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
![Pollara](https://scholars.duke.edu/profile-images/thumbnail200/0300144.jpg)
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.
![Duffy](https://scholars.duke.edu/profile-images/thumbnail200/0607751.jpg)
Ryan Alexander Duffy
![Shen](https://scholars.duke.edu/profile-images/thumbnail200/0337613.jpg)
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.
![Pickup](https://scholars.duke.edu/profile-images/thumbnail200/0108084.jpg)
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.
![Staats](https://scholars.duke.edu/profile-images/thumbnail200/0100315.jpg)
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.
![Montefiori](https://scholars.duke.edu/profile-images/thumbnail200/0099412.jpg)
David Charles Montefiori
Dr. Montefiori is Professor and Director 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. His major research interests are viral immunology and HIV and COVID-19 vaccine development, with a special emphasis on neutralizing antibodies.
Multiple aspects of HIV-1 neutralizing antibodies are studied in his laboratory, including mechanisms of neutralization and escape, epitope diversity among the different genetic subtypes and geographic distributions of the virus, neutralizing epitopes, requirements to elicit protective neutralizing antibodies by vaccination, optimal combinations of neutralizing antibodies for immunoprophylaxis, and novel vaccine designs for HIV-1. Dr. Montefiori also directs large vaccine immune monitoring programs funded by the NIH and the Bill & Melinda Gates Foundation that operate in compliance with Good Clinical Laboratory Practices and has served as a national and international resource for standardized assessments of neutralizing antibody responses in preclinical and clinical trials of candidate HIV vaccines since 1988.
At the onset of the COVID-19 pandemic he turned his attention to SARS-CoV-2, with a special interest in emerging variants and how they might impact transmission, vaccines and immunotherapeutics. His rapid response to emerging SARS-CoV-2 variants of concern provided some of the earliest evidence of the potential risk the variants pose to vaccines. In May 2020, his laboratory was recruited by the US Government to lead the national neutralizing antibody laboratory program for COVID-19 vaccines.
His laboratory utilizes FDA approved validated assay criteria to facilitate regulatory approvals of COVID-19 vaccines. He has published over 750 original research papers that have helped shape the scientific rationale for antibody-based vaccines.
![Moody](https://scholars.duke.edu/profile-images/thumbnail200/0028821.jpg)
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).
![Tomaras](https://scholars.duke.edu/profile-images/thumbnail200/0204832.jpg)
Georgia Doris Tomaras
Dr. Georgia Tomaras is a tenured Professor of Surgery, Professor of Immunology, Professor of Molecular Genetics and Microbiology and is a Fellow of the American Academy of Microbiology (AAM) and a Fellow of the American Association for the Advancement of Science (AAAS). Dr. Tomaras is Co-Director of the Center for Human Systems Immunology (CHSI) Duke University and Director of the Duke Center for AIDS Research (CFAR). Her national and international leadership roles include: Executive Management Team (EMT) leader and mPI for the HIV Vaccine Trials Network (HVTN); Director of Lab Sciences (HVTN); and Chair of NIH Vaccine Research Center (VRC) Board of Scientific Counselors. Her prior leadership roles include serving as the Director of Research, Duke Human Vaccine Institute (DHVI); Director of the DHVI Training Program; Associate Director of DHVI Research; Co-Director of the Interdisciplinary Research Training Program in AIDS (IRTPA) Duke; Chair of the National Institutes of Health (NIH) AIDS Vaccine Research Subcommittee (AVRS), and Advisory Counsel member of the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID). Dr. Tomaras’ primary research focus is deciphering mechanisms of protective human immunity and identification of immune correlates of protection to further development of effective vaccines against infectious diseases.
![Haynes](https://scholars.duke.edu/profile-images/thumbnail200/0114780.jpg)
Barton Ford Haynes
Barton F. Haynes, M.D. is the Frederic M. Hanes Professor of Medicine and Immunology, and Director of the Duke Human Vaccine Institute. Prior to leading the DHVI, Dr. Haynes served as Chief of the Division of Rheumatology, Allergy and Clinical Immunology, and later as Chair of the Department of Medicine. As Director of the Duke Human Vaccine Institute, Bart Haynes is leading a team of investigators working on vaccines for emerging infections, including tuberculosis, pandemic influenza, emerging coronaviruses, and HIV/AIDS.
To work on the AIDS vaccine problem, his group has been awarded two large consortium grants from the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) known as the Center for HIV/AIDS Vaccine Immunology (CHAVI) (2005-2012), and the Center for HIV/AIDS Vaccine Immunology-Immunogen Discovery (CHAVI-ID) (2012-2019) to conduct discovery science to speed HIV vaccine development. In July 2019, his team received the third of NIH “CHAVI” awards to complete the HIV vaccine development work - CHAV-D.
Since the beginning of the COVID-19 pandemic, Haynes and the DHVI Team has been working non-stop to develop vaccines, rapid and inexpensive tests and therapeutics to combat the pandemic. Since March 2020, he has served as a member of the NIH Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) committee to advise on COVID-19 vaccine development, and served as the co-chair of the ACTIV subcommittee on vaccine safety. Haynes is the winner of the Alexander Fleming Award from the Infectious Disease Society of America and the Ralph Steinman Award for Human Immunology Research from the American Association of Immunologists. He is a member of the National Academy of Medicine, National Academy of Inventors and the American Academy of Arts and Sciences.
About the Haynes LaboratoryThe Haynes lab is studying host innate and adaptive immune responses to the human immunodeficiency virus (HIV), tuberculosis (TB), and influenza in order to find the enabling technology to make preventive vaccines against these three major infectious diseases.
Mucosal Immune Responses in Acute HIV Infection
The Haynes lab is working to determine why broadly neutralizing antibodies are rarely made in acute HIV infection (AHI), currently a major obstacle in the development of an HIV vaccine. The lab has developed a novel approach to define the B cell repertories in AHI in order to find neutralizing antibodies against the virus. This approach uses linear Immunoglobulin (Ig) heavy and light chain gene expression cassettes to express Ig V(H) and V(L) genes isolated from sorted single B cells as IgG1 antibody without a cloning step. This strategy was used to characterize the Ig repertoire of plasma cells/plasmablasts in AHI and to produce recombinant influenza mAbs from sorted single human plasmablasts after influenza vaccination.
The lab is also studying the earliest effect HIV-1 has on B cells. Analyzing blood and gut-associated lymphoid tissues (GALT) during acute HIV infection, they have found that as early as 17 days after transmission HIV-1 induces B cell class switching and 47 days after transmission, HIV-1 causes considerable damage to GALT germinal centers. They found that in AHI, GALT memory B cells induce polyclonal B cell activation due to the presence of HIV-1-specific, influenza-specific, and autoreactive antibodies. The team concluded from this study that early induction of polyclonal B cell differentiation, along with follicular damage and germinal center loss, may explain why HIV-1 induced antibody responses decline rapidly during acute HIV infection and why plasma antibody responses are delayed.
The lab is also looking at ways of generating long-lived memory B cell responses to HIV infection, another major hurdle in the development of a successful HIV-1 vaccine. The lab has found that in HIV-1 gp120 envelope vaccination and chronic HIV-1 infection, HIV-1 envelope induces predominantly short-lived memory B cell-dependent plasma antibodies.
Immunogen Design
To overcome the high level of genetic diversity in HIV-1 envelope genes, the Haynes lab is developing strategies to induce antibodies that cross-react with multiple strains of HIV. The lab has designed immunogens based on transmitted founder Envs and mosaic consensus Envs in collaboration with Dr. Bette Korber at Los Alamos National Laboratory. These immunogens are designed to induce antibodies that cross-react with a multiple subtype Env glycoproteins. The goal is to determine if cross-reactive mAbs to highly conserved epitopes in HIV-1 envelope glycoproteins can be induced. The team recently characterized a panel of ten mAbs that reacted with varying breadth to subtypes A, B, C, D, F, G, CRF01_AE, and a highly divergent SIVcpzUS Env protein. Two of the mAbs cross-reacted with all tested Env proteins, including SIVcpzUS Env and bound Env proteins with high affinity.
Mucosal Immune Responses in TB and Influenza
The Haynes lab is helping to develop novel approaches to TB vaccine development. The current therapeutic vaccine for TB, called BCG, may prevent complications from TB in children, but offers little protection against infection and disease in adults. The lab is focused on using live attenuated Mycobacterium tuberculosis mutants as vaccine candidates and is currently evaluating this approach in non-human primate studies. As part of the DHVI Influenza program, they are studying the B cell response to influenza in order to generate a “universal” flu vaccine. They are currently trying to express more highly conserved influenza antigens in recombinant vesicular stomatitis virus (rVSV) vectors in order to elicit robust T cell and antibody responses to those antigens.
![Ferrari](https://scholars.duke.edu/profile-images/thumbnail200/0108355.jpg)
Guido Ferrari
The activities of the Ferrari Laboratory are based on both independent basic research and immune monitoring studies. The research revolves around three main areas of interest: class I-mediated cytotoxic CD8+ T cell responses, antibody-dependent cellular cytotoxicity (ADCC), gene expression in NK and T cellular subsets upon infection with HIV-1. With continuous funding over the last 11 years from the NIH and Bill & Melinda Gates Foundation along with many other productive collaborations within and outside of Duke, the Ferrari Lab has expanded its focus of research to include the ontogeny of HIV-1 specific immune responses that work by eliminating HIV-1 infected cells and how these can be induced by AIDS vaccine candidates.
![Permar](https://scholars.duke.edu/profile-images/thumbnail200/0554303.jpg)
Sallie Robey Permar
Dr. Permar's work focuses on the development of vaccines to prevent vertical transmission of neonatal viral pathogens. She has utilized the nonhuman primate model of HIV/AIDS to characterize the virus-specific immune responses and virus evolution in breast milk and develop a maternal vaccine regimen for protection against breast milk transmission of HIV. In addition, Dr. Permar's lab has advanced the understanding of HIV-specific immune responses and virus evolution in vertically-transmitting and nontransmitting HIV-infected women, defining maternal immune responses that may protect against neonatal transmission of HIV. Importantly, Dr. Permar has established a nonhuman primate model of congenital CMV infection adn is using this model to establish the maternal immune responses that are necessary for protection against placental virus transmission. Finally, Dr. Permar is studying the impact and prevention of postnatal CMV transmission in preterm infants.
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