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B cell

T cells will save us from COVID-19, part 3

29 July 2021 by Vincent Racaniello

In the two previous installments (one, two) of what has now become my praise of T cells, I explained that the SARS-CoV-2 protein sequences recognized by T cells do not change, likely explaining why vaccines prevent serious disease and death caused by any variant. Today I will explain that virus-specific T cells appear a week after mRNA vaccination when neutralizing antibodies are weakly detectable. Their presence is likely responsible for vaccine-mediated protection against severe disease.

Since the first COVID-19 vaccines were tested in clinical trials, much has been made of their ability to block infection. At ten days after the first vaccine dose, clear protection against severe disease is observed. But at this early time, neutralizing antibodies can barely be detected. That job is likely being done by T cells, the other arm of the adaptive immune response.

T lymphocytes come in two broad types: CD8+ and CD4+. The former, also known as cytotoxic T lymphocytes (CTLs) can recognize a virus infected cell and kill it (pictured). The latter T cells produce cytokines that are important for maturation of both CTLs and B cells, the antibody-producing cells. The importance of antibody versus T cells in controlling infection depends on the virus. For many viruses, antibody can block infection, but T cells are important for recovery. In COVID-19, antibodies rise late in the course of infection, when virus titers are already declining. This observation is in line with the resolution of infection by T cells.

People with agammaglobulinemia, who cannot make antibodies, or who have been depleted of B cells do not have a serious course of COVID-19, further supporting a role for T cells in preventing severe disease.

During the trials of mRNA vaccines it was observed that protection against severe COVID-19 arose at 10 days after the first inoculation, a time when neutralizing antibodies are barely detectable in serum. The logical candidate for this effect is the T cells.

To address this question, a group of mRNA vaccine recipients were sampled at different times after the first and second doses. CD8+ T cells in blood were examined for the ability to recognize a few spike-specific epitopes. A rapid and substantial induction of CD8+ T cells in these individuals was observed beginning at 6-8 days after the first vaccine dose. At this time, neutralizing antibodies in sera of these subjects were barely detectable. CD8+ T cell numbers are substantially increased by the second vaccine dose, which also leads to much higher levels of neutralizing antibodies. CD4+ T cells are also detected after the first vaccine dose and likely coordinate the expansion of CD8+ T cells and B cells.

mRNA vaccination also induces spike-specific memory B and T cells which circulate for at least several months. Their exact longevity remains to be determined by longer term studies.

The gradual escape of multiple variants of concern from neutralization by sera from vaccinated individuals has been met with alarm by public health officials. At least one prominent leader has suggested that the virus might even mutate so as to escape vaccine protection. An even cursory examination of the facts reveals otherwise. Despite reduced neutralization by vaccine-induced antibodies, vaccine recipients are still protected from severe disease and death by all variants. In contrast to changing B cell epitopes, T cell epitopes do not change in any variant. Furthermore, virus-specific T cells are induced early after the first mRNA vaccine dose, and confer protection against severe COVID-19 at a time when neutralizing antibodies are barely detectable. These observations indicate that T cells will save us from COVID-19.

In vaccinology, the correlate of protection refers to what is needed – antibodies or T cells – to protect from infection or disease. High levels of antibodies appear to correlate with protection against infection by SARS-CoV-2. However, when antibody levels decline, as they always do after infection or vaccination, infection can no longer be prevented. In this case, protection against severe disease and death is accomplished by T cells.

Filed Under: Basic virology Tagged With: antibody, B cell, coronavirus, COVID-19, pandemic, SARS-CoV-2, T cell, vaccine, viral, virology, virus, viruses

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

An explanation for the low quality antibodies produced during serious SARS-CoV-2 infection

22 October 2020 by Vincent Racaniello

coronavirus

Although we are less than a year into the SARS-CoV-2 pandemic, it appears that the antibodies induced by infection are often of poor quality, and B cell memory seems limited. An explanation for this outcome might be a consequence of the loss of germinal centers in COVID-19 patients.

Examination of lymph nodes and spleen of patients who succumbed to COVID-19 revealed a striking absence of germinal centers. During a virus infection, foreign antigens brought into the secondary lymphoid organs are recognized by B cells, which then proliferate and differentiate. This activity takes place within germinal centers, which also provides an environment for the production of high affinity antibodies by the process of somatic hypermutation. The production of long-lived memory B cells also depends on the germinal center.

The absence of germinal centers in patients with severe COVID-19 may explain why these patients produce poor quality antibody that is not durable. However, these patients do produce antiviral antibodies, often at higher levels than in patients with mild disease. These antibodies are not produced in germinal centers, which explains why they do not provide optimal or durable immunity.

It seems likely that the cytokine storm produced during severe COVID-19 is at least partly responsible for the loss of germinal centers. Loss of germinal centers during cytokine storm in mice has been shown to be reversed by blockade of TNF-alpha. This cytokine is abundant in lymph nodes from SARS-CoV-2 infected patients, and was recently identified as a biomarker that may predict serious disease. Monoclonal antibodies to TNF-alpha are licensed for the treatment of other diseases such as rheumatoid arthritis, and could be assessed for the ability to improve outcomes in COVID-19.

An important question is why only some SARS-CoV-2 infected patients progress to serious COVID-19. Such patients might have defects in lymphocyte function yet to be determined. Furthermore, they might be unable to mount an effective early innate response to infection, and consequently virus reproduces to high levels, causing an over-exuberant immune response. This scenario is no doubt simplistic and will surely be modified by the results of further studies of immune responses in infected patients. Whether patients with less severe disease are able to produce germinal centers is unknown but should be determined.

Other viral infections, including those caused by influenza H5N1 virus, Ebolaviruses, SARS- and MERS-CoV are also characterized by cytokine storm and depletion of lymphoid cells. It is possible that similar underlying immune mechanisms govern the serious disease caused by these infections.

What are the implications of these findings for vaccines to prevent COVID-19? It is unlikely that vaccination with any of the candidates currently in development will lead to germinal center loss because most of these vaccines do not comprise infectious SARS-CoV-2. Consequently the vaccine antigens – mainly spike glycoprotein – need only induce durable protective immunity. A tall order, but one that can be achieved as long as germinal centers remain intact.

Filed Under: Basic virology Tagged With: B cell, coronavirus, COVID-19, germinal center, lymph node, memory B cells, pandemic, SARS-CoV-2, somatic hypermutation, spleen, viral, virology, virus

Longevity of SARS-CoV-2 memory B cells

10 September 2020 by Vincent Racaniello

Immunity conferred by influenza virus vaccine is short-lived. After immunization with inactivated influenza virus vaccine, serum antibody levels peak within a few months and then decline rapidly. This decline was recently shown to be caused by loss of bone marrow plasma cells, a major source of serum antibodies. Results of a recent study partially address the relevance of this observation to infection with SARS-CoV-2.

[Read more…] about Longevity of SARS-CoV-2 memory B cells

Filed Under: Basic virology, Information Tagged With: antibody, B cell, bone marrow plasma cell, COVID-19, influenza vaccine, memory B cell, pandemic, plasmablast, SARS-CoV-2, viral, virology, virus, viruses

TWiV 597: A lot of immunology and some COVID-19 with Jon Yewdell

3 April 2020 by Vincent Racaniello

Immunologist Jon Yewdell joins Vincent and Rich to discuss immune responses in the context of infection with SARS-CoV-2.

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Show notes at microbe.tv/twiv

Filed Under: This Week in Virology Tagged With: antibody, B cell, coronavirus, COVID-19, immunology, interferon, SARS-CoV-2, T cell, viral, virology, virus, viruses

Immune 2: Lymphocytes after dark

25 November 2017 by Vincent Racaniello

Cindy, Steph, and Vincent reveal that lymphocyte trafficking through lymph nodes and lymph is circadian – it is dependent on the time of day.

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Filed Under: Immune Tagged With: 24 hour clock, adaptive immunity, B cell, circadian, clock gene, immune, immunology, lymph, lymph node, lymphocyte, T cell

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