Among other factors, higher levels of maternal antibodies to RV in developing countries are hypothesized to be one of the factors that might interfere with vaccine response and explain the regional disparity in RV vaccine performance. Supporting this hypothesis are data from randomized clinical trials (RCTs) of RV1 in South Africa, the Philippines and Vietnam showing that a delayed 2-dose schedule of RV1 had a superior immune response to an early 2-dose schedule.8 , 9 Similar trends were seen in recent RCTs evaluating RV1 at 6/10 versus 10/14 versus 6/10/14 weeks in Ghana (seroconversion of 29% vs. 37% vs. 43%, respectively)10 but not in Pakistan (seroconversion of 36% vs. 39% vs. 37%, respectively)11; however, neither study showed a statistically significant difference between the 6/10 and 10/14 schedules. While immunogenicity of RV vaccines does not necessarily correlate with efficacy, a post hoc analysis of data from a previously conducted RCT of RV5, pooled across 3 African countries (Ghana, Kenya, Mali),12 also found a lower efficacy in children receiving the first dose of RV vaccine at <8 weeks [23.7%; 95% confidence interval (CI): −8.2% to 46.3%] compared with those immunized at ≥8 weeks (59.1%; 95% CI: 34.0%–74.6%).
Given that all of the above studies were RCTs, and that the results are neither definitive nor in complete agreement, gathering more data on this question is useful. Existing case–control studies of vaccine effectiveness (VE) provide a means of evaluating the effectiveness of RV vaccine in infants receiving the first dose earlier as compared with later. These evaluations typically leverage existing hospital-based RV surveillance systems and compare RV vaccination completeness in children hospitalized for RV diarrhea versus children hospitalized for non-RV diarrhea. Using data from 2 postlicensure evaluations in Bolivia,13 , 14 we conducted a post hoc analysis to describe the effectiveness of RV vaccination (1) in infants who received their first dose early (≤56 days) versus on-time (57–70 days) or late (>70 days) and (2) in infants who received their second dose early (<110 days) versus on-time (110–150 days) or late (>150 days). In each analysis, the unvaccinated children act as the reference.
MATERIALS AND METHODS
Study Design and Population
We conducted a post hoc analysis of data from 2 case–control VE evaluations conducted in 4 cities in Bolivia, a lower-middle income country in South America that introduced RV1 in August 2008.15 , 16 The design, methods and results of these evaluations have previously been reported in detail.13 , 14 Briefly, the first evaluation was conducted between March 2010 and June 2011 in 6 hospitals in 4 major cities in Bolivia,13 while the second evaluation was conducted between April 2013 and March 2014 in the same 4 cities in 5 of the 6 same hospitals.14 In both studies, children admitted to the hospital for at least 1 night for the treatment of acute gastroenteritis (AGE; defined as at least 3 loose stools in a 24-hour period before hospitalization, with diarrhea lasting <14 days before hospitalization) were enrolled. Cases were those AGE patients who tested positive for RV by enzyme immunoassay testing of a fecal specimen, and controls were AGE patients who tested negative for RV. Cases and controls also had to be age-eligible for RV vaccination [born after June 1, 2008 (6 weeks before RV vaccine introduction in Bolivia) and were at least 8 weeks of age upon admission]. Although the first evaluation also recruited nondiarrhea hospital controls, these are not used in the present analysis to ensure consistency in controls for the 2 studies. Vaccine information for participants was confirmed by visual inspection of the vaccination card or clinic record of the child.
Definitions and Statistical Methods
Data from the 2 evaluations were merged. The immunization schedule in Bolivia recommends 2 doses of RV1 given at 2 and 4 months of age.16 Age at each RV1 dose was calculated from the date of birth and date of immunizations for each child. Improbable or outlying ages at each dose (<28 or >112 days for dose 1; <75 or >365 days for dose 2) were set to missing, and remaining vaccine doses were counted provided they had been administered at least 14 days before admission. Categories were based on distribution of age at vaccination, rather than strictly on adherence to the recommended schedule. For dose 1, children were categorized as “early receipt” if their calculated age at vaccination was 28–56 days, “on-time receipt” if their calculated age at vaccination was 57–70 days, “late receipt” if their calculated age at vaccination was 71–112 days and “unvaccinated” if they did not report receipt of RV1. For dose 2, children were categorized as “early receipt” if their calculated age at vaccination was 75–109 days, “on-time receipt” if their calculated age at vaccination was 110–150 days, “late receipt” if their calculated age at vaccination was 151–365 days and “unvaccinated” if they did not report receipt of RV1. Children with missing dates for the first dose of vaccine were excluded from all analyses, while children with missing dates for the second dose of vaccine were excluded from the dose 2 analyses. For analyses regarding the timing of dose 2, children who received only 1 dose of RV1 were excluded. For all analyses, children less than 6 months of age at the time of admission were excluded to avoid residual confounding by age.
To assess VE in each group, separate unconditional logistic regression models were constructed for “early,” “late” and “on-time” receipt, using “unvaccinated” infants as the reference group in each model. We also calculated VE for the overall study population. VE was calculated as (1 – odds ratio) × 100%. Models were adjusted a priori for hospital, age and time since RV1 introduction (via controlling for month and year of birth). Dose 2 models were also adjusted for “early” receipt of dose 1. Potential sociodemographic confounders, including nutritional status, were selected based on bivariate logistic regression on vaccination status and RV status. These were included in final models if their removal changed VE estimates by >10%. Collinearity was assessed using condition indices and variance inflation factors and found not to be an issue. Statistical comparisons could not be made between vaccination categories given overlapping reference groups.
Participants and Age at RV1 Doses
From the first evaluation, 1116 children (399 cases, 717 controls) were available for analysis (ie, had sufficient controls, RV test result and vaccination information); from the second evaluation, 868 children (401 cases, 467 controls) were available for analysis. After excluding children with missing ages at vaccination, unverified vaccination records and those younger than 6 months of age, the final sample size was 1439 (581 cases, 858 controls). Age at the first dose of RV1 was right skewed (Fig. 1). The sample included 198 unvaccinated children, 22 children with an “early receipt” of dose 1, 840 children with an “on-time receipt” of dose 1 and 379 with a “late receipt” of dose 1 (Table 1). Unvaccinated children were slightly older at admission than those receiving their first dose of RV1 early, but this difference was not statistically significant. Children who received their first dose of RV1 on-time had slightly more educated mothers. Nutrition and most household assets were similar across most groups. Unvaccinated children were significantly more likely to have RV-positive diarrhea as compared with children receiving at least 1 dose of RV1. Age at the second dose of RV1 was also right skewed (Fig. 2). Sixty-five children were categorized as receiving dose 2 “early,” 807 as receiving dose 2 “on-time” and 219 as receiving dose 2 “late.” Overall age at admission ranged from 6 to 58 months (interquartile range, 10–17 months). Among infants completing a full course of RV1, the time between completion of vaccination and admission for AGE ranged from 1 to 48 months (interquartile range, 5.5–13 months).
VE for 2 doses of RV1 tended to be higher in infants receiving the first dose of RV1 early [adjusted VE 92% with 95% confidence interval (CI): 70%–98%], when compared with infants receiving their first dose on-time [adjusted VE, 72% (60%–81%)] or infants receiving their first dose late [adjusted VE, 68% (51%–79%)], though CIs were overlapping (Table 2). Estimates of VE for a single dose of RV1 had wide CIs.
Estimates of VE for 2 doses of RV1 were not substantially different when comparing children by age at receipt of the second dose [adjusted VE, 76% (50%–89%) for early receipt; 70% (57%–79%) for on-time receipt; 75% (60%–84%) for late receipt]. While the point estimate for early receipt was slightly higher than other groups, CIs were wide and overlapping across all models (Table 3).
In this secondary analysis of VE data from 2 evaluations in Bolivia, we found that VE tended to be higher in children receiving an earlier first dose of RV1 as compared with children receiving this dose later, although statistical significance could not be evaluated because of overlapping reference groups and small sample size when stratified by age at dose receipt. It may be that VEs are not significantly different when comparing among infants receiving dose 1 early, infants receiving dose 1 on-time and infants receiving dose 1 later. No meaningful differences were noted based on timing of the receipt of the second dose.
Our results of higher effectiveness in infants receiving RV1 early were in contrast to several studies showing higher immune response in infants receiving RV1 late,8–12 or no differences.17 These differences could be attributable to different study populations: our analysis population was Bolivian, while the previously conducted studies featured African10 , 12 , 17 or Asian9 , 11 populations. It is possible that maternal antibody levels in Bolivian mothers could be different from those in Asian or African mothers, thus resulting in different interference. Further, the previous studies primarily used an immunologic rather than a clinical endpoint in a controlled setting, while the present analysis was an observational effectiveness evaluation. It could be that younger infants have not yet experienced as many insults to their gut health, and thus have a healthier gut and gut flora as compared with older infants, and are thus more able to mount an immune response to the vaccine.18 Additionally, age at vaccination may simply be outweighed by other factors in more impoverished settings, as the previous study demonstrating no difference by age was in Pakistan.11
This analysis is subject to the following limitations. First, because it was a post hoc analysis of data from 2 observational evaluations, the number of children in the “early” vaccine receipt strata is quite low, which can negatively impact power and the stability of the estimates. Additionally, statistical significance of differences in VE estimates could not be tested given the fact that each model used the same reference population. Further, it is possible that residual confounding could be present, for instance, by the timing of dose 1 in dose 2 models. Nonetheless, the point estimates for the “early” as compared with the “late” dose 1 children are distinct, and this difference was larger in the adjusted model. Second, although vaccine records were verified for all participants, it is possible that some infants who are classified as unvaccinated did in fact receive one or more doses of RV vaccine; this would tend to decrease the VE estimates across all groups. Last, this analysis only included children from a single country, so results may not be generalizable to other countries or regions. Though this analysis did not specifically address VE by RV genotype, previous research has demonstrated good effectiveness across strains19; strain-specific VE estimates from the 2 evaluations included in the present analysis have been previously reported.13 , 14 Strengths of this analysis include the ability to merge data across multiple years of study and the ability to control for age, hospital and sociodemographics.
In summary, our analysis indicated that early administration of RV1 provides similar and potentially even better protection against severe RV disease as compared with later administration. Though sample sizes were small, this evaluation provides support for keeping current RV vaccine schedules consistent with standard Expanded Program on Immunization immunizations (eg, at 2 and 4 months of age, coinciding with the first dose of oral poliovirus vaccine and diphtheria-tetanus toxoids-pertussis), as opposed to changing the RV schedule to begin the series in older infants (eg, giving first dose of RV with the second dose of oral poliovirus vaccine or diphtheria-tetanus toxoids-pertussis). Early administration of RV vaccines could also have the benefit of reducing potential risk of intussusception,20 as well as providing earlier protection from RV. More research is needed in diverse populations to determine the potential impact of changing to an earlier or later dosing schedule for RV vaccines.
The authors thank the sentinel hospital rotavirus surveillance team and other study staff in Bolivia for their efforts in the enrollment of the participants for the rotavirus vaccine effectiveness evaluation. The authors also thank the following individuals for their role in the study: Leovigildo Alvarez, Michael Bowen, Lucia Inchauste Jordan, Volga Iniguez, Raul Montesano, Aleida Nina, Desiree Pastor, Maritza Patzi, Osbourne Quaye, Rosario Rivera, Yelin Roca, Ka Ian Tam and Adolfo Zarate.
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