Rotavirus Epidemiology and Monovalent Rotavirus Vaccine Effectiveness in Australia: 2010–2017 Julia E. Maguire, BSc, MSci(Epi), MPhil(AppEpi),a,b Keira Glasgow, BIntSt (Hons), MIPH,c Kathryn Glass, PhD,b Susie Roczo-Farkas, BBSc (Hons),d Julie E. Bines, MBBS, MD,d,e,f Vicky Sheppeard, MBBS, MPH (Hons), FAFPHM,c Kristine Macartney, MBBS, BMedSci, MD,a,g Helen E. Quinn, MAppEpi, PhDa,g

BACKGROUND: Rotavirus vaccine has been funded for infants under the Australian National abstract Immunisation Program since 2007, with Rotarix vaccine used in New South Wales, Australia, from that time. In 2017, New South Wales experienced a large outbreak of rotavirus gastroenteritis. We examined epidemiology, genotypic profiles, and vaccine effectiveness (VE) among cases. METHODS: Laboratory-confirmed cases of rotavirus notified in New South Wales between January 1, 2010 and December 31, 2017 were analyzed. VE was estimated in children via a case-control analysis. Specimens from a sample of hospitalized case patients were genotyped and analyzed. RESULTS: In 2017, 2319 rotavirus cases were reported, representing a 3.1-fold increase on the 2016 notification rate. The highest rate was among children aged ,2 years. For notified cases in 2017, 2-dose VE estimates were 88.4%, 83.7%, and 78.7% in those aged 6 to 11 months, 1 to 3 years, and 4 to 9 years, respectively. VE was significantly reduced from 89.5% within 1 year of vaccination to 77.0% at 5 to 10 years postvaccination. Equinelike G3P[8] (48%) and G8P[8] (23%) were identified as the most common genotypes in case patients aged $6 months. CONCLUSIONS: Rotarix is highly effective at preventing laboratory-confirmed rotavirus in Australia, especially in infants aged 6 to 11 months. Reduced VE in older age groups and over time suggests waning protection, possibly related to the absence of subclinical immune boosting from continuously circulating virus. G8 genotypes have not been common in Australia, and their emergence, along with equinelike G3P[8], may be related to vaccine- induced selective pressure; however, further strain-specific VE studies are needed.

’ a b WHAT S KNOWN ON THIS SUBJECT: There are limited National Centre for Immunisation Research and Surveillance, Westmead, New South Wales, Australia; National monovalent rotavirus vaccine effectiveness estimates in Centre for Epidemiology and Public Health, College of Health and Medicine, Australian National University, developed countries, including Australia, that include an Canberra, Australian Capital Territory, Australia; cCommunicable Diseases Branch, Health Protection New South extended follow-up period and accompanying genotypic Wales, Sydney, New South Wales, Australia; dEnteric Diseases Group, Murdoch Children’s Research Institute, analysis. Parkville, Victoria, Australia; eDepartment of Paediatrics, The University of Melbourne, Parkville, Victoria, WHAT THIS STUDY ADDS: High 1- and 2-dose monovalent Australia; fDepartment of Gastroenterology and Clinical Nutrition, Royal Children’s Hospital, Parkville, Victoria, g rotavirus vaccine effectiveness was observed in New Australia; and Discipline of Child and Adolescent Health, The University of Sydney Children’s Hospital Westmead South Wales, Australia, but was not adequate to prevent Clinical School, Westmead, New South Wales, Australia an outbreak due to emerging strains. Assessing genotypic variation is important to understand the complexities of Ms Maguire designed the study, conducted analyses, and drafted the initial manuscript; Dr Quinn rotavirus epidemiology. designed the study and performed initial data analysis; Dr Glass assisted with the design of the study; Ms Glasgow, Dr Sheppeard, and Dr Macartney provided input into aspects of the study during its To cite: Maguire JE, Glasgow K, Glass K, et al. Rotavirus development and conduct and critically reviewed the manuscript for important intellectual content; Ms Epidemiology and Monovalent Rotavirus Vaccine Roczo-Farkas and Dr Bines collected and analyzed the biological specimens and data and conducted Effectiveness in Australia: 2010–2017. Pediatrics. 2019; fi the initial analyses; and all authors conceptualized the study, reviewed, revised, and approved the nal 144(4):e20191024 manuscript as submitted, and agree to be accountable for all aspects of the work.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 4, October 2019:e20191024 ARTICLE Rotavirus is the most common causal the 2 previous Australian rotavirus Australian Rotavirus Surveillance agent of severe dehydrating vaccine effectiveness (VE) studies Program at the Murdoch Children’s 18 gastroenteritis in unvaccinated young have only included specific Research Institute. All available children, and infection is more likely populations, that of indigenous samples positive for rotavirus with to result in hospitalization compared children in the Northern Territory adequate volume are processed and to other causes of gastroenteritis in showing moderate effectiveness of genotyped by RT-PCR. Results from Australia.1,2 The virus, of the RV1 and children in the state of a deidentified sample of fecal Reoviridae family, is characterized by Queensland demonstrating high RV5 specimens collected in New South G and P genotypes. The most common VE.6,11 Wales from January 1, 2017, through December 31, 2017, were analyzed. genotypes before vaccine In 2017, the most populous Information regarding contributing introduction in Australia were G1P Australian state of New South Wales laboratories, specimen collection, and [8], G2P[4], and G3P[8]. However, in experienced a large rise in rotavirus the vaccine era, newer genotypes 12,13 analysis have been described notifications in young children. 18 elsewhere by Roczo-Farkas et al. such as equinelike G3P[8] and G12P To better understand RV1 [8] have emerged, although G2P[4] effectiveness over time and in the remains a main genotype that has context of this outbreak, we aimed to Vaccine Coverage and Vaccination 3 Status caused multiple outbreaks. measure VE from 2010 to 2017, to Rotavirus vaccines RotaTeq (RV5) describe the epidemiology of The Australian Immunisation Register (Merck and Co, Kenilworth, NJ) and rotavirus notifications, and to (AIR), a population-level national Rotarix (RV1) (GlaxoSmithKline, characterize the circulating rotavirus register, was used to identify the Brentford, United Kingdom) were genotypes in the 2017 outbreak. rotavirus immunization status of added to the Australian National children residing in New South 19 Immunisation Program as funded METHODS Wales. The vaccination status of routine vaccinations for infants in patients notified as having rotavirus July 2007.1 In the first decade of the Data Sources was obtained from the case report in fi program, states and territories Setting the New South Wales Noti able exclusively used 1 of the 2 respective Conditions Information Management This study was set in New South vaccines; however, as of July 2017, all System and the AIR, and the Wales, Australia (7.48 million total states and territories only offer RV1 vaccination status of controls selected population in 2016; annual birth under the National Immunisation for the case-control VE analysis (see cohort of ∼96 000), and involved all Program.2,4 In New South Wales, RV1 below) was obtained from the AIR. subjects residing in New South Wales has been used since 2007. RV1 is The AIR contains data on all children over the study period.14,15 a monovalent attenuated human G1P in Australia with a Medicare number [8] strain, which has been shown to Notification Data (the universal health insurance protect against severe rotavirus scheme) and data on any child Notifications of all laboratory- caused by G1 to G4, G9, P[4], P[6], vaccinated in Australia, even if the confirmed rotavirus between January and P[8] genotypes, as well as child is a temporary visitor. Any child 1, 2010 (when notification provides heterotypic protection who did not have rotavirus – commenced), and December 31, against other genotypes.3,5 7 vaccination status recorded on the 2017, as reported under legislation to AIR was classified as unvaccinated. Clinical trial data for RV1 have the New South Wales Notifiable fi ∼ revealed vaccine ef cacy of 96% for Conditions Information Management Statistical Analysis severe rotavirus infection in Europe System were included.16,17 and 83% to 90% in Finland and South Laboratory-definitive evidence Population-Based Analysis American countries.8 Three years includes the detection of rotavirus Notification rates were calculated by postimplementation of rotavirus antigen in stool samples by enzyme using the midyear estimated resident vaccine in Australia, hospitalizations immunoassay, latex agglutination, or populations released by the due to rotavirus in children aged reverse transcriptase polymerase Australian Bureau of Statistics for 17 ,5 years had declined by 71% chain reaction (RT-PCR). 2010–2016 and population 20 nationally.2,9 National notification projections for 2017. Incidence rate data of laboratory-notified rotavirus Genotyping Data ratios and 95% confidence intervals have revealed persistently low levels Genotype analysis of samples positive (CIs) were presented for comparison of rotavirus activity over many years, for rotavirus from hospitalized of notification rates by age, sex, and albeit with seasonal variations in patients at select sites around notification year. Genotyping data reported case numbers.10 Authors of Australia is performed as part of the were analyzed by age, sex, and G and

Downloaded from www.aappublications.org/news by guest on September 28, 2021 2 MAGUIRE et al 24 P type and defined as either assuming 2-dose receipt. The Health and the Australian vaccinelike or wild-type strain. inclusion of case patients in the VE Government Department of Health analyses is described in Fig 1. were granted. VE Estimates VE estimates and 95% CIs were Case patients (rotavirus notifications calculated by using a matched case- RESULTS from the New South Wales Notifiable control analysis, using the formula VE Conditions Information Management =12 odds ratio (OR) 3 100%. Study Population System) were individually matched to Conditional logistic regression There were 9517 rotavirus controls (deidentified from the AIR) models were used to determine the notifications during the 8-year study by date of birth 61 day. For each OR for the VE calculations. Analyses period. The median age was 5 years, identified case patient, up to 10 included stratification by age group at with the range being 0 to 103 years; controls were randomly selected. This notification (aged 6–11 months, 1–3 63.2% were ,10 years old and method has been used previously and years, and 4–9 years) and year of 26.3% were ,2 years old. There were allows for likely exclusion of the case notification. ORs were adjusted for 4758 (50.0%) boys and men, and of patient from being randomly selected sex if the addition of this changed the all with a recorded Aboriginal and as a control by virtue of a similar, but point estimate by .5%. For the time Torres Strait Islander status; 176 – not the same, date of birth.6,21 23 since vaccination model, 5 defined (7.6%) identified as Aboriginal or time periods after dose 2 (,1, 1–,2, Torres Strait Islander. There were no Children were included in the VE 2–,3, 3–,5, and 5–,10 years) were deaths recorded as attributed to analyses if they were eligible for at analyzed, with children who were rotavirus in this notification data set. least 1 dose of the funded rotavirus unvaccinated set as the reference vaccine (ie, children born between Fifty percent of case patients category. The analyses were January 1, 2008, the first full calendar (n = 4752) were not eligible for conducted by using Stata version 14.0 year of National Immunisation vaccination because of their age. Of (Stata Corp, College Station, TX). Program–funded rotavirus vaccine, the vaccine-eligible individuals, 496 and June 31, 2017) and were aged The study was approved by the case patients (10.4%) reported $6 months at the time of notification. Australian National University receiving 1 dose of rotavirus vaccine, This age cutoff for the analysis was Human Research Ethics Committee. 2814 case patients (59.1%) reported applied to avoid inclusion of young Approvals for access to data held by receiving $2 doses of vaccine before infants notified as having rotavirus the New South Wales Ministry of notification, and 1455 case patients disease but who had vaccine virus shedding (see genotypic analysis and results below). Rotavirus became notifiable in December 2009; thus, notifications from January 1, 2010, were included as the first full calendar year of notifications. A dose was considered valid if the rotavirus infection notification date was .14 days after receipt of the rotavirus vaccine to allow for time to develop a protective immune response. A dose of rotavirus vaccine was considered invalid if dose 1 was administered at ,5 weeks of age, if dose 2 was administered ,4 weeks after dose 1, or when the child was $52 weeks old. These children, and any who received a dose of RV5, for example during residence in another jurisdiction, were excluded from the analyses. If a child had a vaccine dose recorded as dose 2 on the register, but a first dose was not recorded, the FIGURE 1 “prior dose” assumption was made, Flowchart for inclusion in VE analyses.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 4, October 2019 3 (30.5%) did not have the vaccine recorded in the AIR. Secular Trends In 2017, 2319 cases of rotavirus were reported, representing a rate of 29.7 per 100 000 population (Fig 2). This was significantly higher than the 2016 notification rate of 9.7 per 100 000 (incidence rate ratio: 3.1; 95% CI: 2.8 to 3.3). Before this, annual rotavirus notification rates also fluctuated with increases in 2012 and 2015. The number of rotavirus notifications reported in 2017 was 1.3 times (95% CI: 1.2 to 1.3) the previous highest recorded annual number of notifications in 2012. FIGURE 3 Rotavirus notification rates by age group and year, New South Wales (2010–2017). Age and Sex Distribution There was no significant difference in the rotavirus notification rate proportion of case patients aged $10 were successfully genotyped, 186 between males and females (P = .36). than ,10 years in 2017 compared to (44.3%) were children aged ,5 years The highest notification rates in 2017 2010 (P , .001) (Fig 4). The median and 200 (55.7%) were individuals were among children aged 1 year, age of case patients increased from aged $5 years. The RV1 vaccine followed closely by infants aged 3.9 years in 2010 to 7.1 years strain G1P[8] was identified in 27 of ,1 year (Fig 3). Rates decreased with in 2017. 38 (71%) infants aged #6 months. In age but rose again in the elderly aged other age groups (except those aged $80 years. In 2017, the notification Genotypic Variation $80 years), equinelike G3P[8] was rate for all age groups was at least In 2017, 430 of the 2319 notified the dominant strain, and G8P[8] was 1.4 times the rate in 2010–2016. The specimens were sent to Murdoch the second most common (Fig 5). The age of case patients increased over Children’s Research Institute for G8P[8] strain predominated in the time, with a significantly higher genotypic testing. Of the 386 that elderly aged $80 years (41.5%).

VE There were 3587 children with notified rotavirus born on or after January 1, 2008 (37.7% of all notified cases), excluding children aged ,6 months. As shown in Fig 1, of those included in the VE analysis, 214 children received 1 RV1 dose, 2407 received $2 RV1 doses, and 966 had no reported RV1 doses received. The median age at rotavirus notification was 25 months (range: 6 months–9 years). There is some evidence that boys and men were more likely to have a notification for rotavirus (P = .008); however, for those children included in the VE model, sex did not change the estimate by FIGURE 2 .5% and hence was not included in Rotavirus notifications and notification rate by year, all ages, New South Wales (2010–2017). the final VE model.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 4 MAGUIRE et al years, with the exception of 2010, which had the highest 2-dose VE of 89.7% (95% CI: 86.5% to 92.0%) for the cohort of children aged 6 months to 2 years (Table 1, Supplemental Table 3). The 2-dose VE estimates were highest among infants aged 6 to 11 months in all study years, except in 2011 when there were low case numbers. The VE point estimates for children aged 6 months to 3 years were higher than for children aged 4 to 9 years; however, there was substantial overlap in CIs.

VE by Time Since Last Dose As assessed in 2017, 2-dose VE estimates declined with time since vaccination from 89.5% within 1 year of vaccination to a significantly lower VE 5 to ,10 years after vaccination of FIGURE 4 77.0% (Table 2). Percentage of rotavirus notifications in age group by year, New South Wales (2010–2017). DISCUSSION The overall VE for the years was significantly higher at 83.0% and 2010–2017 was estimated as 68.0% 82.5% for 1 dose and 2 doses, The 2017 rotavirus outbreak in New and 73.7% for 1 dose and 2 doses, respectively. The 2017 VE was higher South Wales, Australia, resulted in an respectively. In 2017 alone, the VE than the VE in all previous individual increase in notification rates across all age groups. The majority of cases were in children aged ,4 years, particularly those aged 1 to 2 years. As seen in this outbreak, young children are well recognized as the primary population group affected by 25 rotavirus. However, our study also revealed that the median age of rotavirus cases has increased in Australia over the last 8 years from 3.9 years in 2010 to 7.1 years in 2017. Adults and older children born before the availability of vaccination in Australia are unimmunized and may have been less likely to have repeated subclinical infections because of reductions in virus circulation overall, resulting in less 26 immune boosting. The increasing proportion of cases among adults, as well as increased notifications in 2017, may be influenced by vaccine introduction and also by a number of FIGURE 5 other factors such as increased Percentage of rotavirus genotype by age group, New South Wales (2017 sample). recognition of rotavirus disease in

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 4, October 2019 5 TABLE 1 Estimated 1-Dose and 2-Dose VE Estimates Against Notified Rotavirus in Children Aged 6 Months to 9 Years in 2017 Compared to the 2010–2016 Period, New South Wales Cohort Case Patients Controls VE (95% CI) 2017 All ages (6 mo–9 y), n 1031 10 300 Unvaccinated, n (%) 295 (28.6) 697 (6.8) Reference 1-dose vaccinated, n (%) 44 (4.3) 593 (5.8) 83.0 (76.2 to 87.9) 2-dose vaccinated, n (%) 692 (67.1) 9010 (87.5) 82.5 (79.4 to 85.1) Aged 6–11 mo, n 91 900 Unvaccinated, n (%) 26 (28.6) 44 (4.9) Reference 1-dose vaccinated, n (%) 5 (5.5) 40 (4.4) 80.3 (43.1 to 93.2) 2-dose vaccinated, n (%) 60 (65.9) 816 (90.7) 88.4 (79.2 to 93.5) Aged 1–3y,n 625 6254 Unvaccinated, n (%) 161 (26.9) 331 (5.3) Reference 1-dose vaccinated, n (%) 26 (4.2) 360 (5.8) 84.9 (76.6 to 90.3) 2-dose vaccinated, n (%) 438 (70.1) 5563 (89.0) 83.7 (79.8 to 86.8) Aged 4–9y,n 315 3146 Unvaccinated, n (%) 108 (34.3) 322 (10.2) Reference 1-dose vaccinated, n (%) 13 (4.1) 193 (6.1) 80.7 (64.5 to 89.5) 2-dose vaccinated, n (%) 194 (61.6) 2631 (83.6) 78.7 (72.1 to 83.7) 2010–2016 All ages (6 mo–8 y), n 2556 25 529 Unvaccinated, n (%) 671 (26.3) 2599 (10.2) Reference 1-dose vaccinated, n (%) 170 (6.7) 1628 (6.4) 60.4 (52.5 to 66.9) 2-dose vaccinated, n (%) 1715 (67.1) 21 302 (83.4) 69.5 (66.3 to 72.4) Aged 6–11 mo, n 397 3945 Unvaccinated, n (%) 127 (32.0) 371 (9.4) Reference 1-dose vaccinated, n (%) 31 (7.8) 276 (7.0) 68.9 (52.3 to 79.8) 2-dose vaccinated, n (%) 239 (60.2) 3298 (83.6) 79.3 (73.6 to 83.8) Aged 1–3y,n 1818 18 174 Unvaccinated, n (%) 456 (25.1) 1817 (10.0) Reference 1-dose vaccinated, n (%) 122 (6.7) 1132 (6.2) 57.6 (47.5 to 65.8) 2-dose vaccinated, n (%) 1240 (68.2) 15 225 (83.8) 68.2 (64.1 to 71.8) Aged 4–8y,n 341 3410 Unvaccinated, n (%) 88 (25.8) 411 (12.1) Reference 1-dose vaccinated, n (%) 17 (5.0) 220 (6.5) 64.5 (38.7 to 79.4) 2-dose vaccinated, n (%) 236 (69.2) 2779 (81.5) 60.9 (48.8 to 70.1)

older age groups and the increasing almost half of all rotavirus strains where RV5 is primarily used (Spain; 29 availability and use of enteric identified. This genotype was 2015). G8P[8] was identified as the multiplex polymerase chain reaction previously reported as a dominant second most dominant genotype in panels in Australia, which has rotavirus strain among Australian the 2017 New South Wales outbreak. increased the likelihood of primary children in 2013 and 2014.3,28 G8 strains are rarely detected outside care physicians ordering fecal Equinelike G3P[8] has similarly been of Africa and had previously only 27 testing. observed in international settings been identified in 12 specimens where RV1 is primarily used, albeit positive for rotavirus between 1995 30 In our genotypic subanalysis of 386 on the private market with lower and 2015 in Australia. This outbreak specimens collected in 2017 in New national coverage, including in is the first time a G8 rotavirus strain South Wales, the equinelike G3P[8] Thailand (2013) and Hungary (2015), has been the major genotype in the strain was dominant, representing but has also been observed in regions 20 years of rotavirus surveillance in

TABLE 2 Estimated VE Against Notified Rotavirus by Time Since Second-Dose Receipt (2017 Notifications) Time Since Second-Dose Receipt Case Patients, n (%) Controls, n (%) VE (95% CI) Unvaccinated 295 (29.9) 697 (7.2) Reference ,1 y 122 (12.4) 1674 (17.2) 89.5% (84.3% to 93.0%) 1–,2 y 201 (20.4) 2413 (24.9) 82.1% (75.1% to 87.2%) 2–,3 y 133 (13.5) 1616 (16.6) 78.1% (68.6% to 84.8%) 3–,5 y 124 (12.6) 1787 (18.4) 84.7% (78.8% to 88.9%) 5–,10 y 112 (11.3) 1520 (15.7) 77.0% (67.5% to 83.7%)

Downloaded from www.aappublications.org/news by guest on September 28, 2021 6 MAGUIRE et al Australia.3 G8P[8] is also emerging in case patients should be excluded, children aged 6 to 11 months. several Asian countries including unless confirmed to have infection Authors of a Brazilian observational 31 Japan, Vietnam, and Thailand. It is with wild-type rotavirus. However, study (2006–2008) indicated possible that vaccine-related selective because most routinely used possible waning of RV1 protection pressure, in the context of high diagnostic tests do not differentiate against hospitalized rotavirus, with vaccine coverage, may have between wild-type and vaccine virus a lower VE in children aged 12 to contributed to the emergence of G8 and most notified case patients do not 36 months compared with infants 38 and other unusual genotypes.3 have samples genotyped, many aged 6 to 11 months. Authors of an However, a systematic review of RV1 notified cases in infants aged observational study in the United (and RV5) revealing similar ,6 months would appear to be States concluded RV1 to be most 17 effectiveness against homotypic and related to vaccine virus shedding. effective in the second year of life, heterotypic rotavirus strains, as well and effectiveness decreases in the In our study, 2 doses of RV1 was 35 as a lack of persistence of specific third year of life. Our analysis by 73.7% effective in protecting children strains, has been suggested as time since vaccination provided aged 6 months to 9 years against evidence of absence of vaccine- further evidence of waning vaccine 32 laboratory-confirmed rotavirus over induced selective pressure. protection. VE was generally highest our 8-year study period. Somewhat Unfortunately, we were not able to in the year postvaccination and surprisingly in the 2017 outbreak conduct a genotype-specificVE significantly decreased by 12.5% in year, a high 2-dose VE of 88.4% in analysis in this study because of the the 5 to ,10 years postvaccination. those aged 6 to 11 months was also anonymization of the subsample of There are limited data on the observed. Our VE estimates are specimens genotyped. However, the duration of protection of rotavirus similar to findings from a Queensland high VE seen in infants in 2017 vaccines; in the majority of study (2007–2008) of RV5 but are suggests good short-term protection randomized controlled trials, much higher than RV1 estimates against these novel strains by RV1, researchers do not look past the first during a rotavirus outbreak among albeit in the context of higher 2 years of life.34,36 Waning rotavirus indigenous children in Central notification rates. Future studies in vaccine protection could occur Australia (2009–2010).6,11 Rotavirus New South Wales using data linkage because of the absence of natural vaccines have been shown to have to merge information on genotyping, exposure to the virus over time, reduced efficacy in resource-poor laboratory notification, as well as whereby sequential infections settings such as Bolivia, Malawi, and hospitalization data could provide (usually minimally or asymptomatic) Brazil; Indigenous Australians more insight into vaccine boost immunity to both homotypic experience similar patterns of performance. and heterotypic viruses. Vaccination diarrheal disease morbidity seen in 6,34 of older children or high-risk adults less developed countries. An 39 Notably, the RV1 vaccine strain was has not been considered to date. The observational study in the United identified in 27 of 38 infants aged reduced likelihood of developing States found a similarly high 2-dose #6 months who had genotypic significant symptomatic disease with RV1 VE of 83% against laboratory- analysis conducted but not in any increasing age, notwithstanding confirmed rotavirus and a European older case patients. This was not increased recognition of disease randomized controlled trial showed unexpected and may represent outbreaks in the elderly, is thought to the same vaccine prevented 90% of incidental detection of excreted reduce the beneficial effectiveness severe rotavirus gastroenteritis vaccine virus in stools 35,36 and potential disease prevention from episodes. postvaccination due to the highly vaccination. sensitive RT-PCR testing, with We have shown that RV1 another cause for diarrhea being effectiveness decreased with age in all There were a number of limitations to present given that rates of diarrhea in calendar years in which adequate our study. Because we sourced randomized controlled trials of RV1 case numbers were reported, deidentified controls from the AIR, vaccine did not differ greatly between indicating potential waning of vaccine there is the potential for 33 vaccinated and unvaccinated infants. protection against laboratory- misclassification bias because of the These notifications would artificially confirmed rotavirus infection. RV1 inability to definitively exclude case reduce VE estimates; therefore, case clinical trials of 20 000 participants patients from controls selected from patients aged ,6 months were determined 85% VE against severe the register. If controls were included, excluded from our VE analyses. From rotavirus gastroenteritis, which the OR would be truly equivalent to July 1, 2018, the national notifiable reduced in the second year of life to the relative risk rather than an case definition for rotavirus changed 79%.34,37 This is consistent with our approximation, making the results to reflect that recently vaccinated results revealing the highest VE in more robust and accurate. Other

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 144, number 4, October 2019 7 limitations of the case-control VE specimens are limited to those who whether antigenic changes affect VE 39 analysis include the previously noted sought care during infection and were and challenge vaccination programs. , low completion of data fields such as more likely to have suffered moderate 40 Investigation of population-level indigenous status and the lack of to severe disease. VE in relation to rotavirus genotype socioeconomic data or other variables data should continue in a range of available for adjustment in this settings to improve our model. Additionally, absence of data CONCLUSIONS understanding of rotavirus vaccines on severity or hospitalization should This analysis has revealed high and the impact they have on be noted and may have resulted in effectiveness of RV1 vaccine over an disease across the age spectrum lower VE estimates given that 8-year period in an Australian over time. vaccination may be better at population with high vaccine uptake. preventing severe disease. A strength Although there is evidence of waning of the case-control VE analysis was immunity with age, effectiveness that the AIR was used as the source of remains relatively high over time, ABBREVIATIONS vaccination data for both case even in the context of a large AIR: Australian Immunisation patients and controls, and vaccination outbreak from 2 novel strains, Register status was classified in the same way equinelike G3P[8] and G8P[8]. VE CI: confidence interval for both groups. Because of the was not reduced in 2017 and thus OR: odds ratio variations in disease severity, health does not appear to have contributed RT-PCR: reverse transcriptase care seeking behavior, and diagnostic to the unexpectedly high rotavirus polymerase chain testing, the rotavirus notifications notification rate. However, more reaction reported here underrepresent the analysis is required to investigate RV1: Rotarix total number of rotavirus cases that how novel or unusual strains (such as RV5: RotaTeq have occurred in the population. the equinelike G3, G8, and G12) VE: vaccine effectiveness Notifications and genotyped interact with rotavirus vaccines and

DOI: https://doi.org/10.1542/peds.2019-1024 Accepted for publication Jun 21, 2019 Address correspondence to Julia E. Maguire, BSc, MSci(Epi), MPhil(AppEpi), National Centre for Immunisation Research and Surveillance, Locked Bag 4001, Westmead, NSW 2145, Australia. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: The National Centre for Immunisation Research and Surveillance receives funding from the Australian Government Department of Health and New South Wales Department of Health. The Australian Rotavirus Surveillance Program is supported by research grants from the vaccine companies Commonwealth Serum Laboratories and GlaxoSmithKline (ID116120) as well as the Australian Government Department of Health (RFQ1-2015 Australian Rotavirus Surveillance Program). The Murdoch Children’s Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program. Ms Maguire is supported by an Australian Government Research Training Program Scholarship. POTENTIAL CONFLICT OF INTEREST: Dr Bines is director of the Australian Rotavirus Surveillance Program, which receives funding to support the program from Commonwealth Serum Laboratories and GlaxoSmithKline (ID116120) as well as the Australian Government Department of Health (RFQ1-2015 Australian Rotavirus Surveillance Program); the other authors have indicated they have no potential conflicts of interest to disclose. COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-2426.

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Downloaded from www.aappublications.org/news by guest on September 28, 2021 10 MAGUIRE et al Rotavirus Epidemiology and Monovalent Rotavirus Vaccine Effectiveness in Australia: 2010−2017 Julia E. Maguire, Keira Glasgow, Kathryn Glass, Susie Roczo-Farkas, Julie E. Bines, Vicky Sheppeard, Kristine Macartney and Helen E. Quinn Pediatrics 2019;144; DOI: 10.1542/peds.2019-1024 originally published online September 17, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/144/4/e20191024 References This article cites 29 articles, 0 of which you can access for free at: http://pediatrics.aappublications.org/content/144/4/e20191024#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Epidemiology http://www.aappublications.org/cgi/collection/epidemiology_sub Vaccine/Immunization http://www.aappublications.org/cgi/collection/vaccine:immunization _sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 28, 2021 Rotavirus Epidemiology and Monovalent Rotavirus Vaccine Effectiveness in Australia: 2010−2017 Julia E. Maguire, Keira Glasgow, Kathryn Glass, Susie Roczo-Farkas, Julie E. Bines, Vicky Sheppeard, Kristine Macartney and Helen E. Quinn Pediatrics 2019;144; DOI: 10.1542/peds.2019-1024 originally published online September 17, 2019;

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