title: Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk.
abstract: Maternal vaccination to induce anti-HIV immune factors in breast milk is a potential intervention to prevent postnatal HIV-1 mother-to-child transmission (MTCT). We previously demonstrated that immunization of lactating rhesus monkeys with a modified vaccinia Ankara (MVA) prime/intramuscular (i.m.) protein boost regimen induced functional IgG responses in milk, while MVA prime/intranasal (i.n.) boost induced robust milk Env-specific IgA responses. Yet, recent studies have suggested that prevention of postnatal MTCT may require both Env-specific IgA and functional IgG responses in milk. Thus, to investigate whether both responses could be elicited by a combined systemic/mucosal immunization strategy, animals previously immunized with the MVA prime/i.n. boost regimen received an i.n./i.m. combined C.1086 gp120 boost. Remarkably, high-magnitude Env-specific IgA responses were observed in milk, surpassing those in plasma. Furthermore, 29% of vaccine-elicited Env-specific B cells isolated from breast milk were IgA isotype, in stark contrast to the overwhelming predominance of IgG isotype Env-specific B cells in breast milk of chronically HIV-infected women. A clonal relationship was identified between Env-specific blood and breast milk B cells, suggesting trafficking of that cell population between the two compartments. Furthermore, IgA and IgG monoclonal antibodies isolated from Env-specific breast milk B cells demonstrated diverse Env epitope specificities and multiple effector functions, including tier 1 neutralization, antibody-dependent cellular cytotoxicity (ADCC), infected cell binding, and inhibition of viral attachment to epithelial cells. Thus, maternal i.n./i.m. combined immunization is a novel strategy to enhance protective Env-specific IgA in milk, which is subsequently transferred to the infant via breastfeeding.
  
  
  
  Efforts to increase the availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas have proven remarkably successful at reducing HIV vertical transmission rates. However, more than 200,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence, nearly half by postnatal HIV exposure via maternal breast milk. Intriguingly, in the absence of antiretroviral therapy, only 10% of breastfed infants born to HIV-infected mothers acquire the virus, suggesting the existence of naturally protective immune factors in milk. Enhancement of these protective immune factors through maternal vaccination will be a critical strategy to reduce the global pediatric AIDS epidemic. We have previously demonstrated that a high magnitude of HIV Env-specific IgA in milk correlates with reduced risk of infant HIV acquisition. In this study, we describe a novel HIV vaccine regimen that induces potent IgA responses in milk and therefore could potentially protect against breast milk HIV MTCT.
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Cody S
authors.initials: CS
authors.lastname: Nelson
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Pollara
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Erika L
authors.initials: EL
authors.lastname: Kunz
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jeffries
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Duffy
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Beck
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Stamper
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Minyue
authors.initials: M
authors.lastname: Wang
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shen
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Pickup
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Herman F
authors.identifier: http://orcid.org/0000-0003-1039-1087
authors.initials: HF
authors.lastname: Staats
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hudgens
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kepler
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Montefiori
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: M Anthony
authors.initials: MA
authors.lastname: Moody
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Georgia D
authors.initials: GD
authors.lastname: Tomaras
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Hua-Xin
authors.initials: HX
authors.lastname: Liao
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Barton F
authors.initials: BF
authors.lastname: Haynes
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Ferrari
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Genevieve G A
authors.initials: GGA
authors.lastname: Fouda
authors.affiliation: Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, USA sallie.permar@dm.duke.edu.
authors.forename: Sallie R
authors.initials: SR
authors.lastname: Permar
mesh_terms: D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D015483:HIV Antibodies / Q000032:analysis* / Q000097:blood; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007112:Immunity, Maternally-Acquired; D018928:Immunity, Mucosal; D007117:Immunization, Secondary; D007070:Immunoglobulin A / Q000032:analysis* / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000032:analysis / Q000097:blood / Q000276:immunology; D007223:Infant; D007774:Lactation; D008253:Macaca mulatta; D008892:Milk / Q000276:immunology*; D011247:Pregnancy
chemical_list: D016915:AIDS Vaccines; D057134:Antibodies, Neutralizing; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007070:Immunoglobulin A; D007074:Immunoglobulin G