Induction of HIV Immunity in the Genital Tract After Intranasal Delivery of a MVA Vector: Enhanced Immunogenicity After DNA Prime-Modified Vaccinia Virus Ankara Boost Immunization Schedule

Abstract

Vaccines intended to prevent mucosal transmission of HIV should be able to induce multiple immune effectors in the host including Abs and cell-mediated immune responses at mucosal sites. The aim of this study was to characterize and to enhance the immunogenicity of a recombinant modified vaccinia virus Ankara (MVA) expressing HIV-1 Env IIIB Ag (MVAenv) inoculated in BALB/c mice by mucosal routes. Intravaginal inoculation of MVAenv was not immunogenic, whereas intranasally it induced a significant immune response to the HIV Ag. Intranasal codelivery of MVAenv plus cholera toxin (CT) significantly enhanced the cellular and humoral immune response against Env in the spleen and genitorectal draining lymph nodes, respectively. Heterologous DNAenv prime-MVAenv boost by intranasal immunization, together with CT, produced a cellular immune response in the spleen 10-fold superior to that in the absence of CT. A key finding of these studies was that both MVAenv/MVAenv and DNAenv/MVAenv schemes, plus CT, induced a specific mucosal CD8+ T cell response in genital tissue and draining lymph nodes. In addition, both immunizations also generated systemic Abs, and more importantly, mucosal IgA and IgG Abs in vaginal washings. Specific secretion of β-chemokines was also generated by both immunizations, with a stronger response in mice immunized by the DNA-CT/MVA-CT regimen. Our findings are of relevance in the area of vaccine development and support the optimization of protocols of immunization based on MVA as vaccine vectors to induce mucosal immune responses against HIV.

Comparison of intranasal with targeted lymph node immunization using PR8‐Flu ISCOM adjuvanted HIV antigens in macaques

“…Recent examples of evaluated HIV candidate vaccines include: adenovirus vectors Patterson et al, 2003Patterson et al, , 2004, vesicular stomatitis virus [Rose et al, 2001;Egan et al, 2004b], mycobacteria [Lagranderie et al, 1997], or salmonella [Evans et al, 2003]. Also pathogen derived entero toxins, like cholera toxin or E. coli heat-labile toxin have been applied as vaccine adjuvants [Belyakov et al, 2001;Gherardi et al, 2004;Matoba et al, 2004;Vajdy et al, 2004]. However, these toxins if not detoxified as well as the live vectors, attenuated viral as well as bacterial, may present safety problems, for instance when administered in immunocompromised individuals [Holmgren et al, 2003].…”

CD8+T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little

“…The robust immune response following intravaginal inoculation was somewhat unexpected in light of a recent report that a recombinant poxvirus strain of modified vaccinia virus Ankara failed to elicit CD8 ϩ T-lymphocyte responses in the female reproductive tract of mice when the vaccine was administered intravaginally but did elicit a response after intranasal inoculation (11). Here, we show that the lower female reproductive tract in primates can be an excellent antigen-specific This compartmental analysis reveals some of the potential reasons virus-specific CD8 ϩ T-lymphocyte responses fail to fully contain infection in the LTs targeted by SIV and, by extension, HIV, because of the relatively low frequency of virus-specific CD8 ϩ T lymphocytes in LTs after peak virus production.…”

Immune Responses against a Single CD8+-T-Cell Epitope Induced by Virus Vector Vaccination Can Successfully ControlTrypanosoma cruziInfection

“…Adenovirus and vaccinia virus have been shown to be the most efficient vectors for inducing protective immune responses against human immunodeficiency virus (12,15,16,39) and malaria (22,30,31,36,54). The generation of replication-deficient virus mutants makes this strategy safer and more effective for containing the threat and spread of infections.…”