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.
Highlights
Malaria continues to be a major cause of morbidity and mortality in many countries of Africa, and is estimated to cause more than one million deaths each year [1]
Several malaria vaccine candidates have been tested in malaria endemic countries [2], including the pre-erythrocyte vaccine RTS,S/AS02A, a recombinant polypeptide developed by GSK Biologicals that contains most of the C-terminal half of the circumsporozoite protein (CSP) sequence of P. falciparum fused to hepatitis B virus surface antigen formulated in the AS02A adjuvant system [3,4]
The RTS,S/AS02A trial conducted in Mozambique enrolled two cohorts of children, one for estimation of vaccine efficacy against episodes of clinical malaria (Cohort 1), and the other for estimation of efficacy against infection (Cohort 2) [6]
Summary
Malaria continues to be a major cause of morbidity and mortality in many countries of Africa, and is estimated to cause more than one million deaths each year [1]. A recent trial in young children in Mozambique found that an experimental malaria vaccine, RTS,S/AS02A, reduces the risk of clinical malaria, delays time to new infection, and reduces episodes of severe malaria over 18 months. Because there are different variants of the circumsporozoite protein in the parasite population, the researchers were concerned that the strain-specific protection offered by RTS,S/ AS02A might select for parasites with particular variants of the circumsporozoite gene. They did a follow-up study to investigate this concern, looking to see whether vaccinated children who became infected with malaria had variant forms of the parasite. In children within the trial who were admitted to hospital with clinical malaria, the number of different ‘‘strains’’ of the parasite was no different between vaccinated children and controls
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