A double blind, randomized, controlled Phase 2 clinical trial was conducted to assess the safety, immunogenicity, and biologic impact of the vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1), adjuvanted with Alhydrogel ® . Participants were healthy children 2-3 years old living in or near the village of Bancoumana, Mali. A total of 300 children received either the study vaccine or the comparator. No impact of vaccination was seen on the primary endpoint, the frequency of parasitemia measured as episodes >3000 per μL per day at risk. There was a negative impact of vaccination on the hemoglobin level during clinical malaria, and mean incidence of hemoglobin <8.5 g/dL, in the direction of lower hemoglobin in the children who received AMA1-C1, although these differences were not significant after correction for multiple tests. These differences were not seen in the second year of transmission.

Division of Intramural Research, National Institute of Allergy and Infectious Diseases.

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

Background The extent of SARS-CoV-2 exposure and transmission in Mali and the surrounding region is not well understood. We aimed to estimate the cumulative incidence of SARS-CoV-2 in three communities, and understand factors associated with infection. Methods Between July 2020 and January 2021, we collected blood samples and demographic, social, medical, and self-reported symptoms information from residents aged 6 months and older over two study visits. SARS-CoV-2 antibodies were measured using a highly specific two-antigen ELISA optimized for use in Mali. We calculated cumulative adjusted seroprevalence for each community and evaluated factors associated with serostatus at each visit by univariate and multivariate analysis. Results Overall, 94.8% (2533/2672) of participants completed both study visits. A total of 31.3% (837/2672) were aged &lt;10 years, 27.6% (737/2672) were aged 10-17 years, and 41.1% (1098/2572) were aged ≥18 years. The cumulative SARS-CoV-2 exposure rate was 58.5% (95% CI: 47.5 to 69.4). This varied between sites and was 73.4% in the urban community of Sotuba, 53.2% in the rural town of Bancoumana, and 37.1% in the rural village of Donéguébougou. Study site and increased age were associated with serostatus at both study visits. There was minimal difference in reported symptoms based on serostatus. Conclusion The true extent of SARS-CoV-2 exposure in Mali is greater than previously reported and may now approach hypothetical ‘herd immunity’ in urban areas. The epidemiology of the pandemic in the region may be primarily subclinical and within background illness rates.

Hemoglobin variants C and S protect against severe malaria but their influence on parameters not directly linked to disease severity such as gametocyte carriage and infection chronicity is less well understood. To assess whether these infection-related phenotypes depend on the host hemoglobin genotype, we followed 500 Malian individuals over 1–2 years and determined their parasitological status during monthly visits and incidental clinical episodes. While adults heterozygous for hemoglobin S mutation were less often parasitemic compared to AA adults (odds ratio [OR] 0.50 95% confidence interval [CI] 0.31–0.79, P = 0.003), schoolchildren (but not toddlers or adults) with AC genotype carried parasites, including gametocytes, more often than their AA counterparts (OR 3.01 95% CI 1.38–6.57, P = 0.006). AC children were also likelier to be parasite-positive during the dry season, suggesting longer infections, and were more infectious in mosquito skin feeding assays than AA children. Notably, AC school-aged children, who comprise ~5% of the population, harbor a third of infections with patent gametocytes between May and August, when transmission transitions from very low to intense. These findings indicate that schoolchildren with hemoglobin C mutation might contribute disproportionately to the seasonal malaria resurgence in parts of West Africa where the HbC variant is common.