Host Immune Responses to Antigens of Malaria Parasites

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Studies on asexual stage immunity to P. falciparum 1) Evaluate the merozoite antigen PfRH5 as a vaccine candidate. Our collaborators at Oxford University (Dr. Simon Draper, Dr. Angela Minassian, et al.) 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 recombinant PfRH5 protein 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. We have completed GIA studies from this trial, showing that the GIA results correlated with the reduced parasite growth rate. These results and others 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. 2) The PfRH5 protein in adjuvant vaccine is now being tested in field trials conducted by the Institute for Health Initiatives in Tanzania. We have shown extremely high levels of GIA activity in immunized infants and these very encouraging results will be pursued in future efficacy trials. 3) 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 the in vivo activity. A preprint has been published in medRxiv and a manuscript has been submitted. 4) Several collaborative projects: a) Collaborative projects on anti-malarial monoclonal antibodies (mAbs). We have continued a collaboration with Drs. Peter Crompton/Joshua 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 Dr. Niraj Tolia (LMIV) in studies of P. falciparum MSP1. Using mAbs, epitopes were mapped on the C-terminal MSP1-19 portion of the molecule (submitted for publication); c) We have worked with Dr. Xinzhuan 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 (submitted for publication). Studies on parasite sexual stages and transmission blocking vaccine (TBV) candidates: 1) Search for and evaluate new possible TBV candidates. We have worked with various investigators to evaluate antibodies to a number of sexual stage and mosquito vaccine candidates in different formulations to compare their activity using quantitative measurements of antibody concentration and SMFA. 2) We have also continued studies with Dr. Taka Tsuboi at Ehime University and colleagues in Japan to identify other TBV candidates and to map important epitopes in existing candidates. As part of efforts to map epitopes in the large Pfs230 protein, we have identified a peptide within Pfs230 that will elicit transmission reducing antibodies in SMFA after immunization of mice. This establishes the possibility of testing a synthetic peptide vaccine for a malaria TBV (Miura et al., NPJ Vaccines). 3) Differentiation of malaria sexual stages often takes place 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 of cytokines and chemokines. 4) We are part of a consortium of investigators led by Dr. Sumi 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 (published in Front Immunol.) and other efforts are ongoing. In addition, Drs. Biswas and Matt Higgins (Oxford) have prepared a manuscript on the structure of Pfs48/45 which has been submitted. 5) We have been working with Drs. Rich Eastman (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 mosquito membrane feeding assays with P. falciparum or P. vivax, showing the potential of this approach to identify drugs which could potentially interfere with malaria transmission(manuscript submitted for publication). 6) We continue a collaboration with Dr. Jonathan Lovell (New York State University at Buffalo) to characterize antibody-antigen interactions using various antigens and vaccine formulations including co-display of CSP and Pfs230 on liposomes (Huang et al., Commun. Biol.). 7) We have been collaborating with Drs. Julien, Lovell, and Wu on studies with Pfs48/45, an important sexual stage vaccine candidate. We have shown that using a structure-based computational approach, we could produce highly potent Pfs48/45 antigen which induce 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. In press in Immunity