Effectiveness of Pentavalent Rotavirus Vaccine Under Conditions of Routine Use in Rwanda

Clinical Infectious Diseases, Apr 2016

Background. Rotavirus vaccine efficacy is lower in low-income countries than in high-income countries. Rwanda was one of the first low-income countries in sub-Saharan Africa to introduce rotavirus vaccine into its national immunization program. We sought to evaluate rotavirus vaccine effectiveness (VE) in this setting. Methods. VE was assessed using a case-control design. Cases and test-negative controls were children who presented with a diarrheal illness to 1 of 8 sentinel district hospitals and 10 associated health centers and had a stool specimen that tested positive (cases) or negative (controls) for rotavirus by enzyme immunoassay. Due to high vaccine coverage almost immediately after vaccine introduction, the analysis was restricted to children 7–18 weeks of age at time of rotavirus vaccine introduction. VE was calculated as (1 – odds ratio) × 100, where the odds ratio was the adjusted odds ratio for the rotavirus vaccination rate among case-patients compared with controls. Results. Forty-eight rotavirus-positive and 152 rotavirus-negative children were enrolled. Rotavirus-positive children were significantly less likely to have received rotavirus vaccine (33/44 [73%] unvaccinated) compared with rotavirus-negative children (81/136 [59%] unvaccinated) (P = .002). A full 3-dose series was 75% (95% confidence interval [CI], 31%–91%) effective against rotavirus gastroenteritis requiring hospitalization or a health center visit and was 65% (95% CI, −80% to 93%) in children 6–11 months of age and 81% (95% CI, 25%–95%) in children ≥12 months of age. Conclusions. Rotavirus vaccine is effective in preventing rotavirus disease in Rwandan children who began their rotavirus vaccine series from 7 to 18 weeks of age. Protection from vaccination was sustained after the first year of life.

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Effectiveness of Pentavalent Rotavirus Vaccine Under Conditions of Routine Use in Rwanda

CID Effectiveness of Pentavalent Rotavirus Vaccine Under Conditions of Routine Use in Rwanda Jacqueline E. Tate 2 3 Fidele Ngabo 1 2 Philippe Donnen 1 2 Maurice Gatera 0 2 Jeannine Uwimana 2 6 Celse Rugambwa 2 5 Jason M. Mwenda 2 4 Umesh D. Parashar 2 3 0 Rwanda Biomedical Center 1 Universite Libre de Bruxelles, Ecole de Santé Publique , Brussels , Belgium 2 MS-A34 , Atlanta, GA 30333 , USA 3 Centers for Disease Control and Prevention , Atlanta , Georgia 4 World Health Organization , Regional Office for Africa, Brazzaville , Republic of Congo 5 World Health Organization , Rwanda Office, Kigali 6 University Teaching Hospital Background. Rotavirus vaccine efficacy is lower in low-income countries than in high-income countries. Rwanda was one of the first low-income countries in sub-Saharan Africa to introduce rotavirus vaccine into its national immunization program. We sought to evaluate rotavirus vaccine effectiveness (VE) in this setting. Methods. VE was assessed using a case-control design. Cases and test-negative controls were children who presented with a diarrheal illness to 1 of 8 sentinel district hospitals and 10 associated health centers and had a stool specimen that tested positive (cases) or negative (controls) for rotavirus by enzyme immunoassay. Due to high vaccine coverage almost immediately after vaccine introduction, the analysis was restricted to children 7-18 weeks of age at time of rotavirus vaccine introduction. VE was calculated as (1 - odds ratio) × 100, where the odds ratio was the adjusted odds ratio for the rotavirus vaccination rate among case-patients compared with controls. Results. Forty-eight rotavirus-positive and 152 rotavirus-negative children were enrolled. Rotavirus-positive children were significantly less likely to have received rotavirus vaccine (33/44 [73%] unvaccinated) compared with rotavirus-negative children (81/ 136 [59%] unvaccinated) (P = .002). A full 3-dose series was 75% (95% confidence interval [CI], 31%-91%) effective against rotavirus gastroenteritis requiring hospitalization or a health center visit and was 65% (95% CI, −80% to 93%) in children 6-11 months of age and 81% (95% CI, 25%-95%) in children ≥12 months of age. Conclusions. Rotavirus vaccine is effective in preventing rotavirus disease in Rwandan children who began their rotavirus vaccine series from 7 to 18 weeks of age. Protection from vaccination was sustained after the first year of life. - In May 2012, Rwanda became the first country in sub-Saharan Africa to introduce the pentavalent rotavirus vaccine (RV5), RotaTeq (Merck & Co) into its routine immunization program with 3 doses recommended at 6, 10, and 14 weeks of age. A clinical trial of RV5 in 3 low-income countries in sub-Saharan Africa found modest efficacy of 64% against severe rotavirus disease that was similar to the efficacy of 61% observed in a clinical trial conducted in 2 sub-Saharan African countries with the monovalent rotavirus vaccine (RV1), Rotarix (GlaxoSmithKline), the other rotavirus vaccine currently available on global markets [ 1, 2 ]. The efficacy of 61%–64% in sub-Saharan Africa was lower than the efficacy of 85%–98% observed in clinical trials in developed countries [ 1–4 ]. Although it is not fully understood, lower efficacy in low-income settings has been hypothesized to be due to a variety of reasons including higher levels of comorbidities and coinfections, environmental enteropathy, interference by high titers of maternal antibodies, coadministration with oral polio vaccine, and malnutrition. However, given the substantial rotavirus disease burden in low-income countries, the World Health Organization recommends the use of rotavirus vaccine in all countries globally and particularly in those countries with high child mortality due to diarrhea [ 5–7 ]. As Rwanda was one of the first low-income countries in sub-Saharan Africa to introduce rotavirus vaccine into its national immunization program, we sought to evaluate the effectiveness of RV5 under conditions of routine use, which may differ considerably than the ideal conditions in a clinical trial, in Rwanda. METHODS Rotavirus vaccine effectiveness (VE) was assessed using a casecontrol design. Cases and controls were identified through an ongoing active surveillance platform. Eight sentinel district hospitals and 10 associated health centers located throughout the country conducted active surveillance for rotavirus diarrhea from September 2012 to May 2015 using the World Health Organization generic protocol [ 8 ]. Because rotavirus vaccine coverage among children ≤6 weeks of age at the time of vaccine introduction reached >95% almost immediately after vaccine introduction and continued at this level throughout the period of our evaluation, VE could not be assessed in this age cohort. Therefore, we restricted our analysis to children who were 7–18 weeks of age at the time of vaccine introduction. These children had not yet completed their complete infant immunization series at the time of rotavirus vaccine introduction, with doses recommended at 6, 10, and 14 weeks of age, and thus visited vaccination clinics during the initial weeks of rotavirus vaccine rollout. Coverage among children in this 7- to 18-week of age window was variable and allowed VE to be assessed. Cases were defined as children born between 15 January 2012 and 15 April 2012 (ie, were 7–18 weeks of age when rotavirus vaccine was introduced in May 2012) who presented with a diarrheal illness to a participating surveillance health facility and had a stool specimen that tested positive for rotavirus by enzyme immunoassay (EIA). A diarrheal illness was defined as the occurrence of ≥3 episodes of diarrhea (stools of a less formed character than usual) within a 24-hour period, <7 days prior to enrollment. “Test-negative” controls were defined as children born between 15 January 2012 and 15 April 2012 who presented with a diarrheal illness to a participating surveillance facility and had a stool specimen that tested negative for rotavirus by EIA. Clinical and sociodemographic information were collected from the clinical evaluation of the child and through interview of the parent or guardian. Vaccination data were collected from the child’s vaccination card. If the card was unavailable during the child’s hospital stay, the health facility where the child was reported to be vaccinated was visited by project staff and the vaccination data were abstracted from clinic records. Photocopies of the vaccine card were retained. A dose of rotavirus vaccine was considered relevant if it was administered at least 14 days prior to the child’s admission date. A whole stool specimen (approximately 5 mL) was obtained from enrolled children during the acute illness. All attempts were made to obtain a stool specimen within 48 hours of hospital admission to avoid the detection of nosocomial infection. Stool specimens were refrigerated at 2°C–8°C until tested for rotavirus antigen using a commercially available EIA (ProSpecT, Oxoid, United Kingdom) at the University Teaching Hospital laboratory in Kigali by trained staff. Bivariate analyses were conducted to assess differences in sociodemographic and clinical characteristics of cases and controls using the χ2 test for categorical variables and the Wilcoxon rank-sum test for continuous variables. VE was calculated using the following formula: VE = (1 – odds ratio) × 100, where the odds ratio is the adjusted odds ratio for the rotavirus vaccination rate among case-patients compared with controls. The odds ratio was calculated using unconditional logistic regression. Age at enrollment was included in the model a priori to account for possible waning immunity. Potential confounders identified in bivariate analyses were included in the initial model and retained if their removal from the model changed the odds ratio for the primary outcome by >10%. Only children with card-confirmed vaccination status were included in the analyses. The primary analysis included all verified reports of vaccine status for children who had received a full vaccine series vs no doses of the vaccine. This evaluation was reviewed and approved by the Rwanda National Ethics Committee and received a public health nonresearch determination from the Centers for Disease Control and Prevention. RESULTS A total of 200 children born between 15 January 2012 and 15 April 2012 were enrolled in the surveillance program between September 2012 and May 2015. Of these, 48 (24%) tested positive for rotavirus by EIA. Stool specimens were collected within 2 days of admission for 93% of children. Rotavirus-positive children were significantly older (median age: 15.5 months) than children who were rotavirus negative (median age: 10 months) (P < .001). There were no other significant differences in sociodemographic factors between rotavirus-positive and rotavirusnegative children (Table 1). Rotavirus-positive children were more likely to have a higher number of vomiting episodes, sunken eyes, an abnormal thirst status, and lower skin turgor than children who tested negative for rotavirus (Table 2). The proportion of children with confirmed vaccination status either by vaccine card or clinic record was similar between rotavirus-positive children (94%) and rotavirus-negative children (90%) (P = .65). Rotavirus-positive children were significantly less likely to have received rotavirus vaccine (73% unvaccinated) compared with rotavirus-negative children (59% unvaccinated) (P = .002; Table 3). The age at vaccination was similar among rotavirus-positive and -negative children with doses 1, 2, and 3 given at 10.5 weeks, 15 weeks, and 18 weeks of age, respectively, in rotavirus-positive children and 11 weeks, 15 weeks, and 19 weeks of age, respectively, in rotavirus-negative children. No differences were observed in the vaccination status for rotavirus-positive and -negative children with respect to the other infant immunizations including pentavalent vaccine, oral polio vaccine, and pneumococcal vaccine. Rotavirus-positive children were more likely to have received measles vaccine than rotavirus-negative children, but rotavirus-positive children were significantly older than rotavirus-negative children and this difference was not statistically significant after adjusting for age (P = .96). Among all enrolled children, a full 3-dose series of RV5 was 75% (95% confidence interval [CI], 31%–91%) effective against rotavirus gastroenteritis requiring hospitalization or a health center visit (Table 4). RV5 was 80% (95% CI, 28%–94%) effective against rotavirus disease requiring hospitalization. Vaccine effectiveness was 65% (95% CI, −80% to 93%) in children 6–11 months of age and 81% (95% CI, 25%–95%) in children ≥12 months of age. Data are presented as No. (%). Abbreviations: IV, intravenous; ORT, oral rehydration therapy. a Fever based on parental report. Rotavirus Negative (n = 152) A full course of rotavirus vaccine was 80% effective against rotavirus disease requiring hospitalization among Rwandan children who began their rotavirus vaccine series between 7 and 18 weeks of age. Protection from vaccination was sustained after the first year of life. The high observed VE is consistent with the declines of 61%–70% in rotavirus hospitalizations and 17%–49% in all-cause diarrhea hospitalizations observed in the first 2 years following rotavirus vaccine introduction in Rwanda [ 9 ]. The population included in this evaluation was unique in several aspects. First, due to rapid uptake of the vaccine among age-eligible children in Rwanda, we were unable to evaluate rotavirus VE among children vaccinated on the recommended schedule of 6, 10, and 14 weeks of age. Instead, we evaluated VE among children who were >6 weeks of age at time of rotavirus vaccine introduction but who were still visiting vaccine clinics to receive their routine infant immunizations during the time of initial rotavirus vaccine rollout. Only some of these children began the rotavirus vaccine series, albeit on a slightly delayed schedule, with median ages at vaccination of 11, 15, and 19 weeks for the 3 doses, respectively. Given the limited time period during which children were completing their primary vaccine series, we had a somewhat limited sample size for our analysis. Second, given the timing of vaccine introduction and the seasonality of rotavirus disease, these children were beginning the rotavirus vaccine series just prior to or at the beginning of the rotavirus season. Reasons for lower effectiveness of oral rotavirus vaccines in developing compared with developed countries are not fully understood and likely multifaceted, but interference by high titers of maternal antibodies has been suggested as one factor that may influence an infant’s response to the vaccine [ 10 ]. The cohort of infants included in this evaluation were born immediately prior to the start of the season, when passively acquired antibodies transferred from mother to child either transplacentally or through breastfeeding are likely to be at their lowest level. Furthermore, these infants were a median of 5 weeks older than the recommended age for vaccination when they began the series, providing further time for maternal antibodies to wane. Thus, our VE estimate may be higher than that in the age-eligible population that received the vaccine on the recommended schedule. However, given the large declines that were observed in rotavirus and all-cause diarrhea hospitalizations following vaccine introduction [ 9 ], the vaccine is likely effective in the age-eligible population as well. Rotavirus vaccine is effective in preventing rotavirus disease in children in Rwanda. Further understanding of the factors influencing effectiveness of oral rotavirus vaccines, particularly with regard to the age and timing of vaccination, is needed. Continued surveillance is also important to document the long-term impact of rotavirus vaccine on the burden of rotavirus disease in Rwanda. Disclaimer. The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC). The views expressed by the authors do not necessarily reflect the views of PATH, the CDC Foundation, the Bill and Melinda Gates Foundation, or GAVI, the Vaccine Alliance. Supplement sponsorship. This article appears as part of the supplement “Health Benefits of Rotavirus Vaccination in Developing Countries,” sponsored by PATH and the CDC Foundation through grants from the Bill and Melinda Gates Foundation and GAVI, the Vaccine Alliance. Financial support. This evaluation was funded by Gavi, the Vaccine Alliance. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. 1. Armah GE , Sow SO , Breiman RF , et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial . Lancet 2010 ; 376 : 606 - 14 . 2. Madhi SA , Cunliffe NA , Steele D , et al. Effect of human rotavirus vaccine on severe diarrhea in African infants . N Engl J Med 2010 ; 362 : 289 - 98 . 3. Vesikari T , Matson DO , Dennehy P , et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine . N Engl J Med 2006 ; 354 : 23 - 33 . 4. Ruiz-Palacios GM , Perez-Schael I , Velazquez FR , et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis . N Engl J Med 2006 ; 354 : 11 - 22 . 5. Rotavirus vaccines: an update . Wkly Epidemiol Rec 2009 ; 84 : 533 - 40 . 6. Meeting of the Strategic Advisory Group of Experts on immunization, October 2009 -conclusions and recommendations . Wkly Epidemiol Rec 2009 ; 84 : 517 - 32 . 7. Meeting of the immunization Strategic Advisory Group of Experts, April 2009-conclusions and recommendations . Wkly Epidemiol Rec 2009 ; 84 : 220 - 36 . 8. World Health Organization. Generic protocols for (i) hospital-based surveillance to estimate the burden of rotavirus gastroenteritis in children and (ii) a community-based survey on utilization of health care services for gastroenteritis in children . Geneva, Switzerland: WHO, 2002 . 9. Ngabo F , Tate JE , Gatera M , et al. Decline in diarrhea and rotavirus hospitalizations following introduction of pentavalent rotavirus vaccine in Rwanda. Lancet Global Health . In press. 10. Glass RI , Parashar UD , Bresee JS , et al. Rotavirus vaccines: current prospects and future challenges . Lancet 2006 ; 368 : 323 - 32 .


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Jacqueline E. Tate, Fidele Ngabo, Philippe Donnen, Maurice Gatera, Jeannine Uwimana, Celse Rugambwa, Jason M. Mwenda, Umesh D. Parashar. Effectiveness of Pentavalent Rotavirus Vaccine Under Conditions of Routine Use in Rwanda, Clinical Infectious Diseases, 2016, S208-S212, DOI: 10.1093/cid/civ1016