Immunogenicity of self-associated aggregates and chemically cross-linked conjugates of the 42 kDa Plasmodium falciparum merozoite surface protein-1.

Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
PLoS ONE (Impact Factor: 3.53). 06/2012; 7(6):e36996. DOI: 10.1371/journal.pone.0036996
Source: PubMed

ABSTRACT Self-associated protein aggregates or cross-linked protein conjugates are, in general, more immunogenic than oligomeric or monomeric forms. In particular, the immunogenicity in mice of a recombinant malaria transmission blocking vaccine candidate, the ookinete specific Plasmodium falciparum 25 kDa protein (Pfs25), was increased more than 1000-fold when evaluated as a chemical cross-linked protein-protein conjugate as compared to a formulated monomer. Whether alternative approaches using protein complexes improve the immunogenicity of other recombinant malaria vaccine candidates is worth assessing. In this work, the immunogenicity of the recombinant 42 kDa processed form of the P. falciparum merozoite surface protein 1 (MSP1(42)) was evaluated as a self-associated, non-covalent aggregate and as a chemical cross-linked protein-protein conjugate to ExoProtein A, which is a recombinant detoxified form of Pseudomonas aeruginosa exotoxin A. MSP1(42) conjugates were prepared and characterized biochemically and biophysically to determine their molar mass in solution and stoichiometry, when relevant. The immunogenicity of the MSP1(42) self-associated aggregates, cross-linked chemical conjugates and monomers were compared in BALB/c mice after adsorption to aluminum hydroxide adjuvant, and in one instance in association with the TLR9 agonist CPG7909 with an aluminum hydroxide formulation. Antibody titers were assessed by ELISA. Unlike observations made for Pfs25, no significant enhancement in MSP1(42) specific antibody titers was observed for any conjugate as compared to the formulated monomer or dimer, except for the addition of the TLR9 agonist CPG7909. Clearly, enhancing the immunogenicity of a recombinant protein vaccine candidate by the formation of protein complexes must be established on an empirical basis.

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    ABSTRACT: Background. Acquired immunity to malaria develops with increasing age and repeated infections. Understanding immune correlates of protection from malaria infection would facilitate vaccine development and identification of biomarkers that reflect changes in susceptibility resulting from ongoing malaria control efforts.Methods. The relationship between IgG antibody and IFN-γ and IL-10 responses to the 42 kD C-terminal fragment of Plasmodium falciparum Merozoite Surface Protein 1 (MSP142) and risk-of-(re)infection were examined following drug-mediated clearance of parasitemia in 94 adults and 95 children in a holoendemic area of western Kenya.Results. Positive IFN-γ ELISA and ELISPOT responses to MSP-142 3D7 were associated with delayed time-to-(re)infection whereas high-titer IgG antibodies to MSP-142 3D7 or FVO alleles were not independently predictive of risk-of-(re)infection. When IFN-γ and IL-10 responses were both present, the protective effect of IFN-γ was abrogated. A Cox proportional hazard model including IFN-γ, IL-10, MSP142 3D7 IgG antibody responses, hemoglobin S genotype, age and infection status at baseline, showed time to blood-stage infection correlated positively with IFNγ+ responses and negatively with IL-10+ responses, younger age, and asymptomatic parasitemia.Conclusion. Evaluating combined allele-specific cellular and humoral immunity elicited by malaria provides a more informative measure of protection relative to either measure alone.
    The Journal of Infectious Diseases 03/2013; · 5.85 Impact Factor

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