All ETDs from UAB

Advisory Committee Chair

Julian Rayner

Advisory Committee Members

Edwin Blalock

Debasish Chattopadhyay

Gerald Fuller

Louis Justement

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malaria causes an estimated 1-3 million deaths each year, with the majority of deaths being a result of infection with Plasmodium falciparum. No commercially available vaccine currently exists, but multiple subunit-based vaccines are in development including one based on the promising vaccine candidate P. falciparum Merozoite Surface Protein-3 (PfMSP3). PfMSP3 varies in sequence between P. falciparum isolates, but all variation is restricted to the N-terminal domain. This observation has lead to the development of a PfMSP3-based vaccine comprised solely of the highly conserved, yet poorly immunogenic, C-terminal domain. The rationale for supporting the C-terminal domain relies entirely on its conserved sequence, but so far no study has measured of the effect of N-terminal domain diversity on antibody responses in the endemic setting. To address this urgent question, we used both P. falciparum DNA and human sera samples from individuals infected with P. falciparum from a longitudinal cohort study near Iquitos, Peru. We demonstrate that, in this hypoendemic transmission setting, sequence polymorphisms in PfMSP3 were extremely limited with only 10 mutations occurring over a 4-year period, whereas allele class frequency variation was significant, suggesting a possible immunologically driven selection pressure. By studying antibody responses against PfMSP3 domains by ELISA, we determined that the N-terminal domain was significantly more immunogenic than the C-terminal domain. Additionally, N-terminal domain antibodies are capable of providing significant cross-reactivity across sequence variants within the same allele class, and some level of cross-reactivity between allele classes. N-terminal domain antibodies also exhibited potent IgG1/IgG3 antibody responses, an IgG isotype profile well known to correlate with protection against P. falciparum malaria, compared to the C-terminal domain, which had higher IgM levels. These data suggests that the impact of PfMSP3 genetic diversity on antibody cross-protection may be more limited than was anticipated, and supports the development of a novel trivalent PfMSP3-based vaccine constituent comprised of both highly immunogenic N-terminal domain alleles in addition to the conserved C-terminal domain.

Share

COinS