Malaria transmission blocking immunity exerts its effect by interrupting the transfer of the malaria parasite from an infected host to a susceptible host via reducing or blocking the obligate sexual stage development in the mosquito vector. In Plasmodium falciparum malaria two key sexual stage proteins, Pfs25 and Pfs 48/45, are vaccine candidates capable of inducing potent humoral immune responses that reduce or block malaria transmission.
We evaluated vaccination of BALB/c mice and baboons using in vivo electroporation (EP) with intramuscular injection of either Pfs25 or Pfs48/45 DNA plasmids to determine whether EP could enhance the immunogenicity and functional transmission blocking effects of these two vaccines. EP enhanced the immunogenicity of the Pfs25 DNA plasmid vaccine in mice by a magnitude of two logs with comparable antibody levels being achieved with either 0.25µg of DNA with EP or 25µg of DNA without EP. Significant functional transmission blocking was demonstrated by the standard membrane feeding assay (MFA) for all three quantities of Pfs25 DNA given with EP (0.25µg, 2.5µg or 25µg). In the baboons there was a mild increase in immunogenicity of the Pfs25 DNA vaccine given with EP after a prime and one boost; however this enhancement was not seen after a prime and two boosts. EP was associated with a modest increase in transmission blocking after DNA prime, two DNA boosts and a recombinant protein boost. Pfs48-45 DNA plasmids given with or without EP in mice showed a modest improvement in antibody production and increased transmission blocking effect with EP.
To examine age-related acquisition of naturally induced immune responses to malaria asexual and sexual stage antigens, a sero-epidemiologic field study in south west Zambia was conducted over a period of one year which encompassed two peak and one trough malaria transmission seasons. One hundred forty six subjects in three age cohorts (0-5 years, 6-10 years and 11-15 years) were enrolled. There was a significant, positive age-dependent correlation of antibody levels to recombinant Pfs48/45 to assess sexual stage immune responses and to an asexual stage parasite lysate to assess erythrocytic stage immune responses. Functional transmission blocking antibody was demonstrated by MFA with a significant rise in the oldest age group. There was a high degree of concordance between the asexual and sexual antibody levels. Significant rise in antibody levels to the asexual stage antigens occurred by four years of age whereas the rise in antibody levels to the sexual stage protein occurred later at age ten years. Further studies were suggested by these observations to evaluate the importance of such natural immunity for vaccine development.
|Advisor:||Kumar, Nirbhay, Krag, Sharon|
|School:||The Johns Hopkins University|
|School Location:||United States -- Maryland|
|Source:||DAI-B 71/01, Dissertation Abstracts International|
|Subjects:||Microbiology, Public health, Epidemiology|
|Keywords:||Immune responses, Malaria, Malaria immunology, Plasmodium falciparum, Transmission-blocking, Vaccine, Zambian|
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