Coronavirus Research Tracking - 3 July
Cellular immune responses to infection.
In this week’s Research Tracker the focus is on research into cellular immune (or T cell) responses to Covid-19. Last week we looked at research on humoral (antibody) responses. We also highlight results from an mRNA vaccine trial, and a paper reporting a recent strain of swine flu.
The Research Tracker is prepared by Dr Robert Hickson for the Science Media Centre. As this is a new service, please don’t hesitate to provide feedback.
First some definitions
T cells & B cells
T cells, a type of white blood cell, form a key part of the cellular immune response. Their name comes from being produced by the thymus. T cells recognise specific foreign antigens that signal a pathogen-infected or abnormal cell.
There are various types of types of T cells. Helper T cells (such as T cells with the CD4 cell surface protein, usually called “CD4 cells” or CD4+ T cells) produce cytokines that act as a signal for other immune cells to target infected or defective cells. Cytotoxic T cells (such as “CD8” and “CD3” cells) produce enzymes that kill the infected cells.
Memory T cells persist after an infection and are able to quickly respond and restimulate the immune system if the specific antigen they recognise reappears. This helps the immune system respond quickly and strongly to the reappearance of the same pathogen.
B cells are white blood cells created in the bone marrow. They produce antibodies.
A cytokine storm is an immune system reaction where there is an uncontrolled and large release of signalling molecules called cytokines (such as interferons, interleukins, and growth factors). This can lead to uncontrolled inflammation. If not controlled cytokine storms may result in death or permanent disabilities.
There is no simple test for cellular immunity
Because of the many different cell types and compounds involved, studying cellular immunity is more complex than antibody testing. There isn’t the equivalent of a simple antibody test. Consequently, research into cellular immunity usually involves smaller groups of subjects. This makes it difficult to extrapolate the research findings.
Understanding of cellular immunity in response to SARS-CoV-2 is slowly improving.
T cells targeting coronaviruses can still respond decades later
T cells taken from people who had SARS 17 years ago still reacted to the virus’ nucleocapsid protein. T cells from patients with no history of contact with SARS or SARS-CoV-2 also showed some binding to SARS-CoV-2 proteins that are also found in other coronaviruses. These cells did not bind to the SARS-CoV-2 spike or nucleocapsid proteins. Further research is needed to understand the cross-reactivity of T cells to different coronaviruses. (This paper has not yet been peer reviewed).
Study shows T cell responses were are found in most patients recovering from Covid-19
Research published in Cell found that all 20 subjects recovering from mild to moderate Covid-19 symptoms had SARS-CoV-2-specific CD4+ cells, and 70% had CD8+ cells. The strongest response of CD4+ cells was targeted to the virus’ spike protein, but some also targeted other viral proteins. CD8+ cells also reacted to several viral proteins. These results suggest that a vaccine that can target several viral proteins could be more effective, although this has yet to be tested.
T cells from other coronaviruses may also react to SARS-CoV-2
In addition to the previous study, several others have reported that T cells from people not infected with SARS-CoV-2 can react to the virus. This is suggestive that previous coronavirus infections may help to some degree fight SARS-CoV-2 infection.
In blood samples collected from people before the pandemic, five of 10 had CD4+ cells that reacted to proteins from SAR-CoV-2, and two had reactive CD8+ cells.
Low levels of SARS-CoV-2-reactive T cells were also found in 2 out of 10 healthy subjects who had not been exposed to SARS-CoV-2. This research was published in Science Immunology.
A separate research group also found CD4+ T cells from apparently uninfected people reacted to the virus’ spike protein, but less strongly than CD4+ cells from Covid-19 patients. Unlike the research published in Cell mentions above, the CD4+ cells from infected and uninfected groups targeted different parts of the spike protein. This study hasn’t yet been peer reviewed.
Another study (not yet peer reviewed) determined that 81% of 165 uninfected people had T-cell responses to SARS-CoV-2.
The effectiveness of these earlier coronavirus T cells in controlling infection hasn’t been tested. The fact that they may target other parts of the virus than SARS-CoV-2-specific T cells suggests immune responses may be different. Studies of T-cell responses in the same people before and after they became infected with SARS-CoV-2 would help understand the effects of previous coronavirus infections.
Reactive T cells can be found when there are no antibodies
SARS-CoV- 2-specific T cells can be detected even if a person does not have antibodies to the virus. This means that antibody testing may under estimate levels of infection. Whether a T cell response without antibody production provides good protective immunity against the virus is unknown.
This study (not yet peer reviewed), undertaken in Sweden, also found that for patients recovering from Covid-19 expression levels of the protein CD38 was a good indicator of acute symptoms. The researchers also observed that SARS-CoV-2 elicits memory T cell responses similar to those found for successful vaccines of other diseases. This may mean that natural exposure or infection may prevent recurrent episodes of severe COVID-19, but requires further investigation.
A French study (in pre-print) also found a T cell response without an antibody response.
Not everyone has the same cellular immune response
One study (not yet peer reviewed) has found that while many of the hospitalised Covid-19 patients had strong T and B cell responses, about 30% did not demonstrate T and B cell activation. Patients with T and B cell responses also did not all have the same cellular profile.
A study, published in the journal Immunity, involving a small number of recovered patients who had mild symptoms, found variability in the levels of neutralising antibodies. (Neutralising antibodies not only bind to the virus, but prevent it from infecting cells). There was, though, a strong correlation between levels of these antibodies and the numbers of virus-specific T cells. If confirmed by other studies this suggests that measuring levels of neutralising antibodies may be a useful indicator of T cell responses in Covid-19 patients.
However, other research (in pre-print) on over 100 non-hospitalised patients found that the intensity of T-cell responses did not correlate with antibody levels or disease severity.
There can, though, be similarities
A small study of 10 patients in intensive care with severe acute respiratory distress syndrome caused by Covid-19 showed similar T cell dynamics. SARS-CoV-2-specific CD4+ and CD8+ T cells were found in the first two weeks after symptoms began (in all patients for CD4+, and CD8+ in eight of the patients). Their levels increased over time. These authors noted that larger studies are required to understand the roles of T cells in responses to Covid-19.
Different immune responses can reflect disease progression or outcome
Research published in Cellular & Molecular Immunology compared several types of immune cells. The study involved 95 hospitalised patients who recovered from Covid-19 and 62 who died. Patients who died had lower levels of specific immune cells throughout or in the late stages of disease progression.
The authors propose that dysregulation of the immune response may be associated with death, or more severe responses to infection. A better understanding of the dynamics of the immune response during disease progression may help develop better treatment options.
A small comparative study (in pre-print) of people with different severities of Covid-19, and uninfected people, found a much stronger immune response in those with severe symptoms (28 patients). This response was seen across several cell types, including neutrophils, monocytes, natural killer cells, and B and T cells.
The possibility of a Covid-19 immune signature
A recent significant study (in pre-print) identifies what it calls a “consensus immune signature” to Covid-19. The study, involving 63 hospitalised Covid-19 patients (with different degrees of severity), found that most had a similar profile, compared to healthy subjects. This immune profile includes the presence of antibodies, along with similar relative abundance of other immune cell types and levels of chemokines (signalling proteins). The authors note that this immune response combines elements of protection (antibodies) and responses seen following tissue injury.
Some of the proteins and cells that this study measured may be useful in predicting the course of the disease, and so help inform treatment.
Encouraging results for test of a mRNA vaccine candidate
A pre-print reports the results of testing on 36 healthy adults of one of Pfizer and BioNTech’s mRNA vaccine candidates. This contains the spike protein receptor binding domain. The potential vaccine stimulated antibody production and increased the ability to neutralise the virus (compared to responses from people recovering from the virus). There were mild reactions to the vaccine, but what would be expected form a strong immune response. Further clinical trials are underway. Pfizer and BioNTech also have three other mRNA vaccine candidates to test.
Over-reaction to a paper about a new strain of swine flu
A report on a strain of flu in Chinese pig farms, published in the Proceedings of the National Academy of Sciences behind a paywall, has generated a lot of media headlines about “the next pandemic”. That overstates the conclusions of the paper. The virus has been in pigs since 2011, and while some pig farmers appear to have been infected they have not developed symptoms. The virus does need monitoring, but it won’t necessarily lead to a human pandemic.
A global virome project
Last week we noted the Global Immunological Observatory proposal. A Global Virome Project was started several years ago. This project is intended to improve, and coordinate, the understanding of viral threats, and what causes their emergence. The project has the goal of identifying half a million viruses over 10 years, but requires billions of dollars to do this. They have not secured all the funding to achieve this.