Combined HIV-1 Envelope Systemic and Mucosal Immunization of Lactating Rhesus Monkeys Induces a Robust Immunoglobulin A Isotype B Cell Response in Breast Milk.

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.

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.

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.

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.

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.

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).

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.  

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.

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.

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.