PI 3-Kinase/Akt Signaling

The vaccine is aimed at inducing high titre antibodies to block the sporozoites prior to infection of hepatocytes

The vaccine is aimed at inducing high titre antibodies to block the sporozoites prior to infection of hepatocytes. CD8+ T cells. This work has INK4C identified two promising liver-stage candidate antigens that will now undergo further testing in humans. Development of a vaccine against the parasite, the causative agent of malaria, has proven more difficult than for other pathogens, largely because of KU 0060648 its complex life-cycle, its thousands of antigens and its immune evasion mechanisms. The gold-standard malaria vaccine (the most effective in human challenge trials) is the administration of irradiated sporozoites1, yet despite encouraging developments2 this method of vaccination still appears unsuitable for large-scale deployment. Irradiated sporozoites are capable of invading hepatocytes but their development is arrested, providing a repertoire of antigens for the immune system to react against whilst not producing a blood-stage (or symptomatic) infection3. Protection by irradiated sporozoites in mice and non-human primates is dependent upon CD8+ T cells specific for liver-stage antigens4,5. An alternative approach to a malaria vaccine is the development of sub-unit vaccines comprising a particular antigen expressed at one or more stages of the parasites life-cycle. The most advanced sub-unit vaccine, RTS,S/AS01, which targets the circumsporozoite protein (CSP) at the pre-erythrocytic stage, may be licensed in the near future but still lacks high levels of durable efficacy6. The vaccine is aimed at inducing high titre antibodies to block the sporozoites prior to infection of hepatocytes. The alternative sub-unit vaccination strategy is the induction of high numbers of CD8+ T cells to kill infected hepatocytes. The most successful regimen to date has been the use of viral vectors expressing the chosen antigen in a heterologous prime-boost regimen, as for the ME-TRAP vaccine. The ME-TRAP vaccine combines the pre-erythrocytic antigen thrombospondin-related adhesion protein (TRAP) with a multi-epitope string (ME) and is delivered via the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA)7. Whilst this vaccine displays moderate levels of efficacy in na?ve-adults, it induces exceptionally high CD8+ T cell responses. A number of approaches are being assessed with the aim of increasing the efficacy of such sub-unit vaccines, including the use of new adjuvants, different sub-unit vaccination platforms and the use or addition of new antigens. There is increasing evidence that antigens other than CSP or TRAP may contribute to a protective immune response8,9,10,11, and it is likely that multiple antigens will be needed to reach the high levels of efficacy achievable with large doses of irradiated sporozoites. However, only a few antigens have been assessed as sub-unit vaccines partly owing to the difficulty in screening vaccines pre-clinically. accounts for the majority of the malaria burden in humans, but it does not naturally infect small animals. Therefore, rodent malaria parasite species are routinely used for proof-of-concept studies, yet several newly identified antigen candidates do not have orthologs in murine malaria parasite species. Another strategy to study immunology and assess malaria vaccines has been the generation of transgenic rodent malaria parasites expressing proteins12. In this study, we sought to determine whether eight alternative liver-stage antigens could induce strong CD8+ KU 0060648 T cell responses when delivered using a heterologous ChAd63-MVA prime-boost vaccination regimen. Next, in an effort to determine efficacy of KU 0060648 these vaccines, we created ten transgenic parasites, eight that express these new candidate antigens and another two expressing CSP or TRAP, enabling a homologous efficacy challenge in mice. Here, we report the successful production of eight KU 0060648 vaccines inducing strong CD8+ T cell responses and KU 0060648 preliminary results demonstrating superior efficacy of ChAd63-MVA.