Vaccine Reports
Case Control Study of Rotavirus Vaccine Effectiveness in Portugal During 6 Years of Private Market Use Robin Marlow, MA,*† Muriel Ferreira, MD,‡ Eugénio Cordeiro, MD,§ Caroline Trotter, PhD,¶ Luis Januário, MD,‡ Adam Finn, PhD,*† and Fernanda Rodrigues, PhD‡‖ Background: Although recommended by the vaccine committee of the Portuguese Paediatric Society, rotavirus vaccines have not been included in the routine immunization schedule. They have been available privately since 2006 with estimated coverage reaching approximately 30%. However, unlike other European countries using the vaccine, sentinel surveillance has detected fluctuations but no clear trends in the rate of gastrointestinal disease presentations. In this study, we set out to establish the real world effectiveness of rotavirus immunization in this low vaccine coverage setting. Methods: We carried out a test-negative case control study on a population of children attending a regional pediatric hospital, between 2006 and 2012, with symptoms of acute gastroenteritis and producing a stool sample for routine rotavirus testing. We calculated exposure odds ratio (ratio of odds of antecedent vaccination among cases compared with controls) to derive vaccine effectiveness ([1 − adjusted odds ratio]/100) against both hospital attendance and admission. Results: Vaccine effectiveness against attendance with rotavirus acute gastroenteritis was 83.7% (95% confidence interval: 73.9–89.8) and against hospital admission was 96.1% (95% confidence interval: 83.8–99.1). No significant difference between the 2 available vaccines was detected. Conclusion: Both rotavirus vaccines offer a high degree of individual protection in this population. Key Words: rotavirus, vaccine, vaccine effectiveness, case control, pediatric (Pediatr Infect Dis J 2015;34:509–512)
R
otavirus is the predominant infectious cause of viral gastroenteritis. By the age of 5, almost all children will have been
Accepted for publication November 18, 2014. From the *Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; †Schools of Clinical Sciences & Cellular & Molecular Medicine, University of Bristol, United Kingdom; ‡Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; §Public Health Department, Administração Regional de Saúde do Centro, Coimbra, Portugal; ¶Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, United Kingdom; and ‖Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal. Robin Marlow has received travel bursaries to attend educational meetings from GlaxoSmithKline (GSK). Luís Januário has received travel bursaries to attend educational meetings from Sanofi Pasteur (SP-MSD). Caroline Trotter has carried out consultancy on behalf of GSK for meningococcal vaccines. Adam Finn undertakes consultancy and clinical research for all the main vaccine companies including GSK and SP-MSD who market Rotarix and Rotateq in Europe. All income is paid to the University of Bristol and University Hospitals Bristol NHS Foundation Trust, his employers. Fernanda Rodrigues (Associação de Saúde Infantil de Coimbra, Portugal) has received funding for research conducted by him from SP-MSD and for consultancy and postgraduate speaking and travel bursaries to attend educational meetings from SP-MSD and GSK, the manufacturers of licensed rotavirus vaccines in Europe. Muriel Ferreira and Eugénio Cordeiro have no conflicts of interest. The authors have no other conflicts of interest or funding to disclose. Address for correspondence: Robin Marlow, MA, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, United Kingdom. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-0509 DOI: 10.1097/INF.0000000000000647
infected by it at least once.1 It prevails in all settings, despite improvements in sanitation, due to its high infectivity. In resourcepoor countries, it is estimated to be responsible for the deaths of 600,000 children per year.1 In more developed nations, although mortality is low, it nevertheless places a large burden on families and healthcare systems. Currently, 2 rotavirus vaccines are available: Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) and RotaTeq (Sanofi Pasteur MSD, Lyon, France). Rotarix is a monovalent attenuated human rotavirus strain given as 2 doses. RotaTeq is a pentavalent bovine derived rotavirus strain, given as 3 doses. Prelicensure trials showed both to be highly protective.2,3 Although vaccine efficacy has been found to be reduced in deprived settings,4,5 due to higher disease burden and rates of mortality; here, they may result in a greater absolute benefit. Thus the World Health Organization (WHO) recommends that all countries include rotavirus vaccine in their routine childhood vaccination schedules.6 Worldwide there has been gradual uptake, now reaching 75 countries predominantly in South America and Africa.7 In Europe, the risk of death or severe illness due to acute gastroenteritis is much lower. Vaccine use is justified primarily on health economic grounds, but these calculations are very dependent on the structure of a particular healthcare system,8 local epidemiology and political will. As a result, in many wealthy countries, vaccine use is limited to the private market.9 Although rotavirus vaccine has not yet been incorporated into the Portuguese childhood immunization program, it is recommended by the vaccine committee of the Portuguese Paediatric Society,10 and both vaccines are used privately. Previous European studies of vaccine effectiveness in areas of high coverage have all seen significant effects on rotavirus epidemiology shortly after vaccine introduction. However, over 6 years of surveillance, despite rising national vaccination coverage (17–45%), we have seen fluctuations in our rates of hospital attendance and admissions for acute gastroenteritis but no clear trends.11 In this study, we used a test-negative case control study design based on the WHO protocol for assessment of rotavirus vaccine effectiveness,12 to determine whether the vaccines are effective in our low vaccine coverage setting.
METHODS Study population and setting Coimbra Children’s Hospital (Hospital Pediátrico de Coimbra) serves a population of approximately 275,000 children aged less than 13 years in central Portugal. It is the sole regional pediatric tertiary care facility as well as providing secondary care and all out-of-hours pediatric primary care for the municipality of Coimbra. Since 2006, during the January to June rotavirus season, routine stool analysis has been carried out on all children ≤36 months presenting with symptoms of acute gastroenteritis (≥3 watery or looser than normal stools within a 24-hour period with or without vomiting), using immunochromatographic rapid rotavirus tests (2006–2009 VIKIA [Biomerieux, France] and 2009–2012 Rida Quick [R-Biopharm, Germany]).
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
www.pidj.com | 509
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Marlow et al
Case Control Definition Attendances were defined as all clinical presentations to the pediatric emergency service with symptoms of acute gastroenteritis. Subjects had to live within the hospital catchment area and have been at least 8 weeks old at time of attendance (thus eligible to have received at least 1 dose of rotavirus vaccine and made an immunological response). Admissions were the subset of attendances that required admission to a ward. Cases were defined as those who tested positive for rotavirus and controls as those who tested negative. Untested patients were excluded. For multiple attendances, only the first (within a season or between years) where a sample was provided was analyzed. Details of all children in the 6 geographical and administrative districts served by the hospital that were registered as having received rotavirus vaccine were obtained from the Portuguese public health authorities. These data were linked to attendance data using full name and date of birth. Children who had received vaccine doses less than 14 days before attendance were considered unvaccinated.
Study Population During the study period, there were 5309 attendances with acute gastroenteritis. In all, 1798 (35%) were able to provide a sample, 157 of these were excluded (83 were too young and 74 were repeated attendances), leaving 542 cases and 1099 potential controls (Fig. 1). Comparing those who gave samples with those who did not, there was no difference in rates of rotavirus vaccination (15.28%/15.21%, P = 0.97). However, patients who were able to give samples were 5 times more likely to be admitted (relative risk: 5.4; 95% confidence interval: 4.6–6.4). Over the period 2006–2012, adjusting for declining birth cohort (Portuguese office for national statistics), we found fluctuations in rates of attendance and admission with confirmed rotavirus gastroenteritis rather than the sustained drop seen in other European countries using rotavirus vaccines in their routine schedules (Fig. 2). There was no statistically significant (P = 0.29) trend in this fluctuation, although it may represent an early cycling phenomenon. There appears to be a trend (P = 0.08) toward increasing age at attendance.
510 | www.pidj.com
Attendances For the primary analysis, cases were matched to controls 1:1 (338), 1:2 (76) and 1:3 (128), giving an effective sample size of 631 matched pairs. The median age difference between cases and matched controls was 0 days (interquartile range: −1 to 1 day). 5% of cases had been vaccinated compared with 21% of controls. Of those who were vaccinated, 62% received RotaTeq and 38% Rotarix. There was no significant difference between course completion rates of the 2 vaccines: RotaTeq, 82% and Rotarix, 84% (P = 0.7; Table 1). Adjusting for district of residence and year attendances / 10,000
RESULTS
FIGURE 1. Flow diagram of participants.
240
vaccine coverage (%)
Our primary objective was to assess the effectiveness of at least 1 dose of either vaccine against hospital attendance with rotavirus acute gastroenteritis over the period 2007–2012. Secondary analyses were to estimate effectiveness against admission with rotavirus acute gastroenteritis and to compare effectiveness between vaccines and by whether or not a complete vaccination course was administered. For both attendance and admission conditions, cases were matched to controls by age in days (±30) at attendance, with at least 1 and up to 3 per case, depending on availability of controls of an appropriate age. Demographic and socioeconomic data for cases and control groups were compared using χ2 or Fisher exact tests and linear regression to test for trends. Vaccine effectiveness was defined as 1 − odds ratio of vaccination. To control for variation in socioeconomic status between districts and the gradual uptake of vaccine over the period studied, district of residence and year of attendance were included as covariates in the conditional logistic regression model. All statistical analyses were done using R13 and the optmatch package.14 To confirm vaccine effectiveness of 90% (95% confidence interval: 80–95%) with 40% vaccine coverage (estimated from sales data) we calculated, we would require a sample size of 230 cases with 2 matched controls. The study was approved by the local ethics committee of the Administração Regional de Saúde do Centro in Coimbra, Portugal.
30
age in months
Statistical Analysis
230 220 210 200 190
20 10 0
30 20 10 0 2006
2007
2008
2009
2010
2011
2012
Year
FIGURE 2. Graphs showing epidemiology of acute gastroenteritis in Portugal 2006–2012. A, Rates of attendance with acute gastroenteritis per 10,000 children ≤36 months (see also Rodrigues et al11). B, Rotavirus vaccine coverage rate. C, Age (months) at attendance with gastroenteritis. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Rotavirus Vaccine in Portugal
TABLE 1. Comparison of Cases and Control Populations Attendance
Gender M:F (%) District Aveiro Castelo Branco Coimbra Guarda Leiria Viseu Year of attendance 2007 2008 2009 2010 2011 2012 Age at attendance 6–12 mo >12–18 mo >18–24 mo >24–30 mo 30–36 mo Rotavirus vaccination any Y:N Complete course Rotarix:RotaTeq:unknown
Admissions
Cases (n = 542)
Controls (n = 874)
P
Cases (n = 174)
Controls (n = 435)
P
337:205
522:352
0.39
105:69
268:167
0.84
76 14 405 3 35 9
105 15 662 9 69 14
0.31 0.35 0.71 0.39 0.37 1.0
27 7 126 1 10 3
46 9 334 3 38 5
0.12 0.17 0.28 1.0 0.28 0.69
68 55 92 140 84 103
84 131 185 171 148 155
0.1 0.01 0.06
Case Control Study of Rotavirus Vaccine Effectiveness in Portugal During 6 Years of Private Market Use Robin Marlow, MA,*† Muriel Ferreira, MD,‡ Eugénio Cordeiro, MD,§ Caroline Trotter, PhD,¶ Luis Januário, MD,‡ Adam Finn, PhD,*† and Fernanda Rodrigues, PhD‡‖ Background: Although recommended by the vaccine committee of the Portuguese Paediatric Society, rotavirus vaccines have not been included in the routine immunization schedule. They have been available privately since 2006 with estimated coverage reaching approximately 30%. However, unlike other European countries using the vaccine, sentinel surveillance has detected fluctuations but no clear trends in the rate of gastrointestinal disease presentations. In this study, we set out to establish the real world effectiveness of rotavirus immunization in this low vaccine coverage setting. Methods: We carried out a test-negative case control study on a population of children attending a regional pediatric hospital, between 2006 and 2012, with symptoms of acute gastroenteritis and producing a stool sample for routine rotavirus testing. We calculated exposure odds ratio (ratio of odds of antecedent vaccination among cases compared with controls) to derive vaccine effectiveness ([1 − adjusted odds ratio]/100) against both hospital attendance and admission. Results: Vaccine effectiveness against attendance with rotavirus acute gastroenteritis was 83.7% (95% confidence interval: 73.9–89.8) and against hospital admission was 96.1% (95% confidence interval: 83.8–99.1). No significant difference between the 2 available vaccines was detected. Conclusion: Both rotavirus vaccines offer a high degree of individual protection in this population. Key Words: rotavirus, vaccine, vaccine effectiveness, case control, pediatric (Pediatr Infect Dis J 2015;34:509–512)
R
otavirus is the predominant infectious cause of viral gastroenteritis. By the age of 5, almost all children will have been
Accepted for publication November 18, 2014. From the *Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol, United Kingdom; †Schools of Clinical Sciences & Cellular & Molecular Medicine, University of Bristol, United Kingdom; ‡Hospital Pediátrico de Coimbra, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; §Public Health Department, Administração Regional de Saúde do Centro, Coimbra, Portugal; ¶Disease Dynamics Unit, Department of Veterinary Medicine, University of Cambridge, United Kingdom; and ‖Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal. Robin Marlow has received travel bursaries to attend educational meetings from GlaxoSmithKline (GSK). Luís Januário has received travel bursaries to attend educational meetings from Sanofi Pasteur (SP-MSD). Caroline Trotter has carried out consultancy on behalf of GSK for meningococcal vaccines. Adam Finn undertakes consultancy and clinical research for all the main vaccine companies including GSK and SP-MSD who market Rotarix and Rotateq in Europe. All income is paid to the University of Bristol and University Hospitals Bristol NHS Foundation Trust, his employers. Fernanda Rodrigues (Associação de Saúde Infantil de Coimbra, Portugal) has received funding for research conducted by him from SP-MSD and for consultancy and postgraduate speaking and travel bursaries to attend educational meetings from SP-MSD and GSK, the manufacturers of licensed rotavirus vaccines in Europe. Muriel Ferreira and Eugénio Cordeiro have no conflicts of interest. The authors have no other conflicts of interest or funding to disclose. Address for correspondence: Robin Marlow, MA, Bristol Royal Hospital for Children, University Hospitals Bristol NHS Foundation Trust, Bristol BS2 8BJ, United Kingdom. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0891-3668/15/3405-0509 DOI: 10.1097/INF.0000000000000647
infected by it at least once.1 It prevails in all settings, despite improvements in sanitation, due to its high infectivity. In resourcepoor countries, it is estimated to be responsible for the deaths of 600,000 children per year.1 In more developed nations, although mortality is low, it nevertheless places a large burden on families and healthcare systems. Currently, 2 rotavirus vaccines are available: Rotarix (GlaxoSmithKline Biologicals, Rixensart, Belgium) and RotaTeq (Sanofi Pasteur MSD, Lyon, France). Rotarix is a monovalent attenuated human rotavirus strain given as 2 doses. RotaTeq is a pentavalent bovine derived rotavirus strain, given as 3 doses. Prelicensure trials showed both to be highly protective.2,3 Although vaccine efficacy has been found to be reduced in deprived settings,4,5 due to higher disease burden and rates of mortality; here, they may result in a greater absolute benefit. Thus the World Health Organization (WHO) recommends that all countries include rotavirus vaccine in their routine childhood vaccination schedules.6 Worldwide there has been gradual uptake, now reaching 75 countries predominantly in South America and Africa.7 In Europe, the risk of death or severe illness due to acute gastroenteritis is much lower. Vaccine use is justified primarily on health economic grounds, but these calculations are very dependent on the structure of a particular healthcare system,8 local epidemiology and political will. As a result, in many wealthy countries, vaccine use is limited to the private market.9 Although rotavirus vaccine has not yet been incorporated into the Portuguese childhood immunization program, it is recommended by the vaccine committee of the Portuguese Paediatric Society,10 and both vaccines are used privately. Previous European studies of vaccine effectiveness in areas of high coverage have all seen significant effects on rotavirus epidemiology shortly after vaccine introduction. However, over 6 years of surveillance, despite rising national vaccination coverage (17–45%), we have seen fluctuations in our rates of hospital attendance and admissions for acute gastroenteritis but no clear trends.11 In this study, we used a test-negative case control study design based on the WHO protocol for assessment of rotavirus vaccine effectiveness,12 to determine whether the vaccines are effective in our low vaccine coverage setting.
METHODS Study population and setting Coimbra Children’s Hospital (Hospital Pediátrico de Coimbra) serves a population of approximately 275,000 children aged less than 13 years in central Portugal. It is the sole regional pediatric tertiary care facility as well as providing secondary care and all out-of-hours pediatric primary care for the municipality of Coimbra. Since 2006, during the January to June rotavirus season, routine stool analysis has been carried out on all children ≤36 months presenting with symptoms of acute gastroenteritis (≥3 watery or looser than normal stools within a 24-hour period with or without vomiting), using immunochromatographic rapid rotavirus tests (2006–2009 VIKIA [Biomerieux, France] and 2009–2012 Rida Quick [R-Biopharm, Germany]).
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
www.pidj.com | 509
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Marlow et al
Case Control Definition Attendances were defined as all clinical presentations to the pediatric emergency service with symptoms of acute gastroenteritis. Subjects had to live within the hospital catchment area and have been at least 8 weeks old at time of attendance (thus eligible to have received at least 1 dose of rotavirus vaccine and made an immunological response). Admissions were the subset of attendances that required admission to a ward. Cases were defined as those who tested positive for rotavirus and controls as those who tested negative. Untested patients were excluded. For multiple attendances, only the first (within a season or between years) where a sample was provided was analyzed. Details of all children in the 6 geographical and administrative districts served by the hospital that were registered as having received rotavirus vaccine were obtained from the Portuguese public health authorities. These data were linked to attendance data using full name and date of birth. Children who had received vaccine doses less than 14 days before attendance were considered unvaccinated.
Study Population During the study period, there were 5309 attendances with acute gastroenteritis. In all, 1798 (35%) were able to provide a sample, 157 of these were excluded (83 were too young and 74 were repeated attendances), leaving 542 cases and 1099 potential controls (Fig. 1). Comparing those who gave samples with those who did not, there was no difference in rates of rotavirus vaccination (15.28%/15.21%, P = 0.97). However, patients who were able to give samples were 5 times more likely to be admitted (relative risk: 5.4; 95% confidence interval: 4.6–6.4). Over the period 2006–2012, adjusting for declining birth cohort (Portuguese office for national statistics), we found fluctuations in rates of attendance and admission with confirmed rotavirus gastroenteritis rather than the sustained drop seen in other European countries using rotavirus vaccines in their routine schedules (Fig. 2). There was no statistically significant (P = 0.29) trend in this fluctuation, although it may represent an early cycling phenomenon. There appears to be a trend (P = 0.08) toward increasing age at attendance.
510 | www.pidj.com
Attendances For the primary analysis, cases were matched to controls 1:1 (338), 1:2 (76) and 1:3 (128), giving an effective sample size of 631 matched pairs. The median age difference between cases and matched controls was 0 days (interquartile range: −1 to 1 day). 5% of cases had been vaccinated compared with 21% of controls. Of those who were vaccinated, 62% received RotaTeq and 38% Rotarix. There was no significant difference between course completion rates of the 2 vaccines: RotaTeq, 82% and Rotarix, 84% (P = 0.7; Table 1). Adjusting for district of residence and year attendances / 10,000
RESULTS
FIGURE 1. Flow diagram of participants.
240
vaccine coverage (%)
Our primary objective was to assess the effectiveness of at least 1 dose of either vaccine against hospital attendance with rotavirus acute gastroenteritis over the period 2007–2012. Secondary analyses were to estimate effectiveness against admission with rotavirus acute gastroenteritis and to compare effectiveness between vaccines and by whether or not a complete vaccination course was administered. For both attendance and admission conditions, cases were matched to controls by age in days (±30) at attendance, with at least 1 and up to 3 per case, depending on availability of controls of an appropriate age. Demographic and socioeconomic data for cases and control groups were compared using χ2 or Fisher exact tests and linear regression to test for trends. Vaccine effectiveness was defined as 1 − odds ratio of vaccination. To control for variation in socioeconomic status between districts and the gradual uptake of vaccine over the period studied, district of residence and year of attendance were included as covariates in the conditional logistic regression model. All statistical analyses were done using R13 and the optmatch package.14 To confirm vaccine effectiveness of 90% (95% confidence interval: 80–95%) with 40% vaccine coverage (estimated from sales data) we calculated, we would require a sample size of 230 cases with 2 matched controls. The study was approved by the local ethics committee of the Administração Regional de Saúde do Centro in Coimbra, Portugal.
30
age in months
Statistical Analysis
230 220 210 200 190
20 10 0
30 20 10 0 2006
2007
2008
2009
2010
2011
2012
Year
FIGURE 2. Graphs showing epidemiology of acute gastroenteritis in Portugal 2006–2012. A, Rates of attendance with acute gastroenteritis per 10,000 children ≤36 months (see also Rodrigues et al11). B, Rotavirus vaccine coverage rate. C, Age (months) at attendance with gastroenteritis. © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Pediatric Infectious Disease Journal • Volume 34, Number 5, May 2015
Rotavirus Vaccine in Portugal
TABLE 1. Comparison of Cases and Control Populations Attendance
Gender M:F (%) District Aveiro Castelo Branco Coimbra Guarda Leiria Viseu Year of attendance 2007 2008 2009 2010 2011 2012 Age at attendance 6–12 mo >12–18 mo >18–24 mo >24–30 mo 30–36 mo Rotavirus vaccination any Y:N Complete course Rotarix:RotaTeq:unknown
Admissions
Cases (n = 542)
Controls (n = 874)
P
Cases (n = 174)
Controls (n = 435)
P
337:205
522:352
0.39
105:69
268:167
0.84
76 14 405 3 35 9
105 15 662 9 69 14
0.31 0.35 0.71 0.39 0.37 1.0
27 7 126 1 10 3
46 9 334 3 38 5
0.12 0.17 0.28 1.0 0.28 0.69
68 55 92 140 84 103
84 131 185 171 148 155
0.1 0.01 0.06
