The outer surface proteins OspA and OspB of Borrelia burgdorferi have recently been demonstrated to be major target proteins for protective antibodies in mice against infection with the homologous spirochaetal strain. However, it has become clear from a variety of studies that B. burgdorferi isolates of different geographical origin and/or sources are heterogeneous and that they can be divided into at least six subgroups according to their distinct OspA/OspB genotypes. In order to analyse cross-protection between these subgroups we have now generated immune sera to various isolates of B. burgdorferi with different OspA/OspB genotypes. We show that passive immunization with antisera specific for whole spirochaetes or recombinant OspA of one spirochaetal isolate protects severe combined immunodeficiency mice against infection with strains of the corresponding OspA/OspB genotype but only partially or not at all against infection with isolates expressing distinct OspA/OspB genotypes. The incomplete protection mediated by individual antisera against independent isolates of B. burgdorferi suggests that an effective subunit vaccine against
Lyme disease should consist of a mixture of OspA structures covering the heterogeneity of this protein within the species B. burgdorferi.