COVID-19: The Three Immunotypes

Yesterday, I covered a Nature paper that found 100% of 36 subjects who had recovered from COVID-19 had virus-specific T cells capable of providing immunity. Another paper was published yesterday in Science, however, showing that COVID-19 cases can be classified into three immunotypes, one of which has virtually no T cell or antibody response at all.

The Nature paper looked at people who had recovered from COVID-19 and had tested negative between 2 and 28 days prior to data collection.

The Science paper, by contrast, focused on people who were hospitalized for COVID-19. They were enrolled approximately nine days after developing symptoms, and blood samples were collected 1 to 3 days after enrollment. For those who were still hospitalized on day 7, additional blood samples were taken. Subjects were followed for 30 days to assess the state of their recovery or whether they died.

There were 149 hospitalized subjects, and alongside them were 46 subjects who had recovered from COVID-19 and 70 healthy donors who were not known to have gotten COVID-19. The study focused on the characteristics of the immune cells circulating in the blood, and adequate cell samples were obtained from 125 hospitalized patients, 36 recovered patients, and 60 healthy controls.

Whereas the Nature paper was looking for specific T cells capable of mounting a response to specific viral protein fragments, the Science paper had a broader mission: collect data on approximately 200 different markers of cell type, and look for broad, overarching patterns. As such, we don't actually know if any of the subjects studied in the Science paper didn't have any virus-specific T cells. We instead know that some of them didn't seem to mount any significant T cell response. Thus, the papers are not in direct conflict with one another.

The Science paper classified people into one of three immunotypes:

• Immunotype 1 is characterized by hyperactive helper (CD4) and killer (CD8) T cells, but low activation of follicular B-helper T cells, which help B cells make antibodies. The B cell populations were often over 30% plasmablasts, which are immature B cells that produce large numbers of antibodies, but the antibodies are less specific than those produced by mature B cells. High levels of plasmablasts are also a feature of Ebola and Dengue infection. There is very low expression of CXCR5, which is needed for B cells to migrate to lymph nodes where they can get assistance from T cells to mature. In short, immunotype 1 is characterized by overactive T cells and poorly matured B cells.

• Immunotype 2 is characterized by a robust but not excessive activation of CD8 killer T cells, a lesser activation of CD4 helper T cells, and a preponderance of memory B cells, which form after activated B cells move into the spleen or lymph nodes and mature with the help of follicular B-helper T cells. Memory cells provide antibody protection that can be reactivated often for decades after the infection is over. In short, immunotype 2 has a healthy balance of T cell and B cell activity.

• Immunotype 3 is characterized by little to no activation of T cells or B cells.

The cluster of markers associated with immunotype 1 was labeled “component 1,” while the cluster of markers associated with immunotype 2 was labeled “component 2.”

Compared to immunotype 1, immunotype 2 had a low activation of component 1 and a high activation of component 2. Component 1 was associated with C-reactive protein, ferritin, interleukin-6, coagulation, and disease severity. Compoent 2 was not associated with severity.

Immunotype 3 had low activation of both components 1 and 2, and strong identification with immunotype 3 was associated with less severe disease.

Recovered COVID-19 patients had an activation of component 1 that was intermediate between currently infected COVID-19 patients and healthy controls.

In short, the immunotypes break down as follows:

• Immunotype 1: more severe than normal

• Immunotype 2: normal severity

• Immunotype 3: less severe than normal

However, this entire study was done on hospitalized COVID-19 patients. So, within hospitalized patients over the course of a 30-day followup, immunotype 3 is associated with less severe disease, but the disease was still severe enough for them to be hospitalized. Furthermore, one of them died, so severity can get quite bad in at least some people with immunotype 3.

It should be noted that, as I wrote about in the elderberry post, severe disease is associated with lower CD4 and CD8 T cell counts. The same was true in this study. Immunotype 1 does not necessarily have higher counts of these cells. Rather, it has greater degrees of activation of those cells, making them more inflammatory, and showing signs of having extensively differentiated and multiplied, often to the point of eventual exhaustion.

The authors hint that immunotype 3 might involve a different type of damage than immunotype 1:

Respiratory viral infections can cause pathology as a result of an immune response that is too weak and results in virus-induced pathology, or an immune response that is too strong and leads to immunopathology.

In other words, immunotype 1 involves damage done by the immune system, while immunotype 3 involves damage done by the virus itself, which fails to be cleared adequately.

They note that immunotype 3 is associated with less severe cases, but this is only after 30 days. If they failed to clear the virus because of a poor immune response, what is their outcome at 2, 3, or even 6 months later? Anecdotally, there are some people who remain sick for months. Are many of them immunotype 3?

Immunotype 3 represented 20% of the subjects in this study, so it is a common phenomenon and it is important to examine their long-term outcomes.

This study lays the groundwork for identifying people who should be treated differently, perhaps some with immune-calming agents and others with more immune-boosting agents. However, at this point all it has done is lay the groundwork for tailoring treatment to immunotype. Much more study will have to be done in order to render that a practical approach.

Stay safe and healthy,
Chris

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Disclaimer

I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.

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*Footnotes

*  The term “preprint” is often used in these updates. Preprints are studies destined for peer-reviewed journals that have yet to be peer-reviewed. Because COVID-19 is such a rapidly evolving disease and peer-review takes so long, most of the information circulating about the disease comes from preprints.