Need for Local Laboratory Reference Values in Recruitment into Studies of Emerging Infectious Diseases: Insight from Participant Screening for an Ebola Vaccine Trial in a Rural African Setting

Introduction: The EBOVAC-Salone trial of a candidate Ebola two-dose vaccine regimen (Ad.ZEBOV/MVA-BN-Filo) was conducted in a research-naïve setting in rural northern Sierra Leone, where no local laboratory reference values (LRV) had been established. In the first stage (n = 43) of the trial, laboratory screening was based on internationally-derived protocol LRV (PLRV). For postrecruitment participant care, LRV derived from a West African population (WALRV) were used. We assessed what difference using WALRV rather than PLRV for screening might have made to the eligibility of volunteers. METHODS: We reviewed the laboratory screening results of study volunteers. Red blood cells (RBC), white blood cells (WBC), platelets (PTT), haemoglobin, haematocrit, creatinine, and alanine (ALT) and aspartate (AST) transaminases were measured. Overall and for each parameter, we compared the actually eligible proportion of volunteers using PLRV with the potentially eligible proportion using WALRV. Results: Of 102 (82 males, 20 females) volunteers, overall 55 (53.9% males) met PLRV eligibility criteria for inclusion, compared with 91 (89.2% males) who were within WALRV normal limits (p < 0.0001). Thus, 36 volunteers who failed laboratory screening using PLRV (76.6% of screening failures) might have been eligible if WALRV had been applied. Parameters with significant effect were haemoglobin (33 ineligible by PLRV, vs. 2 ineligible by WALRV; p < 0.0001); RBC (27 vs. 1; p < 0.0001); and PTT (18 vs. 6; p = 0.0093). Levels of creatinine and ALT did not present any differences. Discussion: Use of WALRV in eligibility assessment would potentially have led to considerable differences in the baseline laboratory characteristics of enrolled volunteers. Clinical trials are increasingly common and crucial in emerging infectious disease research. Our findings underscore the importance of locally-derived LRV in clinical trials in sub-Saharan Africa, to avoid excluding potentially eligible study volunteers, and to better support routine clinical care and safety assessments. Appropriately designed studies are needed in each region to establish local LRV

Asymptomatic Malaria Infection and the Immune Response to the 2-Dose Ad26.ZEBOV, MVA-BN-Filo Ebola Vaccine Regimen in Adults and Children

Background Malaria infection affects the immune response to some vaccines. As Ebola virus (EBOV) outbreaks have occurred mainly in malaria-endemic countries, we have assessed whether asymptomatic malaria affects immune responses to the 2-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen. Methods In this sub-study of the EBOVAC-Salone Ebola vaccine trial in Sierra Leone, malaria microscopy was performed at the time of Ebola vaccination. Participants with symptomatic malaria were treated before vaccination. Ebola vaccine responses were assessed post-dose 1 (day 57) and post-dose 2 (day 78) by the EBOV glycoprotein FANG enzyme-linked immunosorbent assay (ELISA), and responses expressed as geometric mean concentrations (GMCs). Geometric mean ratios (GMRs) of the GMCs in malaria-positive versus malaria-negative participants were derived with 95% confidence intervals (CIs). Results A total of 587 participants were studied, comprising 188 adults (≥18 years) and 399 children (in age groups of 12–17, 4–11, and 1–3 years). Asymptomatic malaria was observed in 47.5% of adults and 51.5% of children on day 1. Post-dose 1, GMCs were lower in 1–3-year-old malaria-positive compared with malaria-negative children (age group–specific GMR, .56; 95% CI, .39–.81) but not in older age groups. Post-dose 2, there was no consistent effect of malaria infection across the different age groups but there was a trend toward a lower response (GMR, .82; 95% CI, .67–1.02). Conclusions The Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen is immunogenic in participants with asymptomatic malaria. Therefore, it is not necessary to screen for asymptomatic malaria infection prior to vaccination with this regimen

Safety and immunogenicity of an Ad26.ZEBOV booster dose in children previously vaccinated with the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen: an open-label, non-randomised, phase 2 trial.

BACKGROUND: Children account for a substantial proportion of cases and deaths during Ebola virus disease outbreaks. We aimed to evaluate the safety and immunogenicity of a booster dose of the Ad26.ZEBOV vaccine in children who had been vaccinated with a two-dose regimen comprising Ad26.ZEBOV as dose one and MVA-BN-Filo as dose two. METHODS: We conducted an open-label, non-randomised, phase 2 trial at one clinic in Kambia Town, Sierra Leone. Healthy children, excluding pregnant or breastfeeding girls, who had received the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen in a previous study, and were aged 1-11 years at the time of their first vaccine dose, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) and were followed up for 28 days. Primary outcomes were safety (measured by adverse events) and immunogenicity (measured by Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration) of the booster vaccine dose. Safety was assessed in all participants who received the booster vaccination; immunogenicity was assessed in all participants who received the booster vaccination, had at least one evaluable sample after the booster, and had no major protocol deviations that could have influenced the immune response. This trial is registered with ClinicalTrials.gov, NCT04711356. FINDINGS: Between July 8 and Aug 18, 2021, 58 children were assessed for eligibility and 50 (27 aged 4-7 years and 23 aged 9-15 years) were enrolled and received an Ad26.ZEBOV booster vaccination, more than 3 years after receiving dose one of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen. The booster was well tolerated. The most common solicited local adverse event during the 7 days after vaccination was injection site pain, reported in 18 (36%, 95% CI 23-51) of 50 participants. The most common solicited systemic adverse event during the 7 days after vaccination was headache, reported in 11 (22%, 12-36) of 50 participants. Malaria was the most common unsolicited adverse event during the 28 days after vaccination, reported in 25 (50%, 36-64) of 50 participants. No serious adverse events were observed during the study period. 7 days after vaccination, the Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration was 28 561 ELISA units per mL (95% CI 20 255-40 272), which was 44 times higher than the geometric mean concentration before the booster dose. 21 days after vaccination, the geometric mean concentration reached 64 690 ELISA units per mL (95% CI 48 356-86 541), which was 101 times higher than the geometric mean concentration before the booster dose. INTERPRETATION: A booster dose of Ad26.ZEBOV in children who had received the two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen more than 3 years earlier was well tolerated and induced a rapid and robust increase in binding antibodies against Ebola virus. These findings could inform Ebola vaccination strategies in paediatric populations. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section