Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk.
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2016-05
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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.Importance
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.Type
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Nelson, Cody S, Justin Pollara, Erika L Kunz, Thomas L Jeffries, Ryan Duffy, Charles Beck, Lisa Stamper, Minyue Wang, et al. (2016). Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk. Journal of virology, 90(10). pp. 4951–4965. 10.1128/jvi.00335-16 Retrieved from https://hdl.handle.net/10161/31453.
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Scholars@Duke

Justin Joseph Pollara
Dr. Justin Pollara is a member of the Duke Human Vaccine Institute and the Duke Center for Human Systems Immunology, and is Associate Director of the Duke Center for AIDS Research (CFAR) Developmental Core. He received his PhD from North Carolina State University and completed his postdoctoral training as a recipient of the Duke NIH Interdisciplinary Research Training Program in AIDS (IRTPA) T32 award in the laboratory of Dr. Guido Ferrari. He joined the faculty of the Duke Department of Surgery in 2016.
A common theme of research performed in Dr. Pollara’s laboratory is a focus on interactions between innate and adaptive immunity. Dr. Pollara’s work has contributed significantly to the understanding of the roles played by non-neutralizing antibodies in limiting HIV-1 disease progression, and in prevention of infection or control of virus replication in preclinical and clinical HIV-1 vaccine trials. Dr. Pollara’s research has also identified specific components of the immune response that reduce the risk of vertical transmission of both HIV-1 and human cytomegalovirus. The Pollara lab characterizes the phenotype and functionality of antibody-interacting innate immune cells and explores how natural genetic variation in antibodies and antibody receptors may contribute to vaccine responsiveness and immune competence. Further, with a strong interdisciplinary and collaborative approach, the Pollara Lab has broadened its scope beyond infectious diseases and is now actively leading studies aimed at understanding how inflammation, antibodies, innate immune cells, and newly described populations of T cells promote allograft injury that underlies rejection of transplanted organs.

Ryan Alexander Duffy

Xiaoying Shen
Dr. Shen is an Associate Director and Deputy of the Laboratory for HIV and COVID-19 Vaccine Research & Development in the Department of Surgery, Division of Surgical Sciences at Duke University Medical Center. Her research interest focuses on the humoral immune response following virus infection or vaccination. During the past decade, she has worked intensively on the specificity and breadth of binding antibody responses against HIV.
Dr. Shen’s team developed assays and analytical tools for a peptide microarray assay for finely mapping of HIV-1 cross-subtype linear epitopes targeted by antibody responses in human specimens as well as animal models, and adopted a multiplex binding antibody assay for evaluating binding antibody responses. With these technologies, her team evaluated various clinical HIV-1 vaccine studies and NHP studies. Building upon the data generated by her team and other collaborators, Dr. Shen works with bioinformatics and biostatistics personnel on deciphering immune correlates in both human clinical trials and nonhuman primate studies. During the COVID-19 pandemic, her team expanded their research to SARS-COV-2 antibody responses.
In 2021, Dr. Shen became the Deputy Director of the Laboratory for HIV and COVID-19 Vaccine Research & Development, alongside Laboratory Director Dr. Montefiori. The laboratory established a lentivirus-based pseudovirus SARS-CoV-2 neutralization assay that has been FDA-approved. The laboratory is assessing neutralizing antibody responses for multiple phase 3 COVID-19 vaccine trials. In addition to supporting clinical trials, the lab has a strong focus on characterizing SARS-CoV-2 variants for their neutralizing susceptibility and potential to escape from vaccine-elicited immune responses.
Meanwhile, Dr. Shen’s team remains highly active in HIV-1 vaccine research, evaluating neutralizing responses in preclinical and clinical HIV vaccine trials as a core laboratory for multiple networks including the HIV Vaccine Trials Network (HVTN), the Collaboration for AIDS Vaccine Discovery (CAVD) funded by Bill & Melinda Gates Foundation, as well as the NIH Nonhuman Primate Core Humoral Immunology Laboratory for AIDS Vaccine which Dr. Shen directs.

David James Pickup
Viral inhibition of host immune defenses
Many viruses have evolved mechanisms to protect themselves from host immune defenses. Among this group are the orthopoxviruses, whose members include smallpox virus, one of the deadliest of human viruses, and cowpox virus, the virus that Edward Jenner used to begin the eradication of smallpox.
One of the especially interesting features of theses viruses is their ability to interfere with a wide range of innate and adaptive immune responses to infection. For example, we have found that cowpox virus inhibits inflammation by suppressing the actions of cytokines controlling inflammatory processes. Moreover, the virus does this in several ways: by preventing the synthesis of cytokines; by interfering with normal cytokine-receptor interactions; and by inhibiting cytokine-signaling pathways.
Our main research objectives are to identify mechanisms of virus-host interaction leading to the modification or alteration of host functions. Our working model is that such interactions are amongst the most important factors in viral pathogenesis. In addition, knowledge of these virus-host interactions should help in the development of new vaccines and therapies for a variety of conditions associated with infectious diseases, inflammatory diseases, autoimmune diseases, cancers, and organ transplantation.
Development of improved viral vaccines
Several excellent vaccine platforms exist, but among these vaccinia virus vaccines have unusual potential for targeting multiple different pathogens because of the extraordinary capacity of these vectors to encode multiple foreign proteins. Replication-defective vaccinia vectors are extremely safe. However, this safety comes at a cost. Because only a small amount of antigen can be produced during the single cycle of viral replication, vectors of this type typically require high doses and multiple boosts to induce protective immune responses. We are interested in finding ways to enhance the immunogenicity of these replication-defective vaccine viruses without compromising on safety.

Herman Ford Staats
Areas of Research Interest:
Our laboratory studies methods to induce and regulate antigen-specific immune responses at the mucosal surfaces of the host. The mucosal tissues and surfaces are often the first site of contact with infectious agents, a common location of life-threatening cancers and in constant contact with environmental antigens. A better understanding of factors that control the induction and regulation of mucosal immune responses may aid the development of vaccines and treatments for infectious agents such as HIV and agents of bioterrorism, cancers and environmental allergies.
Research interests in the Staats’ lab currently focus on:
1. DISCOVERING AND DEVELOPING NOVEL MUCOSAL ADJUVANTS AND THEIR MECHANISM OF ACTION
Adjuvants are substances commonly added to vaccines that enhance the induction of protective immune responses to the vaccine antigen. We have been successful at identifying substances with mucosal adjuvant activity such as the pro-inflammatory cytokine interleukin 1α/β (IL-1α/β). IL-1α/β provides effective nasal adjuvant activity in mice, rabbits and non-human primates. Recent studies performed in collaboration with Dr. Soman Abraham have determined that the chemical mast cell activator compound 48/80 provides effective nasal adjuvant activity in mice and rabbits. Recent funding in the laboratory supported the discovery of small molecule mast cell activators with vaccine adjuvant activity. Current funding in the laboratory supports the discovery of IL-1 receptor agonists (small molecules, peptides, aptamers) that exhibit vaccine adjuvant activity.
2. OPTIMIZING NASAL IMMUNIZATION TO MAXIMIZE VACCINE IMMUNOGENICITY
Nasal immunization studies in mice have demonstrated the ability of nasal immunization to induce protective immune responses equal to those induced by a vaccine delivered with a needle. However, when nasal immunization is performed in rabbits or non-human primates, animals with a nasal cavity structure/anatomy that closely resembles the human nasal cavity, nasal immunization is often not as effective as immunization delivered with a needle. Studies in our lab have demonstrated that an increased nasal residence time in rabbits correlates with increased vaccine immunogenicity. Studies are being performed to develop vaccine delivery techniques and vaccine formulations that maximize nasal residence time and therefore, the immunogenicity of the vaccine. Nasal immunization studies performed in rabbits and non-human primates are performed to optimize nasal vaccine methods that may be tested in humans in the future.
3. EVALUATING FACTORS THAT INFLUENCE THE INDUCTION OF FOOD ALLERGY AND DEVELOPING NOVEL MUCOSAL TREATMENTS FOR FOOD ALLERGY
The number of individuals with food allergy in steadily increasing in developed countries. The administration of food allergens via mucosal routes, a procedure known as “mucosal immunotherapy”, has provided encouraging results suggesting that mucosal immunotherapy is able to modify the host anti-food allergen response to reduce the severity of allergic responses. A recent avenue of research in the laboratory is to 1) develop novel mucosal immunotherapy formulations to treat existing food allergy and 2) evaluate the influence of environmental factors on the induction and severity of food allergies.

Michael Anthony Moody
Tony Moody, MD is a Professor in the Department of Pediatrics, Division of Infectious Diseases and Professor in the Department of Integrative Immunobiology at Duke University Medical Center. Research in the Moody lab is focused on understanding the B cell responses during infection, vaccination, and disease. The lab has become a resource for human phenotyping, flow characterization, staining and analysis at the Duke Human Vaccine Institute (DHVI). The Moody lab is currently funded to study influenza, syphilis, HIV-1, and emerging infectious diseases.
Dr. Moody is the director of the Duke CIVICs Vaccine Center (DCVC) at (DHVI) and co-director of the Centers for Research of Emerging Infectious Disease Coordinating Center (CREID-CC). Dr. Moody is mPI of a U01 program to develop a syphilis vaccine; this program is a collaboration with mPI Dr. Justin Radolf at the University of Connecticut. Dr. Moody is also the director of the DHVI Accessioning Unit, a biorepository that provides support for work occurring at DHVI and with its many collaborators around the world by providing processing, shipping, and inventory support for a wide array of projects.
Dr. Moody and his team are involved in many networks studying vaccine response including the Collaborative Influenza Vaccine Innovation Centers (CIVICs) and the COVID-19 Prevention Network (CoVPN).
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