Malaria transmission-blocking conjugate vaccine in ALFQ adjuvant induces durable functional immune responses in rhesus macaques

Abstract

Malaria transmission-blocking vaccines candidates based on Pfs25 and Pfs230 have advanced to clinical studies. Exoprotein A (EPA) conjugate of Pfs25 in Alhydrogel® developed functional immunity in humans, with limited durability. Pfs230 conjugated to EPA (Pfs230D1-EPA) with liposomal adjuvant AS01 is currently in clinical trials in Mali. Studies with these conjugates revealed that non-human primates are better than mice to recapitulate the human immunogenicity and functional activity. Here, we evaluated the effect of ALFQ, a liposomal adjuvant consisting of TLR4 agonist and QS21, on the immunogenicity of Pfs25-EPA and Pfs230D1-EPA in Rhesus macaques. Both conjugates generated strong antibody responses and functional activity after two vaccinations though activity declined rapidly. A third vaccination of Pfs230D1-EPA induced functional activity lasting at least 9 months. Antibody avidity increased with each vaccination and correlated strongly with functional activity. IgG subclass analysis showed induction of Th1 and Th2 subclass antibody levels that correlated with activity.

Potent transmission-blocking monoclonal antibodies from naturally exposed individuals target a conserved epitope on Plasmodium falciparum Pfs230

“…Accordingly, Pfs230 is the most clinically advanced TBV candidate, with Pfs230D1M-EPA/Alhydrogel showing superior clinical efficacy to Pfs25 in comparative studies in humans and Rhesus macaques . 20 , 54 Importantly, the humoral response to gametocyte TBV immunogens such as Pfs230 may be reinforced by prior and/or subsequent natural infection. 55 Humoral responses against Pfs230 are common in malaria endemic regions, 56 , 57 and we have recently shown that affinity-purified Pfs230-specific antibodies can indeed block transmission.…”

Vaccination with a structure-based stabilized version of malarial antigen Pfs48/45 elicits ultra-potent transmission-blocking antibody responses

“…Beyond antigen stabilization, vaccine formulation—both in terms of multivalent antigen display and adjuvant selection—is a major component of subunit vaccine design. Several display platforms exist and have been used for TBV antigen presentation, including genetic fusions and affinity linkages ( Brod et al., 2018 ; Chichester et al., 2018 ; Mabrouk et al., 2020 ; Scaria et al., 2020 , 2021 ; Jardine et al., 2013 ; Huang et al., 2018 , 2020 ; Mabrouk et al., 2021 ). An advantage of the CPQ platform used in the present study is its ability to easily incorporate antigenic designs along with adjuvants for rapid immunogenicity screening.…”

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

“…Both vaccine conjugates generated strong antibody responses after two vaccinations. Although functional activity declined rapidly, a third vaccination of Pf s230D1-EPA induced functional activity which lasted for a few months ( 144 ).…”