVAXIS(R)) in adults with unknown vaccination history. Hum Vaccin. 2010;6(10):829-34. 52. Weston W, Messier M, Friedland LR, Wu X, Howe B. Persistence of antibodies 3 years after booster vaccination of adults with combined acellular pertussis, diphtheria and tetanus toxoids vaccine. Vaccine. 2011;29(47):8483-6. 53. McIntyre PB, Burgess MA, Egan A, Schuerman L, Hoet B. Booster vaccination of adults with reduced-antigen- content diphtheria, Tetanus and pertussis vaccine: immunogenicity 5 years post-vaccination. Vaccine. 2009;27(7):1062-6. 54. Mertsola J, Van Der Meeren O, He Q, Linko-Parvinen A, Ramakrishnan G, Mannermaa L, et al. Decennial administration of a reduced antigen content diphtheria and tetanus toxoids and acellular pertussis vaccine in young adults. Clin Infect Dis. 2010;51(6):656-62. 55. Booy R, Van der Meeren O, Ng SP, Celzo F, Ramakrishnan G, Jacquet JM. A decennial booster dose of reduced antigen content diphtheria, tetanus, acellular pertussis vaccine (Boostrix) is immunogenic and well tolerated in adults. Vaccine. 2010;29(1):45-50. 56. Halperin SA, Scheifele D, De Serres G, Noya F, Meekison W, Zickler P, et al. Immune responses in adults to revaccination with a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine 10 years after a previous dose. Vaccine. 2012;30(5):974-82.

28 Antigen Review–2012: Diphtheria 57. Choi JH, Choo EJ, Huh A, Choi SM, Eom JS, Lee JS, et al. Immunogenicity and safety of diphtheria-tetanus vaccine in adults. J Korean Med Sci. 2010;25(12):1727-32. 58. Tahkokallio O, Koskinen A, Kentala E, Olander RM, Mattila PS. Antibody responses to tetanus and diphtheria vaccine in chronic and recurrent rhinosinusitis. Rhinology. 2011;49(1):90-4. 59. Gall SA, Myers J, Pichichero M. Maternal immunization with tetanus-diphtheria-pertussis vaccine: effect on maternal and neonatal serum antibody levels. Am J Obstet Gynecol. 2011;204(4):334 e1-5. 60. Kwon HJ, Lee JW, Chung NG, Cho B, Kim HK, Kang JH. Assessment of serologic immunity to diphtheria- tetanus-pertussis after treatment of Korean pediatric hematology and oncology patients. J Korean Med Sci. 2012;27(1):78-83. 61. Cheng FW, Leung TF, Chan PK, Lee V, Shing MK, Chik KW, et al. Humoral immune response after post- chemotherapy booster diphtheria-tetanus-pertussis vaccine in pediatric oncology patients. Pediatr Blood Cancer. 2009;52(2):248-53. 62. Zengin E, Sarper N. Humoral immunity to diphtheria, tetanus, measles, and hemophilus influenzae type b in children with acute lymphoblastic leukemia and response to re-vaccination. Pediatr Blood Cancer. 2009;53(6):967-72. 63. Skovrankova J, Petras M. Persistence of humoral immunity to tetanus and diphtheria in hematopoietic stem cell transplant recipients after post-transplant immunization. Pediatr Blood Cancer. 2012;59(5):908-13. 64. Jahromi AS, Pourahmd M, Azhdari S, Manshoori G, Madani A, Moosavy SH. Immunity to diphtheria in haemodialysis patients. American Journal of Infectious Diseases. 2011;7(1):20-3. 65. Klein NP, Weston WM, Kuriyakose S, Kolhe D, Howe B, Friedland LR, et al. An open-label, randomized, multi-center study of the immunogenicity and safety of DTaP-IPV (Kinrix) co-administered with MMR vaccine with or without varicella vaccine in healthy pre-school age children. Vaccine. 2012;30(3):668-74. 66. Berner R, Boisnard F, Thomas S, Mwawasi G, Reynolds D. Safety and immunogenicity of fully liquid DTaP(5)- IPV-Hib pediatric combination vaccine (Pediacel(R)) compared to DTaP(3)-HBV-IPV/Hib (Infanrix(R) Hexa) when coadministered with heptavalent pneumococcal conjugate vaccine (PCV7) as a booster at 11-18 months of age: a phase III, modified double-blind, randomized, controlled, multicenter study. Vaccine. 2012;30(35):5270-7. 67. Bernstein HH, Noriega F, Group MAPS. Immunogenicity and safety of a combined diphtheria, tetanus, 5-component acellular pertussis, inactivated poliomyelitis, Haemophilus type b conjugate vaccine when administered concurrently with a pneumococcal conjugate vaccine: a randomized, open-label, phase 3 study. Vaccine. 2011;29(11):2212-21. 68. Grimprel E, Wysocki J, Boisnard F, Thomas S, Mwawasi G, Reynolds D. Immunogenicity and safety of fully liquid DTaP(5)-IPV-Hib compared with DTaP(3)-IPV/Hib when both coadministered with a heptavalent pneumococcal conjugate vaccine (PCV7) at 2, 3, 4, and 12 to 18 months of age: a phase III, single-blind, randomised, controlled, multicentre study. Vaccine. 2011;29(43):7370-8. 69. Lin TY, Lu CY, Chang LY, Chiu CH, Huang YC, Bock HL, et al. Immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) co- administered with routine childhood vaccines in Taiwan. Journal of the Formosan Medical Association = Taiwan yi zhi. 2012;111(9):495-503. 70. Gimenez-Sanchez F, Kieninger DM, Kueper K, Martinon-Torres F, Bernaola E, Diez-Domingo J, et al. Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine. Vaccine. 2011;29(35):6042-8. 71. Garcia-Sicilia J, Schwarz TF, Carmona A, Peters K, Malkin JE, Tran PM, et al. Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical coadministered with combined diphtheria-tetanus-acellular pertussis-inactivated poliovirus vaccine to girls and young women. J Adolesc Health. 2010;46(2):142-51. 72. Weston WM, Chandrashekar V, Friedland LR, Howe B. Safety and immunogenicity of a tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine when co-administered with influenza vaccine in adults. Hum Vaccin. 2009;5(12):858-66.

Antigen Review–2012: Diphtheria 29 73. Weston WM, Friedland LR, Wu X, Howe B. Vaccination of adults 65 years of age and older with tetanus toxoid, reduced diphtheria toxoid and acellular pertussis vaccine (Boostrix (R)): results of two randomized trials. Vaccine. 2012;30(9):1721-8. 74. Gasparini R, Conversano M, Bona G, Gabutti G, Anemona A, Dull PM, et al. Randomized trial on the safety, tolerability, and immunogenicity of MenACWY-CRM, an investigational quadrivalent meningococcal glycoconjugate vaccine, administered concomitantly with a combined tetanus, reduced diphtheria, and acellular pertussis vaccine in adolescents and young adults. Clin Vaccine Immunol. 2010;17(4):537-44. 75. Kitchin NR. Review of diphtheria, tetanus and pertussis vaccines in clinical development. Expert Rev Vaccines. 2011;10(5):605-15. 76. Broker M. Adsorbed monovalent diphtheria vaccine. Travel Med Infect Dis. 2010;8(4):272. 77. Lee S, Park WB, Shin K-H, Ahn DH, Yoon SH, Cho J-Y, et al. Immunogenicity and safety of a single intramuscular dose of a diphtheria-tetanus toxoid (Td) vaccine (GC1107) in Korean adults. Vaccine. 2011;29(44):7638-43. 78. Hirobe S, Matsuo K, Quan YS, Kamiyama F, Morito H, Asada H, et al. Clinical study of transcutaneous vaccination using a hydrogel patch for tetanus and diphtheria. Vaccine. 2012;30(10):1847-54. 79. Centers for Disease CaP. Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine in adults aged 65 years and older - Advisory Committee on Immunization Practices (ACIP), 2012. MMWR Morb Mortal Wkly Rep. 2012;61(25):468-70. 80. Centers for Disease CaP, American Academy of Pediatrics Committee on Infectious Diseases. Additional recommendations for use of tetanus toxoid, reduced-content diphtheria toxoid, and acellular pertussis vaccine (Tdap). Pediatrics. 2011;128(4):809-12. 81. Middleman AB, Bruner A. Tetanus, diphtheria, and acellular pertussis vaccine: a position statement of the Society for Adolescent Medicine. J Adolesc Health. 2009;45(3):316-7. 82. Committee on Obstetric P. ACOG Committee Opinion No. 521: Update on immunization and pregnancy: tetanus, diphtheria, and pertussis vaccination. Obstetrics and gynecology. 2012;119(3):690-1.

30 Antigen Review–2012: Diphtheria Antigen Review–2012: Diphtheria 31