Heat shock protein complex vaccines induce antibodies against Neisseria meningitidis via a MyD88-independent mechanism.

BACKGROUND: Neisseria meningitidis are common colonizers of the human nasopharynx. In some circumstances, N. meningitidis becomes an opportunistic pathogen that invades tissues and causes meningitis. While a vaccine against a number of serogroups has been in effective use for many years, a vaccine against N. meningitidis group B has not yet been universally adopted. Bacterial heat shock protein complex (HSPC) vaccines comprise bacterial HSPs, purified with their chaperoned protein cargo. HSPC vaccines use the intrinsic adjuvant activity of their HSP, thought to act via Toll-like receptors (TLR), to induce an immune response against their cargo antigens. This study evaluated HSPC vaccines from N. meningitidis and the closely related commensal N. lactamica. RESULTS: The protein composition of N. lactamica and N. meningitidis HSPCs were similar. Using human HEK293 cells we found that both HSPCs can induce an innate immune response via activation of TLR2. However, stimulation of TLR2 or TLR4 deficient murine splenocytes revealed that HSPCs can activate an innate immune response via multiple receptors. Vaccination of wildtype mice with the Neisseria HSPC induced a strong antibody response and a Th1-restricted T helper response. However, vaccination of mice deficient in the major TLR adaptor protein, MyD88, revealed that while the Th1 response to Neisseria HSPC requires MyD88, these vaccines unexpectedly induced an antigen-specific antibody response via a MyD88-independent mechanism. CONCLUSIONS: N. lactamica and N. meningitidis HSPC vaccines both have potential utility for immunising against neisserial meningitis without the requirement for an exogenous adjuvant. The mode of action of these vaccines is highly complex, with HSPCs inducing immune responses via both MyD88-dependent and -independent mechanisms. In particular, these HSPC vaccines induced an antibody response without detectable T cell help.

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

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.