Development of hepatitis B virus capsids into a whole-chain protein antigen display platform: new particulate Lyme disease vaccines.

The immunogenicity of peptides and small protein fragments can be considerably enhanced by their presentation on particulate carriers such as capsid-like particles (CLPs) from hepatitis B virus (HBV). HBV CLPs are icosahedral nanoparticles formed by 90 or 120 core protein dimers. Insertions into the immunodominant c/e1 B cell epitope, a surface-exposed loop on the HBV capsid protein, are especially immunogenic. Here we investigated whether the HBV core protein can be exploited as a vaccine carrier for whole-chain protein antigens, using two clinically relevant proteins derived from a bacterial human pathogen, the Lyme disease agent Borrelia burgdorferi. For this purpose we analyzed CLP formation by core fusions with the entire 255-amino-acid ectodomain of outer surface lipoprotein A (OspA), and with two distinct, 189 amino acid long variants of the dimeric OspC (OspC(a), OspC(b)) of B. burgdorferi. OspA appropriately inserted into the HBV core protein yielded a multimerization-competent fusion protein, termed coreOspA. Although only partially assembling into regular CLPs, coreOspA induced antibodies to OspA, including the Ig isotype profile and specificity for the protective epitope "LA-2", with an efficiency similar to that of recombinant lipidated OspA, the first generation vaccine against Lyme disease. Moreover, coreOspA actively and passively protected mice against subsequent challenge with B. burgdorferi. Fusions with the two OspC variants were found to efficiently form regular CLPs, most probably by OspC dimerization across different core protein dimers. In mice, both coreOspC preparations induced high-titered antibody responses to the homologous but also to the heterologous OspC variant, which conferred protection against challenge with B. burgdorferi. The data demonstrate the principal applicability of HBV CLPs to act as potent immunomodulator even for structurally complex full-length polypeptide chains, and thus open new avenues for novel vaccine designs.

A fusion product of the complete Borrelia burgdorferi outer surface protein A (OspA) and the hepatitis B virus capsid protein is highly immunogenic and induces protective immunity similar to that seen with an effective lipidated OspA vaccine formula.

The immunogenicity of peptides and protein fragments can be considerably enhanced by their presentation on particulate carriers such as capsid-like particles (CLP) from hepatitis B virus (HBV). Here we tested the suitability of the HBV capsid protein as a carrier for a relevant full-length pathogen-derived protein antigen. The entire 255-amino acid ectodomain of the outer surface protein A (OspA) from Borrelia burgdorferi, the causative agent of Lyme disease, was inserted into the major B cell epitope of the HBV capsid, yielding a multimerization-competent fusion protein, termed coreOspA. CoreOspA, consisting only in part of regular CLP, induced antibodies to OspA, including the Ig isotype profile and specificity for the protective epitope LA-2, with an efficiency similar to that of recombinant lipidated OspA, the first generation vaccine against Lyme disease. Moreover, coreOspA actively and passively protected mice against subsequent challenge with B. burgdorferi. The data demonstrate the capacity of the HBV capsid protein to act as a potent immunomodulator even for full-length and structurally complex polypeptide chains and thus opens new avenues for novel vaccine designs.