Mucosal AIDS vaccine reduces disease and viral load in gut reservoir and blood after mucosal infection of macaques

Abstract

Given the mucosal transmission of HIV-1, we compared whether a mucosal vaccine could induce mucosal cytotoxic T lymphocytes (CTLs) and protect rhesus macaques against mucosal infection with simian/human immunodeficiency virus (SHIV) more effectively than the same vaccine given subcutaneously. Here we show that mucosal CTLs specific for simian immunodeficiency virus can be induced by intrarectal immunization of macaques with a synthetic-peptide vaccine incorporating the LT(R192G) adjuvant. This response correlated with the level of T-helper response. After intrarectal challenge with pathogenic SHIV-Ku2, viral titers were eliminated more completely (to undetectable levels) both in blood and intestine, a major reservoir for virus replication, in intrarectally immunized animals than in subcutaneously immunized or control macaques. Moreover, CD4+ T cells were better preserved. Thus, induction of CTLs in the intestinal mucosa, a key site of virus replication, with a mucosal AIDS vaccine ameliorates infection by SHIV in non-human primates.

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

“…Consistent findings were observed in our previous studies where, of two cohorts of SIV/HIV-infected macaques, one of four in the first cohort (4,36) and three of four in the second cohort (5) in the adjuvant-only group failed to get infected. We identified that the enhanced A3G expression was widely distributed in DCs, monocyte/macrophage, and CD4 + T cells.…”

“…In this macaque study, we demonstrated that repeated mucosal administration of TLR agonists and IL-15 alone without antigen was sufficient to enhance A3G expression, and this alone was sufficient to account for a certain level of protection against subsequent SIV challenge. This result supports the idea that certain adjuvants, able to induce persistent innate immunity, could play a role in preventing SIV transmission, and may explain some adjuvant-only animals in previous studies (4,5). Because the outcomes of early SIV infection are mainly dependent on the race between viral replication and dissemination and immune responses against it, the development of rapid or preexisting innate immune responses are essential to allow adaptive immunity sufficient time to mount an effective protective response.…”

“…Previous studies from our laboratory showed that mucosal immunization of macaques with an HIV/SIV peptide vaccine was more effective against SIV/HIV challenge than systemic vaccination (4) and that a peptide-prime/poxviral boost approach that induced a strong cytotoxic T lymphocyte (CTL) mucosal response could impact dissemination of intrarectally administered pathogenic SIV/HIV-ku2 (5). An improved regimen might actually abort the local mucosal infection before dissemination.…”

Intramuscular rather than oral administration of replication-defective adenoviral vaccine vector induces specific CD8+ T cell responses in the gut

“…Future studies may focus on using adenoviral vectors with alternate mucosal delivery routes such as intranasal, vaginal, and rectal immunization [43] or further characterization of the mucosal response upon systemic administration, particularly in the effector compartments of the lamina propria [44] or the intestinal epithelium. There have been heterologous prime-boost studies done with chimpanzee-derived adenoviral vectors [45] as well as other viruses and vectors [46] to drive an increase of effector memory CD8 + T cell population in the gut.…”

Rice-based mucosal vaccine as a global strategy for cold-chain- and needle-free vaccination

“…T he majority of emerging and reemerging infectious pathogens, including Vibrio cholerae, Escherichia coli, HIV, influenza virus, or coronavirus causing severe acute respiratory syndrome, invade and infect the host via the mucosal surfaces of the gastrointestinal, respiratory, and/or genitourinary tracts (1)(2)(3). Mucosal immunity forms a first line of defense by means of secretory IgA and cytotoxic T cells against epitheliumtransmitted pathogens, and so it would seem important to develop vaccines that induce effective immune responses at mucosal barriers.…”