Malaria Transmission Blocking Vaccine Discovery

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Antigen discovery has focused on using human serum samples collected from individuals that are naturally exposed to malaria and appear to develop effective immunity that prevents gametocytemia or blocks parasite transmission to mosquitoes, as tools to identify candidate vaccine antigens. Specifically, serum samples or antibodies that have activity of interest are compared to sera/antibodies that lack this activity, for their ability to select or recognize individual recombinant proteins constructs of P. falciparum. Recombinant proteins identified through differential screening are then prepared as immunogens and tested for their ability to induce effective anti-gametocyte or transmission-blocking antibodies. From our publication this year, we report the following advances in FY2021: Coelho CH, Tang WK, Burkhardt M, Galson JD, Muratova O, Salinas ND, Alves ESTL, Reiter K, MacDonald NJ, Nguyen V, et al: A human monoclonal antibody blocks malaria transmission and defines a highly conserved neutralizing epitope on gametes. Nat Commun 2021, 12:1750. LMIV is using structural studies to improve the design of TBV candidates. We characterized B cell receptor responses among Malian adults vaccinated against Pfs230D1, our leading TBV candidate. Among nine Pfs230 human monoclonal antibodies (mAbs) that we generated, one potently blocked transmission to mosquitoes in a complement-dependent manner and reacts to the gamete surface; the other eight showed only low or no blocking activity. The structure of the transmission-blocking mAb in complex with vaccine antigen revealed a large discontinuous conformational epitope, specific to domain 1 of Pfs230 and comprising six structural elements in the protein. The epitope is conserved, suggesting the transmission-blocking mAb is broadly functional. This study provided a rational basis to improve malaria vaccines and develop therapeutic antibodies for malaria elimination. MalariaGen, Ahouidi A, Ali M, Almagro-Garcia J, Amambua-Ngwa A, Amaratunga C, Amato R, Amenga-Etego L, Andagalu B, Anderson TJC, et al: An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples. Wellcome Open Res 2021, 6:42. MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. This work described a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries, and we contributed samples to this community effort. Genes expressed during the mosquito stage of the parasite life-cycle were prominent among loci that showed strong geographic differentiation. This highlights the need to examine TBV candidates for variant-transcending immunity. Coelho CH, Jore MM, Canepa GE, Barillas-Mury C, Bousema T, Duffy PE: Antibody Therapy Goes to Insects: Monoclonal Antibodies Can Block Plasmodium Transmission to Mosquitoes. Trends Parasitol 2020, 36:880-883. In this publication, we discussed targets of monoclonal antibodies in mosquito sexual stages of Plasmodium. Therapeutic antibodies may be useful for the LMIV program, either as tools to confirm TBV candidates, or as potential therapeutics for clinical testing and development. Coelho CH, Nadakal ST, Gonzales Hurtado P, Morrison R, Galson JD, Neal J, Wu Y, King CR, Price V, Miura K, et al: Antimalarial antibody repertoire defined by plasma IG proteomics and single B cell IG sequencing. JCI Insight 2020, 5. Plasma antimalarial Ab can mediate antiparasite immunity but has not previously been characterized at the molecular level. We developed an innovative strategy to characterize humoral responses by integrating profiles of plasma immunoglobulins (IGs) or Abs with those expressed on B cells as part of the B cell receptor. We applied this strategy to define plasma IG and to determine variable (V) gene usage after vaccination with the Plasmodium falciparum zygote antigen Pfs25. Among 13 recombinant human mAbs generated from IG sequences of Pfs25-specific single B cells, a single mAb named IGH4 displayed strong neutralizing activity, reducing the number of P. falciparum oocysts in infected mosquitoes by more than 80% at 100 g/mL. Our approach characterized the human plasma Ab repertoire in response to the Pfs25-EPA/Alhydrogel vaccine and will be useful for studying circulating Abs in response to other vaccines, as well as those induced during infections or autoimmune disorders.