Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5.

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines.

Autoantibodies inhibit Plasmodium falciparum growth and are associated with protection from clinical malaria.

Many infections, including malaria, are associated with an increase in autoantibodies (AAbs). Prior studies have reported an association between genetic markers of susceptibility to autoimmune disease and resistance to malaria, but the underlying mechanisms are unclear. Here, we performed a longitudinal study of children and adults (n = 602) in Mali and found that high levels of plasma AAbs before the malaria season independently predicted a reduced risk of clinical malaria in children during the ensuing malaria season. Baseline AAb seroprevalence increased with age and asymptomatic Plasmodium falciparum infection. We found that AAbs purified from the plasma of protected individuals inhibit the growth of blood-stage parasites and bind P. falciparum proteins that mediate parasite invasion. Protected individuals had higher plasma immunoglobulin G (IgG) reactivity against 33 of the 123 antigens assessed in an autoantigen microarray. This study provides evidence in support of the hypothesis that a propensity toward autoimmunity offers a survival advantage against malaria.

Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria.

BACKGROUND: Subcutaneous administration of the monoclonal antibody L9LS protected adults against controlled Plasmodium falciparum infection in a phase 1 trial. Whether a monoclonal antibody administered subcutaneously can protect children from P. falciparum infection in a region where this organism is endemic is unclear. METHODS: We conducted a phase 2 trial in Mali to assess the safety and efficacy of subcutaneous administration of L9LS in children 6 to 10 years of age over a 6-month malaria season. In part A of the trial, safety was assessed at three dose levels in adults, followed by assessment at two dose levels in children. In part B of the trial, children were randomly assigned, in a 1:1:1 ratio, to receive 150 mg of L9LS, 300 mg of L9LS, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection, as detected on blood smear performed at least every 2 weeks for 24 weeks. A secondary efficacy end point was the first episode of clinical malaria, as assessed in a time-to-event analysis. RESULTS: No safety concerns were identified in the dose-escalation part of the trial (part A). In part B, 225 children underwent randomization, with 75 children assigned to each group. No safety concerns were identified in part B. P. falciparum infection occurred in 36 participants (48%) in the 150-mg group, in 30 (40%) in the 300-mg group, and in 61 (81%) in the placebo group. The efficacy of L9LS against P. falciparum infection, as compared with placebo, was 66% (adjusted confidence interval [95% CI], 45 to 79) with the 150-mg dose and 70% (adjusted 95% CI, 50 to 82) with the 300-mg dose (P<0.001 for both comparisons). Efficacy against clinical malaria was 67% (adjusted 95% CI, 39 to 82) with the 150-mg dose and 77% (adjusted 95% CI, 55 to 89) with the 300-mg dose (P<0.001 for both comparisons). CONCLUSIONS: Subcutaneous administration of L9LS to children was protective against P. falciparum infection and clinical malaria over a period of 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05304611.).

Susceptibility to febrile malaria is associated with an inflammatory gut microbiome.

Malaria is a major public health problem, but many of the factors underlying the pathogenesis of this disease are not well understood. Here, we demonstrate in Malian children that susceptibility to febrile malaria following infection with Plasmodium falciparum is associated with the composition of the gut microbiome prior to the malaria season. Gnotobiotic mice colonized with the fecal samples of malaria-susceptible children had a significantly higher parasite burden following Plasmodium infection compared to gnotobiotic mice colonized with the fecal samples of malaria-resistant children. The fecal microbiome of the susceptible children was enriched for bacteria associated with inflammation, mucin degradation, gut permeability and inflammatory bowel disorders (e.g., Ruminococcus gauvreauii, Ruminococcus torques, Dorea formicigenerans, Dorea longicatena, Lachnoclostridium phocaeense and Lachnoclostridium sp. YL32). However, the susceptible children also had a greater abundance of bacteria known to produce anti-inflammatory short-chain fatty acids and those associated with favorable prognosis and remission following dysbiotic intestinal events (e.g., Anaerobutyricum hallii, Blautia producta and Sellimonas intestinalis). Metabolomics analysis of the human fecal samples corroborated the existence of inflammatory and recovery-associated features within the gut microbiome of the susceptible children. There was an enrichment of nitric oxide-derived DNA adducts (deoxyinosine and deoxyuridine) and long-chain fatty acids, the absorption of which has been shown to be inhibited by inflamed intestinal epithelial cells, and a decrease in the abundance of mucus phospholipids. Nevertheless, there were also increased levels of pseudouridine and hypoxanthine, which have been shown to be regulated in response to cellular stress and to promote recovery following injury or hypoxia. Overall, these results indicate that the gut microbiome may contribute malaria pathogenesis and suggest that therapies targeting intestinal inflammation could decrease malaria susceptibility.

[Epidemiological and etiological profile of vulvovaginal candidiasis in women in consultation in the gynecology-obstetrics department, CHU Gabriel Toure, Bamako - Mali]. / Profil epidemiologique et etiologique des candidoses vulvovaginales chez les femmes en consultation dans le service de gynecologie-obstetrique, CHU Gabriel Toure, Bamako - Mali.

Vulvovaginal candidiasis (VVC) is a fungal infection caused by yeasts of the genus Candida that leads to vulvar pruritus and vaginal discharge. METHOD: In order to evaluate the epidemiological and etiological Profile of vvc, we carried out a cross-sectional study among women in consultation in the gynecological department of the CHU-Gabriel Toure in Bamako. Two swabs were taken from each woman for mycological diagnosis. The presence of yeasts and pseudo-filaments was observed on direct examination. The culture was performed on Sabouraud-Chloramphenicol medium and at 37°C for 24 to 48 hours. Identification was based on the macroscopic and microscopic characteristics of the colonies, the germinative tube test and the Vitek•2 instrument. of the colonies, the germinative tube test and the VITEK® 2 instrument. RESULT: A total of 240 women were included with a mean age of 31.5 ± 3.15 [15-64 years]. Married women represented 91.67% (n=220) and 51.25% were housewises. Pruritus 49.17% (118/240) and dyspareunia 42.08% (101/240) were the most frequent clinical signs. Previous use of antifungals was demonstrated in 85.83% of women. Candida species were confirmed in 60.42% (145/240) of cases. C. albicans was the most frequent species followed by C. famata, C. dubliniensis, C. krusei.. This study allowed us to identify the most frequent cases of C. albicans, followed by C. famata, C. dubliniensis, and C. krusei..Further studies are still needed to characterize the antifungal susceptibility profile of the Candida species involved.

La candidose vulvo-vaginale (CVV) est une infection fongique causée par des levures du genre Candida provoquant du prurit vulvaire et des pertes vaginales. MÉTHODE: Afin d'évaluer le profil épidémiologique et étiologique des CVV, nous avons réalisé une étude transversale chez les femmes en consultation dans le service de gynécologie du CHU-Gabriel TOURE de Bamako. Deux écouvillons vaginaux ont été prélevés sur chaque femme pour le diagnostic mycologique. La présence de levures et de pseudo-filaments a été observée à l'examen direct. La culture a été réalisée sur milieu Sabouraud-Chloramphénicol et à 37°C pendant 24 à 48 heures. L'identification a été basée sur les caractéristiques macroscopiques et microscopiques des colonies, le test du tube germinatif et l'instrument VITEK® 2. RÉSULTAT: Un total de 240 femmes ont été incluses avec un âge moyen de 31,5 ans ± 3,15 [15-64 ans]. Les femmes mariées représentaient 91,67% et 51,25% étaient des menagères. Le prurit 49,17 % et la dyspareunie 42,08 % (101/240) étaient les signes cliniques les plus fréquents. La prise antérieure d'antifongiques a été retrouvée chez 85,83% des femmes. La présence des espèces de Candida a été confirmée dans 60,42 % des cas. L'espèce C. albicansétait lus fréquente suivies de C. famata, C. dubliniensis, C. krusei.. CONCLUSION: Les résultats de cette étude permettent d'élargir les connaissances sur l'épidémiologie du CVV au Mali. D'autres études restent nécessaires pour caractériser le profil de sensibilité aux antifongiques des espèces de Candida impliquées.