Impact of a Plasmodium falciparum AMA1 vaccine on antibody responses in adult Malians

Abstract

Background: Apical 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/results: A 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 microg 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 microg 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.

Conclusions: Although 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 registration: ClinicalTrials.gov NCT00343005.

Figure 1. CONSORT Flow Chart.

Figure 2. Comparison of pre-vaccination (A) and post-vaccination (B) antibody responses to AMA1-3D7 and AMA1-FVO.

Sera collected on day 0 and 42 were assayed from all study participants. Concordance between the responses to the 3D7 and FVO alleles of AMA1 were highly significant on both days (RMAC, 0.97 on day 0 and 0.96 on day 42)

Figure 3. Change from baseline in anti-AMA1-3D7 antibody levels after the second and third vaccinations.

Differences between study days 0 (day of vaccination 1) and 42 (14 days post-vaccination 2) (A) and between study days 360 (day of third vaccination) and 374 (14 days post-vaccination 3) (B) are shown. Bars represent the median change in antibody units against AMA1-3D7; R, Recombivax

Figure 4. Longitudinal anti-AMA1 antibody responses in study participants from the first (A), second (B) and third (C) cohorts.

Antibody units were measured by ELISA in sera collected on: day 0 (vaccination 1), day 14 (14 days post-vaccination 1), day 28 (vaccination 2), day 42 (14 days post-vaccination 2), day 90, day 180, day 270, day 360 (vaccination 3), day 374 (14 days post-vaccination 3), days 420, 480, and 540. Points represent the geometric mean antibody units against AMA1-3D7, error bars the standard error, and arrows the vaccination time points; TS, transmission season; °, 5 µg AMA1-C1; □, 20 µg AMA1-C1; Δ, 80 µg AMA1-C1; ×, Recombivax

Figure 5. Post-vaccination changes in anti-AMA1-3D7 antibody levels compared to baseline levels.

Change in anti-AMA1-3D7 antibody levels between study days 0 (day of vaccination 1) and 42 (14 days post-vaccination 2), are compared to the anti-AMA1-3D7 antibody level on day 0, in the Recombivax (open circles) and 80 µg AMA1-C1 (black circles) dose groups