title: Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques.
abstract: Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4(+) T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity.
  
  
  
  Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses.
authors.affiliation: Department of Microbiology and Immunology and Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Kara
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Rafiq
authors.initials: R
authors.lastname: Nabi
authors.affiliation: California National Primate Research Center, University of California at Davis, Davis, California, USA.
authors.forename: Koen K A
authors.initials: KKA
authors.lastname: Van Rompay
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Robichaux
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
authors.affiliation: AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Jacobs
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Fennelly
authors.affiliation: California National Primate Research Center, University of California at Davis, Davis, California, USA.
authors.forename: Don
authors.initials: D
authors.lastname: Canfield
authors.affiliation: Lineberger Cancer Center and Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Mollan
authors.affiliation: Gillings School of Public Health and Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Michelle H
authors.initials: MH
authors.lastname: Larsen
authors.affiliation: Department of Microbiology, Immunology and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA.
authors.forename: Angela M
authors.initials: AM
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: Department of Microbiology and Immunology and Center for AIDS Research, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA abelk@med.unc.edu.
authors.forename: Kristina
authors.initials: K
authors.lastname: De Paris
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000831:Animals, Newborn; D000914:Antibodies, Viral / Q000032:analysis* / Q000097:blood*; D000917:Antibody Formation; D004337:Drug Carriers / Q000008:administration & dosage; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000032:analysis; D007074:Immunoglobulin G / Q000097:blood; D018445:Infectious Disease Transmission, Vertical / Q000517:prevention & control; D008253:Macaca mulatta; D009169:Mycobacterium tuberculosis / Q000235:genetics; D018449:SAIDS Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control* / Q000821:virology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014766:Viremia / Q000517:prevention & control*
chemical_list: D000914:Antibodies, Viral; D004337:Drug Carriers; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D018449:SAIDS Vaccines; D014614:Vaccines, Synthetic