Malaria Vaccines: Pfs25-rEPA and Pfs230-rEPA

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 FY2023: Sagara I, Healy SA, Assadou MH, Kone M, Swihart BJ, Kwan JL, Fintzi J, Sissoko K, Kamate B, Samake Y, Guindo MA, Doucoure M, Niar K, Dolo A, Diarra B, Rausch KM, Narum DL, Jones DS, MacDonald NJ, Zhu D, Gorres JP, Imeru A, Mohan R, Thera I, Zaidi I, Salazar-Miralles F, Duan J, Neal J, Morrison RD, Muratova O, Sylla D, OConnell EM, Wu Y, Hume JCC, Coulibaly MB, Anderson CF, Traore SF, Doumbo OK, Duffy PE. A randomized controlled phase 1 trial of malaria transmission-blocking vaccines Pfs230D1-EPA and Pfs25-EPA in Alhydrogel in healthy Malian adults. 2023. Lancet Infectious Diseases. In press. We compared gamete vaccine Pfs230D1-EPA/Alhydrogel to zygote vaccine Pfs25-EPA/Alhydrogel in malaria-experienced Malians (ClinicalTrials.gov NCT02334462). We did a pilot dose-escalation then double-blind, block-randomised, comparator-controlled main-phase trial in malaria-intense Bancoumana, Mali. 1850-year-old healthy non-pregnant, non-breastfeeding consenting adult residents were randomly assigned (1:1:1:1) to receive four doses at months 0, 1, 45, and 165 of either 47 g Pfs25, 40 g Pfs230D1 or comparator (Twinrix or Menactra)all co-administered with normal saline for blindingor 47 g Pfs25 plus 40 g Pfs230D1 co-administered. We documented safety and tolerability (primary endpoint in the as-treated populations) and immunogenicity (secondary endpoint in the as-treated populations: ELISA, standard-membrane-feeding assay, and mosquito direct skin feed assay). Vaccinations were well tolerated in dose-escalation and main phases. Most vaccinees became seropositive after two Pfs230D1 or three Pfs25 doses; peak titres increased with each dose thereafter. Functional activity (mean peak transmission-reducing activity) appeared for Pfs230D1 alone and for Pfs25 plus Pfs230D1 after the third dose and after the fourth dose, but not for Pfs25 alone. Pfs230D1 transmission-reducing activity persisted 10 weeks after the fourth dose. Transmission-reducing activity of 80% was estimated at 1659 ELISA units for Pfs25, 218 for Pfs230D1, and 223 for Pfs230D1 plus Pfs25. After 3850 direct skin feed assays, 35 participants (12 Pfs25, eight Pfs230D1, five Pfs25 plus Pfs230D1, and ten comparator) had transmitted parasites at least once. The proportion of positive assays in vaccine groups did not differ from that of the comparator, nor did Pfs230D1 and combination groups differ. Pfs230D1 but not Pfs25 vaccine induced durable serum functional activity in Malian adults. Direct skin feed assays detected parasite transmission to mosquitoes but increased event rates are needed to assess vaccine effectiveness. MacDonald NJ, Singh K, Reiter K, Nguyen V, Shimp R, Gittis AG, Chen B, Burkhardt M, Zhang B, Wang Z, Herrera R, Moler M, Lee D-Y, Orr-Gonzalez S, Herrod J, Lambert LE, Rausch KM, Muratova O, Jones DS, Wu Y, Jin AJ, Garboczi DN, Duffy PE, Narum DL. Structural and immunological differences in Plasmodium falciparum sexual stage transmission-blocking vaccines comprised of Pfs25-EPA nanoparticles. 2023. npjVaccines. Apr 15;8(1):56. doi: 10.1038/s41541-023-00655-5. We characterized monomeric Pfs25M biochemically and biophysically for identity, purity, and integrity including protein structure to assess its comparability with Pfs25H. Although the biological activities of Pfs25H and Pfs25M, whether generated by monomeric forms or conjugated nanoparticles, appeared similar, fine-mapping studies with two transmission-blocking monoclonal antibodies detected structural and immunological differences. In addition, evaluation of antisera generated against conjugated Pfs25H or Pfs25M nanoparticles in nonhuman primates identified polyclonal IgG that recognized these structural differences. In addition to these publications, we have seen progress in our trials of Pfs25 and Pfs230 vaccines, listed below under these protocol titles: NIAID protocol 17-I-N006 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 NIAID Protocol 000576: Phase 1, Dose-Escalating, Double-Blind, Randomized, Comparator-Controlled Trial of the Safety, Tolerability, and Immunogenicity of the Transmission-Blocking Vaccine Pfs230D1EPA/Matrix-M against Plasmodium falciparum in Adults in Mali We are currently closing datasets for both trials 17-I-N006 and 19-I-N086 with planned publications in FY 2024. Trial NIAID Protocol 000576 continues clinical follow up of subjects who received Pfs230D1EPA/Matrix-M in this first-in-human trial.