RTS,S/AS02A Malaria Vaccine Does Not Induce Parasite CSP T Cell Epitope Selection and Reduces Multiplicity of Infection

Abstract

Objective:The candidate malaria vaccine RTS,S/AS02A is a recombinant protein containing part of the circumsporozoite protein (CSP) sequence of Plasmodium falciparum, linked to the hepatitis B surface antigen and formulated in the proprietary adjuvant system AS02A. In a recent trial conducted in children younger than age five in southern Mozambique, the vaccine demonstrated significant and sustained efficacy against both infection and clinical disease. In a follow-up study to the main trial, breakthrough infections identified in the trial were examined to determine whether the distribution of csp sequences was affected by the vaccine and to measure the multiplicity of infecting parasite genotypes.Design: P. falciparum DNA from isolates collected during the trial was used for genotype studies.Setting:The main trial was carried out in the Manhiça district, Maputo province, Mozambique, between April 2003 and May 2004.Participants:Children from the two cohorts of the main trial provided parasite isolates as follows: children from Cohort 1 who were admitted to hospital with clinical malaria; children from Cohort 1 who were parasite-positive in a cross-sectional survey at study month 8.5; children from Cohort 2 identified as parasite-positive during follow-up by active detection of infection.Outcome:Divergence of DNA sequence encoding the CSP T cell–epitope region sequence from that of the vaccine sequence was measured in 521 isolates. The number of distinct P. falciparum genotypes was also determined.Results:We found no evidence that parasite genotypes from children in the RTS,S/AS02A arm were more divergent than those receiving control vaccines. For Cohort 1 (survey at study month 8.5) and Cohort 2, infections in the vaccine group contained significantly fewer genotypes than those in the control group, (p = 0.035, p = 0.006), respectively, for the two cohorts. This was not the case for children in Cohort 1 who were admitted to hospital (p = 0.478).Conclusions:RTS,S/AS02A did not select for genotypes encoding divergent T cell epitopes in the C-terminal region of CSP in this trial. In both cohorts, there was a modest reduction in the mean number of parasite genotypes harboured by vaccinated children compared with controls, but only among those with asymptomatic infections.

From the circumsporozoite protein to the RTS,S/AS candidate vaccine

“…The vaccine, Engerix-B TM , targets the hepatitis B protection in children was found not to be strain specific and reduced multiplicity of infection. 58 Importantly, over the 45 month period of surveillance, RTS,S/AS02 A had an acceptable safety profile, with significantly less serious adverse events and a trend towards reduced all cause mortality compared to recipients of control vaccine.…”

Molecular Epidemiology of Malaria

“…The synthetic peptide combination SPf66 that contains a short sequence from near the N terminus of the P. falciparum merozoite surface protein 1 (MSP1) was tested in The Gambia (91), and the recombinant protein-based RTS,S/AS02A that contains a large portion of the P. falcipa- VOL. 20, 2007 MOLECULAR EPIDEMIOLOGY OF MALARIA 197 on May 12, 2018 by guest http://cmr.asm.org/ rum circumsporozoite protein was tested in The Gambia (3) and Mozambique (69). The RTS,S/AS02A vaccine had a significantly protective effect and the SPf66 vaccine did not, but neither affected the allele frequencies of their respective antigens in the infections that occurred in the vaccine group compared to the control group (3,69,91).…”

“…20, 2007 MOLECULAR EPIDEMIOLOGY OF MALARIA 197 on May 12, 2018 by guest http://cmr.asm.org/ rum circumsporozoite protein was tested in The Gambia (3) and Mozambique (69). The RTS,S/AS02A vaccine had a significantly protective effect and the SPf66 vaccine did not, but neither affected the allele frequencies of their respective antigens in the infections that occurred in the vaccine group compared to the control group (3,69,91). In contrast, a smaller trial in Papua New Guinea of a combination vaccine that included one allelic form of MSP2 showed that subjects who were vaccinated had subsequent P. falciparum infections with disproportionately higher relative frequencies of the alternative MSP2 allelic type, suggesting that this vaccine had an allele-specific effect on MSP2 (84).…”

Using Population Genetics to Guide Malaria Vaccine Design

“…Because CSP is polymorphic, an obvious question was whether diversity in CSP may explain the partial efficacy of the RTS,S vaccine. Analyses of infecting genotypes in one phase II trial of RTS,S suggested that this was not the case as there was no evidence of selection for infections containing non-vaccine genotypes among vaccinated versus control subjects [197,198]. These findings highlight that although antigen polymorphism needs to be considered in vaccine development, it may not be a major issue for all vaccines.…”