Characterization of a Novel Mycobacterium Tuberculosis-Simian Immunodeficiency Virus Vaccine to Prevent Oral Pediatric HIV Transmission

Abstract

Over 3.3 million children are living with HIV, infected primarily by mother-to-child transmission (MTCT). Breast milk exposure of HIV accounts for up to 44% of MTCT events. Despite serious efforts to prevent vertical HIV transmission, infant testing is often delayed and access to antiretroviral therapies is still limited. Compared to adults, HIV-infected infants experience enhanced disease progression and more severe co-morbidities with pathogens like Mycobacterium tuberculosis (Mtb). The live attenuated BCG vaccine is the only licensed tuberculosis vaccine but BCG can disseminate in immunosuppressed, HIV-infected infants. Considering the significant geographical overlap of the HIV and TB epidemics and the high vulnerability of infants to both pathogens, a pediatric vaccine to safely protect against HIV and Mtb is urgently needed. We hypothesized that human-adapted attenuated Mtb strains engineered to co-express HIV genes (rAMtb-HIV) would safely induce the development of dually-immunogenic HIV- and Mtb-specific cellular and humoral responses. Three distinct attenuated Mtb-SIV strains were evaluated in the neonatal rhesus macaque model. Oral priming with strain mc26435 plus systemic MVA-SIV boosts successfully induced the development of Mtb- and SIV-specific cellular and humoral responses and was identified to be safe in healthy and immunosuppressed, SIV-infected neonatal macaques. However, despite vaccine-induced immunity, vaccination did not protect infants against low-dose oral SIV challenges designed to mimic oral MTCT during breastfeeding. Two important results emerged from the challenge study. First, higher Env-specific mucosal IgA activities and plasma IgG avidities positively correlated with controlled viremia in a subset of vaccinated animals. These animals also maintained peripheral CD4+ T cell populations and IL-17-expressing lymphocytes in the intestinal mucosa. However, the majority of vaccinated animals required fewer low-dose SIV exposures to become infected than unvaccinated animals. Enhanced viral acquisition was associated with vaccine-induced persistent immune activation. At the time of challenge, CCR5-expressing CD4+ T cells were observed with greater frequencies in blood, oral and intestinal tissues in vaccinated animals only, providing increased frequencies of SIV target cells. Due to the potential impact of these data on BCG vaccine safety and pediatric HIV and TB vaccine development, additional studies are required to confirm these complex and intriguing results.Doctor of Philosoph