COVID Transmissions for 12-6-2021

Children/infants and: Omicron, viral RNA counts, and vaccination

Dec 06, 2021

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

It has been 750 days since the first documented human case of COVID-19. In 750, the Abbasid Revolution against the Umayyad Caliphate had a great success in the Battle of Great Zab, and an Abbasid Caliphate was proclaimed. The Umayyad Caliphate collapses, though an Emirate in Iberia would continue to claim continuity with it for some centuries.

Today I share a number of stories that, primarily, are centered around young children and COVID-19. We have one on kids and Omicron, one on potentially higher viral loads in infants, and one on vaccine safety in kids 5-12.

Also a story where I revisit data on mRNA vaccination schedules and acknowledge that it’s clear a longer schedule could be superior.

Then, a selected reader comment that drives at a misunderstood principle in viral evolution.

I know Omicron is worrying a lot of people, and I don’t have a lot to say except that I don’t think it will be so extreme as it may sound. What I can say is this: let’s have a good week. We will learn more about Omicron in time, and while there’s reason to be concerned, it’s not warranted or productive to panic.

Bolded terms are linked to the running newsletter glossary.

Keep COVID Transmissions growing by sharing it! Share the newsletter, not the virus. I rely on you to help spread good information, which you can do with this button:

Share COVID Transmissions

Now, let’s talk COVID.

Omicron variant apparently connected to a huge rise in pediatric cases of COVID-19 in South Africa

In news that made my heart sink this weekend, there are reports from South Africa that with the Omicron variant on the rise there, hospitals are seeing a massive uptick in young pediatric cases; that is, patients under 5 years old. The Daily Beast reports (with some hyperbole, but good quotations from SA health officials): https://www.thedailybeast.com/omicron-variant-puttings-huge-numbers-of-kids-under-5-years-old-in-hospital-in-south-africa

This is a yikes moment. We do not know if this is particular to the South African health system or current epidemiological circumstances in that country, and we do not know what will happen elsewhere. We do not know a whole ton about how the Omicron variant may be different from other variants yet, in a practical sense, and we cannot be sure that this uptick in SA is specifically due to Omicron, either.

But the fact is it could be due to Omicron, and that would be terrible. Around the same time I saw this story, I saw the following from my old colleague Florian Krammer:

Florian Krammer @florian_krammer

I think I speak for almost everybody here: Omicron sucks. I don't like it.

Yeah, I agree, Florian. Not a fan of this thing so far.

Evidence suggests that babies under 6 months of age carry a high amount of virus RNA when infected with SARS-CoV-2

A paper from a group in Argentina looked at the RNA levels for SARS-CoV-2 in infected children of various ages: https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiab577/6438522

Please note that the paper refers to this as “viral load,” but that is incorrect. The amount of virus RNA that you can detect is not necessarily a linear correlate of the amount of functional virus that you have. Some or many of the virus RNA signals detected might be damaged or destroyed virus particles’ genome fragments, and not representative of an actual infectious dose.

However, the paper does have a concerning finding that should be further explored. In a group of about 45,000 COVID-19 testing samples, these authors looked at the RT-PCR “cycle threshold” value (Ct), a complicated concept that I’ve explored before. I encourage you to visit the glossary link and read up on it if you’re not familiar.

The bottom line is that a lower Ct value represents exponentially more virus RNA detected than a higher Ct value. Each 1-point reduction represents a factor of 2 increase. So, a 10-point Ct difference between two samples is 1024 times more RNA in the lower Ct value-sample than in the higher-Ct sample.

Here, the authors found that children 0-9 years old as an aggregate group had Ct values about 2-3 points higher than most adults, suggesting that children have about 4-8 times less virus RNA in the collected samples. However, when they further broke down the 0-9 year old group into subgroups of 0-6 months, 7-12 months, 1-4 years, and 5-9 years, they saw a different picture.

Children in the 5-9 year group had Cts that were only 1-2 points higher than the adults,, so maybe 2-4 times less RNA. Children in the 7-12 month and 1-4 year groups were up around 30, which is about 5-6 points different from adults. That represents 32-64 times less RNA.

It’s in the 0-6 month group that they saw their most surprising result. Infants 0-6 months old had Ct values that were about 4-5 points lower than adults. That’s potentially 16-32 times more virus RNA in very young infants than in adults.

If this finding bears out with more exploration, it would suggest that very young infants might be particularly potent sources of SARS-CoV-2 viruses, despite a lower rate of severe symptoms than other age groups. If that’s true, it might impact the approaches we take, to control spread of the virus.

On the other hand, there are a lot of reasons that this finding could have happened without there being any effect on the threat of transmission posed by infants. For example, infants may have a manifestation of disease where many nonfunctional virus particles are created for whatever reason, which might explain both their relatively low frequency of severe disease and also might explain this finding. Additionally, the authors note that there was a similar frequency of symptomatic disease across all age groups in the study. While they portray this as a strength of the study’s findings, it raises an eyebrow for me. It is thought that kids have milder disease, so I would expect a lower proportion of children to have come up with symptoms if the population was representative of who is getting infected in the wider world. Instead, we see a similar symptomatic rate among children in this study to that seen in adults. This suggests to me that there could be some sampling bias here, with children being more likely to report for testing if actively sick. Perhaps only in sick babies do we see higher viral genome numbers.

That latter point would be interesting on its own—a symptomatic baby might be something to watch out for even more diligently—but the findings as described here would thus be harder to generalize.

The way to resolve these questions is to study this more deeply. I’d like to see actual virus recovered from different age groups, and the amounts of infectious virus compared. I’d like to see a patient sample prospectively created, and tested not when disease is suspected but instead at regular intervals. Those types of investigations could really definitively show the situation.

That said, I find this worrisome. Infants do not go around masked. In fact, having an infant myself right now, I’d never put a mask on her. There are too many problems that young babies can have with breathing, and of course she’d never really be able to keep it on. It’s not wise or practical. So the study leaves me wondering if infants are particularly dangerous SARS-CoV-2 spreaders; they’re unmasked and potentially carrying higher amounts of virus. I think we need to find out the answers here for certain.

5 million vaccinated children under 11, so far no cases of myocarditis

According to Dr. Eric Topol, 5 million children have now received at least one dose of the Pfizer vaccine and 1 million have gotten to their second dose. He is not aware of any reported cases of myocarditis (and neither am I):

Eric Topol @EricTopol

About 5 million children age 5-11 now vaccinated with their first dose (nearly ~1 million with 2nd dose) and I've yet to see a case of myocarditis reported 👍

I will admit to having been concerned about the possibility for this, in the past. The pediatric trial was, unsurprisingly, a little small. Pediatric trials are often smaller than adult trials for a variety of reasons. This gave me certain reservations about how it might ultimately play out when millions of children received the vaccine. Myocarditis was already a rare effect, seen largely in physically fit males under 30, and the pediatric dosage was reduced relative to the dosage with which myocarditis had been seen even rarely. I didn’t have reason to expect it would occur more frequently in the younger set, but I also could not be sure it would be rarer than in the 12-30 year old group.

Now I see that it is clearly rarer than in that group—and it was already pretty rare there. This was my last real reservation about school mandates. I want to give things a little bit longer before saying I think that schools should mandate this vaccine (I’d like to get 6 weeks out from the earliest substantial batch of second doses), but I’m starting to get a lot more comfortable with saying it should go that direction. The numbers are coming in, and the pediatric formulation so far looks to have a great safety profile in 5-11 year old kids.

An extended vaccine schedule would probably have been better

This is a moment where I have to admit that I was wrong about something. Earlier on in the pandemic, there were people advocating for an extended vaccination schedule for the mRNA vaccines. Instead of putting a maximum of 1 month between doses, these folks suggested that the single-dose protection numbers were good enough that we could let people ride on 1 dose for a few months, and then give the second dose about 3 months later when it might be even more immunogenic than after 3-4 weeks.

Some countries advocated doing this without a clinical trial. Some even did do it without a clinical trial. I personally think this was ethically wrong, and I continue to think that. I don’t think any untested medical regimen should be made into official public health policy, not without clinical trial evidence or overwhelming real-world evidence.

However, there were people (such as Zeynep Tufecki and Michael Mina), who advocated simply that a clinical trial of the extended regimen should be performed. They and I disagreed on the strength of the data about a single dose over 3 months, however, their suggested approach of a clinical trial was the correct way to resolve that disagreement. Unfortunately, their advocacy was largely shut down by people calling the shots for the study of vaccines, a situation which continues to disappoint me.

In retrospect, it is now obvious that they were correct, because we have data from people who got the vaccine on an extended schedule. For example, Dr. Topol also shared this recently:

Eric Topol @EricTopol

Adding to a strong body of evidence that longer spacing (16 vs 4 weeks) substantially improves the immune response to mRNA vaccine. And Prior Covid benefit from 1 shot. cell.com/action/showPdf… @cellhostmicrobe

This paper has a small number of patients in it, but even at that small number it is clear that there are higher levels of antibodies, higher rates of successful antibody generation, better affinity of the generated antibodies for SARS-CoV-2 spike, and better neutralizing antibody titers in patients with a longer-interval vaccination than in patients with a short-interval vaccination. I am convinced that I was wrong to think waiting longer would have been bad. We would have vaccinated more people more quickly with at least one dose, and we would have probably generated immunity that is both more durable and less susceptible to escape by virus evolution.

I’m saying this all with hindsight, of course. I still think the ethical course of action would have been to conduct a clinical trial on this question as early as it was first proposed. But we cannot go back. We have evidence and it does appear this schedule was correct.

For those of us who got the vaccine on the original schedule, I (speculatively) think that the provision of booster doses 6 months later will probably plug this hole. If we consider that the first two doses were perhaps too close together, then we can approximately think of them as one long first dose, and the 6-month booster as a nice second dose. The boosted patient, then, is likely to have a nice response.

For new vaccinees going forward, I think it would be worthwhile for the evidence that exists to be collected and reviewed by the FDA, EMA, and the various Vaccine Technology Committees in various countries using the mRNA vaccines. In the US that would be the CDC’s American Committee on Immunization Practices (ACIP). These committees and regulatory bodies have the authority needed to change the approved schedules on the strength of available evidence. Since this schedule does appear to be superior, I think authorities ought to acknowledge that.

Perhaps those authorities will still want a clinical trial. Since we now know a lot more about what a vaccine-protected person’s immune response looks like, these trials could be done a bit quicker than they might have been done otherwise. Companies could study the pull-back of immune responses to dose 1 in a randomized setting, then three months later dose with a booster, and examine the boost effect on antibodies. This could be related back to the antibody levels that we know to be protective in patients who got the shorter schedule. They could also be followed serologically for durability of that response. The whole thing could be done in 3-5 months, dependent on enrollment.

At any rate, I think altering the schedule for new vaccinees would be good at this point, particularly for countries and populations where vaccine uptake and/or availability are still low.

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

Celebrating a dear friend’s birthday

This past Friday was the birthday of one of my closest friends—also a reader—and I went to a birthday party for him, which was largely an outdoor event. You know who you are. Happy birthday.

There were a lot of comments on the immediate past issue, so I can’t include them all here today. But they led to interesting conversations and I encourage you to go back and read.

I do want to highlight one that I think has wider appeal, since I see this question from time to time elsewhere. Reader Joel Blatt wrote:

Isn't it likely that, as time goes on, that the most successful mutations will result in a virus that is more transmissible, but causes milder (non-fatal) illness? If I remember my evolutionary theory correctly, this combination would result in the most favorable set of characteristics for any parasitic entity (i.e., "don't kill the host").

I wish it were so, Joel. Unfortunately this is based on a simplistic, one-size-fits-all model of what a pathogenic virus is, and this doesn’t neatly fit every viral pathogen. As I explain in my (lengthy) reply:

This is a good question. It is true that in many cases there is a push-pull between virulence and transmissibility. This is particularly true when the contagious period for the virus overlaps with the symptomatic period. If the virus incapacitates its hosts during its period of peak transmissibility, it is going to have a fitness issue.
However, once the virus has transmitted effectively and passed its peak of transmissibility, it really doesn't matter whether it causes some horrible disease, at least not in an evolutionary sense. As an example, HIV has a 99% case-fatality rate when untreated, but it takes literal years to get to that lethal point. There is very little selective pressure on the virus related to that lethality, because it can effectively and successfully spread itself to new hosts without worrying about its current host's ultimate survival. Here, the pressures on transmission and propagation are separated from the pressures on virulence factors.
For SARS-CoV-2, peak transmissibility can occur before symptoms ever appear. At first detection, most eventually severe cases appear relatively mild. Look, for example, at the case of Donald Trump, who was likely the index patient for an outbreak that began in the White House's Rose Garden. By all reports, President Trump basically felt like he had a mild cold going into this event. He tested positive shortly after the ceremony in the Rose Garden, and from that event, 52 additional cases of COVID-19 were generated. That event was on September 26th, so likely between 4 and 7 days after Trump became infected.
He was hospitalized for COVID-19 on October 1st of 2020. By then, the damage was largely done in terms of passing on the virus, and from what we know about the kinetics of such infections, he was probably well past peak transmissibility by that time as well. At that point, the virus he was infected with seems to have been fantastically successful, even compared its fellow relatives in the SARS-CoV-2 strain. 53 is a huge number of cases in a single cluster. If it had killed President Trump after October 1st, this would not have had an impact on its overall evolutionary success.
SARS-CoV-2 has a number of pathogenesis factors, but many of them rely on virus-host interactions and the production of inflammatory signals by the host in order to bring about tissue damage. A lot of the treatments that are used in hospitals for COVID-19 focus on lessening host inflammatory responses, rather than on doing anything to the virus itself. My point in this is that in your severe and potentially fatal cases, the immune system has generally responded, and that response usually takes place after peak transmissibility. It's hard to see what fitness a virus could achieve if it acquired a mutation that reduced these pathogenic effects.
We know that asymptomatic and presymptomatic patients can make a big contribution to the transmission of SARS-CoV-2, also. There are plenty of these patients; the presymptomatic population may substantially overlap with the ~7% who are hospitalized and the ~1% who die.
So overall my point is that a lot of the transmission of this virus is happening well before peak symptoms, and evolutionary pressures are all about transmission. Fit viruses survive to replicate and transmit; unfit viruses do not survive to replicate and transmit. If the virus can do those activities before killing its hosts, then evolution will exert little pressure on whether it kills those hosts or not in the end.
This isn't true for every virus. Some viruses only transmit when the host is symptomatic. Those viruses will probably (but not always) be under evolutionary pressure favoring a reduction in pathogenicity, because the less debilitated the host is, the more likely the virus is to spread. Unfortunately, SARS-CoV-2 isn't a virus of that type.
This doesn't mean all hope is lost for gradual reduction in virulence, but it does mean we have no reason to assume there should be such a reduction. It is possible that there is an overlap between sequence that supports pathogenicity factors and sequence that supports transmission, and that changes to enhance one will compromise the other. If that's the case, then the virus could very well have this kind of trend. But I know of no evidence of such a thing, so I can't assume that it will happen this way.
At the present time, the evidence I have available tells me that the capacity of SARS-CoV-2 to cause disease, and its capacity to infect, survive, replicate, and transmit are not directly linked. So I don't expect it to become less virulent as a result of evolutionary pressure.

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.

Viral Transmissions

Discussion about this post