Abstract
BackgroundApical Membrane Antigen 1 (AMA1) of Plasmodium falciparum merozoites is a leading blood-stage malaria vaccine candidate. Protection of Aotus monkeys after vaccination with AMA1 correlates with antibody responses.Study Design/ResultsA randomized, controlled, double-blind phase 1 clinical trial was conducted in 54 healthy Malian adults living in an area of intense seasonal malaria transmission to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of yeast-expressed recombinant proteins based on sequences from the FVO and 3D7 clones of P. falciparum, adsorbed on Alhydrogel. The control vaccine was the hepatitis B vaccine (Recombivax). Participants were enrolled into 1 of 3 dose cohorts (n = 18 per cohort) and randomized 2∶1 to receive either AMA1-C1 or Recombivax. Participants in the first, second, and third cohorts randomized to receive AMA1-C1 were vaccinated with 5, 20 and 80 µg of AMA1-C1, respectively. Vaccinations were administered on days 0, 28, and 360, and participants were followed until 6 months after the final vaccination. AMA1-C1 was well tolerated; no vaccine-related severe or serious adverse events were observed. AMA1 antibody responses to the 80 µg dose increased rapidly from baseline levels by days 14 and 28 after the first vaccination and continued to increase after the second vaccination. After a peak 14 days following the second vaccination, antibody levels decreased to baseline levels one year later at the time of the third vaccination that induced little or no increase in antibody levels.ConclusionsAlthough the AMA1-C1 vaccine candidate was well-tolerated and induced antibody responses to both vaccine and non-vaccine alleles, the antibody response after a third dose given at one year was lower than the response to the initial vaccinations. Additionally, post-vaccination increases in anti-AMA1 antibody levels were not associated with significant changes in in vitro growth inhibition of P. falciparum. Trial RegistrationClinicalTrials.gov NCT00343005
Highlights
Due to the limited number of drugs available for treatment of Plasmodium falciparum malaria and increasing drug resistance, development of a malaria vaccine has become a global health priority
The results of this study demonstrate that the Apical Membrane Antigen 1 (AMA1)-C1/Alhydrogel vaccine induces a significant humoral immune response in malaria-exposed individuals even after a single dose of vaccine that increases after a second vaccination given one month following the first
Vaccinations were initiated in May 2004; all cohorts received their second vaccination by the end of July 2004 before the onset of significant malaria transmission
Summary
Due to the limited number of drugs available for treatment of Plasmodium falciparum malaria and increasing drug resistance, development of a malaria vaccine has become a global health priority. A vaccine is considered feasible given that individuals repeatedly exposed to the parasite gradually develop immunity to the clinical manifestations of infection This resistance to clinical disease is partly mediated by antibodies to antigens expressed during the asexual blood stages of the P. falciparum life cycle [1,2]. Due to the strain-specificity in antibody responses to AMA1 [9] and the sequence polymorphism of the AMA1 gene that exists among circulating strains of P. falciparum [12,13,14], the AMA1-C1 vaccine was designed as an equal mixture of the recombinant AMA1 proteins derived from the FVO and 3D7 clones of P. falciparum, in an attempt to induce protective immunity against diverse parasite strains present in endemic areas.
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