Safety and Immunogenicity of Malaria Vectored Vaccines Given with Routine Expanded Program on Immunization Vaccines in Gambian Infants and Neonates: A Randomized Controlled Trial.

BACKGROUND: Heterologous prime-boost vaccination with chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) encoding multiple epitope string thrombospondin-related adhesion protein (ME-TRAP) has shown acceptable safety and promising immunogenicity in African adult and pediatric populations. If licensed, this vaccine could be given to infants receiving routine childhood immunizations. We therefore evaluated responses to ChAd63 MVA ME-TRAP when co-administered with routine Expanded Program on Immunization (EPI) vaccines. METHODS: We enrolled 65 Gambian infants and neonates, aged 16, 8, or 1 week at first vaccination and randomized them to receive either ME-TRAP and EPI vaccines or EPI vaccines only. Safety was assessed by the description of vaccine-related adverse events (AEs). Immunogenicity was evaluated using IFNγ enzyme-linked immunospot, whole-blood flow cytometry, and anti-TRAP IgG ELISA. Serology was performed to confirm all infants achieved protective titers to EPI vaccines. RESULTS: The vaccines were well tolerated in all age groups with no vaccine-related serious AEs. High-level TRAP-specific IgG and T cell responses were generated after boosting with MVA. CD8+ T cell responses, previously found to correlate with protection, were induced in all groups. Antibody responses to EPI vaccines were not altered significantly. CONCLUSION: Malaria vectored prime-boost vaccines co-administered with routine childhood immunizations were well tolerated. Potent humoral and cellular immunity induced by ChAd63 MVA ME-TRAP did not reduce the immunogenicity of co-administered EPI vaccines, supporting further evaluation of this regimen in infant populations. CLINICAL TRIAL REGISTRATION: The clinical trial was registered on http://Clinicaltrials.gov (NCT02083887) and the Pan-African Clinical Trials Registry (PACTR201402000749217)

Consort 2010 flow diagram

<p>Consort 2010 flow diagram</p

Baseline characteristics

<p>Baseline characteristics</p

Vaccine efficacy by Cox regression for any parasitaemia and parasitaemia >10 per ml

<p>Vaccine efficacy by Cox regression for any parasitaemia and parasitaemia >10 per ml</p

Vaccine immunogenicity.

<p>(A and B). Anti-TRAP IgG titres and IFN-γ ELISpot responses to TRAP peptide pools before and after vaccination. **** p<0.0001, Kruskall-Wallis with Dunn’s post-test; ^^^^ p<0.0001, 2-tailed Mann Whitney test. Lines represent geometric means. (C). Correlation between humoral and cellular immunogenicity for ME-TRAP vaccinees, 2-tailed Pearson’s test, n = 54. (D). Proportion of vaccinees with positive responses to TRAP peptide pools after boosting with MVA. Labels on x-axis refer to peptide pools described in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0167951#pone.0167951.s003" target="_blank">S3 Table</a>. E. Epitope mapping of TRAP peptide TT1-10, 11–20 and 21–30 using cryopreserved PBMC. Each colour represents a different volunteer, n = 6. F. Neutralising antibody titres to the ChAd63 vector measured in Senegalese and UK volunteers, 2-tailed Mann-Whitney.</p

Local and systemic adverse event profiles for each vaccination, stratified by severity.

<p>Local and systemic adverse event profiles for each vaccination, stratified by severity.</p

Pooled vaccine efficacy by Cox regression for the studies in Kenya and Senegal.

<p>Pooled vaccine efficacy by Cox regression for the studies in Kenya and Senegal.</p

Parasite density as measured by PCR for each trial.

<p>Each line represents an individual volunteer. P = PCR testing performed. During the PCR monitoring follow-up period, blood samples were tested by PCR three times a week from day 70 to day 95 and once per week from day 98 to day 119.</p

Kaplan-Meier plots of time to first infection.

<p>(A) First episode of PCR positivity at any threshold for the trial in Senegal. (B). Combined analysis of data from the Senegal and Kenya trials. (C). First episode of PCR positivity at >10 parasites per ml for the trial in Senegal. (D). Combined analysis of data from the Senegal and Kenya trials</p