Genetic Vaccines for Infectious Disease and Cancer

Alistair Ramsay PhD

Our overall focus is the development of novel genetic vaccination strategies against infectious diseases, including HIV/AIDS and tuberculosis (TB), against which conventional vaccines have failed.  Our approach may also be effective in stimulating protective immune responses against certain forms of cancer. 

Our vaccine strategy is based on the use of different recombinant "gene-delivery" vectors, including DNA vaccines, poxviruses, and replication-defective adenoviruses, to carry genes encoding vaccine antigens to the immune system.  We use these agents in "prime-boost" combination, since we have shown that this drives the generation of high-level immune responses in the vaccinated host - indeed many times greater than when our vectors are used individually or when most conventional vaccines are used.  The immune responses that develop following prime-boosting appear also to have a greatly enhanced capacity to recognize their vaccine "targets" and this quality may be of particular benefit early following the infection of a cell in the body, or in the case of tumor cells, since in each of these cases there is often limited expression of such pathogen or tumor targets that may go undetected by less sensitive immune cells. 

At present, our major efforts, in addition to a fundamental program of study into the development of high quality vaccine-induced T cell populations, are directed towards generating effective prime-boost vaccines against tuberculosis and also to test the potential of this approach against certain forms of cancer. 

We have recently shown that prime-boosting against important proteins of the TB bacterium that are expressed at the acute phase of infection generates T cell responses both in the circulation and also in pulmonary target tissues that afford protection against TB challenge.   The level of protection that we have achieved is as good as or better than the current "gold standard" vaccine, BCG.  A key component of our approach is the inclusion of a mucosal delivery component.  The localization and efficacy of vaccine-induced immunity is superior when the booster vaccine is given directly to a mucosal target organ, in this case the pulmonary tissues (see Figure).  These studies address the pressing problem of developing better preventive vaccines against tuberculosis.  Of potential importance to immune therapy of existing TB infection, we have now also identified, as vaccine targets, TB proteins that are expressed by the bacterium only after infection has been established.  Prime-boost vaccination against some of these "chronic phase" proteins generates immune responses that are also highly protective against acute TB challenge.  In moving this work forward we will further characterize vaccine-induced immunity with a view to optimizing immunization schedules, and also begin to test these vaccines for their therapeutic potential in the setting of a long-standing TB infection.

We have also recently begun to test the ability of our prime-boost approach as an effective therapy against two different tumors, prostate cancer and chronic myeloid leukemia.  These studies are in their early stages and we have now identified promising tumor proteins to target with our vaccines and have begun to establish appropriate models in which to study vaccine efficacy against disease.  These models will provide us with the opportunity to test both therapeutic and preventive immunization strategies, at least in the case of prostate cancer.  We are also investigating more "universal" tumor antigens, such as the oncofetal antigen, as generic targets for prime-boost vaccination against different forms of cancer.

Link to Dr. Ramsay's faculty page