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TWiV 975: Crossing the Ts with Daniela Weiskopf

15 January 2023 by Vincent Racaniello 1 Comment

Daniela joins TWiV to discuss her career and her research on T cells, their role in infection with SARS-CoV-2, T cell epitopes and why a variant that evades T cell immunity is not likely to emerge.

Hosts: Vincent Racaniello, Alan Dove, and Brianne Barker

Guest: Daniela Weiskopf

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Intro music is by Ronald Jenkees

Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: coronavirus, COVID-19, epitope, Omicron, pandemic, SARS-CoV-2, T cell, viral, virology, virus, viruses

TWiV 881: 50 ways to zap your virus

27 March 2022 by Vincent Racaniello

TWiV describes the identification of a monoclonal antibody that provides broad protection against a variety of hantaviruses, and development of an oral remdesivir-like antiviral that ameliorates viral disease in mice.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Amy Rosenfeld

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: COVID-19, epitope, hantavirus, monoclonal antibody, oral antiviral, pandemic, remdesivir, SARS-CoV-2, viral, virology, virus, viruses

TWiV 866: EV antibodies rEVolutionize our thinking

15 February 2022 by Vincent Racaniello

Amy returns to TWiV to discuss her work on the identification of cross-reactive antibody responses among diverse enteroviruses, and the implications for our understanding of viral pathogenesis and seroprevalence studies.

Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit Brianne Barker, and Amy Rosenfeld

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: antibody, cross-reactive antibody, enterovirus, epitope, neutralization, plaque assay, poliovirus, serology

T cells will save us from COVID-19

25 March 2021 by Vincent Racaniello

In our quest to stop the COVID-19 pandemic by vaccination, we have been myopically focussed on inducing antibodies against the spike protein. As variants of SARS-CoV-2 have emerged that reduce the ability of such antibodies to block infection, concern has arisen that we will not be able to halt the disease. Such concerns appear to ignore the other important arm of the adaptive immune response: T cells.

Anti-viral antibodies can prevent infection of cells, but when antibody titers are low – years after infection or vaccination – some cells will inevitably be infected. In this case, T cells come to the rescue. Cytotoxic T cells can sense that a cell is infected and kill it (illustrated). T cells sense infected cells by virtue of viral peptides that are presented by major histocompatibility molecules on the plasma membrane. Such T cell peptides may be produced from nearly any viral protein. In contrast, only certain viral proteins, like the spike of SARS-CoV-2, can give rise to antibodies that block infection.

The T cell response to SARS-CoV-2 infection has been largely ignored for the past year. Certainly, some laboratories have studied T cell responses in patients, and the vaccine makers have dutifully included them along with assays for neutralizing antibodies. But the dialogue has never included T cells as important for resolving disease – but they are for most viral infections. Because T cells can kill virus infected cells, they can help prevent disease and end the infection.

The recent finding that amino acid changes in the spike protein of SARS-CoV-2 variants of concern do not impact T cell reactivity is very good news. In this study, the authors synthesized short peptides covering the entire proteome of multiple SARS-CoV-2 isolates, including the original Wuhan strain, and variants B.1.1.7, B.1.351, P.1, and CAL.20C. They found little difference in the ability of T cells from either convalescent or vaccinated patients to recognize peptides from these viruses. This result means that the amino acid changes in the variants are not likely to impact the ability of T cells to clear infection.

This observation explains why some COVID-19 vaccines have effectively prevented hospitalization and death even in regions where variants circulate widely. In some cases the ability of sera from vaccinated individuals have reduced ability to neutralize infection with some variants. Nevertheless, the vaccines prevent severe COVID-19 and death because T cells can still recognize variant virus-infected cells and clear them.

It’s highly unlikely that vaccination will prevent infection with SARS-CoV-2. Antibody levels rapidly decline after infection or vaccination, especially in the respiratory mucosa. When a virus enters the nasopharynx of an immune individual, it will encounter little antibody opposition and will initiate an infection. However memory B and T cells will spring into action and within a few days produce virus-specific antibodies and T cells. The antibodies will limit infection while the T cells will clear the virus-infected cells. The result is a mild or asymptomatic infection that likely is not transmitted to others.

The recent observations that vaccination appears to prevent asymptomatic infections is a red herring. These studies are being done soon after vaccination when antibody levels in serum and mucosa are high. If these studies were done a year after immunization, the results would be quite different.

Now imagine that you are fully vaccinated and become infected with a SARS-CoV-2 variant. The virus may begin to reproduce rather well in the nasopharynx even in the face of a memory response, because the antibodies are just not good enough to block infection. T cells to the rescue: the T cell epitopes on the surface of the infected cells are readily recognized because they are mainly the same in the variants as in the ancestral strain of SARS-CoV-2. You may have a mild infection but you will not be hospitalized or die. Isn’t that the goal of vaccination?

Why don’t T cell epitopes change as do B cell (antibody) epitopes? A B cell epitope is the same in everyone and so if a virus emerges with a slightly different epitope, it will evade antibody in anyone infected with that virus. T cell epitopes are different. T cell epitopes are presented to T cells on the infected cell surface by MHC molecules, which are encoded by highly polymorphic genes. That means that your MHC is likely different from mine, and so will be the viral peptides displayed in them. So if a T cell epitope varies during your infection, it won’t matter to other people – their infected cells will be displaying different T cell peptides.

It is possible that SARS-CoV-2 will continue to produce altered spike proteins that will completely evade antibody neutralization. In this case T cells might not be enough to prevent severe disease – they could be overwhelmed by so many infected cells. Our rush to make vaccines – understandable given the urgency – have led us to such a situation. Most of the vaccines were based only on the spike protein. If we change the spike protein to accommodate variants, we might get in a never-ending cycle of changing COVID-19 vaccines on a regular basis. A better approach would be to produce second-generation COVID vaccines that include other viral proteins besides spike protein. Inactivated and attenuated vaccines fall into this category; another solution would be to modify authorized mRNA vaccines to encode additional viral proteins.

Filed Under: Basic virology, Commentary Tagged With: antibody, B cell, COVID-19, epitope, pandemic, SARS-CoV-2, T cell, variant of concern, viral, virology, virus, viruses

TWiV 550: Covering up the shiny parts

2 June 2019 by Vincent Racaniello

TWiV explains the use of a neuronal cell line to study herpes simplex virus latency and reactivation, and a strategy for creating vaccines that induce antibodies against specific epitopes.

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: antigenic hole, broadly neutralizing antibodies, epitope, herpes simplex virus, immunofocusing, latency, neuronal cell line, reactivation, universal influenza vaccine, vaccine, viral, virology, virus, viruses

TWiV 467: Jon and Ted’s Excellent Adventure

14 November 2017 by Vincent Racaniello

Jon and Teddy Yewdell join the TWiV team to talk about their careers, their research, and the problems with biomedical research.

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Show notes at microbe.tv/twiv.

Filed Under: This Week in Virology Tagged With: AID, biomedical research, class switch recombination, defective ribosomal products, DRiP, epitope, immunodominance, influenza virus, lamprey, monoclonal antibody, viral, virology, virus, Yewdell

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