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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.

Gastric adenocarcinoma is globally the third leading cause of death due to malignancy, with the bulk of this disease burden being suffered by low and middle income countries (LMIC), especially in Asia. The majority of these cancers develop as a result of a chronic gastritis that arises in response to infection with the stomach-dwelling bacterium, Helicobacter pylori. A vaccine against this pathogen would therefore be a powerful tool for preventing gastric adenocarcinoma. However, notwithstanding a proof-of-concept that vaccination can protect children from acquisition of H. pylori infection, there are currently no advanced vaccine candidates with only a single vaccine in Phase I clinical trial. Further, the development of a vaccine against H. pylori is not a current strategic priority of major pharmaceutical companies despite the large global disease burden. Given the involvement of such companies is likely to be critical for late stage development, there is therefore a need for an increased appreciation of the burden of this disease in LMIC and more investment to reinvigorate research in H. pylori vaccine Research and Development.

Helicobacter pylori, the major cause of gastric cancer, have mechanisms that allow colonization of the inhospitable gastric mucosa, including enzymes such as superoxide dismutase (SOD) which protect against reactive oxygen species. As SOD is essential for in vivo colonization, we theorized it might constitute a viable vaccine target. H. pylori SOD was expressed in E. coli and a purified recombinant protein used to vaccinate mice, prior to live H. pylori challenge. Partial protective immunity was induced, similar to that commonly observed with other antigens tested previously. This suggests SOD may have utility in a combination vaccine comprising several protective antigens.

Background The development of a vaccine against the human gastric pathogen Helicobacter pylori , the main causative agent of gastric adenocarcinoma, has been hampered by a number of issues, including the lack of a mucosal adjuvant for use in humans. Heat shock proteins (Hsp), highly conserved molecules expressed by both bacteria and mammalian species, possess a range of functions, including acting as chaperones for cellular proteins and the ability to activate innate immune receptors. Hsp complex (HspC) vaccines, containing Hsp derived from pathogenic bacteria, are immunostimulatory without addition of an exogenous adjuvant and can induce immunity against their chaperoned proteins. In this study we explored in mice the potential utility of a H. pylori HspC vaccine. Results Vaccination with H. pylori HspC, by either the subcutaneous or respiratory mucosal route, induced a strong antibody response, elevated gastric cytokine levels and significant protection against subsequent live challenge with this pathogen. The level of protection induced by non-adjuvanted HspC vaccine was equivalent to that which resulted from vaccination with adjuvanted vaccines. While protection induced by immunisation with adjuvanted vaccines was associated with the development of a moderate to severe atrophic gastritis, that induced by H. pylori HspC only resulted in a mild inflammatory response, despite an increase in pro-inflammatory gastric cytokines. This reduced gastritis correlated with an increase in IL-10 and IL-13 levels in the gastric tissues of HspC vaccinated, H. pylori challenged mice. Conclusions H. pylori HspC vaccines have the potential to overcome some of the issues preventing the development of a human vaccine against this pathogen: HspC induced protective immunity against H. pylori without addition of an adjuvant and without the induction of a severe inflammatory response. However, complete protection was not obtained so further optimisation of this technology is needed if a human vaccine is to become a reality.

Helicobacter pylori is an important pathogen of the human stomach, and the development of a protective vaccine has been an enticing goal for many years. The H. pylori antioxidant enzymes superoxide dismutase (SOD) and catalase (KatA) have been shown to be protective as vaccine antigens in mice, demonstrating that the organism's antioxidant enzyme system is a fruitful target for vaccine development. The research described here demonstrates that an additional antioxidant enzyme, thiolperoxidase (Tpx), is effective as a prophylactic vaccine antigen via both systemic and mucosal routes. The functional relationship between SOD, KatA and Tpx also provided an opportunity to investigate synergistic or additive effects when the three antigens were used in combination. Although the antigens still provided equivalent protection when administered in combination, no additional protection was observed. Moreover a decrease in antibody titres to the individual antigens was observed when delivered in combination via the nasal route, though not when injected subcutaneously. The findings of this paper demonstrate that the antioxidant system of H. pylori presents a particularly rich resource for vaccine development.

Deep pulmonary delivery of an influenza ISCOMATRIX™ vaccine has previously been shown to induce a combined mucosal and systemic antibody response. To explore whether this combined response is influenced by intrinsic properties of the component antigen, we examined the efficacy of deep pulmonary delivery of ISCOMATRIX™ vaccines containing different recombinant antigens, specifically gB glycoprotein from cytomegalovirus and a fragment of catalase from Helicobacter pylori. Both these vaccines induced antigen-specific mucosal and systemic immunity, as well as antigen-specific proliferative cellular responses. Pulmonary immunisation with ISCOMATRIX™ vaccines may therefore be a generic way of inducing combined systemic and mucosal immunity.

The formation of mucosa-associated lymphoid tissue (MALT) in response to Helicobacter pylori infection is closely associated with the development of primary gastric MALT lymphoma. Aim: To examine whether immunisation against Helicobacter felis can protect against development of MALT lymphoma. Results: The majority of control infected mice demonstrated MALT formation (13/15) and five developed lymphoma. Fifteen immunised mice were protected against bacterial challenge, of which only five had evidence of MALT formation and none developed lymphoma. Interestingly, of the four mice in which immunisation failed, all developed MALT and two of these had lymphoma. Conclusion: Effective immunisation against Helicobacter infection can protect against gastric MALT lymphoma. To our knowledge this is the first demonstration of vaccination protecting against a bacteria-induced malignancy.

This review discusses recent progress in the development of a vaccine against Helicobacter pylori. This progress includes demonstration that: effective immunisation is independent of antibodies but dependent upon CD4+ T helper cells, although their role remains unknown; the immunisation regime can be improved to increase efficacy; successful immunisation against H. pylori is possible using a live vector; a strain of H. pylori suitable for experimental infection of humans has been developed. Important issues that remain to be addressed include incomplete protection, non-availability of suitable mucosal adjuvants and post-immunisation gastritis. Significantly, commercial development of products for clinical trial is underway.

Immunisation against Helicobacter infection in mouse models has thus far produced neither complete protection against the bacteria, nor a complete prevention of the associated gastritis. This study aimed firstly to compare the sensitivities of the various methods used to assess H. pylori infection in the mouse model, and secondly to develop the experimental design to induce a more effective immunity, aimed at further reducing bacterial burden in the gastric tissue. Various mouse strains were prophylactically immunised with whole bacterial sonicate and cholera toxin before challenge with H. pylori -SS1. The relative sensitivities of the urease assay, histological assessment and the colony forming assay to detect levels of H. pylori colonisation were compared. Comparisons of different antigen doses and different timecourses of immunisation were performed. The colony forming assay was found to be far more sensitive than either the urease assay or histological assessment for determining the protective efficacies of immunisation. Mice which had 10 5 H. pylori per gram of stomach by colony assay were negative by histology and urease. Lower doses of whole cell sonicate were more protective than high doses and more effective immunisation was achieved by leaving at least 3 weeks between immunisation instead of weekly immunisations. In conclusion, for assessment of H. pylori colonisation in the mouse model, the colony forming assay should be used. The experimental protocol for immunisation has been altered to produce a significant improvement in protection. However, full protection has still not yet been achieved and more work is still required.

Toxoplasmosis is a major parasitic disease, responsible for foetopathy in humans and domestic animals, especially sheep. Toxoplasma gondii infection generally protects immunocompetent hosts against subsequent reinfection, suggesting that efficacious vaccines can be developed against this disease. Excreted/secreted T. gondii antigens have previously been shown to provide immunoprotection in small rodents, and protective immunity is thought to be cell-mediated. Mycobacterium bovis BCG is known to be a good inducer of cellular immunity. In this study, we have developed a BCG strain which produces and secretes GRA1, one of the major excreted/secreted T. gondii antigens. This strain does not carry antibiotic-resistance determinants and is therefore safe for the environment. The intraperitoneal immunisation of OF1 outbred mice with this BCG strain failed to induce GRA1-specific humoral or cellular immune responses and only conferred a very limited degree of protection against challenge with virulent T. gondii. However, in sheep immunised subcutaneously and boosted intravenously, this recombinant BCG strain induced GRA1-specific cell-mediated responses, as evidenced by the proliferation of peripheral blood mononuclear cells and by the production of IFN-gamma, although it failed to elicit GRA1-specific antibody responses. Following oocyst challenge infection, sheep immunised with recombinant BCG exhibited an abbreviated temperature response compared with controls, suggesting partial protection.