Safety and immunogenicity of the RTS,S/AS01 malaria vaccine in infants and children identified as HIV-infected during a randomized trial in sub-Saharan Africa

Abstract

Background: We assessed the safety and immunogenicity of the RTS,S/AS01 malaria vaccine in a subset of children identified as HIV-infected during a large phase III randomized controlled trial conducted in seven sub-Saharan African countries.

Methods: Infants 6-12 weeks and children 5-17 months old were randomized to receive 4 RTS,S/AS01 doses (R3R group), 3 RTS,S/AS01 doses plus 1 comparator vaccine dose (R3C group), or 4 comparator vaccine doses (C3C group) at study months 0, 1, 2 and 20. Infants and children with WHO stage III/IV HIV disease were excluded but HIV testing was not routinely performed on all participants; our analyses included children identified as HIV-infected based on medical history or clinical suspicion and confirmed by polymerase chain reaction or antibody testing. Serious adverse events (SAEs) and anti-circumsporozoite (CS) antibodies were assessed.

Results: Of 15459 children enrolled in the trial, at least 1953 were tested for HIV and 153 were confirmed as HIV-infected (R3R: 51; R3C: 54; C3C: 48). Among these children, SAEs were reported for 92.2% (95% CI: 81.1-97.8) in the R3R, 85.2% (72.9-93.4) in the R3C and 87.5% (74.8-95.3) in the C3C group over a median follow-up of 39.3, 39.4 and 38.3 months, respectively. Fifteen HIV-infected participants in each group (R3R: 29.4%, R3C: 27.8%, C3C: 31.3%) died during the study. No deaths were considered vaccination-related. In a matched case-control analysis, 1 month post dose 3 anti-CS geometric mean antibody concentrations were 193.3 EU/mL in RTS,S/AS01-vaccinated HIV-infected children and 491.5 EU/mL in RTS,S/AS01-vaccinated immunogenicity controls with unknown or negative HIV status (p = 0.0001).

Conclusions: The safety profile of RTS,S/AS01 in HIV-infected children was comparable to that of the comparator (meningococcal or rabies) vaccines. RTS,S/AS01 was immunogenic in HIV-infected children but antibody concentrations were lower than in children with an unknown or negative HIV status.

Clinical trial registration: ClinicalTrials.gov: NCT00866619.

Keywords: Children; HIV; Immunogenicity; Malaria; RTS; S/AS01 vaccine; Safety.

Conflict of interest statement

Declaration of Competing Interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Marc Lievens is employed by the GSK group of companies. Yolanda Guerra Mendoza, Opokua Ofori-Anyinam, Lode Schuerman and Pascale Vandoolaeghe are employed by the GSK group of companies and hold shares in the GSK group of companies. Peter Kremsner and Godfrey Allan Otieno report grants from PATH-MVI and from the GSK group of companies during the conduct of the study. Lucas Otieno reports grants from PATH-MVI and from the GSK group of companies during the conduct of the study and outside the submitted work. Bertrand Lell reports grants from PATH-MVI, during the conduct of the study. Marcel Tanner has received support for board membership from Optimus Foundation, outside the submitted work. The institute of Marcel Tanner (Swiss Tropical and Public Health Institute, University of Basel, Basel, Switzerland) has received grants and support for travel to meetings from PATH-MVI and from the GSK group of companies for the submitted work; support for board membership from the Scientific advisory board of the Novartis Institute for Tropical Diseases, grants from PATH-MVI and the Bill & Melinda Gates Foundation, support from MVI and Sanaria Corp. for travel, accommodations and meeting expenses outside the submitted work. All other authors report no conflicts of interest.

Copyright © 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1

Flow diagram. R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/AS01 plus 1 dose of comparator vaccine; C3C, group receiving 4 doses of comparator vaccine; ITT, intent-to-treat. aNot all HIV tests were recorded in the database for all centers; 1953 is therefore the minimum number of children tested for HIV at least once during the study.

Fig. 2

Survival curves (ITT population of HIV-infected participants). ITT, intent-to-treat; R3R, group receiving 4 doses of RTS,S/AS01; R3C, group receiving 3 doses of RTS,S/ AS01 plus 1 dose of comparator vaccine; C3C, group receiving 4 doses of comparator vaccine.

Fig. 3. Plain language summary presenting the findings and highlighting their clinical relevance.