Impact of a Plasmodium falciparum AMA1 Vaccine on Antibody Responses in Adult Malians

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

Allelic Diversity and Naturally Acquired Allele-Specific Antibody Responses to Plasmodium falciparum Apical Membrane Antigen 1 in Kenya

“…We found that levels of antibodies to the three allelic recombinant proteins of the AMA1 ectodomain were highly correlated in this cohort of children. This is in keeping with previous studies of naturally acquired (14,47) and vaccineinduced (17) antibodies to AMA1. Of note, during acute infections and at convalescence, the correlation coefficients between antibodies to the three proteins had declined compared to those at the preseason time point, suggesting that antibodies to allele-specific epitopes had been induced by infection.…”

In VitroGrowth-Inhibitory Activity and Malaria Risk in a Cohort Study in Mali

“…The lack of correlation in other studies may be explained partly by saturation of inhibitory activity in older study populations, with mean ages reaching 23.9 years (45) and 27.5 years (37) in some studies, versus 8.9 years in our study. This possibility is consistent with results from a phase 1 trial of the AMA1 vaccine in semi-immune Malian adults, which showed no increase in growth-inhibitory activity after vaccination despite a significant increase in antibody titers (16). Regarding the inverse correlation between age and growth-inhibitory activity, it is possible that polyclonal antibody responses to repeated infections over time generate antibodies to merozoite proteins that block invasion of RBC but also interfere with invasion-blocking antibodies (22,35).…”

Safety and Immunogenicity of a Recombinant Nonglycosylated Erythrocyte Binding Antigen 175 Region II Malaria Vaccine in Healthy Adults Living in an Area Where Malaria Is Not Endemic

“…Moreover, good functional properties of antibodies produced in response to a malaria vaccine candidate in naïve subjects may not translate to similar findings in semi-immune subjects. For example, Malian subjects who received a vaccine based on AMA-1 had good antibody responses, but the biologic activity of the total IgG did not change from that prevaccination, despite findings of high P. falciparum growth inhibition and antibody levels when the vaccine was tested in naïve subjects (10,20). Subsequent analysis suggested that this difference was due to the fact that other antimalarial antibodies in the Malian volunteers reduced the GIA effect of anti-AMA-1 antibodies (22).…”