Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization.
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2020-02
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HIV-1-infected infants develop broadly neutralizing antibodies (bnAbs) more rapidly than adults, suggesting differences in the neonatal versus adult responses to the HIV-1 envelope (Env). Here, trimeric forms of HIV-1 Env immunogens elicit increased gp120- and gp41-specific antibodies more rapidly in neonatal macaques than adult macaques. Transcriptome analyses of neonatal versus adult immune cells after Env vaccination reveal that neonatal macaques have higher levels of the apoptosis regulator BCL2 in T cells and lower levels of the immunosuppressive interleukin-10 (IL-10) receptor alpha (IL10RA) mRNA transcripts in T cells, B cells, natural killer (NK) cells, and monocytes. In addition, immunized neonatal macaques exhibit increased frequencies of activated blood T follicular helper-like (Tfh) cells compared to adults. Thus, neonatal macaques have transcriptome signatures of decreased immunosuppression and apoptosis compared with adult macaques, providing an immune landscape conducive to early-life immunization prior to sexual debut.
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Han, Qifeng, Todd Bradley, Wilton B Williams, Derek W Cain, David C Montefiori, Kevin O Saunders, Robert J Parks, Regina W Edwards, et al. (2020). Neonatal Rhesus Macaques Have Distinct Immune Cell Transcriptional Profiles following HIV Envelope Immunization. Cell reports, 30(5). pp. 1553–1569.e6. 10.1016/j.celrep.2019.12.091 Retrieved from https://hdl.handle.net/10161/20297.
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Scholars@Duke
Wilton Bryan Williams
Dr. Williams completed a PhD in Biomedical Sciences (Immunology and Microbiology) from the University of Florida and did his postdoctoral work in the laboratory of Dr. Barton Haynes at the Duke Human Vaccine Institute (DHVI).
The key goals of HIV vaccine development are to define the host-virus events during natural HIV infection that lead to the induction of broadly neutralizing antibodies, and to recreate those events with a vaccine. As a junior faculty member in the DHVI, Dr. Williams is further characterizing SHIV non-human primate models for HIV infection, and evaluates B cell responses to HIV-1 vaccination in humans and non-human primates.
Derek Wilson Cain
My research focuses on the interactions of T cells and B cells during infection or following vaccination. I am particularly interested in the inter- and intracellular events that take place within germinal centers, the anatomic site of antibody evolution during an immune response.
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.
Kevin O'Neil Saunders
Kevin O. Saunders, PhD, graduated from Davidson College in 2005 with a Bachelor of Science in biology. At Davidson College, he trained in the laboratory of Karen Hales, PhD, identifying the genetic basis of infertility. Saunders completed his doctoral research on CD8+ T cell immunity against HIV-1 infection with Georgia Tomaras, PhD, at Duke University in 2010. He subsequently trained as a postdoctoral fellow in the laboratories of Drs. Gary Nabel and John Mascola at the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center.
In 2014, Saunders joined the faculty at the Duke Human Vaccine Institute as a medical instructor. In this role, he analyzed antibody responses in vaccinated macaques, which led to the identification of glycan-dependent HIV antibodies induced by vaccination. Dr. Saunders was appointed as a non-tenure track assistant professor of surgery and the director of the laboratory of protein expression in the Duke Human Vaccine Institute in 2015. He successfully transitioned to a tenure-track appointment in 2018 and was later promoted to the rank of associate professor in surgery in 2020. In 2022, Saunders became an associate professor with tenure. He rose to the rank of professor with tenure in 2024 and was subsequently awarded the Norman L. Letvin, MD Professor in Immunology and Infectious Diseases Research in Surgery and the Duke Human Vaccine Institute distinguished professorship. Saunders previously served as DHVI's associate director of research, director or research, and currently serves as the associate director for DHVI. Additionally, Saunders serves as the faculty chairperson for DHVI's Diversity, Equity, and Inclusion Committee.
Saunders has given invited lectures at international conferences such as HIVR4P and the Keystone Symposia for HIV Vaccines. He has authored book chapters and numerous journal articles and holds patents on vaccine design concepts and antiviral antibodies. As a faculty member at Duke, Saunders has received the Duke Human Vaccine Institute Outstanding Leadership Award and the Norman Letvin Center For HIV/AIDS Vaccine Immunology and Immunogen Discovery Outstanding Investigator Award, Ruth and A. Morris Williams Faculty Research Prize, and the Duke Medical Alumni Emerging Leader Award. His current research interests include vaccine and antibody development to combat HIV-1, coronavirus, and other emerging viral infections.
About the Saunders Laboratory
The Saunders laboratory aims to understand the immunology of broadly protective antibodies and the molecular biology of their interaction with viral glycoprotein. The laboratory utilizes single B cell PCR, bulk B cell sequencing, and antigen-specific next-generation sequencing to probe the antibody repertoire during natural infection and after vaccination. The lab's overall goal is to develop protective antibody-based vaccines; therefore, the laboratory is divided into two sections–Immunoprofiling and Vaccine/Therapeutics design. They employ a reverse vaccinology approach to vaccine design where they study broadly protective antibodies in order to design vaccines that elicit such antibodies. To elicit broadly protective antibody responses, the Saunders laboratory utilizes epitope-focused nanoparticle vaccines. While eliciting broad protection is their overall goal, they are also interested in the immunologic mechanisms that make the vaccines successful.
Anti-glycan HIV-1 antibody biology. Their research premise is that vaccine-elicited antibodies will broadly neutralize HIV-1 if they can bind directly to the host glycans on Env. However, Env glycans are poorly immunogenic and require specific targeting by a vaccine immunogen to elicit an antibody response. Using this technique they identified two monoclonal antibodies from HIV Env vaccinated macaques called DH501 and DH502 that bind directly to mannose glycans and to HIV-1 envelope (Env). They have characterized these antibodies using glycan immunoassays, antibody engineering, and x-ray crystallography to define the mechanisms of Env-glycan interaction by these antibodies. Glycan-reactive HIV antibodies have mostly been found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore they are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. During this work, they discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. They translated this finding into a vaccine design strategy that they have termed “glycan learning.” This approach modifies the number of glycans and type of glycosylation of HIV-1 Env immunogens to be optimal for engagement of the precursor antibody. The Env glycosylation sites and glycan type are then modified on subsequent Env immunogens to select antibodies that are maturing towards a broadly neutralizing phenotype. They have developed cell culture procedures and purification strategies combined with mass spectrometry analyses to create Env immunogens with specific glycosylation profiles. While the overall goal is to elicit protective neutralizing antibodies in vivo, they use these Env antigens in vitro to investigate the biology of B cell receptor engagement.
HIV-1 Sequential vaccine design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. Utilizing viral sequences from individuals that make broadly neutralizing antibodies, we further engineer the viral protein to preferentially bind the desired type of antibody. The Saunders lab partners heavily with structural biologists and bioinformaticians to design optimized vaccine immunogens for in vitro and preclinical testing. They are investigating the hypothesis that broadly neutralizing antibodies can be engaged with envelope immunogens specifically designed to target them, and that engineered envelopes can select for the broadly neutralizing antibody precursors to develop into a broadly neutralizing antibody. They examine antibody responses in vaccinated humanized mice and monkeys to discern if the vaccine elicits antibodies that are similar to the known human broadly neutralizing antibody targets. Vaccines that are effective in animal models are translated for manufacturing and evaluation in Phase I clinical trials.
Pancoronavirus vaccine development. During the COVID-19 pandemic, the Saunders lab and DHVI as a whole worked to isolate broadly neutralizing antibodies against SARS-CoV-2 and related viruses. These antibodies then served as a template for the development of receptor binding domain nanoparticle vaccines we call RBD-scNP. These vaccines protected monkeys and mice from SARS-CoV-2 and animal coronaviruses. This vaccine has been translated to GMP manufacturing and will be examined in a Phase I clinical trial. The lab continues to apply similar approaches against other targets on coronaviruses to ultimately generate protective immunity against most coronaviruses. The lab explores different delivery methods including slow-release technology and nucleoside-modified mRNA delivery.
Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of viral glycoproteins in order to produce protective vaccines.
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.
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.
Kevin J Wiehe
Dr. Kevin Wiehe is the director of research, director of computational biology and co-director of the Quantitative Research Division at the Duke Human Vaccine Institute (DHVI). He has over 20 years of experience in the field of computational biology and has expertise in computational structural biology, computational genomics, and computational immunology.
For the past decade, he has applied his unique background to developing computational approaches for studying the B cell response in both the infection and vaccination settings. He has utilized his expertise in computational structural biology to structurally model and characterize HIV and influenza antibody recognition. Dr. Wiehe has utilized his expertise in computational genomics and computational immunology to develop software to analyze large scale next generation sequencing data of antibody repertoires as well as develop computational programs for estimating antibody mutation probabilities. Dr. Wiehe has shown that low probability antibody mutations can act as rate-limiting steps in the development of broadly neutralizing antibodies in HIV.
Through his PhD, postdoc work, and now his roles at DHVI, Dr. Wiehe always approaches the analysis and the scientific discovery process from a structural biology perspective. Supporting the Duke Center for HIV Structural Biology (DCHSB), Dr. Wiehe will conduct antibody sequence analysis for antibodies used in computational and molecular modeling analyses conducted.
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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