Vaccines are amongst the most cost-effective tools in reducing the burden of infectious diseases. With the ability to induce both cellular and humoral immunes responses, viral-vectored vaccines have become a promising approach against a variety of diseases. While the standard route of vaccination, intra-muscular injection, is highly effective at inducing circulating responses and protecting from severe disease, there is increasing evidence that improved vaccine efficacy will come by targeting the immune response to the site of pathogen exposure. We have previously shown that intravenous Adenovirus administration leads to induction of liver resident T cells that alone are able to protection against liver-stage malaria.
In this study we aimed to identify the key factors driving the induction and maintenance of Trm cells to optimise viral vector vaccination regimens for translation to the clinic. We compared three different viral vectors, Adenovirus (Ad), modified vaccinia Ankara (MVA) poxvirus and Adeno-associated virus (AAV), for their capacity to target the immune response to the liver. Quantity and quality of the immune response was measured by flow cytometry while vaccine efficacy was assessed in a mouse malaria challenge model.
Although the kinetics of antigen expression differed between vectors, an intravenous targeting dose of all vectors induced high numbers of antigen specific T cells in the liver and protection from malaria. However, optimal induction of liver Trm cells was dependant on the level of antigen presentation in the liver during the induction phase, with liver tropic vectors (Ad and AAV) better able to target T cells to the liver. While the local inflammatory microenvironment induced by different vectors did not appear to impact Trm numbers, differences in the cytokine profiles between vectors was observed. Sporozoite exposure enhanced the maintenance of long-lived protective T cells but only following Ad and AAV vector administration, suggesting an underlying relationship between antigen expression and Trm maintenance. As Adenoviral vectors are being developed for a broad variety of disease, we are now exploring their capacity to target the immune response to other organs.