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The Impact of Helminthic Infection on the Efficacy of the Bacille Calmette-Guérin (BCG) Vaccine Against Pulmonary Tuberculosis Sadie Forrester Department of Biological Sciences, York College of Pennsylvania PROJECT SUMMARY REVIEW OF LITERATURE OBJECTIVES EXPECTED RESULTS The efficacy of bacille Calmette-Guérin (BCG), the only vaccine prescribed against tuberculosis, varies from 0% to 80%. That variability has not been explained, although low protection characterizes regions endemic for helminths. This proposal intends to test the impact of helminthic infection on BCG efficacy through a two-phase study. Rhesus monkeys in phase one will be infected with the helminth Schistosoma mansoni before or after BCG vaccination, and subsequently challenged with Mycobacterium tuberculosis. If clinical assessments, cellular proliferation analyses, cytokine assays, bacterial counts, and pathologic examinations indicate that helminthic infection reduces efficacy, phase two will be conducted. Monkeys in phase two will be infected with S. mansoni and treated with the antihelminthic drug praziquantel before or after BCG vaccination, followed by exposure to M. tuberculosis. Should pretreatment with praziquantel appear to improve immune responsiveness to BCG, administering antihelminthics before vaccination may be a cost-effective way to protect worm-burdened peoples from tuberculosis. The immune system is dominated by one of two divergent responses during the course of an infection. To conduct a controlled study that characterizes the effect of schistosomiasis on the cytokine profile of the immune system A prominent Th2 immune profile in monkeys with schistosomiasis The other is primarily humoral and is induced by T helper type 2 (Th2) cytokines (Gallagher 1997). Ethiopian immigrants to Israel with helminthic infections had highly activated immune systems characterized by a Th2 cytokine profile (Borkow et al. 2000) (Figure 1). The Th1 response to tetanus toxoid is suppressed in humans with schistosomiasis (Sabin et al. 1996). To determine how the efficacy of the BCG vaccine is impacted by an altered immune response To test whether antihelminthic treatment is able to restore the immune response and improve the efficacy of the BCG vaccine against challenge RESEARCH DESIGN AND METHODS Table 1. Phase I summary protocol Group Primary Secondary a Treatment Treatment I Saline -II S. mansoni -III BCG -IV S. mansoni BCG V BCG S. mansoni A short-term study revealed that humans treated with antihelminthics before BCG vaccination had elevated in vitro responses compared to vaccinated individuals infected with helminths (Elias et al. 2001) (Figure 2). Figure 1. Helminths Bacille Calmette-Guérin (BCG) is the only vaccine administered against tuberculosis. IL-2 IFN-γ Th1 cytokines Cases of pulmonary tuberculosis infection continue to rise in developing countries because the vaccine’s efficacy is highly variable. IL-4 IL-10 Th2 cytokines The reason for the variability is not understood. The study will also test the ability of the antihelminthic drug praziquantel to restore the immune profile and improve the efficacy of the BCG vaccine upon eradication of helminthic infection. Figure 2. (a) 250 250 (b) 5000 5000 * 200 200 150 150 100 100 ** 50 50 IFN- γ (pg/ml) The proposed study will determine whether the helminthic infection Schistosoma mansoni alters the underlying immune profile of rhesus monkeys and whether that shift in turn reduces the efficacy of the BCG vaccine. Figure 1. The shift of the immune system towards a Th2 cytokine profile as a result of helminthic infection (Adapted from Bentwich et al. 1999). Stimulation index Helminthic infections may reduce the efficacy of the BCG vaccine because they alter the underlying immune profile. of the six monkeys in each group will be challenged with M. tuberculosis after secondary treatments. Cytokine network INTRODUCTION Examination of the impact of helminthic infections, which are common in areas where efficacy is low, has largely been overlooked. a Three PHA PHA PHA PPD PPD PPD VI VII VIII IX Praziquantel S. mansoni BCG Praziquantel S. mansoni Praziquantel Praziquantel BCG ----- X S. mansoni BCG Praziquantel XI S. mansoni Praziquantel BCG of the six monkeys in each group will be challenged with M. tuberculosis after tertiary treatments. ** 3000 3000 Clinical assessments will be conducted daily to monitor for signs of tuberculosis such as coughing Cellular proliferation analysis will be executed regularly to measure the response to tuberculin PPD 2000 2000 1000 1000 00 0 Tertiary a Treatment a Three ** 4000 4000 Table 2. Phase II summary protocol Group Primary Secondary Treatment Treatment PHA PHA PPD PPD Figure 2. Proliferative responses (a) and IFN-γ secretion (b) to mycobacterial antigen in humans treated with antihelminthics prior to vaccination with BCG. Peripheral blood mononuclear cells (PBMC) obtained 8 weeks after the first dose of placebo ( ) or antihelminthic ( ) were stimulated with phytohaemagglutinin (PHA) or tuberculin purified protein derivative (PPD). Data are means + s.e.m. *P<0.001 **P<0.05 (Reproduced from Elias et al. 2001). Trap ELISA and flow cytometry will detect cytokine levels in regularly collected unstimulated venous blood samples Pathologic examinations upon sacrifice will verify S. mansoni and tuberculosis infections Bacterial counts from lung tissue samples will indicate the intensity of tuberculosis infections Reduced cellular proliferation in monkeys with schistosomiasis at the time of BCG vaccination Increased cellular proliferation and a restored Th1 immune profile in S. mansoni-infected monkeys treated with praziquantel prior to vaccination (Figure 3) Vaccinated monkeys never infected with S. mansoni or that were infected but received praziquantel prior to vaccination will be more resistant to challenge with M. tuberculosis Figure 3. 18 Stimulation index One response is primarily cell-mediated and is induced by T helper type 1 (Th1) cytokines. 16 14 12 10 8 6 4 2 0 S S+BCG P P+BCG Figure 3. Expected proliferative response to PPD in S. mansoni infected (S) and praziquantel treated (P) groups before and after BCG vaccination (+BCG). Unstimulated PBMC will be analyzed 1 week before ( ) and 8 weeks after ( ) vaccination. Data are means (Adapted from Elias et al. 2001). LITERATURE CITED Bentwich, Z., Kalinkovich, A., Weisman, Z., Borkow, G., Beyers, N. and Beyers, A.D. 1999. Can eradication of helminthic infections change the face of AIDS and tuberculosis? Trends in Immunology Today 20:485-487. Borkow, G., Leng, Q., Weisman, Z., Stein, M., Galai, N., Kalinkovich, A. and Bentwich, Z. 2000. Chronic immune activation associated with intestinal helminth infections results in impaired signal transduction and anergy. Journal of Clinical Investigation [serial online] 106:1053-1060. Available from: HighWire Press. Elias, D., Wolday, D., Akuffo, H., Petros, B., Bronner, U. and Britton, S. 2001. Effect of deworming on human T cell responses to mycobacterial antigens in helminth-exposed individuals before and after bacille Calmette-Guérin (BCG) vaccination. Clinical and Experimental Immunology 123:219-225. Gallagher, R. 1997. Tagging T cells Th1 or Th2? Science 275:1615-1620. Sabin, E.A., Araujo, M.I., Carvalho, E.M. and Pearce, E.J. 1996. Impairment of tetanus toxoid-specific Th1-like immune responses in humans infected with Schistosoma mansoni. Journal of Infectious Diseases 173:269-72. Acknowledgements: Carolyn Mathur, PhD, YCP Research Mentor Deborah Ricker, PhD