Development of effective and affordable HIV vaccines is one of the best and cost-effective strategies for controlling the HIV epidemic and a top priority in endemic areas. Successful future candidate HIV vaccines are expected to elicit effective antibody and T cell-mediated responses. This is envisaged to be attained through induction of potent T cell-mediated immune responses to control viral replication in the tissues and disease progression as well as a durable antibody immune response which comprises of broadly neutralizing antibodies to block virus entry at the mucosal sites. Both types of immune responses are influenced by a T helper cell type 1 (Th1) immune response. In developing worlds such as Sub-Saharan Africa co-infections of HIV and schistosomiasis are common. Helminth infections such as schistosomiasis induce strong Th2 biased immune responses that have been reported to alter HBV, BCG, Tetanus toxoid and some candidate HIV vaccine-specific immune responses. Because Th1 and Th2 are almost mutually exclusive, it is suggested that, in the presence of chronic helminthic infections, Th1 responses elicited by HIV vaccine may be attenuated, hence, reduce vaccine efficiency. On the other hand, vaccination with an effective HIV vaccine might shift the immune bias towards a Th1 response, resulting in worsening of the helminth-associated pathology, thus, making the vaccine unsafe to the recipients. This study aimed at investigating if chronic helminth infection (Schistosoma mansoni: Sm) has a negative impact on the immunogenicity of HIV vaccine candidates (SAAV DNA-C2, SAAVI MVA-C, and Env gp140 protein) previously shown to induce cellular, mixed and antibody immune responses in mice. The objectives of this study were to (i) infect mice with live Schistosoma mansoni infection in order to induce a predominantly Th2 immune response in a mouse model; (ii) evaluate if helminth-induced Th2 immune biasing negatively affects responses to candidate HIV vaccines; (iii) evaluate the ability of ant ihelminthic chemotherapy in restoring normal responses to HIV vaccines in helminth infected mice; (iv) evaluated if HIV vaccine that predominantly induces strong cellular immune responses result in worsening of the helminth-associated pathology and (v) evaluate if helminth eggs in the absence of live helminth infection drives a Th2-dominant response that can affect HIV vaccine responses. The BALB/c mouse model has been used extensively at the University of Cape Town for studying the Smassociated immunology as well as for initial evaluation of candidate HIV vaccines. Female BALB/c mice were either chronically infected with Sm cercariae or inoculated with Sm eggs (SmE) before being subsequently vaccinated twice, 4 weeks apart with three vaccination regimes that elicit cellular (SAAVI DNA-C2 prime + MVA-C boost denoted: DNA+MVA), antibody (gp140 Env protein) and mixed cellular and antibody (SAAVI MVA-C prime + gp140 Env protein boost denoted: MVA+gp140) responses. Some groups of mice infected with live Sm were treated twice with praziquantel (PZQ) prior to vaccination. Spleens, blood and livers were harvested for analysis of vaccine-specific T cell, antibody responses and histological studies using ELISpot, ELISA, CBA, ICS staining, H&E/CAB staining and hydroxyproline assay. Our findings demonstrated that in a mouse model, chronic Sm-infection induces a predominantly Th2 immune biased response marked with elevated parasite-specific IL-4; IL-6 and IL-10 as well as elevated total IgG1 and IgM, while resulting in decreased Th1 markers. Furthermore, chronic infection significantly inhibited cellular responses to the MVA+gp140 vaccine regimen shown by IFN-γ and IL-2 ELISpot; CBA and ICS staining. Similarly, in DNA+MVA vaccinated mice, a significant reduction in vaccine-specific responses was observed in Sm-infected groups compared to uninfected vaccinated groups shown by IFN-γ and IL-2 ELISpot; CBA and ICS against HIV immunogens. antihelminthic treatment with PZQ resulted in the partial restoration of Th1-Th2 balance in the Sm-infected hosts, with the levels of vaccine-induced IFN-γ; TNF-α and IL-2 being partially restored despite the presence of elevated Th2 cytokines after treatment with PZQ. A significant overall decrease in Env gp140 specific IgG, IgG1, IgG2a and IgG2b antibody responses was observed in the Sm-infected mice vaccinated with gp140 or MVA+gp140 vaccine regimen compared to uninfected vaccinated controls. Surprisingly, antihelminthic treatment did not restore vaccineinduced antibody responses. Our histology data showed that DNA+MVA vaccinated mice develop increased liver pathology during chronic schistosomiasis compared to unvaccinated Sm-infected groups shown by larger livers; spleen and enlarged granuloma formation. However, no significant difference in collagen content (a marker of fibrosis) measured by hydroxyproline assay in both vaccinated and unvaccinated infected groups was observed. Our findings further demonstrated that in a mouse model, inoculation with SmE also induces a predominantly Th2 immune biased response marked with elevated parasite-specific IL-4; IL-6 and IL-10 while resulting in decreased Th1 markers. No significant impact on cellular responses evaluated by ELISpot and CBA were observed. However, gp140 specific IgG, IgG1 IgG2a and IgG2b antibody responses were significantly reduced in groups challenged with SmE. Overall, these findings show that chronic helminthiasis in the mouse model induces a strong Th2 biasing which is associated with attenuation of both T cell and antibody response to HIV vaccines. Elimination of helminths by chemotherapy may partially restore T cell responses, but not necessarily antibody responses. These findings further suggest that vaccinating helminth infected individuals with HIV vaccines that induce strong cellular responses may increase the pathology induced by the parasites, rendering the vaccine unsafe in helminth endemic areas. Furthermore, this study suggested that in the absence of an active chronic Sm-infection, SmE left trapped in the tissues following antihelminthic treatment, may continue to induce strong Th2 responses which are capable of downregulating vaccine-specific responses, especially the antibody-mediated responses. This study strongly recommends that development of HIV vaccines should also focus on designing vaccines that can overcome helminth-induced immunity.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/26880 |
| Date | January 2017 |
| Creators | Dzhivhuho, Godfrey Azwindini |
| Contributors | Chege, Gerald K, Williamson, Anna-Lise, Horsnell, William G C |
| Publisher | University of Cape Town, Faculty of Health Sciences, Division of Virology |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, Doctoral, PhD |
| Format | application/pdf |
Page generated in 0.0124 seconds