Malaria Vaccines: Pfs25-rEPA and Pfs230-rEPA

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

The major challenge facing TBV development is to find a highly safe formulation that induces sustained high antibody responses. LMIV has demonstrated that conjugating Pfs25 and Pfs230 with carrier protein ExoProtein A (EPA) of Pseudomonas aeruginosa greatly enhances the immunogenicity of the recombinant TBVs and has shown to be safe with the adjuvant Alhydrogel, but may need a stronger adjuvant such as AS01 to achieve the antibody responses needed to block transmission. Highlighted in this years summary are results from our publications in FY2021: 1. Healy SA, Anderson C, Swihart BJ, Mwakingwe A, Gabriel EE, Decederfelt H, Hobbs CV, Rausch KM, Zhu D, Muratova O, et al: Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice. J Clin Invest 2021, 131. We previously reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. We hypothesized that the pre-fertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity. In this publication we report preclinical trials and a phase 1 trial in US volunteers demonstrating that Pfs230D1-EPA induces greater serum functional activity than Pfs25-EPA, and that the rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model. 2. 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. 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. 3. 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. In addition to this publication, we have seen progress in our trials of Pfs25 and Pfs230 vaccines, listed below under these protocol titles: - Pfs230D1M-EPA/AS01 and Pfs25M-EPA/AS01 in Healthy Malian Adults - NIAID protocol 19-I-N086: Safety, Immunogenicity and Efficacy of Pfs230D1M-EPA/AS01 Vaccine, a Transmission Blocking Vaccine against Plasmodium falciparum, in an Age De-Escalation Trial of Children and a Family Compound Trial in Mali We are currently completing datasets for both trials with planned data closeout in the coming months