Both Mucosal and Systemic Routes of Immunization with the Live, Attenuated NYVAC/Simian Immunodeficiency Virus SIV_gpeRecombinant Vaccine Result in Gag-Specific CD8⁺T-Cell Responses in Mucosal Tissues of Macaques

Abstract

As most human immunodeficiency virus (HIV) infection occurs via mucosal surfaces, an important goal of vaccination may be the induction of virus-specific immune responses at mucosal sites to contain viral infection early on. Here we designed a study in macaques carrying the major histocompatibility complex class I Mamu-A‫10ء‬ molecule to assess the capacity of the highly attenuated poxvirus NYVAC/simian immunodeficiency virus (SIV) SIV gpe vaccine candidate administered by the intranasal, intramuscular, or intrarectal route to induce mucosal immunity. All macaques, including one naive macaque, were exposed to SIV mac251 by the intrarectal route and sacrificed 48 h after infection. The kinetics of immune response at various time points following immunization with NYVAC/SIV gpe and the anamnestic response to SIV mac251 at 48 h after challenge were assessed in blood, in serial rectal and vaginal biopsy samples, and in tissues at euthanasia with an SIV mac Gag-specific tetramer. In addition, at euthanasia, antigen-specific cells producing gamma interferon or tumor necrosis factor alpha from the jejunum lamina propria were quantified in all macaques. Surprisingly, antigenspecific CD8؉ T cells were found in the mucosal tissues of all immunized macaques regardless of whether the vaccine was administered by a mucosal route (intranasal or intrarectal) or systemically. In addition, following mucosal SIV mac251 challenge, antigen-specific responses were mainly confined to mucosal tissues, again regardless of the route of immunization. We conclude that immunization with a live vector vaccine results in the appearance of CD8 ؉ T-cell responses at mucosal sites even when the vaccine is delivered by nonmucosal routes.

Control of Simian/Human Immunodeficiency Virus Viremia and Disease Progression after IL-2-Augmented DNA-Modified Vaccinia Virus Ankara Nasal Vaccination in Nonhuman Primates

“…Furthermore, the validity of the nasal route of vaccination in the SIV model needs to be addressed. Nasal vaccination with attenuated NYVAC/SIVgpe stimulated significant antiviral responses in two female macaques, both systemically and at different mucosal sites (21). However, the number of animals in the group and the follow-up after challenge for only 48 h prevent the generalization of the results.…”

“…These studies represent important steps in the study of SIV DNA vaccines, but were not designed to evaluate mucosal immunity, and the challenge did not involve mucosal exposure. Only recently has SIV or simian/human immunodeficiency virus (SHIV) 3 DNA been investigated as a mucosal immunogen (21,23,36).…”

HIV infection and the gastrointestinal immune system

“…Indeed, several studies of rhesus macaques have demonstrated vaccine-induced functional SIV-specific CD8 T cells within the GI tract. 65,68,69 Moreover, the frequency of vaccine-induced SIV-specific CD8 T cells in the GI tract was negatively correlated with the peak viral load in plasma after challenge with the pathogenic SHIV-ku2, while there was no such correlation with the frequency of SIV-specific CD8 T cells in peripheral blood. 69 Although HIV-specific T-cell responses may reduce viral replication in vivo, the prevention of initial infection would likely require a mucosal humoral immune response.…”

Aerosol immunization with NYVAC and MVA vectored vaccines is safe, simple, and immunogenic

“…11 and SI Table 2). Intramuscularimmunized animals exhibited mucosal immune responses as well, as seen in a previous intranasal immunization study (14). Because of variable sample sizes, sample compositions, and extents of cell expansions, significant intraanimal quantifications were not possible.…”