A Broadly Conserved Protective Epitope on the Lyme Disease Vaccine Antigen, OspA

Abstract

Lyme disease, caused by the spirochete, Borreliella burgdorferi sensu latu (Bbsl), is a debilitating tickborne infection of increasing incidence in North America, Europe and Asia. While vaccines based on Outer surface protein A (OspA) have proven highly efficacious at blocking Bbsl tick-to-human transmission, the high degree of antigenic variability among the major OspA serotypes (ST) has made the development of a broadly cross protective vaccine difficult. Recent profiling of protective human monoclonal antibodies (mAbs) has suggested the existence of conserved epitopes situated within OspAs central {beta}-sheet (CBS), although direct comparisons of cross-serotype functionality has been hindered by biological differences among the major Bbsl genospecies. To address these issues, we developed a panel of isogenic B. burgdorferi viability reporter strains expressing the seven major OspA serotypes (ST1-7) and probed them with CBS-targeting mAbs to evaluate their complement-dependent borreliacidal activity. The mAbs segregated into three distinct classes with varying degrees of borreliacidal activity: class 1 mAbs exhibited potent killing against all seven OspA serotypes, while classes 2 and 3 had restricted or no activity against two of the seven serotypes. Structural analysis of Fabs derived from each class of mAbs in complex with OspA ST1 showed that they target overlapping epitopes spanning {beta}-strands 6-10 and involve contact with largely invariant residues. Further analysis of B. burgdorferi reporter strains expressing OspA variants from 17 additional Bbsl genospecies identified Lys-107 as a determinant of susceptibility for nearly all CBS mAbs. Taken together, these findings raise the prospect of structure-based design of a broadly protective monovalent Lyme disease vaccine. AUTHOR SUMMARYLyme disease, caused by the spirochete, Borreliella burgdorferi sensu latu (Bbsl), is a potentially debilitating tickborne infection of increasing incidence in North America, Europe and Asia. While vaccines based on Outer surface protein A (OspA) have proven highly efficacious at blocking Bbsl tick-to-human transmission, the genetic and serological heterogeneity of OspA across Borrelia genospecies has complicated matters. In this report, we use a collection of transmission-blocking human monoclonal antibodies to delineate a protective region (epitope) within the central core of OspA that is conserved across all major OspA serotypes. These results have important implications for engineering a broadly reactive Lyme disease vaccine.