Chronic schistosomiasis suppresses HIV-specific responses to DNA-MVA and MVA-gp140 Env vaccine regimens despite antihelminthic treatment and increases helminth-associated pathology in a mouse model

Abstract

Future HIV vaccines are expected to induce effective Th1 cell-mediated and Env-specific antibody responses that are necessary to offer protective immunity to HIV infection. However, HIV infections are highly prevalent in helminth endemic areas. Helminth infections induce polarised Th2 responses that may impair HIV vaccine-generated Th1 responses. In this study, we tested if Schistosoma mansoni (Sm) infection altered immune responses to SAAVI candidate HIV vaccines (DNA and MVA) and an HIV-1 gp140 Env protein vaccine (gp140) and whether parasite elimination by chemotherapy or the presence of Sm eggs (SmE) in the absence of active infection influenced the immunogenicity of these vaccines. In addition, we evaluated helminth-associated pathology in DNA and MVA vaccination groups. Mice were chronically infected with Sm and vaccinated with DNA+MVA in a prime+boost combination or MVA+gp140 in concurrent combination regimens. Some Sm-infected mice were treated with praziquantel (PZQ) prior to vaccinations. Other mice were inoculated with SmE before receiving vaccinations. Unvaccinated mice without Sm infection or SmE inoculation served as controls. HIV responses were evaluated in the blood and spleen while Sm-associated pathology was evaluated in the livers. Sm-infected mice had significantly lower magnitudes of HIV-specific cellular responses after vaccination with DNA+MVA or MVA+gp140 compared to uninfected control mice. Similarly, gp140 Env-specific antibody responses were significantly lower in vaccinated Sm-infected mice compared to controls. Treatment with PZQ partially restored cellular but not humoral immune responses in vaccinated Sm-infected mice. Gp140 Env-specific antibody responses were attenuated in mice that were inoculated with SmE compared to controls. Lastly, Sm-infected mice that were vaccinated with DNA+MVA displayed exacerbated liver pathology as indicated by larger granulomas and increased hepatosplenomegaly when compared with unvaccinated Sm-infected mice. This study shows that chronic schistosomiasis attenuates both HIV-specific T-cell and antibody responses and parasite elimination by chemotherapy may partially restore cellular but not antibody immunity, with additional data suggesting that the presence of SmE retained in the tissues after antihelminthic therapy contributes to lack of full immune restoration. Our data further suggest that helminthiasis may compromise HIV vaccine safety. Overall, these findings suggested a potential negative impact on future HIV vaccinations by helminthiasis in endemic areas.

Schistosoma mansoni treatment reduces HIV entry into cervical CD4+ T cells and induces IFN-I pathways

“…Although a one-time praziquantel treatment in our study did not alter the elevated levels of α4β7, the transcriptome analysis indicated that Sm treatment was associated with changes in expression of multiple other integrins by blood mononuclear cells, including α2, αE and αM (see Supplementary Note 5), suggesting treatment-induced reprogramming of cell homing in agreement with studies in murine models of schistosomiasis 41 . Given that schistosomiasis-associated pathological changes are not reversed up to six months post-treatment 42 and eggs retained in tissues continue to exert negative immune effects after chemotherapy 43 , it is perhaps unsurprising that we saw only partial restoration of immune function in our study. Future research will need to assess these parameters at later time points to understand the longer-term effects of schistosomiasis therapy on HIV susceptibility and antiviral defenses.…”

Effects of schistosomes on host anti-viral immune response and the acquisition, virulence, and prevention of viral infections: A systematic review

“…Eight animal studies reported decreased Th1 and increased Th2/T reg responses to HIV during schistosome infection [ 55 – 62 ]. In the first, splenocytes from S .…”

Maternal Schistosomiasis: Immunomodulatory Effects With Lasting Impact on Allergy and Vaccine Responses

“…Murine models have also displayed reduced vaccine efficacy following schistosoma infection, for example, against Mycobacterium tuberculosis (51), reducing type 1 responses typified by IFN-γ and instead increasing type 2 responses. Recently, experimental murine S. mansoni infection inhibited effective cellular and antibody responses against novel HIV vaccines, with even the presence of schistosoma eggs alone (as a result from de-worming) able to reduce humoral vaccine responses (52). Nevertheless, effects of antihelminthic treatment on vaccine efficacy in human cohorts remains unclear (53, 54).…”