Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

Abstract

ObjectiveRTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals' proprietary Adjuvant Systems AS02A or AS01B. A recent trial of the RTS,S/AS02A and RTS,S/AS01B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02A and RTS,S/AS01B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias.DesignThe distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine.SettingThe study was conducted in Kombewa District, western Kenya.ParticipantsSemi-immune adults from the three study arms provided isolates at baseline and during break-through infections.OutcomeParasite isolates used for determining MOI and divergence of csp T cell–epitopes were 191 at baseline and 87 from break-through infections.ResultsGrouping recipients of RTS,S/AS01A and RTS,S/AS02B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01B group, but not the RTS,S/AS02A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups.ConclusionsIt is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct.

Plasmodium vivax Ookinete Surface Protein Pvs25 Linked to Cholera Toxin B Subunit Induces Potent Transmission-Blocking Immunity by Intranasal as Well as Subcutaneous Immunization

“…‫,ء‬ P Ͻ 0.001 versus the nonimmune (N) group as determined by the Wilcoxon-Mann-Whitney test; ‫,ءء‬ P Ͻ 0.001 between the S and L groups as determined by the Wilcoxon-Mann-Whitney test; ‫,ءءء‬ P Ͻ 0.001 among the three groups (S, M, and L) as determined by the KruskalWallis test; †, P Ͻ 0.005 versus the nonimmune (N) group as determined by the chi-square test; † †, P Ͻ 0.005 between the indicated two groups as determined by the chi-square test. (20,29), and the GlaxoSmithKline adjuvant systems (GlaxoSmithKline, Brentford, United Kingdom) (8,27), will expedite malaria vaccine development. It is also possible that protein delivery molecules will ultimately be combined with effective oil or other adjuvants, including aluminum hydroxide.…”

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.…”

Advancement Towards an Approved Vaccine to Target Plasmodium Falciparum Malaria

“…43 RTS contains three distinct portions, the first of which is a single polypeptide chain that corresponds to a large region of the highly conserved tandem repeat (R) tetra-peptide sequence from CSP; each repeat tetra-peptide is called NANP. 44,45 There are 19 copies of NANP and it is named for its amino acid sequence.…”

“…42,44 The 'R' and 'T' components correspond to amino acids 207-395 on CSP of the 3D7 standard laboratory strain of P. falciparum. 42,44,45 Fig. 3 shows a simplified representation of the 'RT' peptide chain.…”