A parainfluenza virus 5 (PIV5)-vectored intranasal vaccine for Lyme disease provides long-lasting protection against tick transmitted Borrelia burgdorferi in mice

Abstract

Lyme disease (LD) is the most prevalent vector borne disease in North America and Europe and its geographic range continues to expand. Strategies for disease control are necessary to effectively reduce incidence of LD including development of safe vaccines for human use. Parainfluenza virus 5 (PIV5) vector has an excellent safety record in animals and PIV5-vectored COVID-19 and RSV vaccines are currently under clinical development. We constructed PIV5-vectored LD vaccine candidates expressing OspA from B. burgdorferi sensu stricto (OspA _B31) and a chimeric protein containing sequences from B. burgdorferi and B. afzelii (OspA _BPBPk). Immunogenicity and vaccine efficacy were analyzed in C3H-HeN mice after prime-boost intranasal (IN) vaccination with PIV5-OspA _B31 and PIV5-OspA _BPBPk, subcutaneous (SC) vaccination with rOspA _B31+Alum as well as the respective controls. Mice vaccinated with either PIV5-A _B31 or PIV5-A _BPBPk intranasally had high endpoint titers of serum antibody against OspA antigen beyond 1 year post vaccination, similar to levels detected in mice vaccinated SC with rOspA _B31. Flowcytometric analysis of spleen cells at 9-months post-immunization demonstrated that immunization with the intranasal PIV5 vaccine candidates led to an overall increase in the number of memory B cells, cytotoxic T and cytotoxic effector T cells compared to SC groups. Borreliacidal activity measured by neutralization assay was maintained up to 18 months post-immunization, with the response greater in intranasal PIV5-delivered OspA vaccines, than that induced by SC rOspA _B31. Challenge with infected ticks (10-19 strains of B. burgdorferi) performed at 4-, 9- or 15-months post-immunization showed increased breakthrough infections in mice vaccinated with SC rOspA _B31 compared to IN PIV5-A _B31 or IN PIV5-A _BPBPk at 9- and 15-months, as determined by qPCR of B. burgdorferi in tissues, culture of B. burgdorferi from tissues, and antibodies against B. burgdorferi protein VIsE. These data demonstrate that intranasal PIV5-based immunization is superior to parenteral immunization with the same recombinant protein and provides long-lasting protection (> 1 year) against Lyme disease.