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

      Isanaka, S; Guindo, O; Langendorf, C; Matar Seck, A; Plikaytis, BD; Sayinzoga-Makombe, N; McNeal, MM; Meyer, N; Adehossi, E; Djibo, A; et al. (Massachusetts Medical Society, 2017-03-23)
      Background Each year, rotavirus gastroenteritis is responsible for about 37% of deaths from diarrhea among children younger than 5 years of age worldwide, with a disproportionate effect in sub-Saharan Africa. Methods We conducted a randomized, placebo-controlled trial in Niger to evaluate the efficacy of a live, oral bovine rotavirus pentavalent vaccine (BRV-PV, Serum Institute of India) to prevent severe rotavirus gastroenteritis. Healthy infants received three doses of the vaccine or placebo at 6, 10, and 14 weeks of age. Episodes of gastroenteritis were assessed through active and passive surveillance and were graded on the basis of the score on the Vesikari scale (which ranges from 0 to 20, with higher scores indicating more severe disease). The primary end point was the efficacy of three doses of vaccine as compared with placebo against a first episode of laboratory-confirmed severe rotavirus gastroenteritis (Vesikari score, ≥11) beginning 28 days after dose 3. Results Among the 3508 infants who were included in the per-protocol efficacy analysis, there were 31 cases of severe rotavirus gastroenteritis in the vaccine group and 87 cases in the placebo group (2.14 and 6.44 cases per 100 person-years, respectively), for a vaccine efficacy of 66.7% (95% confidence interval [CI], 49.9 to 77.9). Similar efficacy was seen in the intention-to-treat analyses, which showed a vaccine efficacy of 69.1% (95% CI, 55.0 to 78.7). There was no significant between-group difference in the risk of adverse events, which were reported in 68.7% of the infants in the vaccine group and in 67.2% of those in the placebo group, or in the risk of serious adverse events (in 8.3% in the vaccine group and in 9.1% in the placebo group); there were 27 deaths in the vaccine group and 22 in the placebo group. None of the infants had confirmed intussusception. Conclusions Three doses of BRV-PV, an oral rotavirus vaccine, had an efficacy of 66.7% against severe rotavirus gastroenteritis among infants in Niger. (Funded by Médecins sans Frontières Operational Center and the Kavli Foundation; ClinicalTrials.gov number, NCT02145000 .).
    • Factors influencing participation in an Ebola vaccine trial among front-line workers in Guinea

      Grantz, KH; Claudot, C; Kambala, M; Kouyate, M; Soumah, A; Boum, Y; Juan-Giner, A; Jemmy, JP; Cummings, DAT; Grais, RFF (Elsevier, 2019-10-14)
      Background Alongside the clinical aspects of the immunogenicity and safety trial of an Ebola vaccine deployed among front-line workers, a qualitative study was conducted to describe motivations behind individuals’ decisions to participate – or not to participate – in the study. Methods In July and August 2015, focus group discussions and semi-structured individual interviews were conducted in Conakry, Guinea. Individuals were eligible for the qualitative study if they met the inclusion criteria of the immunogenicity and safety study irrespective of their participation. Surveys were also conducted among several institution and department heads of staff included in the study as well as vaccine trial staff members. Discussion and interview transcripts were analyzed using content thematic analysis. Results Interviews and focus groups were conducted among 110 persons, of whom about two-thirds (67%) participated in the vaccine trial. There was at least one group interview conducted at each participating trial site, along with numerous formal and informal interviews and conversations through the enrollment period. Participants were often motivated by a desire to save and protect themselves and others, contribute to scientific progress, or lead by example. Non-participants expressed concerns regarding the risk and costs of participation, particularly the fear of unknown side effects following vaccination, and distrust or fear of stigmatization. Conclusions Despite the unique nature of the 2014–2015 Ebola outbreak, front-line workers employed much of the same logic when choosing to participate as in other clinical trials in similar settings. Special consideration should be given to addressing perceived inequity, misunderstanding, and mistrust among the target populations in future trials.
    • Improving rotavirus vaccine coverage: Can newer-generation and locally produced vaccines help?

      Deen, J; Lopez, AL; Kanungo, S; Wang, XY; Anh, DD; Tapia, M; Grais, RFF (Taylor & Francis, 2017-11-14)
      There are two internationally available WHO-prequalified oral rotavirus vaccines (Rotarix and RotaTeq), two rotavirus vaccines licensed in India (Rotavac and Rotasiil), one in China (Lanzhou lamb rotavirus vaccine) and one in Vietnam (Rotavin-M1), and several candidates in development. Rotavirus vaccination has been rolled out in Latin American countries and is beginning to be deployed in sub-Saharan African countries but middle- and low-income Asian countries have lagged behind in rotavirus vaccine introduction. We provide a mini-review of the leading newer-generation rotavirus vaccines and compare them with Rotarix and RotaTeq. We discuss how the development and future availability of newer-generation rotavirus vaccines that address the programmatic needs of poorer countries may help scale-up rotavirus vaccination where it is needed.
    • A mixture model to assess the the immunogenicity of an oral rotavirus vaccine among healthy infants in Niger

      Hitchings, MDT; Cummings, DAT; Grais, RFF; Isanaka, S (Elsevier, 2020-11-05)
      Analysis of immunogenicity data is a critical component of vaccine development, providing a biological basis to support any observed protection from vaccination. Conventional methods for analyzing immunogenicity data use either post-vaccination titer or change in titer, often defined as a binary variable using a threshold. These methods are simple to implement but can be limited especially in populations experiencing natural exposure to the pathogen. A mixture model can overcome the limitations of the conventional approaches by jointly modeling the probability of an immune response and the level of the immune marker among those who respond. We apply a mixture model to analyze the immunogenicity of an oral, pentavalent rotavirus vaccine in a cohort of children enrolled into a placebo-controlled vaccine efficacy trial in Niger. Among children with undetectable immunoglobulin A (IgA) at baseline, vaccinated children had 5.2-fold (95% credible interval (CrI) 3.7, 8.3) higher odds of having an IgA response than placebo children, but the mean log IgA among vaccinated responders was 0.9-log lower (95% CrI 0.6, 1.3) than among placebo responders. This result implies that the IgA response generated by vaccination is weaker than that generated by natural infection. Multivariate logistic regression of seroconversion defined by ≥ 3-fold rise in IgA similarly found increased seroconversion among vaccinated children, but could not demonstrate lower IgA among those who seroresponded. In addition, we found that the vaccine was less immunogenic among children with detectable IgA pre-vaccination, and that pre-vaccination infant serum IgG and mother’s breast milk IgA modified the vaccine immunogenicity. Increased maternal antibodies were associated with weaker IgA response in placebo and vaccinated children, with the association being stronger among vaccinated children. The mixture model is a powerful and flexible method for analyzing immunogenicity data and identifying modifiers of vaccine response and independent predictors of immune response.
    • Safety of a heat-stable rotavirus vaccine among children in Niger: Data from a phase 3, randomized, double-blind, placebo-controlled trial

      Coldiron, ME; Guindo, O; Makarimi, R; Soumana, I; Matar Seck, A; Garba, S; Macher, E; Isanaka, S; Grais, RFF (Elsevier, 2018-05-08)
      Rotavirus remains a major cause of diarrhea among children under 5 years of age. The efficacy of RotaSIIL, a pentavalent rotavirus vaccine, was shown in an event-driven trial in Niger. We describe the two-year safety follow-up of this trial.
    • Safety of the rVSV ZEBOV vaccine against Ebola Zaire among frontline workers in Guinea

      Juan-Giner, A; Tchaton, M; Jemmy, JP; Soumah, A; Boum, Y; Faga, EM; Cisse, M; Grais, RFF (Elsevier, 2018-09-25)
      As part of the ring vaccination trial in Guinea, Front Line Workers were invited to participate in a sub-study to provide additional information on the immunogenicity and safety of rVSVΔG/ZEBOV-GP. Here we summarize the information on the safety follow-up.
    • Sub-national variation in measles vaccine coverage and outbreak risk: a case study from a 2010 outbreak in Malawi.

      Kundrick, A; Huang, Z; Carran, S; Kagoli, M; Grais, RFF; Hurtado, N; Ferrari, M (BioMed Central, 2019-06-15)
      Background Despite progress towards increasing global vaccination coverage, measles continues to be one of the leading, preventable causes of death among children worldwide. Whether and how to target sub-national areas for vaccination campaigns continues to remain a question. We analyzed three metrics for prioritizing target areas: vaccination coverage, susceptible birth cohort, and the effective reproductive ratio (RE) in the context of the 2010 measles epidemic in Malawi. Methods Using case-based surveillance data from the 2010 measles outbreak in Malawi, we estimated vaccination coverage from the proportion of cases reporting with a history of prior vaccination at the district and health facility catchment scale. Health facility catchments were defined as the set of locations closer to a given health facility than to any other. We combined these estimates with regional birth rates to estimate the size of the annual susceptible birth cohort. We also estimated the effective reproductive ratio, RE, at the health facility polygon scale based on the observed rate of exponential increase of the epidemic. We combined these estimates to identify spatial regions that would be of high priority for supplemental vaccination activities. Results The estimated vaccination coverage across all districts was 84%, but ranged from 61 to 99%. We found that 8 districts and 354 health facility catchments had estimated vaccination coverage below 80%. Areas that had highest birth cohort size were frequently large urban centers that had high vaccination coverage. The estimated RE ranged between 1 and 2.56. The ranking of districts and health facility catchments as priority areas varied depending on the measure used. Conclusions Each metric for prioritization may result in discrete target areas for vaccination campaigns; thus, there are tradeoffs to choosing one metric over another. However, in some cases, certain areas may be prioritized by all three metrics. These areas should be treated with particular concern. Furthermore, the spatial scale at which each metric is calculated impacts the resulting prioritization and should also be considered when prioritizing areas for vaccination campaigns. These methods may be used to allocate effort for prophylactic campaigns or to prioritize response for outbreak response vaccination.
    • Using Simulation to Aid Trial Design: Ring-Vaccination Trials.

      Hitchings, MD; Grais, RFF; Lipsitch, M (Public Library of Science, 2017-03-22)
      The 2014-6 West African Ebola epidemic highlights the need for rigorous, rapid clinical trial methods for vaccines. A challenge for trial design is making sample size calculations based on incidence within the trial, total vaccine effect, and intracluster correlation, when these parameters are uncertain in the presence of indirect effects of vaccination.