Major Areas of Research
- Vaccine and monoclonal antibody development for COVID-19, RSV, influenza, EV-D68, Nipah, Zika, HIV, Ebola, and other viral emerging pathogens
- Structure-based vaccine design and structural basis for antibody-mediated virus neutralization
- Role of functional hierarchy and regulation of T-cell responses in immunity and pathogenesis of viral diseases
- Prototype pathogen approach for pandemic preparedness and response
Viral Pathogenesis Laboratory
The goal of the Viral Pathogenesis Laboratory (VPL) in the Vaccine Research Center (VRC) is to better understand basic aspects of viral pathogenesis and apply that knowledge toward development of safer and more effective vaccines. Many aspects of prior VPL work were instrumental in the rapid response to the COVID-19 pandemic. Under Dr. Graham’s direction, the VPL designed and developed the first COVID-19 vaccine candidate and helped discover the first SARS-CoV-2 neutralizing monoclonal antibody to enter human clinical trials. This was achieved by implementing a plan outlined for rapid pandemic response, based on prototype pathogen preparedness. Guided by structures of HKU1-CoV, MERS-CoV, and SARS-CoV combined with a generalizable spike antigen design solution established for betacoronaviruses, technological tools developed by the VRC for precision vaccinology, and rapid platform manufacturing in collaboration with Moderna, Inc., the first clinical trial participant was injected with a candidate mRNA vaccine expressing stabilized SARS-CoV-2 spike protein 65 days from the time of sequence release. Preclinical testing and assay development were performed in parallel to support advanced clinical trials for mRNA-1273. The VPL’s prior work on the pathogenesis of respiratory syncytial virus (RSV) vaccine-associated enhanced respiratory disease (VAERD) also provided an essential framework for safety evaluations and regulatory decisions required for accelerated vaccine development (Graham, Science 2020).
To define how coronaviruses and other viruses cause disease, the VPL investigates functional and structural features of viral pathogens as well as mechanisms for regulating the composition and timing of host immune responses using in vitro systems, animal models, and clinical trials. Understanding RSV biology and pathogenesis has been a central theme of the VPL. Studying VAERD was the basis for work on T cell function and regulation (reviewed in Ruckwardt et al. Immunity 2019). Solving the structure of the RSV prefusion F (McLellan et al., Science 2013a) and identifying stabilizing mutations (McLellan et al. Science 2013b) led to demonstrating that prefusion specific antibodies were more potent than antibodies to postfusion surfaces (Ngwuta et al., Science Translational Medicine 2015). Those studies led to development of a stabilized prefusion F protein trimer (DS-Cav1) candidate vaccine (Crank et al. Science 2019) that is now in advanced clinical development. This work provided a clinical proof-of concept for structure-based vaccine design (Graham et al., Annual Review of Medicine 2019) and informed the subsequent structural work on coronavirus spike proteins and fusion proteins from Nipah and other paramyxoviruses.
The VPL emphasizes the use of new technologies that have evolved over the last decade driven largely from efforts to develop an HIV vaccine. Some of these include structure-based antigen design, self-assembling nanoparticle display, single-cell analysis for assessing T cell function and discovering monoclonal antibodies, defining antibody repertoires and lineages, and nucleic acid and vector-based vaccine antigen delivery vehicles (Graham, Immunological Reviews 2013). All of the programs have used some of these tools, and the universal influenza vaccine development program has used them all. There are several aims to achieve the objective of durable universal influenza immunity against both seasonal and pandemic strains of influenza virus (Kanekiyo and Graham, Cold Spring Harbor Press, 2020) that include strategies for improved supraseasonal vaccines and those for pandemic preparedness and response. Major approaches include targeting the conserved hemagglutinin (HA) stem domain for both group 1 (Yassine et al., Nature Medicine, 2015) and group 2 (Corbett et al., mBio, 2019) influenza A by displaying structurally-defined headless HA stem trimers on self-assembling ferritin nanoparticles. The immunological intent is to induce defined antibody lineages known to have cross-neutralizing activity. Another approach using self-assembling nanoparticle display of structurally-defined antigens seeks to avoid immunodominant strain-specific HA head responses by a heterotypic mosaic array of antigens on each particle (Kanekiyo et al., Nature Immunology, 2019).
Under Dr. Graham, the VPL addresses the following pathogens: 1) coronavirus (MERS-CoV, SARS-CoV-1, and SARS-CoV-2), 2) influenza (flu), 3) respiratory syncytial virus (RSV) , 4) EV-D68, 5) Nipah and other paramyxoviruses, 6) Zika, and 7) Ebola. This work is performed within the two Sections, the Viral Pathogenesis Section (VPS) and the Biodefense Research Section (BRS). The VPS is organized in three units which operate under Dr. Graham’s leadership assisted by Karin Bok, MS, Ph.D., Senior Advisor for Vaccine Development. The BRS is directed by Dr. Nancy Sullivan.
Viral Pathogenesis Section
The objectives of the VPS directed by Dr. Graham are to: 1) study basic virological and immunological determinants of viral diseases; 2) define immunological correlates of protection from virus infection and disease; 3) develop animal models and immunological assays to support the development of vaccines and monoclonal antibodies for prevention and treatment of viral diseases; and 4) develop vaccines and monoclonal antibodies to prevent viral diseases and to establish a framework for prototype pathogen preparedness.
In anticipation of future pandemic threats, Dr. Graham was part of a multi-divisional NIAID effort that developed the strategy for implementing a Prototype Pathogen Preparedness Plan (P4) over the last few years. This approach involves leveraging in-depth knowledge of selected prototypic viruses within the 25 virus families known to infect humans to inform and accelerate the development of medical countermeasures for new or re-emerging pathogens, recently exemplified by the response to COVID-19.
Vaccine Immunobiology Unit
Tracy Ruckwardt, Ph.D., Staff Scientist and Unit Head; Man Chen, Ph.D., Staff Scientist Core; Rebecca Loomis, Ph.D., Staff Scientist core; Tony DiPiazza, Ph.D., IRTA Postdoctoral Fellow; Azad Kumar, Ph.D., Scientist; Deepika Nair, Biologist; Alexandrine Derrien-Colemyn, Biologist; Kizzmekia Corbett, Ph.D., Research Fellow and Team Lead for Coronavirus Research; Olu Abiona, IRTA Post-Baccalaureate; Anne Werner, IRTA Post-Baccalaureate
The Vaccine Immunobiology Unit (VIU) studies basic aspects T cell biology with an emphasis on neonatal immune responses and understanding determinants of adaptive responses following respiratory virus infections. This unit seeks to understand factors that contribute to age-dependent differences in immune responses to design vaccines that elicit precisely targeted and balanced adaptive immune responses. The VIU directs work on antigen design, animal models, and immune assays to support vaccine development for RSV and other emerging viral infections such as SARS-CoV-2, Zika, EV-D68, Nipah, and other paramyxoviruses.
Molecular Immunoengineering Unit
Masaru Kanekiyo, DVM, Ph.D., Staff Scientist and Unit Head; Seyhan Boyoglu-Barnum, Ph.D., Staff Scientist (core); Adrian Creanga, Ph.D., Staff Scientist (core); Brian Fisher, Ph.D., Biologist, and VPL laboratory manager; Rebeca Gillespie, Biologist; Julia Lederhoffer, Ph.D., IRTA Postdoctoral Fellow; Syed Moin, Ph.D., Scientist; Geoffrey Hutchinson, IRTA Post-Baccalaureate
The Molecular Immunoengineering Unit (MIU) designs and tests new vaccine strategies using a technology-driven approach to address unmet challenges in vaccinology. This unit: 1) investigates basic aspects of protein antigenicity and immunogenicity; 2) uses molecular and single-cell technologies to define mechanistic basis for protective immunity that guides antigen design with an emphasis on influenza; 3) uses structural biology and protein engineering to design immunogens that improve the quality, breadth, and durability of immune responses with an emphasis on influenza; and 4) develops assays and tools that inform vaccine development.
VPL Translational Science Core
Research Group: Karin Bok, M.S., Ph.D.; Senior Advisor Vaccine Development and Unit Head; Gabriela Alvarado, Ph.D., Scientific Program Manager
The VPL Translational Science Core (VPTS) provides scientific advice and scientific program management support for pre-clinical product development and their transition to clinical testing and is essential for maintaining the VRC vaccine development pipeline through the Vaccine Production Program (VPP). The VPTS is also the main liaison to external stakeholders and scientific collaborators. This team also manages the collaborative interactions among the different VRC teams and directly liaises VPL with VRC’s Program Management and Strategy teams.
Biodefense Research Section
The Biodefense Research Section (BRS), within the VPL, is independently led by Dr. Nancy Sullivan, Ph.D., Section Chief, who discovered mAb114 (ansuvimab) in collaboration with the Institut National de Recherche Biomédicale (INRB) in the Democratic Republic of the Congo. This antibody is effective in reducing mortality from Ebola virus disease, and is currently undergoing a biologic license evaluation by the FDA, sponsored by Ridgeback Biotherapeutics. Dr. Sullivan has also developed recombinant adenovirus vector vaccines for Ebola Zaire, Ebola Sudan, and Marburg that are undergoing clinical development.
Dr. Graham serves as Deputy Director of the NIAID Vaccine Research Center and assists the Director in establishing and focusing the scientific direction for the VRC as a premier intramural research organization. As Chief of the Viral Pathogenesis Laboratory, Dr. Graham also leads the development efforts for COVID-19 vaccines and universal influenza vaccines. In addition, he supports VRC product development through strategic advice on vaccine design as well as pre-clinical and clinical evaluation.
Dr. Graham is an immunologist, virologist, and clinical trials physician whose primary interests are viral pathogenesis, immunity, and vaccine development. His laboratory is focused on respiratory viral pathogens, pandemic preparedness, and emerging viral diseases. He applies structural biology, protein engineering, and other new technologies to create vaccines for unmet needs and emerging threats advancing the principles of precision vaccinology. He has been involved in the clinical evaluation of candidate vaccines for more than 30 years and has an ongoing interest in science education and expanding research opportunities for underrepresented minorities.
After graduating from Rice University in 1975, he obtained his MD from the University of Kansas School of Medicine in 1979. From 1979 to 1984 he served as intern, resident, and chief resident in internal medicine and from 1984 to 1986 was a clinical fellow in infectious diseases. He earned a PhD in microbiology and immunology at Vanderbilt University School of Medicine in 1991 and then rose to the rank of professor of medicine with a joint appointment in the department of microbiology and immunology. At Vanderbilt, Dr. Graham directed an R01-funded laboratory focused on RSV pathogenesis and was head of the Vanderbilt AIDS Vaccine Evaluation Unit, one of the original sites for the international clinical trials network funded by NIH designated for evaluating candidate HIV vaccines. In 2000, Dr. Graham was recruited as one of the founding investigators for the VRC.
Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh CL, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 2020 Mar 13; 367(6483):1260-1263.
Graham BS. Rapid COVID-19 Vaccine Development. Science. 2020 May 29; 368(6494):945-946.
Jackson LA, Anderson EJ, Rouphael NG, Roberts PC, Makhene M, Coler RN, McCullough MP, Chappell JD, Denison MR, Stevens LJ, Pruijssers AJ, McDermott A, Flach B, Doria-Rose NA, Corbett KS, Morabito KM, O'Dell S, Schmidt SD, Swanson PA 2nd, Padilla M, Mascola JR, Neuzil KM, Bennett H, Sun W, Peters E, Makowski M, Albert J, Cross K, Buchanan W, Pikaart-Tautges R, Ledgerwood JE, Graham BS, Beigel JH; mRNA-1273 Study Group. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med. 2020 Jul 14.
Crank MC, Ruckwardt TJ, Chen M, Morabito KM, Phung E, Costner PJ, Holman LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Kumar A, Chang LA, Moin SM, Hill JP, DiPiazza AT, Schwartz RM, Kueltzo L, Cooper JW, Chen P, Stein JA, Carlton K, Gall JG, Nason MC, Kwong PD, Chen GL, Mascola JR, McLellan JS, Ledgerwood JE, Graham BS, VRC 317 Study Team. A proof of concept for structure-based vaccine design targeting RSV in humans. Science. 2019 Aug 2;365(6452):505-509.
Kanekiyo M, Joyce MG, Gillespie RA, Gallagher JR, Andrews SF, Yassine HM, Wheatley AK, Fisher BE, Ambrozak DR, Creanga A, Leung K, Yang ES, Boyoglu-Barnum S, Georgiev IS, Tsybovsky Y, Prabhakaran MS, Andersen H, Kong WP, Baxa U, Zephir KL, Ledgerwood JE, Koup RA, Kwong PD, Harris AK, McDermott AB, Mascola JR, Graham BS. Mosaic Nanoparticle Display of Diverse Influenza Virus Hemagglutinins Elicits Broad B Cell Responses. Nature Immunology. 2019 Mar;20(3):362-372.
Graham BS, Sullivan NJ. Emerging viral diseases from a vaccinology perspective: preparing for the next pandemic. Nature Immunol. 2018 Jan; 19(1): 20–28.