Activation of TRIF-dependent and independent immune responses by neisserial heat shock protein complex vaccines

Abstract

ASBTRACT Heat shock protein Complex (HspC) vaccines are composed of Hsp purified from pathogenic bacteria along with their chaperoned protein cargo. Mouse studies have shown that HspC vaccines can induce a strong immune response against pathogenic bacteria without addition of an exogenous adjuvant. These vaccines are now entering clinical trials. It was predicted, but not previously tested, that HspC vaccines induce an immune response due to the activation of Toll-Like Receptors (TLR) by their component Hsp. Recently we tested this supposition and found that while this held true for the cellular response to neisserial HspC vaccines, strong antigen-specific antibody responses were surprisingly generated in mice deficient in MyD88 and thus most TLR signaling. This suggested an unidentified mechanism by which HspC vaccines induce an antibody response. We have now examined the antigenic profile of this response and found no evidence that this is due to the induction of T-independent antibodies. Examination of the MyD88-dependent signaling pathways involved in the cellular response to neisserial HspC showed that both TRIF-dependent and TRIF-independent pathways are activated, each resulting in the secretion of different cytokines. Hence the mechanism of action of HspC vaccines is clearly more complicated than originally thought.

Bioconjugation Approaches to Producing Subunit Vaccines Composed of Protein or Peptide Antigens and Covalently Attached Toll-Like Receptor Ligands

“…The ability of HSPs to act as danger signals and induce T H 1 and T H 17-type responses makes them potential adjuvants for fusing with protein or peptide antigens. , r4M2e.HSP70c was constructed and expressed in E. coli by linking four tandem repeats of influenza A virus M2e with a Mycobacterium tuberculosis C-terminal truncated HSP70 . Compared with r4M2e, rHSP70c, or r4M2e adjuvanted with alum, r4M2e.HSP70c induced stronger and longer lasting humoral and cellular immune responses characterized by the enhanced production of M2e-specific IgG2a antibodies and the T H 1 cytokine IFN-γ .…”