COVID Transmissions for 2-3-2021

Truly AMAZING vaccine news

Feb 03, 2021

Good morning and welcome to COVID Transmissions.

It has been 443 days since the first documented human case of COVID-19. In the time since the first case of COVID-19, the Voyager 1 spacecraft has traveled about 404,016,000 miles.

Today, we have some EXCELLENT vaccine news, and I also cover a story about profession-based risks of COVID-19 death, among other things.

Also, a response to a reader question in the talk back section.

Actually, there was so much content today that I had to put off coverage of a couple of other things I’d planned to talk about.

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

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Now, let’s talk COVID.

THE BEST NEWS OF THE YEAR: Oxford-AstraZeneca vaccine single-dose efficacy and transmission benefits

We had some very good news yesterday from ongoing trials of the Oxford-AstraZeneca vaccine. Specifically, new results with longer follow-up reveal that the vaccine is 76% effective after only a single dose, starting from Day 22 after that dose through Day 90 (starting at 14 days, it was 66%, so that extra week seems to matter). This is actually, apparently, better than the 70% efficacy that was originally reported for two doses of the vaccine, though we can’t really cross-compare there because the follow-up is quite a bit different here.

To underscore this, the new study also looked at a two-dose regimen, but looked at different intervals between doses. When there were less than six weeks between doses (as in the original trial), the efficacy was only 54.9%, but with up to 12 weeks between doses, the efficacy was 82.4%. For this particular vaccine, at least, this seems to justify the UK’s strategy of waiting 3 months between doses. This is pretty fascinating—partly because I think it’s unique to this vaccine design, and it’s also a result I didn’t expect, but in hindsight it makes a certain kind of sense.

Now, here, I’m speculating, but I feel at least somewhat confident about this hypothesis. This is a viral vector vaccine that uses a chimera between SARS-CoV-2 and a chimpanzee adenovirus. There is an immune response to both components, and that immune response might interfere with the second dose somewhat. In the original trial, we saw that a half-dose “prime” followed by a full-dose “boost” with this vaccine led to a big gain in efficacy, and that is probably because it reduced interference from the first dose with the boost effect of the second. It’s worth noting that standard dose sizes were used for the both doses in the study I’m reporting here.

Similarly to the lower-dose regimen though, here, by extending the period between doses, they may be allowing the response to the chimpanzee adenovirus vector to mellow out a little bit more. This might provide “room” for a nice solid boost effect. Give the booster dose too soon, and the immune system is on such high alert for this vaccine product that you don’t see as good protection, but wait a little while and the vaccine virus you’re adding in may not get attacked by the preexisting immune response so quickly, allowing for a better boost effect.

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.

Something that also jumps out at me is that the low vaccine efficacy when the doses are spaced closely together suggests that a robust immune response to this vaccine may be able to neutralize input vaccine virus relatively quickly, perhaps even eliminating a portion of it before it gets into cells. I think this bodes particularly well for the vaccine and for all of us, because it implies there may be some ability to prevent infection with SARS-CoV-2. I’m kind of out on a limb here too, however, the researchers looked at something close to this idea.

This part is why I called this “the best news of the year.” Specifically, the researchers looked at the amount of patients in the trial who were PCR-positive for SARS-CoV-2 infection. Until now, it has been possible that the effects of these vaccines are to reduce the severity of disease to where disease no longer occurs, with no effect on infection by the actual virus. If that’s true, every vaccinated patient might be just another asymptomatic carrier of SARS-CoV-2.

To figure out if that happens or not, we need to know not just how many patients get disease, but also how many patients get infected. That’s where the PCR-positive rate is important. I want to put these results in a different font, because they’re awesome:

In this trial, the PCR-positive rate for vaccinated patients after just one dose was 67% lower than for patients who received a placebo.

That is amazing! 67% lower is very close to the overall efficacy of the single dose of the vaccine, suggesting that this vaccine genuinely reduces the ability of patients to become infected with SARS-CoV-2. If they cannot become infected, they cannot transmit the virus.

Now, I’m sure this isn’t a perfect representation of the effect. More results will follow. However, with something around a two-thirds reduction in infections, we can actually expect to reduce the replication of the virus in the community at large, and we can actually expect to achieve herd immunity through vaccination. That would be incredible.

This is the first time we have evidence that any vaccine has the capability to do this. The other vaccines may still not have this capability, but I am hopeful that they do. They generate similar immune responses according to the available data, and while that’s no guarantee of similar effects, it does strongly suggest it.

Still, I haven’t felt this good about a result since the pandemic started. We are really getting somewhere with this evidence. Even if only this vaccine has this effect, we finally have a real tool we can use to protect both individuals and entire societies from this virus that has plagued us for over a year.

You can read a news release about this here: https://www.ox.ac.uk/news/2021-02-02-oxford-coronavirus-vaccine-shows-sustained-protection-76-during-3-month-interval

And you can read the preprint of the full study here: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777268

Cooks and restaurant workers may have the highest-risk profession for death from COVID-19

A new preprint of a study from UCSF is being widely reported as saying that cooks are at the highest risk of death from COVID-19. Here’s a story on the study from SFGate: http://sfgate.com/food/article/Cooks-restaurant-workers-risk-death-COVID-UCSF-15905789.php

And here’s the actual preprint: https://www.medrxiv.org/content/10.1101/2021.01.21.21250266v1.full

What this study did was look at California death records to determine “excess deaths,” specifically the amount of deaths that exceeded what might be seen in a typical year that doesn’t contain a pandemic.

They determined that the highest percentage increase in deaths occurred in people working in food and agriculture, but this actually wasn’t the category with the highest number of excess deaths—that was individuals in facilities jobs.

However, where the headlines come from is a table showing risk of death by profession in “pandemic time” compared to “non-pandemic time”. Here, cooks did lead the list, but close behind them were packaging and filling machine operators as well as agricultural workers. Also, the study doesn’t give us any error bars on these risk ratios, so it could be that the numbers aren’t statistically different at all.

Anyway, what the news isn’t picking up, and what I think is a more important finding, is that there were clear racial differences in excess deaths. Mortality among white working-age Californians increased by 6%. For Asian Californians, the increase was 18%. For Black Californians, 28%. For Latino Californians? 36%. I find that very troubling, and it confirms a trend observed in other studies, so I also find it rather reliable. There is a clear issue here with inequality that is driving excess deaths during the pandemic.

That said, I don’t think excess deaths are the best measurement ever. There wasn’t an effort to exclude deaths any deaths that might be unlikely to be due to COVID-19 here; for example, self-inflicted gunshot wounds. This is a morbid criticism of the study, but it would not surprise me at all if the study had at least partially detected that the closure of many restaurants, resulting in massive job losses, has led to an uptick in suicides among restaurant workers. The reality is that the pandemic can kill in many ways, and I hope that the reviewers of this paper ask its authors to probe a little deeper to understand better what was observed here.

However, I think these are good results and they tell us a lot about who in our society, at least amongst those of working age, is being hit the hardest by the phenomenon of COVID-19.

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

Cooking: Stir-fry

Photo is a plate of stir-fried chicken, with cabbage and black rice

We’ve talked about my efforts to master the stir-fry before, but there are new readers every day, so I’ll summarize: I want to learn to stir-fry authentically, because it’s an amazing chemical process where extreme heat can caramelize almost anything into deliciousness.

I was given a wok as a gift for my 1-year anniversary at my current job, and I’ve been slowly learning to use it properly.

The other night I took some chicken cutlets, pounded them out so they’d be easy to make uniform, and also prepared some thinly sliced onions, sliced shiitake mushrooms, chopped celery, and shredded cabbage. I happened to have some leftover black (aka “forbidden”) rice, as well.

The best thing about the wok is that it has an area of extreme heat at the base, followed by a gradient of decreasing heat as you go up to the edges. So you can hit ingredients with a lot of heat early on, and then move them to a cooler area where they continue to cook while you focus on searing new things at the center.

For this, I did the onions first, with a little ground ginger, five spice, and soy sauce, then added the shiitake mushrooms. Once all that seemed to have caramelized a bit, I threw in the celery, and then the chicken. The chicken had been marinated in a little soy sauce, vinegar, and liquid smoke, so that had to be added progressively to avoid too much liquid getting into the wok. I didn’t want to steam this, after all, I wanted to fry it. With stirring. Once the chicken was handled, I added the cabbage, got that nice and cooked, and finished it off with stirring in the rice.

One of the cool things with using shiitake mushrooms here, and adding them early, is that they really drank up everything that cooked out of all the other ingredients, making them an incredible flavor bomb within the overall dish.

This worked out well. I’m gonna try out some other ingredients in the future, and see how I can expand my skills with this. With these long pandemic nights, I certainly have the time.

Reader Margaret left me a question after I’d already finished yesterday’s issue, so I want to address it now:

I keep hearing that various vaccine manufacturers (Moderna, Novavax) expect to be able to easily tweak their vaccines to focus on new variants. Do you have any information on how that might work in practice? More specifically:
What does the testing and approval process look like for an adjustment like this? Will they have to go through all three testing phases for every new version?
Do you expect the updated versions to be used exclusively as boosters? Would they replace the existing versions entirely? Or would it be feasible to mix them - half the shot designed for original COVID, the other half tailored to a variant, or something like that?

OK, this is a cool question. But it has a long answer, and that’s even with my trying to summarize as much as I can:

Well, this is a complicated question--and a good one!
I think some vaccines take more easily to being modified than others. The examples you cite are in the "easier" category, because they are relatively simple in construction. The Moderna vaccine is an mRNA vaccine, generated by synthesizing RNA molecules and then mixing them into droplets of fat to produce nanoparticles that can be readily taken up by cells. The Novavax vaccine relies on a protein subunit design, which is a protein construct made in a laboratory setting by growth in cultured cells. To do this, they actually employ a whole other virus. They use insect cells, which they infect with a specially-designed insect virus containing DNA instructions to create the protein subunit they want to manufacture. Once they do that, they have a culture dish full of protein factories--in this case, producing a construct made from the SARS-CoV-2 spike protein.
Both of these are essentially programmable. For the Moderna vaccine, RNA synthesis machines can be programmed to make a different RNA molecule relatively easily. For the Novavax option, it is a little more difficult because bioengineering is at the center of it, but a new protein--or a subtle variation on the old one--can be made by changing the virus DNA introduced to the cell platform. Both processes have relatively quick turnaround for changes, though I do think that the RNA vaccines have an advantage by being manufactured in a chemical, rather than biological, reaction system.
Anyway, that's the "how." You wanted more than that. The regulatory process here is indeed a bit different than if the vaccines were being newly invented. For a product like this, the closest analogue is the seasonal influenza vaccine, which is made new every year. For those vaccines, a global organization of influenza surveillance groups determines what strains should be included in a new vaccine, and then various companies produce candidate vaccines. Limited experiments are conducted to demonstrate that these new formulations are what they say they are and work like established influenza vaccine designs. This simple process only works, though, because we have done robust validation on, and have a lot of experience with, seasonal influenza virus.
In an influenza pandemic, things can be a little different. Simple clinical studies are conducted to demonstrate that (1) the immune response to the new vaccine is generally similar to what we would expect from a protective influenza virus vaccine, and (2) no unexpected safety events are observed. These trials will be designed based on negotiation with the FDA based on the degree of similarity between the new vaccine vs existing, validated vaccines. In 2009, the novel H1N1 influenza virus strain was so similar to known viruses that no clinical trials were required--it was treated just like a seasonal strain change.
For the first alterations to COVID-19 vaccines, I imagine that the FDA will employ a balanced approach. The technologies are simple and have been deeply studied, but they are still new and this is still a new virus. I expect that simple, small-scale clinical trials will be conducted to establish that any new vaccines produce similar immune responses as the old designs and that no new safety signals are observed. But, we will see. Either way, I don't expect that the full three-phase approval process will be required.
Regarding the deployment of any new vaccine designs, my expectation is that they will be used as third booster doses. This is going to depend on what variants circulate most commonly in each region, so it's really hard to answer. It may be that we still do two vaccinations, with the prime being with the "earlier" vaccine version and the boost being with the "new." I don't think that we would need to create mixed-dose versions of the new and old. That type of vaccine is called "multivalent" and typically does require fully, new clinical trials because we have never had a multivalent SARS-CoV-2 vaccine before. The fastest approach to get new variations to market would be to release them as separate doses.

You might have some questions or comments! Send them in. As several folks have figured out, you can also email me if you have a comment that you don’t want to share with the whole group.

Join the conversation, and what you say will impact what I talk about in the next issue.

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