Host Immune Responses to Antigens of Malaria Parasites

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Studies from FY 2025 Studies on asexual stage immunity to Plasmodium falciparum: 1) Evaluating the merozoite antigen PfRH5 as a vaccine candidate. Our long-time collaborators at Oxford University (S. Draper, A. Minassian) and their colleagues are pursuing this protein as a blood-stage vaccine candidate and we have collaborated on these studies using our standardized parasite growth-inhibition assay (GIA). A clinical immunization-challenge trial using a recombinant PfRH5 vaccine showed 20% reduction in parasite growth in vivo. This was the first time that positive results have been seen with a blood stage vaccine in a human trial. Our GIA results correlated with the reduced parasite growth rate, and these results as well as others with non-human primates now provide a marker to predict what levels of GIA should be necessary to obtain protection in humans. We continue to collaborate with this group to identify methods to enhance the immunogenicity and functionality of immune responses to PfRH5. Our contribution is the GIA analysis. 2) The PfRH5 protein in Matrix M adjuvant vaccine has now been tested in an important Phase 2b efficacy trial in African children. We have previously shown extremely high levels of GIA activity in PfRH5 immunized African infants (Silk SE, Lancet Infect.Dis., 2024),providing the groundwork for the current trials. Exciting new data shows that there is approximately 50% protection against clinical malaria over 6 months in a Phase 2b study in vaccinated children in Burkina Faso (Natama HM et al. Lancet Infect. Dis., 2025). We have performed GIA on the samples available and our results showed high levels of GIA activity in the PfRH5 vaccinated children. These children have been re-boosted and we will follow their progress with GIA. 3) Recently the NIH has signed an agreement with Oxford University to obtain the clinical data from this trial of PfRH5 and we are working with Dr. Michael Fay of NIAID Statistics to do a detailed analysis of the correlation of GIA with the clinical profiles of individual children in this study. 4) We are working with the Draper lab and several other investigators on optimizing the presentation of PfRH5 as a vaccine candidate. These groups have produced various PfRH5 vaccine candidates and we anticipate that we will conduct an independent comparative review of these products using the GIA. The Gates Foundation will be supporting these comparisons. 5) Because PfRH5 is part of a complex of proteins on the merozoite required for red cell invasion, other members of this complex, designated PCRCR, are also being explored as vaccine targets. PfRH5 interacts with cysteine-rich protective antigen (PfCyRPA) and RH5-interacting protein (PfRIPR), along with two other proteins, PfPTRAMP and PfCSS. We are evaluating these with the Draper laboratory as well as with N. Tolia (LMIV) for their capacity to elicit GIA activity. 6) We continue to collaborate with J. Tan (LIG) on the analysis of human B cell clones from Malians repeatedly infected by malaria parasites to look for other possible immunogens in blood stages. We have screened over 700 human monoclonal antibodies for GIA activity. 7) Patel et al have published (Cell Rep. Med, 2025) previously described work on a human mab directed to AMA-1 which can neutralize parasites without the RON2 ligand. 8) We are collaborating with A. Cowman (WEHI/Australia) to assess the GIA activity of several different drugs they are studying as potential therapeutics for malaria. Studies on parasite sexual stages and transmission blocking vaccine (TBV) candidates: 1) Search for and evaluate possible TBV candidates. We continue to collaborate with various investigators around the world to evaluate antibodies to sexual/mosquito stage vaccine candidates in different formulations to compare their activity using quantitative measurements of antibody concentration and statistical analysis of SMFA. 2) We continue to collaborate with N. Tolia (LMIV) in analysis of the transmission reducing capacity of antibodies to a Pfs230D1-ferritin nanoparticle vaccine, showing that this formulation elicits transmission reducing activity)(TRA). In addition, we have been working with N.Tolia on a vaccine combining sporozoite (CSP) and a sexual stage (Pfs48/45) candidate. We have worked on the TBV portion of the work and this manuscript is under review at njpVaccines. 3) We have continued collaboration with M. Theisen and colleagues on analysis of a multistage vaccine including both a sporozoite (CSP) and transmission reducing components (Pfs48/45 and Pfs230). A Phase 1 clinical trial of this combination (designated (ProC6C) was performed in Burkina Faso. This follow-up study (Naghizadeh et al, Hum. Vacc. Immunother., 2025) indicated that the transmission reducing activity primarily came from the Pfs48/45 component and suggested future studies use a more immunogenic vaccine platform. 4) We have collaborated with JP Julien and J Lovell on several projects. One tested two transmission reducing recombinant proteins of Pfs48/45 and Pfs230. Mice immunized with either protein produced responses which could be boosted by gametocyte extracts, suggesting that natural infections might boost immune responses to these proteins (Song et al., J. Infect. Dis., 2025). 5) The other project with this group involved looking at the immunogenicity of Pfs48/45 in terms of nanoliposome adjuvant. Using a fixed protein dose, the effects of different adjuvant doses and formulations were compared showing significant dose sparing effects (Song, Y. et al., ACS Nano, 2025). 5) To generate infectious gametocytes in vitro for SMFA and other biological studies, human serum has been an essential component in the culture medium for the last 4 decades. After over 10 years of investigation in our laboratory, we have identified a human-serum-free medium that can induce highly infectious gametocytes in vitro. This new medium will allow more investigators to conduct gametocyte research in the future (Miura et al. Sci. Rep. 2024). Currently we are using mass spectrometry to try to identify the critical components of this mixture for gametocyte development in vitro.