COVID Transmissions for 1-26-2022
Evasion by Omicron; antibodies, vaccines, and more
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 771 days since the first documented human case of COVID-19. In 771, King Carloman I, brother to King Charlemagne, dies. This is an important event, because at the time, Frankish princes inherited equal shares of their fathers’ kingdoms. In theory, this would eventually lead to everyone being king of a postage stamp-sized piece of Frankish territory. The death of Carloman allowed Charlemagne to reunite his father’s kingdom—and eventually turn it into an empire.
Unfortunately, Charlemagne went on to have 9 children with a woman he married in 771, and he didn’t exactly fix this inheritance problem.
On the topic of sibling rivalry, today we’ll discuss some work comparing Delta infections with Omicron infections, and showing that a major driver of the difference between these variants is not some major change in the life cycle, replication, or transmission of Omicron, but rather in the ability of Omicron to evade the immunity we have developed through vaccination. Also, a related story about antibody therapies that no longer work in an Omicron world.
Bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
Two antibody EUAs withdrawn
Yesterday, the US FDA withdrew two antibody cocktail drug Emergency Use Authorizations (EUAs) because it is apparent that the drugs in question no longer work against the predominant variant of SARS-CoV-2, the Omicron variant. Well, technically they just revised the EUAs so that these two cocktails—Eli Lilly’s product and Regeneron’s product—can no longer be used anywhere in US jurisdiction, but the door is kept open for localities where there are variants that still respond to these drugs. News story here: https://finance.yahoo.com/news/fda-limits-regeneron-lillys-covid-160104850.html
This reflects the reality that the Omicron variant is different enough to compromise certain antibodies’ effects against it. I’ve covered this here before, showing preliminary work to this effect, but it has become clearer and clearer that this is the case as time goes on.
Here’s where I first discussed this:
For some reason, health authorities in the state of Florida have decided to criticize the FDA for this decision. I really do not understand why there is such insistence from various quarters to use drugs that don’t work. We have effective vaccines and antivirals that are well-supported by evidence! Sometimes viruses change and the products you use against them have to be changed. This really doesn’t need to be a political issue. Governments don’t weigh in whenever some new antibiotic-resistant bacteria emerges, and I don’t see why this issue here needs to be political either.
Studies suggest that Omicron’s spread more due to immune evasion than changes in virus lifecycle biology or kinetics
This is a very interesting preprint that looks at viral RNA loads as well as infectious virus, for a variety of different circumstances: https://www.medrxiv.org/content/10.1101/2022.01.10.22269010v1
I first heard about this paper—and the next one I am about to cover—on This Week in Virology episode 854, which you can view/listen to here:
However, if you’re looking for the couple of most impactful points, here they are:
Different variants of SARS-CoV-2 have different ratios between the amount of virus RNA that is recoverable in a sample and the amount of infectious virus that is recoverable —> this has impacts on how PCR test results might be interpreted, and how they might be related back to infectivity
There is a statistically significant difference between the amount of infectious virus and the amount of viral RNA that can be recovered from unvaccinated vs vaccinated people with breakthrough infections with the Delta variant —> vaccinated people who get COVID-19 shed less virus than unvaccinated people, in general
There is NO difference in viral RNA nor infectious virus that can be recovered from vaccinated people who get infected with the Delta variant vs the Omicron variant —> the second bullet above is likely true for Omicron variant cases as well
These are all critically important points. They establish that the use of virus RNA levels as a benchmark for infectiousness does not necessarily hold true to the same numbers across each variant, a key finding for future epidemiological and diagnostic study design. They establish that vaccinated people shed less virus than unvaccinated people, a key finding for the concept of disease control.
That finding doesn’t necessarily translate to a meaningful real-world difference, mind you—it could be that both groups are well above the threshold necessary to transmit their infection—but it suggests that among a group with random variations, there are more people shedding a small amount of virus among vaccinated breakthrough cases than there are among unvaccinated. That does seem to suggest a good chance of less transmission in a vaccinated population.
And, as mentioned, this seems to carry through for Omicron, as shown in this figure:
At least, what we see suggested here is that Omicron and Delta infections are not different in viral load in vaccinated people; which means the conclusion for seen with Delta, where vaccinated people shed less virus, probably also holds true for Omicron. That would be good news!
I, of course, would like a bigger study. But here we are starting to get some good insight that we can start to apply to what we’ve seen with Omicron variant spread through the population. We know that it has been apparently more contagious in highly vaccinated populations than past variants have been. Here we see that it is not making meaningfully more infectious virus. So any enhanced contagiousness effect must be coming from some other set of phenomena than an increase in viral load.
Possibilities—that are not mutually exclusive—might include a longer contagious period, different persistence of infectious virions in the environment, or an increased set of susceptible hosts because the Omicron variant can evade immunity enough to infect vaccinated people.
I believe that latter one is a major contributor, but I can’t rule out the others either!
One thing that does support the idea of immune evasiveness is this other preprint that was also covered in that TWiV episode: https://www.medrxiv.org/content/10.1101/2021.12.27.21268278v1
In that study, in Danish households that became clusters of infection for either the Delta variant or the Omicron variant, the authors compared the variant-specific “secondary attack rate”—the rate at which one case in a cluster caused additional cases. They were able to specify this to the secondary attack rate for unvaccinated household members vs vaccinated household members, too. Importantly, the authors found that the secondary attack rate of Omicron for unvaccinated people was only marginally, if at all, higher vs that of Delta (1.17 times higher, with a confidence interval that includes them being the same)…while the secondary attach rate of omicron for vaccinated people was much higher than that of Delta (2.61 times) and for people with a booster dose on top of full vaccination, the Omicron secondary attack rate was 3.66 times higher than Delta!
This may be a bit confusing—this does not mean that people with boosted vaccinations were more likely to get Omicron than people with only two doses. Each of these are relative numbers between Omicron and Delta in people with the same vaccination status. What we are seeing is not that people with more vaccine doses are less protected, but rather that people with 2 doses are pretty well protected against infection with Delta, but less well protected against Omicron. People with 3 doses are extremely well protected against infection with Delta, but again, less well protected against Omicron. Unvaccinated people are poorly protected against both Delta and Omicron.
To use completely made up numbers, if the secondary attack rate for unvaccinated, 2x vaccinated, and 3x vaccinated people with Delta was 10%, 1%, and 0.1% respectively, then by these numbers, for Omicron it would be 11.7%, 2.61%, and 0.36%, respectively. As you can see the vaccinated people are still very well protected in this example, just not quite as well. I used the made-up numbers to make the example look clean, but here are the real numbers:
Unvaccinated, Delta vs Omicron: 28% SAR vs 29%
2x vaccinated, Delta vs Omicron: 19% SAR vs 32%
3x vaccinated, Delta vs Omicron: 11% SAR vs 25%
As you can see here, the 3x vaccinated seem to be the only ones protected against Omicron infection (but let’s keep well in mind that we’re not looking at case severity at all here—we’re just looking at who tested positive in a household where someone was already positive; the vaccines are still protecting against severe disease and death substantially). We also need to consider that in each case we are looking at viruses that were selected already as capable of infecting people under each vaccination condition, so a specific individual virus that has already infected a 3x vaccinated person may be more likely to spread to their 3x vaccinated contacts. And then finally, these were not huge numbers and the authors had to plug them into a model that took into account all sorts of human behavior—such as the likelihood of highly vaccinated people to even bother to get tested for SARS-CoV-2. I’m giving you just the raw numbers here to be transparent.
What’s important to see here is that Omicron clearly is more contagious among vaccinated people, though a booster may have something of a protective effect against infection. We know from other information that the vaccines are still very protective against serious disease, I just want to underscore that. What we need to assess here is why Omicron is more contagious among vaccinated people.
The major difference between vaccinated and unvaccinated people these days is that vaccinated people have immunity to the WHN-01 variant of SARS-CoV-2. That immunity is protective against infection with various other variants of SARS-CoV-2, including Delta. It appears to be less protective against infection with Omicron.
If this were due to some change in the inherent biology of the virus lifecycle or its transmission dynamics/kinetics, then we would expect to see enhanced infectiousness in the unvaccinated, because they have no protection at all against either Delta or Omicron. They’re the control here. We see they are equally likely to become infected with either variant upon exposure, suggesting that Delta and Omicron are not wildly different. Maybe Omicron is a little more contagious among this control.
It’s in immune people that we see the biggest increase, which says to me that it is very likely immunity that is at the heart of the explanation for Omicron’s spread. We know that the Omicron variant has many immune-escape mutations. Here we are seeing it spreads better than past variants among vaccinated people. My bet is this is because it evades immunity quite well, at least to establish infection.
All in all, I see the case strengthening that the Omicron variant meaningfully evades immunity, and is not inherently more contagious.
That’s good news, because immunity that is specific to Omicron is something I believe is within our power to create via specific vaccination.
What am I doing to cope with the pandemic? This:
National meeting
The meeting I have been preparing for is upon me!
Today I helped facilitate a breakout session. Tomorrow I have a main stage presentation and am running a communications strategy workshop. It’s a busy time for me.
Reader Sam wanted to let us know that Pfizer has released some details about its trial on an Omicron-specific vaccine:
Pfizer just announced that they're starting their Omicron vaccine trial: https://investors.pfizer.com/Investors/News/news-details/2022/Pfizer-and-BioNTech-Initiate-Study-to-Evaluate-Omicron-Based-COVID-19-Vaccine-in-Adults-18-to-55-Years-of-Age/default.aspx. From the press release:
"The study will evaluate up to 1,420 participants across the three cohorts:
"Cohort #1 (n = 615): Received two doses of the current Pfizer-BioNTech COVID-19 vaccine 90-180 days prior to enrollment; in the study, participants will receive one or two doses of the Omicron-based vaccine
"Cohort #2 (n = 600): Received three doses of the current Pfizer-BioNTech COVID-19 vaccine 90-180 days prior to enrollment; in the study, participants will receive one dose of the current Pfizer-BioNTech COVID-19 vaccine or the Omicron-based vaccine
"Cohort #3 (n=205): Vaccine-naïve participants will receive three doses of the Omicron-based vaccine"
There is a note in the press release that I call out in my reply:
Thanks for sharing this. Did you notice how they describe the trial? "Safety, tolerability, and immunogenicity." They didn't say "efficacy." Back when you and I first discussed the possibility of a variant-specific vaccine, we talked about whether they would just look at immunogenicity, as they do for influenza vaccines, to avoid the need for expensive and time-consuming efficacy analyses. It looks like that's what they're doing!
And that seems justified, since it appears primarily that Omicron evades immunity rather than being very different in terms of its inherent transmissibility.
Looking at the immune response to a variant-specific vaccine, rather than waiting for efficacy data to mature, is a typical approach when a virus has subtly mutated to escape past vaccines. We do this every year with the influenza vaccines, and it gets them to market in time for flu season to help protect people. Glad to see the same common-sense approach is being deployed here.
Reader Dr. Lisa Freitag had the following comment on immune evasiveness:
I realize that we are dealing with different strains and that coronaviruses never generated much permanent immunity, but the idea that an actual viral infection does not result in immunity as (or more) effective as a vaccine goes against my clinical expectations. I thought that reinfection rates have remained fairly low despite shifts in SARS-CoV-2 strains. Is it possible that, when we study vaccine effectiveness, we are measuring immunity to Delta or Omicron in a fairly specific or limited way, thus missing other ways in which an actual infection might generate immunity? Should we perhaps be calling it "measurable Omicron immunity" instead?
Unsurprisingly, Dr. Freitag already gets what I’ve been trying to say in today’s issue—and a little more subtly in past issues. Here’s my reply:
I think we should absolutely be making this distinction. I believe what we have been seeing primarily in Omicron vs prior variants is immune evasion, not immune waning.
I do believe it is clear that there is some waning of immunity among recovered persons, and perhaps also some among vaccinated persons (I am less convinced of this in the latter case, because I haven't seen studies wherein over time, vaccinated people became more susceptible to the WHN-01 variant--only increased susceptibility to variants that escaped immunity to varying degrees). We did see, to some extent at least, reinfection of recovered persons with the same variants that they initially got, back in 2020. So in those cases I think there is a clear case for waning taking place.
I think the word "waning" has been misapplied in the pandemic to situations that represent immune escape. Omicron is clearly a variant that evades preexisting immunity to other variants, to at least some degree.
You might have some questions or comments! Join the conversation, and what you say will impact what I talk about in the next issue. You can also email me if you have a comment that you don’t want to share with the whole group.
Part of science is identifying and correcting errors. If you find a mistake, please tell me about it.
Though I can’t correct the emailed version after it has been sent, I do update the online post of the newsletter every time a mistake is brought to my attention.
No corrections since last issue.
See you all next time. And don’t forget to share the newsletter if you liked it.
Always,
JS
Thanks, as always.
I had never encountered the initialism "FFU" (used in the graph you reproduced), so I looked it up. For anyone else's benefit, it's Focus Forming Units, the equivalent of the plaques I was taught about back in biology school during the dark ages (1980s) for viruses that don't lyse their host cells.