Target-agnostic identification of human antibodies to Plasmodium falciparum sexual forms reveals cross stage recognition of glutamate-rich repeats.

Circulating sexual stages of Plasmodium falciparum (Pf) can be transmitted from humans to mosquitoes, thereby furthering the spread of malaria in the population. It is well established that antibodies (Abs) can efficiently block parasite transmission. In search for naturally acquired Ab targets on sexual stages, we established an efficient method for target-agnostic single B cell activation followed by high-throughput selection of human monoclonal antibodies (mAbs) reactive to sexual stages of Pf in the form of gamete and gametocyte extract. We isolated mAbs reactive against a range of Pf proteins including well-established targets Pfs48/45 and Pfs230. One mAb, B1E11K, was cross-reactive to various proteins containing glutamate-rich repetitive elements expressed at different stages of the parasite life cycle. A crystal structure of two B1E11K Fab domains in complex with its main antigen, RESA, expressed on asexual blood stages, showed binding of B1E11K to a repeating epitope motif in a head-to-head conformation engaging in affinity-matured homotypic interactions. Thus, this mode of recognition of Pf proteins, previously described only for PfCSP, extends to other repeats expressed across various stages. The findings augment our understanding of immune-pathogen interactions to repeating elements of the Plasmodium parasite proteome and underscore the potential of the novel mAb identification method used to provide new insights into the natural humoral immune response against Pf . Impact Statement: A naturally acquired human monoclonal antibody recognizes proteins expressed at different stages of the Plasmodium falciparum lifecycle through affinity-matured homotypic interactions with glutamate-rich repeats.

Naturally acquired antibodies to gametocyte antigens are associated with reduced transmission of Plasmodium vivax gametocytes to Anopheles arabiensis mosquitoes.

Naturally acquired antibodies may reduce the transmission of Plasmodium gametocytes to mosquitoes. Here, we investigated associations between antibody prevalence and P. vivax infectivity to mosquitoes. A total of 368 microscopy confirmed P. vivax symptomatic patients were passively recruited from health centers in Ethiopia and supplemented with 56 observations from asymptomatic P. vivax parasite carriers. Direct membrane feeding assays (DMFA) were performed to assess mosquito infectivity; for selected feeds these experiments were also performed after replacing autologous plasma with malaria naïve control serum (n=61). The prevalence of antibodies against 6 sexual stage antigens (Pvs47, Pvs48/45, Pvs230, PvsHAP2, Pvs25 and PvCelTOS) and an array of asexual antigens was determined by ELISA and multiplexed bead-based assays. Gametocyte (ρ< 0.42; p = 0.0001) and parasite (ρ = 0.21; p = 0.0001) densities were positively associated with mosquito infection rates. Antibodies against Pvs47, Pvs230 and Pvs25 were associated with 23 and 34% reductions in mosquito infection rates (p<0.0001), respectively. Individuals who showed evidence of transmission blockade in serum-replacement DMFAs (n=8) were significantly more likely to have PvsHAP2 or Pvs47 antibodies. Further studies may demonstrate causality for the observed associations, improve our understanding of the natural transmission of P. vivax and support vaccine development.

No time to die: An in-depth analysis of James Bond's exposure to infectious agents.

Global travelers, whether tourists or secret agents, are exposed to a smörgåsbord of infectious agents. We hypothesized that agents pre-occupied with espionage and counterterrorism may, at their peril, fail to correctly prioritize travel medicine. To examine our hypothesis, we examined adherence to international travel advice during the 86 international journeys that James Bond was observed to undertake in feature films spanning 1962-2021. Scrutinizing these missions involved ∼3113 min of evening hours per author that could easily have been spent on more pressing societal issues. We uncovered above-average sexual activity, often without sufficient time for an exchange of sexual history, with a remarkably high mortality among Bond's sexual partners (27.1; 95% confidence interval 16.4-40.3). Given how inopportune a bout of diarrhea would be in the midst of world-saving action, it is striking that Bond is seen washing his hands on only two occasions, despite numerous exposures to foodborne pathogens. We hypothesize that his foolhardy courage, sometimes purposefully eliciting life-threatening situations, might even be a consequence of Toxoplasmosis. Bond's approach to vector-borne diseases and neglected tropical diseases is erratic, sometimes following travel advice to the letter, but more often dwelling on the side of complete ignorance. Given the limited time Bond receives to prepare for missions, we urgently ask his employer MI6 to take its responsibility seriously. We only live once.