Arevalo-Herrera, M. | Search bioRxiv

bioRxiv2024

Cross-reactivity of rPvs48/45, a recombinant Plasmodium vivax protein, with sera from Plasmodium falciparum endemic areas of Africa

BackgroundPs48/45, a Plasmodium gametocyte surface protein, is a promising candidate for malaria transmission-blocking (TB) vaccine. Due to its relevance for a multispecies vaccine, we explored the cross-reactivity and TB activity of a recombinant P. vivax Ps48/45 protein (rPvs48/45) with sera from P. falciparum-exposed African donors. MethodsrPvs48/45 was produced in Chinese hamster ovary cell lines and tested by ELISA for its cross-reactivity with sera from Burkina Faso, Tanzania, Mali, and Nigeria - In addition, BALB/c mice were immunized with the rPvs48/45 protein formulated in Montanide ISA-51 and inoculated with a crude extract of P. falciparum NF-54 gametocytes to evaluate the parasite-boosting effect on rPvs48/45 antibody titers. Specific anti-rPvs48/45 IgG purified from African sera was used to evaluate the ex vivo TB activity on P. falciparum, using standard mosquito membrane feeding assays (SMFA). ResultsrPvs48/45 protein showed cross-reactivity with sera of individuals from all four African countries, in proportions ranging from 94% (Tanzania) to 40% (Nigeria). Also, the level of cross-reactive antibodies varied significantly between countries (p<0.0001), with a higher antibody level in Mali and the lowest in Nigeria. In addition, antibody levels were higher in adults ([≥] 17 years) than young children ([≤] 5 years) in both Mali and Tanzania, with a higher proportion of responders in adults (90%) than in children (61%) (p<0.0001) in Mali, where male (75%) and female (80%) displayed similar antibody responses. Furthermore, immunization of mice with P. falciparum gametocytes boosted anti-Pvs48/45 antibody responses, recognizing P. falciparum gametocytes in indirect immunofluorescence antibody test. Notably, rPvs48/45 affinity-purified African IgG exhibited a TB activity of 61% against P. falciparum in SMFA. ConclusionAfrican sera (exposed only to P. falciparum) cross-recognized the rPvs48/45 protein. This, together with the functional activity of IgG, warrants further studies for the potential development of a P. vivax and P. falciparum cross-protective TB vaccine.

immunology↗

bioRxiv2018

Profiling gene expression of the host response to a Plasmodium vivax irradiated sporozoite immunization and infectious challenge

The development of vaccines that provide sterile protection against human malaria is a major global public health priority requiring a better understanding of the mechanisms involved in natural and vaccine-induced sterile immunity. RNAseq was used to profile gene expression of peripheral blood samples from 12 Duffy positive (Fy+) (Plasmodium vivax susceptible) volunteers enrolled in a phase 2 trial who were vaccinated with radiation attenuated P. vivax sporozoites (RAS; 5 were protected, 7 not) and from 5 Fy- (P. vivax resistant) volunteers exposed to mosquitoes harboring live non-attenuated sporozoites. Blood samples were obtained before and after immunization as well as after controlled infection with live P vivax sporozoites. The most profound changes in gene expression were observed between baseline and post-challenge, with 97 distinct signatures differentiating protected and not protected Fy+ individuals. Differentiation was also observed between Fy- and Fy+ protected individuals, notably with downregulation of multiple inflammatory responses as well as extracellular matrix-related gene activity. Analysis of transcriptional modules shows that both B-cell and T-cell signaling are reduced while cell cycle regulation, interferon response, and other informative signatures are elevated in individuals who are not protected against malaria. An asymptomatic individual had an intermediate profile indicative of differential transcription associated with pathology and symptomology. Systems biology thus provides insight into how whole malaria-attenuated sporozoites prime the immune system to protect against malaria, as well as the transcription responses that are associated with sterile protection.\n\nAUTHOR SUMMARYTranscriptomic analysis has shed considerable light on the molecular mechanisms of vaccine efficacy against a variety of viral pathogens, but has not yet been used in relation to parasite vaccinology. Here we describe whole peripheral blood gene expression profiling to contrast the contributions of myeloid and lymphoid immune responses to vaccine-induced and natural protection against Plasmodium vivax- mediated malaria. Two modes of modular bioinformatic analyses are applied to RNAseq data from pre- and post-vaccination samples from 19 volunteer participants in a clinical trial investigating the efficacy of an irradiated sporozoite vaccine. During active infection, both B- and T-cell activity are reduced in individuals who are not protected by vaccination relative to those who are protected. Lack of the Fy antigen prevents entry of parasite into red blood cells, thereby providing natural clinical immunity, but we also document differences in T-cell and neutrophil activity in these individuals relative to those protected by irradiation of the parasite. One individual who was asymptomatic for malaria but had blood parasite despite vaccination showed an intermediate response indicating how systems biology approaches can distinguish gene expression associated with pathology and infection.

genomics↗