Naturally acquired immune responses to alpha-gal in malaria endemic settings and pre-clinical efficacy testing with R21/MM.

Malaria sporozoite surface glycan alpha-gal (α-gal), which is absent in humans has been shown to elicit an antibody response that can confer protection against malaria in alpha- gal transferase knock- out mice. In humans, several studies have highlighted association of antibodies to this glycan with protection against malaria in endemic regions. Here, we first assess the anti- α-gal IgG and IgM antibody levels in serum samples obtained from sporozoite challenged malaria naïve UK volunteers, and naturally exposed or infected Kenyan adults and Burkina Faso infants. In UK volunteers, there was no significant increase seen in antibody levels 90 days post challenge. We observe increases in anti- α-gal IgG and IgM antibodies over time only in Burkina Faso infants. In Burkina Faso infants, protection from malaria could be correlated to higher anti- α-gal IgM antibody levels and possibly to anti- α-gal IgG antibody levels. We then evaluate Bovine Serum Albumin (BSA) linked α-gal with highly potent adjuvant Matrix-M (MM) for immunogenicity and efficacy in alpha- gal transferase knock-out (α1,3GT KO) mice. BSA-linked α-gal elicits an IgG and IgM response but failed to protect against the sporozoite challenge. Clinical trials registry: VAC049 (NCT01465048), VAC073 (NCT03580824), VAC076 (NCT03896724).