Human B Cell Epitope Map of the Lyme Disease Vaccine Antigen, OspA

The Lyme disease (LD) vaccine formerly approved for use in the United States consisted of recombinant outer surface protein A (OspA) from Borrelia burgdorferi sensu stricto (ss), the bacterial genospecies responsible for the vast majority of LD in North America. OspA is an similar to 30 kDa lipoprotein made up of 21 antiparallel fl-strands and a C-terminal alpha-helix. In clinical trials, protection against LD following vaccination correlated with serum antibody titers against a single epitope near the C-terminus of OspA, as defined by the mouse monoclonal antibody (MAb), LA-2. However, the breadth of the human antibody response to OspA following vaccination remains undefined even as next-generation multivalent OspA-based vaccines are under development. In this report, we employed hydrogen exchange-mass spectrometry (HX-MS) to localize the epitopes recognized by a unique panel of OspA human MAbs, including four shown to passively protect mice against experimental B. burgdorferi infection and one isolated from a patient with antibiotic refractory Lyme arthritis. The epitopes grouped into three spatially distinct bins that, together, encompass more than half the surface-exposed area of OspA. The bins corresponded to OspA fl-strands 8-10 (bin 1), 11-13 (bin 2), and 16-20 plus the C-terminal alpha-helix (bin 3). Bin 3 was further divided into sub -bins relative to LA-2's epitope. MAbs with complement-dependent borreliacidal activity, as well as B. burgdorferi transmission-blocking activity in the mouse model were found within each bin. Therefore, the resulting B cell epitope map encompasses functionally important targets on OspA that likely contribute to immunity to B. burgdorferi.