It is a global public health imperative to develop vaccine strategies that produce effective cell-mediated immunity in schistosome-endemic areas, such as sub-Saharan Africa, where HIV infection is common. Vaccine delivery techniques effective in immune-suppressed populations are critical to combating infectious diseases in these already compromised groups. It is well-known that immune suppression, such as by chronic schistosome infection, can cause Tc1/Th1 type vaccines to fail. Listeria, a strong inducer of cell-mediated immunity, can overcome the Th2 biasing and immune suppression caused by schistosome infection. However, safety concerns cause reluctance among the vaccine community and the public to incorporate this vector into immunization programs. Since neither DNA nor the Listeria vaccine vector are ideal for clinical translation, and Gag is likely not the ideal HIV vaccine antigen, we are using this system as a model for enumeration of Tc1 responses (IFNγ+ CD8+ cytotoxic T lymphocytes, CTL); CTLs are likely necessary components of functional responses for next-generation vaccines targeting diseases that currently lack effective vaccines (HIV, TB, malaria). Here, we investigate why DNA vaccine vectors fail during chronic schistosomiasis when Listeria vaccine vectors can generate robust CTL responses to HIV Gag. Specifically, we are examining live bacteria as adjuvants for an episomally expressed or concurrently administered DNA vaccine for HIV Gag. This project is one step toward our overall goal, which is to generate cell-mediated vaccine immunity in schistosome-infected, immune-suppressed patients.
Schistosomiasis is a neglected tropical disease with 200–300 million people infected worldwide. Schistosome infections are immunomodulatory and induce a Th2 biased immune response. Chronic helminth infections, such as schistosomiasis, can cause Th1/Tc1 type vaccine failure. Schistosomiasis endemicity is geographically coincident for other diseases lacking effective vaccines (HIV, TB, and Malaria). New vaccine vectors are needed to counter the immune suppression displayed during this infection. Listeria monocytogenes has shown to function as an effective vaccine vector to induce cell-mediated immune responses. Wild-type Listeria expressing HIV-Gag was previously proven to be an effective bacterial vector, however there are safety concerns with using a pathogenic vaccine vector in humans. Therefore, it is important to develop a clinically relevant vaccine that instead uses an attenuated strain to overcome safety concerns. There are genetically attenuated strains of Listeria currently in use in human clinical trials as therapeutic cancer vaccine vectors. Here, we are cloning HIV-Gag into the attenuated strains to induce strong cell mediated immunity without risk of adverse effects from the pathogenic wild-type vector. We will confirm appropriate Gag protein expression from the novel vectors using standard methodology. Further, we will confirm the functionality of these vectors in naïve and schistosome-infected animals. Our aim is that these non-pathogenic vectors will be clinically relevant for use in schistosome-endemic areas.
Schistosomiasis is the second most burdensome parasitic disease in the world after malaria and is classified as a neglected tropical disease. Schistosomiasis is caused by an immunomodulatory helminth that can induce a Th2 biased response, which can cause Tc1 vaccine failure. Interestingly, the use of pathogenic Listeria monocytogenes vaccine vectors can overcome this failure through an unknown mechanism. Despite the promise of Listeria-vectored vaccines, there is reluctance among the vaccine community and the public to incorporate this vector into immunization programs, due to safety concerns. Here we ask what the question: Why do Listeria vaccines function when other methods, such as DNA vaccination, fail? To answer this question, we use bone-marrow derived dendritic cells (BMDCs) in vitro to model the development of vaccine immunity during the early steps of the adaptive immune response. To compare the immune environment in naïve and schistosome-infected vaccine recipients, we compare responses from both reactogenic DC1 and tolerogenic DC2 dendritic cells, respectively. The DC1 and DC2 subtypes are exposed to a DNA vaccine for HIV, a Listeria vaccine expressing the HIV-1 Gag protein, or left untouched. Through immunological and transcriptomic approaches, we examine these cells for their activation state and functionality; these results will help to elucidate the mechanism/s by which Listeria vectors can overcome schistosome-induced vaccine failure and identify unique molecular vaccine adjuvants functional in schistosome-endemic areas.
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