Jason McLellan

Last updated
Jason McLellan
DSC 4394 mclellan newyorker copy.jpg
NationalityAmerican
Education
Scientific career
Fields Structural Biology
Institutions University of Texas at Austin
Website www.mclellanlab.org

Jason S. McLellan is a structural biologist, professor in the Department of Molecular Biosciences and Robert A. Welch Chair in Chemistry at The University of Texas at Austin [1] who specializes in understanding the structure and function of viral proteins, including those of coronaviruses. [2] His research focuses on applying structural information to the rational design of vaccines and other therapies for viruses, [3] including SARS-CoV-2, the novel coronavirus that causes COVID-19, [4] and respiratory syncytial virus (RSV). [5] McLellan and his team collaborated with researchers at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center to design a stabilized version of the SARS-CoV-2 spike protein, [6] [7] [8] [9] which biotechnology company Moderna used as the basis for the vaccine mRNA-1273, [10] [11] [12] [13] the first COVID-19 vaccine candidate to enter phase I clinical trials in the U.S. [14] At least three other vaccines use this modified spike protein: those from Pfizer and BioNTech; Johnson & Johnson and Janssen Pharmaceuticals; and Novavax. [7] [15]

Contents

SARS-CoV-2 research

McLellan led a team from The University of Texas at Austin and the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center that produced the first molecular structure, or 3D atomic scale map, of the novel coronavirus’ spike protein, the protein that allows the virus to attach to and infect host cells. [6] The results were published online on February 19, 2020, in Science , [16] one of the world's top academic journals, and was highlighted on the cover of the 13 March 2020 print edition. [17]

The molecular structure provides a blueprint for scientists to learn to disrupt these processes through developing new treatments or vaccines. [18] Aubree Gordon, an associate professor of epidemiology at the University of Michigan who was not a part of the study was quoted by LiveScience as saying: "It's a very important step forward and may help in the development of a vaccine against SARS-COV-2." [18] The achievement was also highlighted as an important step towards a vaccine by the director of the National Institutes of Health, Francis Collins, in the NIH Director's Blog. [19]

McLellan and his team collaborated with researchers at the National Institute of Allergy and Infectious Diseases’ Vaccine Research Center to design a stabilized version of the SARS-CoV-2 spike protein, [6] [7] [9] called S-2P or 2P, which biotechnology company Moderna used as the basis for the vaccine candidate mRNA-1273, [10] [11] [12] [13] the first COVID-19 vaccine candidate to enter phase I clinical trials in the U.S. [14] The UT Austin and NIH teams filed a joint patent application on the mutated spike protein. [20]

Moderna's vaccine candidate, mRNA-1273, contains the genetic code for the stabilized version of the spike protein. [11] When a person is vaccinated with mRNA-1273, their own cells should theoretically produce these modified spike proteins, triggering their immune systems to develop antibodies against the actual coronavirus. [21]

The SARS-CoV-2 spike protein takes on one shape before entering a cell and another shape after, known as the prefusion and postfusion conformations. [22] Antibodies that recognize spike proteins in the prefusion shape are much more effective at preventing infection than antibodies that recognize spike proteins in the postfusion shape. [22] McLellan—along with his team members Daniel Wrapp and Nianshuang Wang, plus Barney Graham and Kizzmekia Corbett at NIAID's Vaccine Research Center—engineered the spike protein to stay in its initial shape so it can be recognized. [16] This, combined with Moderna's technology that uses messenger RNA to encode information about the virus, allows mRNA-1273 to trigger an immune response in vaccinated subjects. [11]

The stabilized spike protein developed by McLellan and his colleagues forms the basis of three COVID-19 vaccines that received emergency use authorization in the U.S. [7] [15]

In May, 2020, he published [23] a new version of the stabilized SARS-CoV-2 spike protein called HexaPro that is currently being used as the basis for a new vaccine, NDV-HXP-S, which is undergoing trials in Brazil, Mexico, Thailand and Vietnam. These new vaccines are using a harmless avian virus that causes Newcastle Disease. This vaccine has the benefit of being easy to grow in chicken eggs, which are the basis of existing Influenza vaccines and are easier for developing nations to produce. [24]

McLellan and his team worked with pharmaceutical company Eli Lilly and Company to develop their monoclonal antibody treatment bamlanivimab (LY-CoV555), [25] which received emergency use authorization from the U.S. Food and Drug Administration in November 2020. [26] In April 2021, the EUA was revoked. [27]

In a separate but related project, McLellan and Daniel Wrapp worked with colleagues at the NIAID Vaccine Research Center and Ghent University to develop an antibody therapy for COVID-19 based on antibodies produced by a Winter (llama), a llama. [28] Initial tests indicate that their antibody blocks viruses that display the SARS-CoV-2 spike protein from infecting cells in culture. They reported their findings in Cell on May 5, 2020. [29] As of May 2020, the team was preparing to conduct preclinical studies in animals such as hamsters or nonhuman primates, with the hopes of next testing in humans. [30]

RSV research

Respiratory syncytial virus (RSV) is a very common, contagious virus that causes infections of the respiratory tract. RSV is the single most common cause of respiratory hospitalization in infants, reinfection remains common throughout the lifetime, and it is an important pathogen in all age groups. [31] [32]

McLellan, along with Barney S. Graham and Peter Kwong of the National Institute of Allergy and Infectious Diseases' Vaccine Research Center, spearheaded the development of a protein subunit vaccine against RSV called DS-Cav1. [33] When the work began, McLellan was a postdoctoral researcher at VRC working in Graham's and Kwong's labs.

The antigen of this RSV vaccine, a stabilized version of the virus' F protein, was developed using structure-based vaccine design. [34] [35] [36] Structure-based vaccines are developed through a rational design process that uses information about the atomic structure of vulnerable parts of a pathogen to create a synthetic molecule that the human immune system recognizes as pathogenic and creates potent antibodies against. [37] [38] [39]

In a phase 1 clinical trial, DS-Cav1 was shown to be safe and to elicit "a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks", according to a study published in April 2021 in The Lancet Respiratory Medicine. [40]

The first FDA-approved RSV vaccine, AREXVY (developed by GSK plc), uses a version of this antigen and was approved in May 2023 for adults aged 60 and older by the U.S. Food and Drug Administration (FDA). [41] [42] [5]

As of October 10, 2022, at least three other companies are testing candidate RSV vaccines based on stabilized prefusion F proteins in older adults in Phase 3 trials: Pfizer, Johnson & Johnson, and Moderna. [43] [44] [45]

Honors and awards

In 2020, Jason McLellan was one of seven researchers honored with a Golden Goose Award from the American Association for the Advancement of Science in recognition of COVID-19 research. [28] [46] He was the 2020 recipient of the William Prusoff Memorial Award from the International Society for Antiviral Research, which honors a young scientist who has shown excellence in antiviral research and promise for future contributions to the field. [47] Previous honors include the Norman P. Salzman Memorial Award in Virology (2012), [48] the Charles H. Hood Foundation Child Health Research Award (2015), [49] the American Crystallographic Association Etter Early Career Award (2018) [50] and the Viruses Young Investigator in Virology Prize (2019). [51]

The Academy of Medicine, Engineering & Science of Texas awarded McLellan its 2022 Edith and Peter O'Donnell Award in Medicine. [52] Also in 2022, Dartmouth College awarded McLellan the inaugural McGuire Family Prize for Societal Impact, [53] and he was named a finalist for the Blavatnik National Award for Young Scientists. [54] In 2023, he was chosen for the NAS Award in Molecular Biology [55] and the Welch Foundation's Norman Hackerman Award in Chemical Research, [56] and named a Senior Member of the National Academy of Inventors. [57]

Related Research Articles

<span class="mw-page-title-main">Respiratory syncytial virus</span> Species of a virus

Respiratory syncytial virus (RSV), also called human respiratory syncytial virus (hRSV) and human orthopneumovirus, is a contagious virus that causes infections of the respiratory tract. It is a negative-sense, single-stranded RNA virus. Its name is derived from the large cells known as syncytia that form when infected cells fuse.

Palivizumab, sold under the brand name Synagis, is a monoclonal antibody produced by recombinant DNA technology used to prevent severe disease caused by respiratory syncytial virus (RSV) infections. It is recommended for infants at high-risk for RSV due to conditions such as prematurity or other medical problems including heart or lung diseases.

An ectodomain is the domain of a membrane protein that extends into the extracellular space. Ectodomains are usually the parts of proteins that initiate contact with surfaces, which leads to signal transduction. A notable example of an ectodomain is the S protein, commonly known as the spike protein, of the viral particle responsible for the COVID-19 pandemic. The ectodomain region of the spike protein (S) is essential for attachment and eventual entry of the viral protein into the host cell.

<i>Human coronavirus HKU1</i> Species of virus

Human coronavirus HKU1 (HCoV-HKU1) is a species of coronavirus in humans and animals. It causes an upper respiratory disease with symptoms of the common cold, but can advance to pneumonia and bronchiolitis. It was first discovered in January 2004 from one man in Hong Kong. Subsequent research revealed it has global distribution and earlier genesis.

<span class="mw-page-title-main">Novavax</span> American biotechnology company

Novavax, Inc. is an American biotechnology company based in Gaithersburg, Maryland, that develops vaccines to counter serious infectious diseases. Prior to 2020, company scientists developed experimental vaccines for influenza and respiratory syncytial virus (RSV), as well as Ebola and other emerging infectious diseases. During 2020, the company redirected its efforts to focus on development and approval of its NVX-CoV2373 vaccine for COVID-19.

AbCellera Biologics Inc. is a Vancouver, British Columbia-based biotechnology firm that researches and develops human antibodies. The company is best known for its leading role in the Pandemic Prevention Platform, a project of DARPA's Biological Technologies Office. AbCellera utilizes a proprietary technology platform, which they claim can develop "medical countermeasures within 60 days." Its platform for single-cell screening was initially developed at the University of British Columbia.

mRNA vaccine Type of vaccine

An mRNAvaccine is a type of vaccine that uses a copy of a molecule called messenger RNA (mRNA) to produce an immune response. The vaccine delivers molecules of antigen-encoding mRNA into immune cells, which use the designed mRNA as a blueprint to build foreign protein that would normally be produced by a pathogen or by a cancer cell. These protein molecules stimulate an adaptive immune response that teaches the body to identify and destroy the corresponding pathogen or cancer cells. The mRNA is delivered by a co-formulation of the RNA encapsulated in lipid nanoparticles that protect the RNA strands and help their absorption into the cells.

A respiratory syncytial virus vaccine, or RSV vaccine, is a vaccine that protects against respiratory syncytial virus. RSV affects an estimated 64 million people and causes 160,000 deaths worldwide each year.

<span class="mw-page-title-main">Kizzmekia Corbett</span> American immunologist

Kizzmekia "Kizzy" Shanta Corbett is an American viral immunologist. She is an Assistant Professor of Immunology and Infectious Diseases at Harvard T.H. Chan School of Public Health and the Shutzer Assistant Professor at the Harvard Radcliffe Institute since June 2021.

Winter is a female llama who lives on a research farm near Ghent, Belgium and is notable for her role in award-winning research on the SARS-CoV2 virus.

<span class="mw-page-title-main">Barney S. Graham</span> American immunologist (born 1953)

Barney S. Graham is an American immunologist, virologist, and clinical trials physician.

Vaccine-associated enhanced respiratory disease (VAERD), or simply enhanced respiratory disease (ERD), is an adverse event where an exacerbated course of respiratory disease occurs with higher incidence in the vaccinated population than in the control group. It is a barrier against vaccine development that can lead to its failure.

<span class="mw-page-title-main">NDV-HXP-S</span> Vaccine candidate against COVID-19

NDV-HXP-S is a COVID-19 vaccine candidate developed under the leadership of Peter Palese, Adolfo García-Sastre, and Florian Krammer at the Icahn School of Medicine at Mount Sinai.

<span class="mw-page-title-main">Coronavirus nucleocapsid protein</span> Most expressed structure in coronaviruses

The nucleocapsid (N) protein is a protein that packages the positive-sense RNA genome of coronaviruses to form ribonucleoprotein structures enclosed within the viral capsid. The N protein is the most highly expressed of the four major coronavirus structural proteins. In addition to its interactions with RNA, N forms protein-protein interactions with the coronavirus membrane protein (M) during the process of viral assembly. N also has additional functions in manipulating the cell cycle of the host cell. The N protein is highly immunogenic and antibodies to N are found in patients recovered from SARS and COVID-19.

<span class="mw-page-title-main">Coronavirus spike protein</span> Glycoprotein spike on a viral capsid or viral envelope

Spike (S) glycoprotein is the largest of the four major structural proteins found in coronaviruses. The spike protein assembles into trimers that form large structures, called spikes or peplomers, that project from the surface of the virion. The distinctive appearance of these spikes when visualized using negative stain transmission electron microscopy, "recalling the solar corona", gives the virus family its main name.

<span class="mw-page-title-main">COVID-19 vaccine clinical research</span> Clinical research to establish the characteristics of COVID-19 vaccines

COVID-19 vaccine clinical research uses clinical research to establish the characteristics of COVID-19 vaccines. These characteristics include efficacy, effectiveness, and safety. As of November 2022, 40 vaccines are authorized by at least one national regulatory authority for public use:

<span class="mw-page-title-main">John R. Mascola</span> American Physician-Scientist

John R. Mascola is an American physician-scientist, immunologist and infectious disease specialist. He was the director of the Vaccine Research Center (VRC), part of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). He also served as a principal advisor to Anthony Fauci, director of NIAID, on vaccines and biomedical research affairs. Mascola is the current Chief Scientific Officer for ModeX Therapeutics.

William Paul Duprex is a British scientist and advocate for vaccines and global health. He serves as Director of the University of Pittsburgh's Center for Vaccine Research and Regional Biocontainment Laboratory. Duprex holds the Jonas Salk Chair in Vaccine Research. He is also a professor of microbiology and molecular genetics at the University of Pittsburgh School of Medicine and serves as Editor-in-Chief of the Journal of General Virology, which is published by the Microbiology Society, and a senior editor of mSphere, published by the American Society for Microbiology. Duprex is an expert in measles and mumps viruses and studies viral spillover from animals to humans, including the SARS-CoV-2 virus that caused the COVID-19 pandemic. Duprex is a Fellow of the American Academy of Microbiology.

Nirsevimab, sold under the brand name Beyfortus, is a human recombinant monoclonal antibody with activity against respiratory syncytial virus (RSV). It is a respiratory syncytial virus (RSV) F protein‑directed fusion inhibitor that is designed to bind to the fusion protein on the surface of the RSV virus.

Clesrovimab (MK-1654) is a fully human monoclonal antibody designed to prevent respiratory syncytial virus (RSV) infections. Developed by Merck, it is in a phase III trial as of 2023. It works differently than nirsevimab.

References

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