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Vaccines are an important public health measure for prevention and treatment of diseases. In addition to the vaccine immunogen, many vaccines incorporate adjuvants to stimulate the recipient's immune system and enhance vaccine-specific responses. While vaccine development has advanced from attenuated organism to recombinant protein or use of plasmid DNA, the development of new adjuvants that safely increase immune responses has not kept pace. Previous studies have shown that the complex mixture of molecules that comprise saline soluble egg antigens (SEA) from Schistosoma mansoni eggs functions to promote CD4 ؉ T helper 2 (Th2) responses. Therefore, we hypothesized that coadministration of SEA with a Listeria vector HIV-1 Gag (Lm-Gag) vaccine would suppress host cytotoxic T lymphocyte (CTL) and T helper 1 (Th1) responses to HIV-1 Gag epitopes. Surprisingly, instead of driving HIV-1 Gag-specific responses toward Th2 type, we found that coadministration of SEA with LmGag vaccine significantly increased the frequency of gamma interferon (IFN-␥)-producing Gag-specific Th1 and CTL responses over that seen in mice administered Lm-Gag only. Analysis of the functionality and durability of vaccine responses suggested that SEA not only enlarged different memory T cell compartments but induced functional and long-lasting vaccine-specific responses as well. These results suggest there are components in SEA that can synergize with potent inducers of strong and durable Th1-type responses such as those to Listeria. We hypothesize that SEA contains moieties that, if defined, can be used to expand type 1 proinflammatory responses for use in vaccines.

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c Schistosome infection induces significant T helper type 2 (Th2) and anti-inflammatory immune responses and has been shown to negatively impact vaccine efficacy. Our goal was to determine if the administration of schistosome soluble egg antigens (SEA) would negatively influence the induction of cytotoxic T lymphocyte (CTL) and Th1-type T cell responses to an HIV candidate vaccine in the Th1-biased C57BL/6 mouse strain. Initial experiments failed, as we were unable to detect any response to the defined class I epitope for HIV-1 IIIB Gag. Therefore, we initiated an epitope mapping study to identify C57BL/6 (H-2 b ) T cell epitopes in HIV-1 IIIB Gag in order to perform the experiments. This analysis defined two previously unreported minimal class I H-2 b and class II I-A b epitopes for HIV-1 IIIB Gag. The newly defined HIV-1 IIIB Gag epitopes were used to evaluate the influence of SEA on the generation of CTL and Th1-type HIV-1 IIIB Gag responses. Surprisingly, in contrast to our hypothesis, we observed that the coadministration of SEA with a Listeria monocytogenes vector expressing HIV-1 IIIB Gag (Lm-Gag) led to a significantly increased frequency of gamma interferon (IFN-␥)-producing CD8؉ and CD4 ؉ T cells in C57BL/6 mice compared to mice immunized with Lm-Gag only. These observations suggest that SEA contains, in addition to Th2-type and immune-suppressive molecules, substances that can act with the Lm-Gag vaccine to increase CTL and Th1-type vaccine-specific immune responses.V accines for human immunodeficiency virus (HIV), tuberculosis, and malaria are in development or in clinical trials. The greatest incidence of each of these diseases is in sub-Saharan Africa, where helminth infection is endemic (1, 2). Helminth parasites bias immune responses to the CD4 ϩ Th2 type and can be immune suppressive (3-10). To evaluate the influence of helminth infection on vaccines, we can evaluate the ability to induce vaccine-specific immune responses in helminth-infected recipients or in recipients who have been treated with immune-biasing helminth antigens (11-13).Schistosomiasis is a helminth parasitic disease that affects Ͼ200 million people worldwide and is listed by the World Health Organization (WHO) as the second leading parasitic disease, after malaria (14). Infection occurs when cercariae that emerge from infected snail intermediate hosts contact and penetrate the skin of the vertebrate host. Larval parasites migrate and mature into adult male and female worms that mate and produce eggs (4, 6). Eggs that become lodged within host tissues are largely responsible for Th2 biasing of the host immune system and induction of antiinflammatory responses (3,4,6,15,16).Immune biasing induced by schistosome infection has been shown to reduce vaccine efficacy in both laboratory and clinical settings (8,11,17,18). Specifically, helminth infection has been shown to suppress immune responses to a Th1-type vaccine and impair the expansion of pathogen-specific cytotoxic CD8ϩ T cell (cytotoxic T lymphocyte [CTL]) responses (18)(19)(...

Malaria, TB and HIV-1 remain tremendous disease burdens in much of the world’s population and functional vaccines are desperately needed. Although Sub-Saharan populations are those that will benefit most from these vaccines, they are also coincident with areas of endemic helminth infection. Infection with one or more species of parasitic helminths suppresses the immune system and has been shown, by our lab and others, to suppress vaccine-specific responses. One goal of our research is to find vaccines that drive significant vaccine-specific immune responses in helminth infected recipients, without the need to eliminate helminth infection prior to vaccination. In the current study, we demonstrate that administration of a Listeria vector HIV-1 gag vaccine to mice chronically infected with the helminth parasite Schistosoma mansoni drives significant immune responses to HIV-1 gag CTL and helper epitopes. This observation suggests that Listeria vector vaccines are capable of driving vaccine-specific responses in helminth-infected populations. Kinetic studies show the antigen-specific responses are both durable and capable of inducing CD8+ central memory. In addition to HIV-1, Listeria vectors should be considered in the development of new generation malaria and TB vaccines to be administered to sub-Saharan Africa populations where helminth infection is endemic. Studies are underway to determine if other vectors are also capable of overcoming helminth-induced immune suppression.