Host Immune Responses to Antigens of Malaria Parasites

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

Studies on asexual stage immunity to P. falciparum: 1) Evaluate the merozoite antigen PfRH5 as a vaccine candidate. Our collaborators at Oxford University (S. Draper, A. Minassian, et al.) 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 is 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 now provide a marker to predict what level 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 functional immune responses to PfRH5. Recently we have completed a detailed analysis of the parasite strain specificity of human responses to PfRH5. 2) The PfRH5 protein in adjuvant vaccine is now being tested in an important Phase 2 efficacy trial in African children. We have previously shown extremely high levels of GIA activity in immunized African infants, providing the groundwork for the current trials, and we will assess the antibody responses in these children during the next year. 3) Because of the importance of GIA in all these studies we have performed an extensive analysis of the precision of this assay (Miura et al., Malaria J.). 4) The immunization-challenge studies with PfRH5 in naive adults also showed that a delayed immunization schedule (0,1,6 months) was far more effective in enhancing antibody titer, GIA and longevity (C. Nielsen, et al, JCI Insight). 5) We have also collaborated with the Oxford group on immunization-challenge studies with the other major human malaria parasite P. vivax. We have established a GIA assay for P. vivax using a transgenic P. knowlesi parasite and have applied this to evaluate antibody responses in humans to the P. vivax Duffy-binding protein (PvDBPII) in two different Phase 1/IIa trials. The parasite multiplication rate was reduced in vaccinees by 51% and our GIA functional assay readout correlated with this in vivo activity (M. Hou et al, Science Transl. Med.). 6) Several collaborative projects: a) Anti-malarial monoclonal antibodies (mAbs). We have continued a collaboration with P. Crompton/J. Tan (LIG) to aid in characterizing human mAbs to whole parasites and recombinant proteins of malaria using B cells from Malians as the source of the antibodies; b) We have collaborated with N.Tolia (LMIV) in studies of P. falciparum MSP1. Using human mAbs, epitopes were mapped on the C-terminal MSP1-19 portion of the molecule showing both neutralizing and interfering activities (Patel et al., Nat. Commun.); c) We have collaborated with P. Srinivasan and N. Tolia on evaluating the impact of PfAMA1 + RON2 as a vaccine candidate, showing broader antibody responses to AMA1 variants using the combination protein (manuscripts submitted). d) We have worked with X. Su on analysis of mechanisms of anemia in malaria using a rodent malaria model. These investigations show that macrophages in erythroid islands in the bone marrow and spleen are defective in promoting terminal differentiation of red blood cells and suggest a new avenue of approaching malaria-induced anemia (revision submitted). Studies on parasite sexual stages and transmission blocking vaccine (TBV) candidates: 1) Search for and evaluate possible TBV candidates. We have worked with several investigators to evaluate antibodies to various sexual stage and mosquito vaccine candidates in different formulations to compare their activity using quantitative measurements of antibody concentration and SMFA. For example, we have collaborated with N. Tolia et al. (LMIV) to map antibody epitopes on their Pfs230 vaccine candidate Pfs230D1(W.Tang et al. Immunity). 2)We have been collaborating with J.P. Julien and J. Lovell on studies with Pfs48/45, an important sexual stage vaccine candidate. Using a structure-based computational approach, the investigators produced a stabilized Pfs48/45 protein which which induced superior transmission reducing activity in mice compared to the original wild-type antigen. This is the first proof that the molecular analysis approach works for any of the parasite vaccine candidates. (B. McLeod et al. Immunity) 3) Differentiation of malaria sexual stages often occurs within the bone marrow of the vertebrate host. We have initiated a project to explore the interaction of developing gametocytes with host myeloid cells within the bone marrow. Surprisingly, we have found that co-culture of P. falciparum parasites with human myeloid cells greatly enhances the numbers of oocysts in the mosquito after SMFA. We have found this using both a cultured parasite line as well as several isolates of field parasites. The latter is important since much of what we know about sexual stage differentiation with P. falciparum comes from a single parasite line. We have found that at least part of the activity comes from secreted products of the myeloid cells so that we are seeking the mechanisms involved using mass spectrometry, RNASeq, and ELISA assays (R. Suresh, submitted). 4) We are part of a consortium of investigators led by S. Biswas of Oxford University and funded by the EU to develop a TBV. A Phase I first-in-human trial of Pfs25-IMX313 has been completed and other efforts are ongoing. In addition, S. Biswas and M. Higgins have analyzed the structure of Pfs48/45 and recognition by antibodies (KT Ko, Nat Commun.). 5) We have been working with Drs. Rich Eastman (previously at NCATS) and Daniel Bargieri (Univ. of Sao Paulo) to identify drugs which can inhibit malaria transmission. They have developed a high-throughput in vitro assay for sexual stage differentiation of P. berghei and used this to screen 6631 compounds for transmission blocking activity. Selected compounds from this initial screen were validated in SMFA assays with P. falciparum or P. vivax, showing the potential of this approach to identify drugs which might interfere with malaria transmission (J.Calit, Antimicrob. Agents Chemother). 6) We continue a collaboration with J. Lovell (SUNY Buffalo) to characterize antibody-antigen interactions using various antigens and experimental adjuvant formulations. 7) We have participated in a clinical trial of Pfs48/45 with M. Theisen and colleagues performed in Burkina Faso. This is the first in humans trial in African malaria-exposed adults of this important sexual stage antigen and examines the safety and immunogenicity of different adjuvant formulations. Our contribution was to show that ProC6C elicited transmission reducing activity in sera from vaccine volunteers. This is currently being prepared for journal submission.