Structural Superimposition

Abstact

Outer surface protein A (OspA) is a ~30 kDa lipoprotein displayed on the surface of Borrelia burgdorferi sensu lato, the etiological agent of Lyme disease. Here we report on the preclinical evaluation of OspA-encoding nucleoside-modified mRNA lipid nanoparticle (OspA mRNA-LNP) vaccines for the prevention of Lyme disease. Crystallographic and binding studies using a panel of transmission-blocking antibodies confirmed that the mRNA-encoded OspA serotype 1 (ST1) expressed in mammalian cells assumes its native structure and retains known protective epitopes. Immunization of mice with OspA ST1 mRNA-LNP elicited functional serum antibodies that promoted spirochete agglutination and complement-dependent borreliacidal activity in vitro. We also examined the impact of combining ST1 OspA mRNA with OspA STs 2-7, which are associated with predominant Borrelia genospecies in Europe (B. garinii, B. afzelii, and B. bavariensis). The additional six STs mRNA did not interfere with ST1 antibody titers and functionality. Finally, mice vaccinated two or three times with different dose levels of OspA ST1 mRNA-LNP or with the heptavalent mRNA vaccine were protected against B. burgdorferi infection in a tick-mediated challenge model. The monovalent and the heptavalent OspA mRNA vaccines (mRNA-1982 and mRNA-1975, respectively) are currently undergoing testing in a Phase 1 clinical trial (NCT05975099).