Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses.

Abstract

Betacoronaviruses caused the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome, as well as the current pandemic of SARS coronavirus 2 (SARS-CoV-2)1-4. Vaccines that elicit protective immunity against SARS-CoV-2 and betacoronaviruses that circulate in animals have the potential to prevent future pandemics. Here we show that the immunization of macaques with nanoparticles conjugated with the receptor-binding domain of SARS-CoV-2, and adjuvanted with 3M-052 and alum, elicits cross-neutralizing antibody responses against bat coronaviruses, SARS-CoV and SARS-CoV-2 (including the B.1.1.7, P.1 and B.1.351 variants). Vaccination of macaques with these nanoparticles resulted in a 50% inhibitory reciprocal serum dilution (ID50) neutralization titre of 47,216 (geometric mean) for SARS-CoV-2, as well as in protection against SARS-CoV-2 in the upper and lower respiratory tracts. Nucleoside-modified mRNAs that encode a stabilized transmembrane spike or monomeric receptor-binding domain also induced cross-neutralizing antibody responses against SARS-CoV and bat coronaviruses, albeit at lower titres than achieved with the nanoparticles. These results demonstrate that current mRNA-based vaccines may provide some protection from future outbreaks of zoonotic betacoronaviruses, and provide a multimeric protein platform for the further development of vaccines against multiple (or all) betacoronaviruses.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1038/s41586-021-03594-0

Publication Info

Saunders, Kevin O, Esther Lee, Robert Parks, David R Martinez, Dapeng Li, Haiyan Chen, Robert J Edwards, Sophie Gobeil, et al. (2021). Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses. Nature, 594(7864). pp. 553–559. 10.1038/s41586-021-03594-0 Retrieved from https://hdl.handle.net/10161/25005.

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Scholars@Duke

Saunders

Kevin O'Neil Saunders

Professor in Surgery

Dr. Kevin O. Saunders graduated from Davidson College in 2005 with a bachelor of science in biology. At Davidson College, he trained in the laboratory of Dr. Karen Hales identifying the genetic basis of infertility. Dr. Saunders completed his doctoral research on CD8+ T cell immunity against HIV-1 infection with Dr. Georgia Tomaras 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, Dr. 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. Dr. Saunders previously served as DHVI's director or research and currently serves as the associate director for DHVI.

Dr. 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, Dr. 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. His current research interests include vaccine and antibody development to combat HIV-1 and coronavirus infections.

About the Saunders Laboratory
The Saunders laboratory aims to understand the immunology of HIV-1 antibodies and the molecular biology of their interaction with HIV-1 envelope (Env) glycoprotein. Our overall goal is to develop protective antibody-based vaccines; therefore, the laboratory has two sections–antibody repertoire analysis and immunogen design. Our 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.

Anti-glycan HIV-1 antibody biology. The laboratory utilizes single B cell PCR to probe the antibody repertoire during natural infection and after vaccination. Using this technique we 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). We 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 are rarely elicited with HIV-1 vaccination; therefore we have studied the ontogeny of DH501 using longitudinal next generation sequencing and reversion of somatic mutations within the antibody variable regions. DH501 and DH502 antibodies are mostly found in the repertoire as IgG2 and IgM isotypes—similar to known natural glycan antibodies. Therefore we are examining whether vaccines mobilize antibodies from the natural glycan pool that affinity mature to interact with HIV-1 envelope. The results of these studies inform us about the similarities and differences between vaccine-induced glycan-reactive antibodies and known broadly neutralizing HIV-1 antibodies from human natural infection. These comparative studies define the molecular biology of glycan-reactive antibodies as well as determine how close current vaccines are to inducing glycan-dependent broadly neutralizing antibodies.

HIV-1 Env immunogen design. The discovery of lineages of broadly neutralizing antibodies in HIV-infected individuals has provided templates for vaccine design. With knowledge of the antibodies we desire to elicit we can engineer the HIV-1 Env to preferentially bind to those antibodies. We discovered that Man9GlcNAc2 is the glycan preferred by early precursors in broadly neutralizing antibody lineages. We translated this finding into a vaccine design strategy that we have termed “glycan learning.” This approach modifies the glycosylation of HIV-1 Env immunogens to be the optimal glycan type for engagement of the precursor antibody of glycan-reactive broadly neutralizing HIV-1 antibody lineages. 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. We 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, we use these Env antigens in vitro to investigate the biology of B cell receptor engagement. More specifically, we investigate the effects of various immunogen delivery platforms, such as protein or gold nanoparticles, nucleic acid, or recombinant viral vectors on B cell activation.

Taken together, our research program is an interdisciplinary approach to understanding the molecular biology underlying antibody recognition of glycoproteins in order to produce protective vaccines.

Alam

S. Munir Alam

Professor in Medicine

Research Interests. 

The Alam laboratory’s primary research is focused on understanding the biophysical properties of antigen-antibody binding and the molecular events of early B cell activation using the HIV-1 broadly neutralizing antibody (bnAb) lineage models. We are studying how HIV-1 Envelope proteins of varying affinities are sensed by B cells expressing HIV-1 bnAbs or their germline antigen receptors and initiate early signaling events for their activation. In the long-term these studies will facilitate design and pre-selection of immunogens for testing in animal models and accelerate HIV-1 vaccine development.
Current research include the following NIAID-funded projects   

Antigen recognition and activation of B cell antigen receptors with the specificity of HIV-1 broadly neutralizing antibodies. This project involves elucidating the early events on the B cell surface following antigen (Ag) engagement of the B cell antigen receptor (BCR) and to provide an assessment of the in vivo potential of an Ag to drive B cell activation. We are performing biophysical interactions analyses and using high-resolution microscopy to define the physico-chemical properties of BCR-Ag interactions that govern signaling and activation thresholds for BCR triggering and the BCR endocytic function in antigen internalization. The overall objective of these studies is to bridge the quantitative biophysical and membrane dynamics measurements of Ag-BCR interactions to ex-vivo and in-vivo B cell activation. This NIAID-funded research is a collaboration with co-investigators Professor Michael Reth (University of Freiburg, Germany) and Dr. Laurent Verkoczy (San Diego Biomedical Research Institute, CA).  

Immunogen Design for Induction of HIV gp41 Broadly Neutralizing Antibodies. This research project addresses the critical problem of vaccine induction of disfavored HIV-1 antibody lineages, like those that target the membrane proximal external region (MPER) of HIV Env gp41. This program combines structure and lineage-based vaccine development strategies to design immunogens that will induce bnAb lineages that are not polyreactive and therefore easier to induce. The overall objective of this program grant is to develop and test sequential immunogens that will initiate and induce HIV-1 bnAb lineages like the potent MPER bnAb DH511. Using a germline-targeting (GT) epitope scaffold design and a prime/boost strategy, we are testing induction of DH511-like bnAbs in knock-in (KI) mice models expressing the DH511 germline receptors. This P01 research program is in collaboration with Dr. William Schief (The Scripps Research Institute, CA), who leads the team that are designing germline targeting (GT)-scaffold prime and boost immunogens and Dr. Ming Tian at Harvard University who developed relevant knock-mice models for the study.
Denny

Thomas Norton Denny

Professor in Medicine

Thomas N. Denny, MSc, M.Phil, is the Chief Operating Officer of the Duke Human Vaccine Institute (DHVI), Associate Dean for Duke Research and Discovery @RTP, and a Professor of Medicine in the Department of Medicine at Duke University Medical Center. He is also an Affiliate Member of the Duke Global Health Institute. Previously, he served on the Health Sector Advisory Council of the Duke University Fuquay School of Business. Prior to joining Duke, he was an Associate Professor of Pathology, Laboratory Medicine and Pediatrics, Associate Professor of Preventive Medicine and Community Health and Assistant Dean for Research in Health Policy at the New Jersey Medical School, Newark, New Jersey. He has served on numerous committees for the NIH over the last two decades and currently is the principal investigator of an NIH portfolio in excess of 65 million dollars. Mr. Denny was a 2002-2003 Robert Wood Johnson Foundation Health Policy Fellow at the Institute of Medicine of the National Academies (IOM). As a fellow, he served on the US Senate Health, Education, Labor and Pensions Committee with legislation/policy responsibilities in global AIDS, bioterrorism, clinical trials/human subject protection and vaccine related-issues.

As the Chief Operating Officer of the DHVI, Mr. Denny has senior oversight of the DHVI research portfolio and the units/teams that support the DHVI mission. He has extensive international experience and previously was a consultant to the U.S. Centers for Disease Control and Prevention (CDC) for the President’s Emergency Plan for AIDS Relief (PEPFAR) project to oversee the development of an HIV and Public Health Center of Excellence laboratory network in Guyana. In September 2004, the IOM appointed him as a consultant to their Board on Global Health Committee studying the options for overseas placement of U.S. health professionals and the development of an assessment plan for activities related to the 2003 PEPFAR legislative act. In the 1980s, Mr. Denny helped establish a small laboratory in the Republic of Kalmykia (former Soviet Union) to improve the care of children with HIV/AIDS and served as a Board Member of the Children of Chernobyl Relief Fund Foundation. In 2005, Mr. Denny was named a consulting medical/scientific officer to the WHO Global AIDS Program in Geneva. He has also served as program reviewers for the governments of the Netherlands and South Africa as well as an advisor to several U.S. biotech companies. He currently serves as the Chair of the Scientific Advisory Board for Grid Biosciences.

Mr. Denny has authored and co-authored more than 200 peer-reviewed papers and serves on the editorial board of Communications in Cytometry and Journal of Clinical Virology. He holds an M.Sc in Molecular and Biomedical Immunology from the University of East London and a degree in Medical Law (M.Phil) from the Institute of Law and Ethics in Medicine, School of Law, University of Glasgow. In 1991, he completed a course of study in Strategic Management at The Wharton School, University of Pennsylvania. In 1993, he completed the Program for Advanced Training in Biomedical Research Management at Harvard School of Public Health. In December 2005, he was inducted as a Fellow into the College of Physicians of Philadelphia, the oldest medical society in the US.

While living in New Jersey, Mr. Denny was active in his community, gaining additional experience from two publicly elected positions. In 2000, Mr. Denny was selected by the New Jersey League of Municipalities to Chair the New Jersey Community Mental Health Citizens’ Advisory Board and Mental Health Planning Council as a gubernatorial appointment.

Woods

Christopher Wildrick Woods

Wolfgang Joklik Distinguished Professor of Global Health

1. Emerging Infections
2. Global Health
3. Epidemiology of infectious diseases
4. Clinical microbiology and diagnostics
5. Bioterrorism Preparedness
6. Surveillance for communicable diseases
7. Antimicrobial resistance

Wiehe

Kevin J Wiehe

Norman L. Letvin Associate Professor in Medicine

Dr. Kevin Wiehe is the associate 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.

Acharya

Priyamvada Acharya

Associate Professor in Surgery

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