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

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 vac- cine 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 con- centrations 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 com- parator (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. Ó 2019 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 1. Introduction Malaria and human immunodeficiency virus (HIV) infection remain among the most important public health challenges of our times. An estimated 219 million malaria cases and 435,000 malaria-related deaths occurred worldwide in 2017, with sub- Saharan Africa carrying more than 90% of the global malaria bur- den [1]. Of all malaria-related deaths worldwide, 61% were in chil- dren under 5 years old [1]. In 2017, of the estimated 36.9 million people living with HIV and 940,000 HIV-related deaths globally, approximately 70% were in sub-Saharan Africa [2]. Children younger than 15 years account for approximately 5% of all people living with HIV and 12% of all HIV-related deaths [2]. Most of these children are infected with HIV in utero, during birth or through breastfeeding. Given their geographic overlap, malaria and HIV co-infection is common in sub-Saharan Africa [3,4]. It is therefore important to evaluate the safety and immunogenicity of any malaria candidate vaccine intended for use in this region in HIV-infected children. The pre-erythrocytic RTS,S/AS01 vaccine (GSK) contains portions of the Plasmodium falciparum circumsporozoite (CS) protein and has been shown to be effective in reducing the malaria burden in children when used alongside other malaria interventions in phase II and III clinical trials [5–10]. The safety profile of the vaccine is in line with that of other pediatric vaccines [5–10] and RTS,S/AS01 received a positive scientific opinion from the European Medicines Agency in 2015 [11]. The World Health Organization (WHO) rec- ommended pilot implementation of the vaccine in children 5– 17 months of age in sub-Saharan Africa to answer outstanding questions on feasibility of reaching children with the 4 doses needed for optimal benefit, monitor the safety profile of RTS,S/ AS01 in real-life settings, and measure impact [12]. One prior randomized controlled phase III trial specifically assessed the safety and immunogenicity of a 3-dose RTS,S/AS01 vaccination series in Kenyan children with WHO stage I or II HIV disease, most of whom received antiretroviral therapy (ART) to delay disease progression and cotrimoxazole prophylaxis to pre- vent opportunistic infections. This prior trial showed that RTS,S/ AS01 was well tolerated and immunogenic in HIV-infected chil- dren on ART [13]. Here, we report results of RTS,S/AS01 vaccination in a small subset of children identified as HIV-infected during a separate large phase III randomized controlled efficacy trial which enrolled more than 15,000 children in seven countries in sub-Saharan Africa. The efficacy, safety and immunogenicity findings for the overall population enrolled in this trial, comparing a 3- or 4-dose RTS,S/AS01 schedule with 4 doses of comparator vaccines, were published [7–10]. Although HIV testing was not routinely per- formed, a small proportion of participants were identified as HIV-infected during the trial based on their medical condition, with HIV diagnoses made in the context of the routine clinical care provided at the study centers (and confirmation by polymerase chain reaction [PCR] or antibody testing). This subset therefore provided another opportunity to evaluate safety and immuno- genicity of RTS,S/AS01 in HIV-infected children. 2. Methods 2.1. Study design, participants and vaccines The initial large phase III double-blind (observer-blind) ran- domized controlled efficacy trial was performed between 27 March 2009 and 31 January 2014 at eleven centers in seven countries in sub-Saharan Africa: Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique and Tanzania. The study centers represented differ- ent geographic areas with diverse malaria transmission intensities [9,14] and overlapping background HIV prevalence [2]. Details on the study centers and methods have been described previously [7–10,15–18]. Insecticide-treated bednets were made available to 898 L. Otieno et al. / Vaccine 38 (2020) 897–906