title: Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine.
abstract: Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (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 compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus 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-vaccinated infant macaques 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.
authors.affiliation: Department of Microbiology and Immunology and Center for AIDS Research, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Microbiology and Immunology and Center for AIDS Research, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Myra Grace
authors.initials: MG
authors.lastname: Dela Pena-Ponce
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shoemaker
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Oswald
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Rutgers New Jersey Medical School, Newark, New Jersey, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Fennelly
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Carissa
authors.initials: C
authors.lastname: Lucero
authors.affiliation: Lineberger Cancer Center and Center for AIDS Research, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Mollan
authors.affiliation: Gillings School of Global Public Health and Center for AIDS Research, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Amedee
authors.affiliation: Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Kozlowski
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jacob D
authors.initials: JD
authors.lastname: Estes
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: California National Primate Research Center, University of California, Davis, Davis, California, USA.
authors.forename: Koen K A
authors.initials: KK
authors.lastname: Van Rompay
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Larsen
authors.affiliation: Department of Microbiology and Immunology and Center for AIDS Research, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA abelk@med.unc.edu.
authors.forename: Kristina
authors.initials: K
authors.lastname: De Paris
mesh_terms: D000818:Animals; D004347:Drug Interactions; D008253:Macaca mulatta; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control*; D016896:Treatment Outcome; D014376:Tuberculosis / Q000517:prevention & control*; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000276:immunology*; D017778:Vaccines, Combined / Q000008:administration & dosage / Q000276:immunology
chemical_list: D018449:SAIDS Vaccines; D032581:Tuberculosis Vaccines; D017778:Vaccines, Combined
keywords: immune activation; myeloid cells; pediatric HIV/SIV; vaccine