TWIV #631 Questions

[wannabe]

Sorry for starting a whole new thread, but I just listened to the latest TWIV podcast, and I had a number of questions for Dr. SLO or Snaggy about a few things that were mentioned/discussed in the episode. Unfortunately, the main Covid thread has gotten much too toxic for me. Feel free to move this thread if you need to.

My question was related to the preprint they referenced early in the episode where the researchers saw a good amount of T-cell activity was maintained for a couple months after recovering from a mild Covid 19 symptoms. (I think 'mild' just means that they didn't go to the hospital.)

I believe that this was the paper: https://www.medrxiv.org/content/10.1101/2020.06.21.20132449v1.full.pdf (It was posted on their show notes.)

Here are my questions:

In the discussion portion of the paper, they mention that they demonstrated that they have seen a 'specific T cell response in absence of seroconversion. Does this imply that in some cases, T cells play a larger role in fighting the COVID19 virus than antibodies do? Or, is this only the case with a 'transient exposure' as mentioned in the paper?

Also, does this imply that people could have the virus and be able to transmit it but still result in negative antibody test results?


Thanks again for recommending the podcast. This is the first one that made me feel like the researchers are actually making progress. :thumbup

 

[budman]

Aris... just to let you know we are cracking down on the toxic aspects.


I need to light up the podcast on my phone.. lost my sound on my computer which sux.

Anyway.. just thought I would let you know that hopefully things will improve and communication will be better.

 

[wannabe]

Thanks, Dennis. I appreciate the update.

Regarding the podcast, the recent ones have not been as interesting to me because they focused a lot on care for the super sick to make sure that they didn't die. This one had an update on things that were more interesting to me including the number and status of the vaccines that are currently being tested. It's really cool to see all the different ways that they are coming at this virus. The chart below summarizes the status of all 172 different vaccines that are currently being tested. :thumbup

They mentioned an expert saying that we are about 8 months away from any vaccine going into Phase III testing which requires 20,000 patients and 10,000 placebos. That level made me feel better about the safety and efficacy of whatever vaccine gets through the testing process.

 

[Dr_SLO]

Sorry for starting a whole new thread, but I just listened to the latest TWIV podcast, and I had a number of questions for Dr. SLO or Snaggy about a few things that were mentioned/discussed in the episode. Unfortunately, the main Covid thread has gotten much too toxic for me. Feel free to move this thread if you need to.

My question was related to the preprint they referenced early in the episode where the researchers saw a good amount of T-cell activity was maintained for a couple months after recovering from a mild Covid 19 symptoms. (I think 'mild' just means that they didn't go to the hospital.)

I believe that this was the paper: https://www.medrxiv.org/content/10.1101/2020.06.21.20132449v1.full.pdf (It was posted on their show notes.)

Here are my questions:

In the discussion portion of the paper, they mention that they demonstrated that they have seen a 'specific T cell response in absence of seroconversion. Does this imply that in some cases, T cells play a larger role in fighting the COVID19 virus than antibodies do? Or, is this only the case with a 'transient exposure' as mentioned in the paper?

Also, does this imply that people could have the virus and be able to transmit it but still result in negative antibody test results?


Thanks again for recommending the podcast. This is the first one that made me feel like the researchers are actually making progress. :thumbup

Starting a thread for TWiV questions is a great idea. You're ahead of me in the TWiV episodes as I've not had chance to catch 631. I'm back in the lab full time and that has reduced podcast listening time.

To answer your question, maybe. I know it's the typically infuriating scientific response to such a question but to cut a long story short the correlates of protection are poorly understood for most, if not all, viruses. Sure, we can design vaccines but the way protection is generally measured is through neutralizing antibody responses and some rudimentary measure of T-cell responses. How the body prevents a secondary infection from a virus is still a bit of a black box.

To the point about T-cells, time to take a step back and recall what I currently know about immunology, which is limited. There are two arms of the immune system that are frequently talked about, humoral (antibodies) and cellular (typically T-cells). However, it's a lot more involved than that. There are types of cells that can seek and destroy infected cells, CD8 cytotoxic cells and NK cells being two examples. However, there are also T-cells needed for the production of antibody, CD4 cells. Without CD4 cells, B-cells, which produce antibody, don't receive signals to proliferate and expand to produce memory B-cells. Thus, the T-cell interplay is a required complex system that constantly communicates back and forth.

Now, to the paper. It's not been peer reviewed and I'm getting a little peeved by the amount of airtime that non-peer reviewed manuscripts are receiving on TWiV. From a skim through the manuscript I can already see problems with the controls and sample size. The unexposed healthy donors have responses to SARS S2, the surface glycoprotein. Now, this is not surprising and should be expected because the T-cell repertoire of an individual might well respond to peptides that have not been previously seen or are cross reactive to other coronaviruses. The generation of T-cell repertoire is remarkable and there will be cells that can respond to antigens that an individual has not experienced before. The other issue that I can immediately see is that the types of T-cells were not determined. The authors use a T-cell marker, CD3. However, this does not distinguish between CD4 or CD8 or their naïve subtypes. This is problematic because the maturity of the immune response to the peptides cannot be determined, which is an important factor to understand whether theses are naïve cells (never seen SARS) or memory cells (have seen SARS previously).

This study might hold out once larger samples sizes are evaluated. I have seen reports where some folk do not elicit an antibody response. However, these are considerably less frequent than those who do make antibody. Is this because of limited exposure that the authors tie in with mild symptoms? That's a bit of a stretch but plausible. What's not clear is whether those who don't elicit an antibody response are indeed protected from SARS-CoV-2, which comes back to your original question of whether T-cells play a larger role in protection against SARS-CoV-2 than anticipated. I'll go out on a limb and say that these folk who only have T-cell responses will not be fully protected from reinfection and might have a second round of signs and symptoms. It's going to be a very long time before that type of data are available.

In summary, yes T-cells are important against SARS-CoV-2, both for the production of antibody and directly targeting cells, but they're unlike to be the only defence against coronaviruses.

 

[wannabe]

Thank you very much for your very complete answer as always. :thumbup

I totally understand how busy you and Snaggy must be. I really appreciate the time you took to read the paper and answer my uneducated questions. And, no need to apologize about saying 'maybe.' I expect and delight in scientific honesty. 'We don't know' is a perfectly acceptable answer and definitely preferred to just pulling stuff out of your butt.

Regarding the study, yes, I was also concerned about the small sample size in this paper. I have some googling to do about the types of T cells, but I appreciate you pointing me in the right direction. Part of the episode was kind of a brainstorming of how big of a sample would be required and how long it would take to do a T cell test. Long story short: it'll take a few days because the culture has to be grown. (I believe that was the term used.)

I don't want to spoil anything for you, but just as a teaser, the other paper that was discussed in the podcast had a much larger sample size. It was an older (few months ago) paper that came out of Italy. They did a study of transmission after a short contact. (face to face within 2 meters for 15 minutes or more) The sample size was 21,410 positive cases and 64,252 people who had close contact with those positive subjects. (So, just a bit larger than the first paper.)

https://arxiv.org/ftp/arxiv/papers/2006/2006.08471.pdf

The results were not a surprise, but it was good to get some numbers. :thumbup

 

[Dr_SLO]

I don't want to spoil anything for you, but just as a teaser, the other paper that was discussed in the podcast had a much larger sample size. It was an older (few months ago) paper that came out of Italy. They did a study of transmission after a short contact. (face to face within 2 meters for 15 minutes or more) The sample size was 21,410 positive cases and 64,252 people who had close contact with those positive subjects. (So, just a bit larger than the first paper.)

https://arxiv.org/ftp/arxiv/papers/2006/2006.08471.pdf

The results were not a surprise, but it was good to get some numbers. :thumbup

Thanks for this. It certainly adds weight to the stratification of disease severity associated with age and sex.

 

[wannabe]

I swear that the episode notes with links to the papers that they discussed is one of my favorite things about this podcast. I can’t always follow along during the podcast, but reading the papers afterward really helps my understanding.

 

[Snaggy]

The premise of your citation is:

Asymptomatic or mildly symptomatic patients don't seem to have a robust, lasting antibody response to Covid. So how do you determine who has had it?

Antibodies are a consumable. Like all other circulating proteins in the bloodstream, they're broken down and recycled periodically. Unless they're continuously produced, you won't find them. But, the body has a rapid reactivation mechanism, consisting of Memory B Cells. Once stimulated, these can differentiate into Plasma Cells, antibody factories, that will dust off an old specific antibody blueprint and rapidly go into full production.

Memory B cells just nap until a T cell (often) wakes them up, and the nudge will (often) be a cytokine. The authors failed to find antibody in people who were likely to have been infected, so instead went looking for the sentry T cells that would produce that cytokine if they saw Covid antigens again. And that's what happened, T cells started producing a cytokine, Interferon gamma/IFN, in reaction to Covid antigens. The authors feel that this response was vigorous enough that it was a remnant of Covid-19 infection, not background noise or reaction to a previous Common Cold-type Coronavirus infection.

There are many cytokines, and each cytokine is a messenger and effector to several different compartments of the immune response. That could be neutrophils, killer T cells, Memory B cells, macrophages, endothelium, bone marrow and stem cells, the web of interaction is incredible.

Those people HAD been infected, and this was a way to determine that when antibody tests could not. They also would likely would have some protection against reinfection.

 

[Snaggy]

I have wanting to throw this study out there, and it also touches on your citation wannabee, trying to come to grips with the asymptomatic patients.

https://www.nature.com/articles/s41591-020-0965-6

Table 4 shows the levels of 48 different cytokines in symptomatic and asymptomatic infection. They were higher in the sicker patients. That's what cytokines do, cause fever, chills, muscle pain, and headache, and activate the immune system. Carried to the extreme, they elicit ARDS, kidney failure, blood clots and other complications of severe Covid infection.

The study also suggests that people with milder infections shed virus longer, and make less IgG. In this study, 40% of patients with asymptomatic infection did not have detectable antibodies at 8 weeks after infection.

There's also some sample chest CT's, and that's a surprising amount of pulmonary disease for an asymptomatic person. That goes with the observation of experienced physicians, that these patients may look sick, and have abnormal vitals signs, labs and imaging, but not feel correspondingly ill.

 

[Butch]

Just thank you. You know who you are.