COVID Transmissions for 2-4-2021

A nice vaccine milestone

Feb 04, 2021

Good morning and welcome to COVID Transmissions.

It has been 444 days since the first documented human case of COVID-19. If they had left port in Europe at the beginning of the COVID-19 pandemic, Magellan’s expedition around the world would right now be close to the end of transiting what eventually became known as the Strait of Magellan (this actually took 446 days, but there won’t be a newsletter on Saturday).

A bunch of headlines today, on every topic we know and love! Vaccines, variants, and virologists’ opinions.

Also, a fair number of conversations with readers in the Talk Back section.

As usual, bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

Total number of vaccine doses administered globally now exceeds the number of confirmed COVID-19 cases

According to the Financial Times, there have now been more vaccine doses administered globally than there have been confirmed cases of COVID-19: https://www.ft.com/content/e29efb8b-46ec-4815-98aa-458deffcd896

This is a hopeful milestone! Obviously we need to administer many many more doses of vaccines to really win this fight, but it’s nice to see this bar get passed.

More findings regarding the B.1.1.7 variant

The UK healthcare system has been producing many regular reports about the epidemiology of the B.1.1.7 variant in their country, and as the data matures, I feel more confident making definitive statements about this variant.

The most recent report is here: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/957504/Variant_of_Concern_VOC_202012_01_Technical_Briefing_5_England.pdf

Having read it, I feel confident in the following two statements:

This variant is around 30 to 50% more likely to be transmitted to a contact of an infected person
This variant is potentially a little more virulent (aka, may cause slightly more severe disease), but I think the evidence of this is less definitive
The variant is definitely able to out-compete older variants and eventually becomes the dominant genetic lineage in areas where it is introduced

I am still not certain what the cause of these observed effects might be. It may be some genuine benefit to transmission of the virus, or it may be that this virus survives longer in its hosts and thus is able to get itself more chances to transmit to new hosts. However, the practical impact is clear: we need to reduce and contain the spread of COVID-19, dramatically.

Our old tactics of distancing and masking will still help here, but we need to all remember that we can’t slip up. Adding vaccines to that strategy could also be a big help, but we have to use every weapon we have in our arsenal—together, as a unified strategy.

The Pfizer vaccine is also effective at eliciting neutralizing antibodies against B.1.1.7

Building on that, I wanted to share this paper from Science demonstrating that antibodies from patients vaccinated with the Pfizer mRNA vaccine are still able to neutralize SARS-CoV-2 from the B.1.1.7 lineage: https://science.sciencemag.org/content/early/2021/01/28/science.abg6105

While these data suggest that the antibodies raised by the vaccine are still effective against the virus, we don’t really know if antibodies are the most important part of a protective immune response to this virus. Cells like T cells may also play a role.

That said, based on this and other evidence, it just doesn’t look like the B.1.1.7 variant meaningfully escapes vaccines, so I think that is pretty good news. The scary thing is that this may not be as true for the other variants out there, but I’m not panicking yet.

The case against delaying the second dose of SARS-CoV-2 mRNA vaccines

It’s almost funny to post this now that we have very nice results for two viral vector vaccines that can be given either as single dose (the Johnson and Johnson vaccine) or as two doses spaced out over a period of months.

However, virologist Paul Bieniasz (pronounced something like “bee-nash”) recently wrote a letter to the editors of Clinical Infectious Diseases laying out the reasons that it might not be such a great idea to space out the doses of the mRNA vaccines specifically. I do think his points still stand until we hear differently from real experimental evidence, so it’s a worthy read: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab070/6121510

What am I doing to cope with the pandemic? This:

Trying to move around the world

One thing that the pandemic has really impacted is my range of travel. In days gone by, I’d get on the subway and be essentially 40 minutes to anywhere. It wasn’t complicated, though at times it was annoying and time consuming.

If I needed to go farther, I could rent a car or get on a plane.

I don’t do any of this stuff anymore. There’s walking, and there’s biking. I walk or bike everywhere that I go. Including when I go to the gym, which is safely open here in New York (0.06% of new cases are traced back to gyms, which is a sign of how responsible gym-goers in NYC have been).

The problem is, it snowed recently. A lot. Last night, I had to bike to the gym on paths that had only been recently cleared of snow, and uh, it was not as easy or as fast as usual. I don’t know if I’d repeat the experience, if I can avoid it.

There was one point, though, where I wanted to see if a CitiBike could handle super hard-packed snow. Turns out it can! Surprisingly good traction on those blue bikes. It was a lot of fun to try for a few yards, but I wouldn’t recommend you try it yourselves.

And, of course, at the end of all this, it was pretty hard to find a CitiBike dock that wasn’t totally full of snow.

The pandemic really brings a lot of challenges with it, large and small, and even for the most mundane things. This one is both mundane and small, but it’s part of the experience of pandemic life.

Readers Robert Berger and Carl Fink both shared the following story with me:

https://health.mountsinai.org/blog/researchers-identify-promising-new-antiviral-drug-for-covid-19/

What’s funny about this is that both of the people pictured in that article are people I worked with in my PhD. I’ve been following this story, but there’s a reason I haven’t covered it in the newsletter, as noted in my reply to Robert:

Hi Robert! Thanks for sharing this. I am actually closely affiliated with the authors of this study--the person pictured, Dr. Kris White, sat behind me in the lab for 7 years and we are still in touch. The senior author was a collaborator of mine on my thesis. I know half of the other authors personally.
I have very intentionally not covered it in the newsletter for one very specific reason, though. It's too early days to make a lot of hay out of the effects of this drug, and I'm afraid about being misleading. Early development of therapeutics--even early clinical development--can contain a lot of promise that doesn't bear out. I do not want to tout something that could become the next false hope.
I'm going to be following the story, and when Phase 3 trial results become apparent, I may cover it in depth.

Carl also had a couple of comments that sparked discussion, the first being about the ENSEMBLE 2 trial:

Hi, John. You wrote, "For this reason, I don’t believe the effect of increased efficacy with longer time between doses will be generalizable to other vaccine designs. It might apply to other viral vector-type COVID-19 vaccines, though, like the Johnson and Johnson vaccine. Maybe we’ll find out in future studies." J&J is actually running ENSEMBLE 2, a Phase 3 study of their vaccine using two doses, with dose 2 administered on Day 57 (counting from first shot as Day 1). Results due pretty soon, IIRC. Took longer than ENSEMBLE (single dose), presumably because of that two-month wait.

Carl is referencing my statement that the Oxford results I shared yesterday won’t necessarily be comparable to other vaccine trials. In that study, the researchers looked at what various different lengths of time between the two vaccine doses did to the ultimate efficacy of the vaccine. No other study has varied the interval between doses, so I replied with the following:

Yep. I made reference to ENSEMBLE 2 in my coverage of the J&J vaccine a little while ago. However, ENSEMBLE 2 doesn't explore the impact of variation in dose timing on vaccine efficacy, using only one fixed dosing schedule. So it won't directly address this exact question. It'll give some indirect insight, though, since the inter-dose period is pretty long compared to what AZ-Oxford used in their first trial.

Carl followed up with another comment that I think you may find interesting as well:

You might know this: once one has been exposed to an antigen, how long does it take for memory cells to reach maximum proliferation? Your proposed mechanism (decreasing sensitivity to the carrier virus) makes sense, but I can visualize one in which it takes six weeks or more for the memory cells to fully develop and "prime" the immune systems. (I'm using "memory cell" loosely to include both T and B cell lines.) Of course, both mechanisms could be operating simultaneously (and even synergistically).

This one is slightly beyond my expertise! But I did do my best to answer, but keep in mind I’m speculating a lot here:

This is a little bit out of my wheelhouse, but I do know the estimates. Memory cell populations tend to appear on the order of weeks postinfection; I have heard about 3 in the past, though I understand that the population can continue to mature for quite some weeks after that. Of course, memory cell populations are quite small though and they take time to proliferate in response to a new infection. While this is usually fast enough to respond to a new infection, I don't think it would really be fast enough to prevent a viral vector vaccine from functioning *necessarily*.
I would expect if there is interference with the viral vector vaccine, it would be due to more active measures than proliferating memory cells; specifically either effector T cells or circulating antibodies are what I would anticipate to be the source of such interference. While it can take months for antibody levels to really decline, antigen-specific effector T cell populations can reduce in a matter of weeks as well. I'm beginning to think that T cells are rather important for the immune response to COVID-19, as perhaps only tangentially related point.
The hypothesis that it takes time for a memory cell population to be fully matured such that the boost would be effective is interesting, although it is defied by the fact that boosting the mRNA vaccines just 21-28 days after the prime produces a clear enhancement of the antibody response. Clearly it is possible to boost a SARS-CoV-2 response and get efficacy gains with a boost occurring only 3-4 weeks after the prime. But for some reason, with this viral vector vaccine, boosting on that timeframe appears to actually harm the overall efficacy. My hypothesis that it has to do with the response to the vector is based on the fact that the viral vector is the main difference between this vaccine vs the mRNA vaccines.
Of course, sometimes when you hear hoofbeats, it's actually zebras. It could be that the reason for this kinetic issue has something to do with the fact that this vaccine actually infects cells with an incompetent virus rather than just providing mRNA. The kinetics of the immune response to these two different mechanisms may be, well, different, and that could be part of it. I'm not an adaptive immunologist so while I can come up with hypotheses, I can't feel extremely confident in them.
No doubt I will hear what some adaptive immunologists have to say about this soon, and I'll report back on that.

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