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Efficacy of a Low-Cost, Heat-Stable Oral Rotavirus Vaccine in Niger

Friday, 24th of March 2017 Print

Efficacy of a Low-Cost, Heat-Stable Oral Rotavirus Vaccine in Niger

Excerpt below; full text is at http://www.nejm.org/doi/full/10.1056/NEJMoa1609462#t=article

 

DISCUSSION

In this phase 3 trial in Niger, we found that three doses of BRV-PV, an oral rotavirus vaccine, protected healthy infants from severe rotavirus gastroenteritis. In a previous double-blind, placebo-controlled trial in Ghana, Kenya, and Mali, the efficacy of the RotaTeq vaccine against severe rotavirus gastroenteritis was 39.3% (95% CI, 19.1 to 54.7).4 In a similar trial in South Africa and Malawi, the efficacy of the Rotarix vaccine was 61.2% (95% CI, 44.0 to 73.2).7 In our trial, against a higher background incidence of severe disease than in the countries in the other two trials and with a vaccine efficacy of 66.7%, there were 4.30 fewer cases of severe rotavirus gastroenteritis per 100 infant-years among infants who received BRV-PV than among those who received placebo.

Efficacy estimates were lower than those observed in trials of other rotavirus vaccines among children in Europe and Latin America (80.5 to 90.4%),10,12,28,29 a finding that is consistent with the results of studies comparing the efficacy of various vaccines against other diseases in these regions.30-33 The same efficacy gradient has also been found in industrialized countries in analyses of differences according to socioeconomic status.34 The underlying mechanisms for this finding remain poorly understood. Considerations have included the epidemiologic features of rotavirus infection (e.g., an earlier age at first infection among children in Africa, which confers natural protection in the placebo group),35 host characteristics (e.g., poor nutritional status and differences in the gut microbiome, enteropathy, and enteric coinfections), and interference from maternal antibodies in breast milk36 and from coadministration of the oral polio vaccine, which can reduce rotavirus antibody levels.37-39 Thus, there is a need to explore the role of prenatal nutritional status on immunogenicity and vaccine efficacy.

We did not identify any safety concerns with BRV-PV. Fewer serious adverse events and hospitalizations were reported among vaccinated infants than among those who received placebo. There was no significant difference in overall mortality between the groups and no plausible temporal or biologic causality for reported adverse events. No confirmed cases of intussusception were observed, a finding that was consistent with the results of other trials of oral rotavirus vaccine in the region.40 However, this study was not powered to detect an increased incidence of rare events such as intussusception.

In 2013, the WHO recommended that rotavirus vaccine be administered whenever children present for routine immunizations, a protocol that would allow for relaxation of upper age restrictions and thus greater coverage.2 In our trial, the vaccine efficacy in the intention-to-treat population (73.0%), in which the vaccine administration schedule was more flexible than that in the per-protocol population, may more closely represent the efficacy under real-world conditions. The use of a reduced two-dose schedule with pentavalent vaccines has advantages with respect to cost and logistics, but evidence has been consistent with respect to the higher efficacy of a three-dose schedule.41

This study has several important limitations. First, the vaccine was not consistently given concomitantly with the oral polio vaccine. However, secondary analyses that estimated vaccine efficacy according to whether BRV-PV was coadministered with oral polio vaccine suggested that the observed efficacy was not due to lower rates of concomitant administration. Second, the Vesikari score was originally designed for use in settings of high parental literacy,25 which may have led to underscoring of some cases in our trial because of low parental literacy, although in such cases the results would not have differed between the two groups. Finally, at the time of the analysis, no extensive genotyping data were available to weigh the vaccine efficacy against a changing pattern of circulating serotypes, and the limited time period for this analysis precluded the inclusion of efficacy data up to 2 years of follow-up.

At present, 33 countries in sub-Saharan Africa either are using or plan to introduce rotavirus vaccines.42 BRV-PV does not require refrigeration and has reasonable efficacy with respect to morbidity and mortality from this preventable disease. Although no adverse-event signal was seen, large-scale surveillance will be needed to establish safety.

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