COVID Transmissions for 6-21-2021

Delta more dangerous in young people?

Jun 21, 2021

Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.

It has been 581 days since the first documented human case of COVID-19. In 581, the Second Council of Macon in Burgundy imposed a number of antisemitic restrictions against Jews, including curfews and other restrictions related to professions. Also, Jews were banned from talking to nuns. Antisemitism in Europe continued to worsen through the medieval period, though there were certain times and certain places where Jews like me were treated as fully human by their European neighbors.

Fear was at the root of these decisions, and fear is also at the root of many of the worst reactions to COVID-19. Hopefully I can arm you with information that will help.

Today we will discuss claims by President Biden that the “Delta” (B.1.617.2) variant is more dangerous to young people, and then also we will cover the risk of MIS-C, the multisystem inflammatory syndrome in children, from a new epidemiology study. Additionally, we’ll talk about a serological study looking at when COVID-19 may have really come to certain parts of the US.

Then, some reader comments that focus on the CureVac failure as well as the possibility for vaccine approval in young children.

Have a great week!

Bolded terms are linked to the running newsletter glossary.

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Now, let’s talk COVID.

B.1.617.2/Delta update: more serious in the young?

In the past few days, President Biden made statements warning the US about the B.1.617.2 variant, also called Delta by the WHO. This variant is considered up to 60% more transmissible than existing dominant lineages, and is certainly becoming dominant wherever it goes. Last week, it was responsible for 6% of infections in the US, and is now up to 10%. This mirrors the path it followed in India and the UK.

One thing that President Biden said is that this variant is likely to be more serious in young people. I am not as confident about this statement, but since young people are among those who are least likely to be vaccinated at this time, he may be right simply because more older people are fully vaccinated and this protected at this time.

You can read more about the government’s position here: https://www.cnbc.com/2021/06/18/biden-says-delta-covid-variant-is-particularly-dangerous-for-young-people.html

One way or another, I am convinced that it is essential for everyone eligible to become fully vaccinated as soon as possible. It’s either that or get COVID-19. Not a hard choice.

Serological evidence of SARS-CoV-2 appearance in the US weeks before initial detected cases

A new antibody study has revealed evidence of SARS-CoV-2 infections in various US states weeks before infections were first detected there: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciab519/6294073

The study here used historical blood samples to look for antibodies against SARS-CoV-2 in a period from January 2, 2020 until March 2020.

This study is not the first of its kind; other work has shown that there is serological evidence of SARS-CoV-2 infection in various places in the US before case spikes first appeared. Some of the results in the above study, though, don’t seem to make a great deal of sense—specifically, some proposed cases are in early January in Illinois and Massachusetts. This suggests a geographically widespread epidemic in the US by early January, something that doesn’t seem to align with the epidemiological and genetic evidence that indicate most cases in the US descended from lineages introduced in New York (though not all). For this reason, I think we need to be a bit cautious with the results in this paper because it is possible for cross-reactivity between SARS-CoV-2 antigens and antibodies against other viruses to give somewhat misleading results. This has been known to happen in studies of this kind.

Still, I feel that the results here are not likely to all be the result of this kind of thing. Instead, the overall picture is that SARS-CoV-2 was spreading in the US for weeks, and maybe longer than that, before it was officially detected in various places.

If we are to combat future emerging viruses, it is essential to understand how the initial spread of SARS-CoV-2 around the world actually worked. Unfortunately, in early 2020, US disease surveillance infrastructure was caught woefully unprepared. In fact, it was pretty shocking to me just how unprepared the US government was, since not many years earlier I had been a part of research institutes dedicated to ensuring that the US doesn’t get caught flat-footed in exactly this situation.

One question that bothers me continually is this: just how unaware were we caught? In January and February of 2020, I thought that the CDC had adequate surveillance to be able to detect travel-related and community-acquired COVID-19 cases. As it turns out, the CDC not only lacked this but also had several errors in trying to implement it, which further delayed US surveillance. The end result is that we do not really know when COVID-19 first came to the US. Through serological studies we can begin to understand just how early it might have entered before the US had meaningful tools to detect it, however.

At this point, it seems evident to me that instead of thinking of COVID-19 as something that began in the US in late February or March, it is appropriate to to think of it as something that may have begun in a January or February timeframe. With that information, we can consider that it likely took only weeks for SARS-CoV-2 to spread from China to the rest of the world, whereas before it seemed that it might have taken months for the pandemic to begin.

With that information, we can begin to try and piece together how we might have done a better job with disease intelligence, and potentially even prevented the arrival of SARS-CoV-2 in the US. It’s possible that we never could have prevented it, but in understanding how we failed this time around, we might learn to prevent the next one.

MIS-C risk

I get a lot of questions about COVID-19 risks in children. Multi-inflammatory syndrome in children (MIS-C) is one of the more concerning risks of COVID-19 to the youngest people who are affected. MIS-C involves severe inflammation of various body and organ systems, which is quite serious and requires extended medical attention in order to resolve successfully.

One of the reasons that MIS-C is called a “syndrome” and not a “disease” is because very little is known about it, so it is characterized by a set of signs and symptoms rather than a distinct disease process with a clear cause and course. For example, we do not currently have a great sense of the risk factors involved in MIS-C.

Recently, however, some epidemiological work was conducted to explore the incidence of MIS-C in various child populations. This work was published in JAMA Network Open: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780861

In this work, the authors establish that MIS-C occurs in 31.6 out of every 100,000 SARS-CoV-2 infections in all children. However, the authors also looked at incidence in specific racial and ethnic groups, and found that in the US context being studied, MIS-C was around 5 times more frequent in Black children with SARS-CoV-2 infection, just under 5 times more frequent in Hispanic or Latino children, and just under 3 times more frequent in Asian or Pacific Islander children than in white children.

This is hardly the first racial disparity identified with COVID-19, but it is also an essential result in beginning to understand what may cause this condition. There are definitive differences in the incidence of other inflammatory diseases in racial and ethnic minorities in the US vs white individuals, and I think that it’s possible that this disparity could be affected by the same root causes as those. We know, for example, that asthma is more common among Black patients than white ones in the US—this may be because of socioeconomic barriers to living in areas with cleaner air. It seems possible that similar disparities and barriers could create conditions conducive to MIS-C.

We’ll need to do more work to really understand this, but it’s a first step.

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

Father’s Day with my grandnieces

By some quirks of age gaps in my family and a nephew who married rather young, I have two beautiful grandnieces. We spent Sunday celebrating Father’s Day with them and my parents. One of my grandnieces was born during the pandemic, and I had never seen her before. It was a really important and lovely experience.

Reader Marcia wanted to probe further on possible reasons that CureVac’s vaccine may not have succeeded:

One more piece I was a little surprised you didn't mention, but which makes a lot of sense to me about variants and dosage: both Pfizer and Moderna are only barely less effective at full immunization* but both have been mentioned to have a much smaller (1/4?) neutralizing antibody response to certain VOC then they do to Covid Classic. Just they already had such a huge immune response that it was still enough. So if Curevac wasn't starting with anywhere near as huge and immune response then I could see it mattering a lot more that the VOCs were pretty much everything it was dealing with.
(Another bit that informs my query here is that some of the initial data from Hopkins' research with transplant patients seem to be that Moderna, with three times the genetic material, was somewhat more likely to produce spike antibodies than Pfizer. (They've just published something about a third dose, mix and match, seeming helpful for these immune compromised patients but I have not looked at it and that's attention anyway))
Am I off base on this, or would embracing the power of And (less mRNA -> less good at variants b/c less NA) be the rest of the story?
https://yourlocalepidemiologist.substack.com/p/vaccine-table-update-june-4-2021 is where I'm getting the 1/4.
* Or after one dose for everybody but Delta so far, but Delta was at around 30ish percent for one dose of Pfizer or AZ; haven't seen the data for Moderna

I think these are interesting ideas that could well be on the mark. Here is my reply, where I hedge on that a fair bit, though, because we still don’t have access to key information:

The reason I didn't mention this is that CureVac had good neutralization titers, as I recall similar to those of the other mRNA vaccines, in its Phase 2 results and earlier. so it seemed like it was on par with these other vaccines. I would like to see CureVac's full Phase 3 data--hopefully there will be some additional information about the immune response--but for the time being it seemed more prudent to compare vaccine efficacy endpoints to each other, because these represent the practical effects. It is a more apples-to-apples comparison.
I've covered the reduction in neutralizing titers for specific variants here before, and communicated the same thing--that there is an apparent reduction in neutralization for certain variants, but the antibody titers are already so high with 2 doses of the approved mRNA vaccines that the reduction doesn't seem to take things down below the apparent protective threshold.
The big quirk to all of this is that we *still* don't know entirely enough about the immune response to COVID-19 to understand if antibodies actually represent the whole picture. While we are working under the assumption that antibodies are a correlate of protection, and using them for immunobridging studies (studies where an immunological correlate of protection is used as the endpoint rather than disease protection) in children, the correlation with protection may not be 100% solid. Given that CureVac showed good antibody titers in early phases but then failed in phase 3, I'm really wondering about that. I would very much like to see data from CureVac on durability of response and also neutralization titers in their phase 3 subjects for this reason, but they left that out of the press release. Which is kind of odd, since it would have potentially bolstered their "but the variants!!" argument.

Carl Fink also wanted to probe deeper regarding the CureVac failure, as well as commenting further on the Indonesian vaccination story that we discussed last week:

I'm pretty embarrassed by my off-the-cuff reaction to the missing numerator from Indonesia.
One thing I didn't notice in the article: CureVac's vaccine uses unmodified mRNA. Moderna and Pfizer make vaccines that contain nucleoside-modified mRNA. This might be in some way responsible for the apparent difference in effect. At least, I'd like to hear your opinion.

As you’ll see in my comment I really don’t think this reaction is something to be embarrassed about. News is written to draw a reaction and thus encourage its own spread—and to grab attention. There may also be some bias in the reporting there due to local agendas in Indonesia (I can’t be sure about that, though). But the fact is, news articles can often be manipulative and we can all get drawn into that. Anyway, here is my reply:

I wouldn't be embarrassed. The article was written in such a way as to encourage hasty reactions. For whatever it is worth.
Good point about the absence of pseudouridine substitution in the CureVac option. That could also be relevant, though I can't entirely figure out how or why that would have impacted efficacy and yet still allowed for induction of an antibody response, to be quite honest.

Reader Sam wanted to expand on VRBPAC comments about vaccination approval in children:

My impression was that most of the VRBPAC members recognized at least some need to vaccinate young children, but expressed concerns about whether the safety and efficacy data will be enough to permit authorization later this year. It seems to me, though, that increasing the follow-up time wouldn't be particularly helpful (Paul Offit said the same in the meeting); and increasing the size of the trial to the point where it could detect rare safety signals would take an untenably long time.
An interesting question hung over the meeting, which is whether we should consider just direct costs vs. benefits to individual patients, or also factor in the benefits to the wider society. I favor the latter position, but I also don't think you need to do so in order to support vaccination of kids under 12. It may not have been clear a year ago that the short- medium- and potential long-term effects of the virus are a very significant danger to people in every age group, but it absolutely is now.

This is all good information. I didn’t have much to say:

I would agree that the argument for vaccinating children looks favorable either way you slice it, but I do want to see more clinical data before saying it definitively IS favorable.

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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