Virus Entry and Its Inhibition by Antibodies: Studies to Aid the Development and Evaluation of Vaccines that Protect against Viral Infectious Diseases
Carol D. Weiss, M.D., Ph.D.
Office of Vaccines Research and Review
Division of Viral Products
Laboratory of Immunoregulation
Dr. Weiss is Chief of the Lab of Immunoregulation in the Division of Viral Products, in the Office of Vaccines Research and Review, Center for Biologics Evaluation and Research, at the U.S. Food and Drug Administration. Her review portfolio includes vaccines to protect against HIV, influenza, and coronaviruses. Her research program focuses on basic and applied research relating to how viruses enter cells, how antibodies block this process, and the qualities of vaccines needed to induce neutralizing antibodies that protect against viral diseases and infections. She is board-certified in Internal Medicine and received her M.D. from the University of Chicago and Ph.D. from the University of California, San Francisco.
All currently licensed vaccines cause the immune system to produce antibodies that help fight off infection and prevent disease. The quality and quantity of these antibodies can directly affect the degree of protection. Therefore, antibodies often serve as a "marker" for the effectiveness of vaccines, and antibody assessments are used to evaluate new vaccines. Protective antibodies are only produced, however, when the immune system sees viral proteins (antigens) in the right forms.
Information about the quality and quantity of antibodies that block (neutralize) virus entry into cells, as well as quality and quantity of viral antigens in vaccines that affect production of such protective antibodies, contributes to a scientific basis for developing and evaluating new vaccines that protect against diseases caused by viruses. Our research program uses cells in culture, animal models, and clinical serum samples to investigate the following dimensions of viral infections and immune responses to them:
- How the proteins on the surface of viruses, including human immunodeficiency virus (HIV), influenza, and coronaviruses, allow the viruses to infect cells;
- How antibodies to these viral surface proteins, which are produced in response to either infection or vaccines, interfere with virus infection and thus protect against disease;
- How different forms of these viral proteins affect production of protective antibodies; and
- What level (titer) of antibodies (if any) correlate with protection in clinical studies and animal models.
Undertaking this research gives CBER regulators the knowledge, skills, and expertise to assure technical competency for:
- Evaluating data used to support approval of vaccines that protect against diseases caused by viruses;
- Advising vaccine stakeholders on aspects of vaccine manufacture and development; and
- Contributing to the foundation of knowledge that supports the development of new, safe and effective vaccines that protect against illnesses caused by viruses.
We are studying how viruses initiate infection and how antibodies protect against infection and disease. Proteins on the surface of enveloped viruses allow viruses to attach to and fuse with cells to initiate infection. Antibodies produced by the immune system after vaccination or infection can bind to viral surface proteins and prevent virus attachment to or fusion with cells, but many viruses quickly mutate to evade neutralization by antibodies. Identifying vulnerable neutralizing sites on viral proteins that cannot readily tolerate mutations and designing vaccines that can elicit broadly potent antibodies to those sites remain important public health goals.
Our research aims to elucidate molecular details of how the envelope proteins of HIV, influenza, and coronaviruses catalyze virus entry and how antibodies neutralize these viruses. This work involves dissecting steps in the viral entry process and the associated structural changes in the envelope proteins that expose conserved sites that are vulnerable to neutralization by broadly potent antibodies. This work helps us evaluate whether viral proteins in vaccines (antigens) have the right form and structure for eliciting antibodies that can neutralize the many strains of a virus.
We use several strategies, including genetics and molecular biology, to identify amino acids and regions of the envelope proteins that are critical for virus entry and neutralization. We are studying (1) mutations that allow a virus to evade neutralization by antibodies or virus entry inhibitors and (2) how those mutations affect virus entry. This information is used to design and evaluate vaccine antigens and immunization strategies in animal models to further help us understand how 1) the protein structure that is recognized by the immune system (antigenicity) and 2) immunization regimens influence the elicitation of neutralizing antibodies (immunogenicity). Antibodies generated in these studies are further used by us and others to evaluate the structure and stability of vaccine antigens. These antibodies also serve as reagents for developing new measures of vaccine potency.
Methods and concepts currently being pursued to develop vaccines that can elicit neutralizing antibodies capable of providing protection against diverse strains of virus are similar. For influenza, however, developing new universal vaccines that protect against many strains of influenza is further complicated by a host's prior immunity to influenza. Immunity to past influenza strains can affect the induction of antibodies to new strains. Therefore, we are also studying how past influenza infections and vaccinations influence induction of new influenza antibodies and the effectiveness of new seasonal influenza vaccines. This work involves analyses of serum samples from clinical vaccine trials and experimental vaccines in animal models.
ORCID ID 0000-0002-9965-1289
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