Diversity Covering AMA1-MSP1(19) Fusion Proteins as Malaria Vaccines

Bart W. Faber*, Sumera Younis, Edmond J. Remarque, Roberto Rodriguez Garcia, Vanessa Riasat, Vanessa Walraven, Nicole van der Werff, Marjolein van der Eijk, David R. Cavanagh, Anthony A. Holder, Alan W. Thomas, Clemens H. M. Kocken

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

To overcome polymorphism in the malaria vaccine candidate Plasmodium falciparum apical membrane antigen 1 (PfAMA1), fusion protein chimeras comprised of three diversity-covering (DiCo) PfAMA1 molecules (D1, D2, and D3) and two allelic variants of the C-terminal 19-kDa region of merozoite surface protein 1 (MSP1(19)) (variants M1 and M2) were generated. A mixture of fusion proteins (D1M1/D2M2D3) and the D1M1D2M2D3 fusion were compared to a single-unit mixture (D1/D2/D3/M1) in an immunological study in groups of rabbits. Following immunization, titers of antibodies (Abs) against four naturally occurring PfAMA1 alleles were high for all groups, as were growth inhibition assay (GIA) levels against two antigenically distinct laboratory parasite strains. Fusion of AMA1 to MSP1(19) did not suppress levels of antibodies against the AMA1 component. In addition, the breadth of antibody responses was unaffected. Anti-AMA1 antibodies were largely responsible for parasite growth inhibition, as shown in reversal-of-inhibition experiments by adding competing AMA1 antigen. For all groups, titration of the MSP1(19) antigen into the GIA led to only a small decrease in parasite inhibition, although titers of antibodies against MSP1(19) were increased 15-fold for the groups immunized with fusion proteins. GIA with affinity-purified anti-MSP1(19) antibodies showed that the 50% inhibitory concentrations of the anti-MSP1(19) antibody preparations were in the same order of magnitude for all animals tested, leading to the conclusion that fusing MSP1(19) to PfAMA1 leads to a small but significant increase in functional antibody levels. This study shows that combination of multiple vaccine candidates in fusion proteins may lead to improved characteristics of the vaccine.

Original languageEnglish
Pages (from-to)1479-1490
Number of pages12
JournalInfection and Immunity
Volume81
Issue number5
DOIs
Publication statusPublished - May 2013

Keywords

  • APICAL MEMBRANE ANTIGEN-1
  • MEROZOITE SURFACE PROTEIN-1
  • PLASMODIUM-FALCIPARUM MEROZOITES
  • PICHIA-PASTORIS
  • FINE SPECIFICITY
  • PFAMA1 ALLELES
  • AMA1
  • IMMUNOGENICITY
  • ANTIBODIES
  • CANDIDATE

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