Barbara A. Gervase

Priming of CD4+ and CD8+ T cell responses using a HCV core ISCOMATRIX vaccine: a phase I study in healthy volunteers.

The disease burden and public health impact of chronic HCV infection continues to be a major problem globally. Current treatment for chronic HCV infection is not effective in all patients and is frequently associated with unacceptable side effects. Clearly a need exists for improved treatments and one such strategy is the use of therapeutic vaccines. Although still not completely understood, emerging data indicate that the generation of CD4+ and CD8+ T cells are important for the clearance of HCV. We have developed a prototype vaccine with the HCV Core protein and ISCOMATRIX™ adjuvant (HCV Core ISCOMATRIX™ vaccine). ISCOMATRIX™ vaccines have been shown to induce CD4+ and CD8+ T cell responses to a range of antigens in both animal models and in human studies. Additionally, ISCOMATRIX™ vaccines have been shown to be safe and generally well tolerated in several clinical trials. Preliminary studies demonstrated that the prototype HCV Core ISCOMATRIX™ vaccine induced strong CD4+ and CD8+ T cell responses in monkeys following immunisation. Here we show the results of a Phase I placebo controlled, dose escalation clinical study designed to evaluate the safety, tolerability and immunogenicity of the HCV Core ISCOMATRIX™ vaccine in healthy individuals. The 30 subjects received 3 immunisations of HCV Core ISCOMATRIX™ vaccines or placebo vaccine on days 0, 28 and 56. The HCV Core ISCOMATRIX™ vaccines contained 5, 20 or 50 μg HCV Core protein with 120 μg ISCOMATRIX™ adjuvant. The adverse events reported were generally mild to moderate in severity, of short duration and self-limiting. The most common adverse events were injection site reactions such as pain and redness as well as myalgia. Antibody responses were detected in all but one of the participants receiving the HCV Core ISCOMATRIX™ vaccine and there was no indication of a dose response. CD8+ T cell responses were only detected in 2 of the 8 participants receiving the highest dose. T cell cytokines were detected in 7 of the 8 participants in the highest dose group. The results of this study support the further evaluation of this prototype HCV Core ISCOMATRIX™ vaccine in HCV infected subjects.

The comparison of the effect of LTR72 and MF59 adjuvants on mouse humoral response to intranasal immunisation with human papillomavirus type 6b (HPV-6b) virus-like particles

Infections with genital human papillomaviruses (HPV) are likely to be neutralised more efficiently if a mucosal immune response can be elicited at the viral entry site. Local IgA antibodies are highly induced when antigens are co-administered with mucosal adjuvants, such as cholera toxin (CT) and Escherichia coli heat labile enterotoxin (LT) which, however, are not expected to have wide application because of their pronounced toxicity. We have immunised mice intranasally with HPV-6b virus-like particles (VLPs) and a genetically modified LT-derived molecule with only residual toxicity, LTR72, and compared the humoral responses with those obtained following systemic immunisation with VLPs and the MF59 adjuvant. Titration of anti-HPV antibodies in sera and vaginal secretions established that LTR72 was able to elicit higher serum and mucosal IgA titers, in addition to IgG serum levels, comparable to those obtained by parenteral immunisation. These results confirm the potential of toxin-derived adjuvants and extend their use in combination with HPV antigens.