Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against HIV-1 and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis (Mtb) strain that co-expresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this AMtb-SIV vaccine is immunogenic, and, although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected when compared to naïve controls.Considering that the current TB vaccine, Bacille Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4(+) T cells were concurrently activated and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants.
Balancing trained immunity with persistent immune activation and the risk of SIV infection in infant macaques vaccinated with attenuated Mycobacterium tuberculosis or BCG vaccines.