Showing papers by "Patrick H. Corran published in 2005"

Estimating medium- and long-term trends in malaria transmission by using serological markers of malaria exposure

Abstract: The implementation and evaluation of malaria control programs would be greatly facilitated by new tools for the rapid assessment of malaria transmission intensity. Because acquisition and maintenance of antimalarial antibodies depend on exposure to malaria infection, such antibodies might be used as proxy measures of transmission intensity. We have compared the prevalence of IgG antibodies with three Plasmodium falciparum asexual stage antigens in individuals of all ages living at varying altitudes encompassing a range of transmission intensities from hyper- to hypoendemic in northeastern Tanzania, with alternative measures of transmission intensity. The prevalence of antibodies to merozoite surface protein-119 was significantly more closely correlated with altitude than either point-prevalence malaria parasitemia or single measures of hemoglobin concentration. Analysis of age-specific seroprevalence rates enabled differentiation of recent (seasonal) changes in transmission intensity from longer-term transmission trends and, using a mathematical model of the annual rate of seroconversion, estimation of the longevity of the antibody response. Thus, serological tools allow us to detect variations in malaria transmission over time. Such tools will be invaluable for monitoring trends in malaria endemicity and the effectiveness of malaria control programs.

Epitope-specific regulation of immunoglobulin class switching in mice immunized with malarial merozoite surface proteins

Abstract: Antibodies that bind to Fc receptors and activate complement are implicated in the efficient control of pathogens, but the processes that regulate their induction are still not well understood. To investigate antigen-dependent factors that regulate class switching, we have developed an in vivo model of class switching to immunoglobulin G2b (IgG2b) using the malaria antigen Plasmodium falciparum merozoite surface protein 2 (MSP2). C57BL/6 mice were immunized with recombinant proteins representing discrete domains of MSP2, and a T-cell epitope (C8) was identified within the conserved C terminus of the protein that preferentially induces IgG2b antibodies. The ability of C8 to induce IgG2b is ablated in both homozygous gamma interferon-negative and interleukin 10-negative mice. The IgG2b-inducing properties of C8 override the IgG1-inducing properties of both the fusion protein partner, glutathione S-transferase, and the adjuvant. Furthermore, when attached to other proteins that normally induce IgG1 responses, C8 induces a switch to IgG2b secretion. This is the first description of a defined T-cell epitope that drives specific IgG2b subclass switching, and our data offer proof of the concept that chimeric vaccines incorporating specific T-cell “switch epitopes” might be used to enhance qualitative aspects of the antibody response.

Extensive Antigenic Polymorphism within the Repeat Sequence of the Plasmodium falciparum Merozoite Surface Protein 1 Block 2 Is Incorporated in a Minimal Polyvalent Immunogen

Abstract: Polymorphism in pathogen antigens presents a complex challenge for vaccine design. A prime example is the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP1), to which allele-specific antibodies have been associated with protection from malaria. In a Zambian population studied here, 49 of 91 alleles sampled were of the K1-like type (the most common of three block 2 types in all African populations), and most of these had unique sequences due to variation in tri- and hexapeptide repetitive motifs. There were significant negative correlations between allelic sequence lengths of different regions of the repeats, so the complete repeat sequence had less length variation than its component parts, suggesting a constraint on overall length. Diverse epitopes recognized by three murine monoclonal antibodies and 24 individual human sera were then mapped by using a comprehensive panel of synthetic peptides, revealing epitopes in all regions of the repeats. To incorporate these different epitopes in a single molecule, a composite sequence of minimal overall length (78 amino acids) was then designed and expressed as a recombinant antigen. More human immune sera reacted with this "K1-like Super Repeat" antigen than with proteins consisting of single natural allelic sequences, and immunization of mice elicited antibodies that recognized a range of five cultured parasite lines with diverse K1-like MSP1 block 2 repeat sequences. Thus, complex allelic polymorphism was deconstructed and a minimal composite polyvalent antigen was engineered, delivering a designed candidate sequence for inclusion in a malaria vaccine.