Abstract
BackgroundThe production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge. Success in vaccine immunogenicity studies in small animal models does not always predict immunogenicity in non-human primates and/or human subjects. The aim of this study was to assess the immunogenicity of a chimeric blood-stage malaria vaccine in Aotus monkeys. This vaccine candidate includes the neutralizing B cell epitopes of P. falciparum merozoite surface protein 1 (rPfMSP119) genetically linked to a highly immunogenic, well-conserved P. falciparum merozoite surface protein 8 (rPfMSP8 (ΔAsn/Asp)) partner.MethodsAotus nancymaae monkeys were immunized with purified rPfMSP1/8 or rPfMSP8 (ΔAsn/Asp) formulated with Montanide ISA 720 as adjuvant, or with adjuvant alone. Antibody responses to MSP119 and MSP8 domains were measured by ELISA following primary, secondary and tertiary immunizations. The functionality of vaccine-induced antibodies was assessed in a standard P. falciparum blood-stage in vitro growth inhibition assay. Non-parametric tests with corrections for multiple comparisons when appropriate were used to determine the significance of differences in antigen-specific IgG titres and in parasite growth inhibition.ResultsThe chimeric rPfMSP1/8 vaccine was shown to be well tolerated and highly immunogenic with boost-able antibody responses elicited to both PfMSP8 and PfMSP119 domains. Elicited antibodies were highly cross-reactive between FVO and 3D7 alleles of PfMSP119 and potently inhibited the in vitro growth of P. falciparum blood-stage parasites.ConclusionsSimilar to previous results with inbred and outbred mice and with rabbits, the PfMSP1/8 vaccine was shown to be highly effective in eliciting P. falciparum growth inhibitory antibodies upon immunization of non-human primates. The data support the further assessment of PfMSP1/8 as a component of a multivalent vaccine for use in human subjects. As important, the data indicate that rPfMSP8 (ΔAsn/Asp) can be used as a malaria specific carrier protein to: (1) drive production of antibody responses to neutralizing B cell epitopes of heterologous vaccine candidates and (2) facilitate production of properly folded, recombinant P. falciparum subunit vaccines in high yield.
Highlights
The production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge
Burns Jr. et al Malar J (2016) 15:159 trials, is a pre-erythrocytic-stage vaccine based on the circumsporozoite protein of Plasmodium falciparum [2]
Recombinant antigens The production and purification of the chimeric rPfMSP1/8 and rPfMSP8 (ΔAsn/Asp) (P. falciparum FVO strain) followed the same protocol, using codon-harmonized, synthetic gene sequences cloned into pET-28 (EMD Biosciences, San Diego, CA, USA) and SHuffleTM T7 Express lysY E. coli cells (New England Biolabs, Ipswich, MA, USA) as host
Summary
The production of properly folded, recombinant sub-unit Plasmodium falciparum malaria vaccine candidates in sufficient quantities is often a challenge. There is mounting agreement in the field that an effective malaria vaccine will require induction of immune responses to multiple, distinct target antigens This concept is central in the development of whole parasite-based vaccines, including radiation (PfSPZ) [11, 12] and genetically (PfGAS) [12,13,14] attenuated sporozoite vaccines, infection-treatment pre-erythrocytic-stage vaccines [15, 16], and chemically inactivated whole blood-stage vaccines [17, 18]. Other significant challenges associated with sub-unit malaria vaccine development have been encountered These include difficulties in producing properly folded candidate antigens, polymorphism in T and B cell epitopes, and poor immunogenicity. This problem has impeded the development of other multi-antigen malaria vaccine formulations [20,21,22,23,24]
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