COVID Transmissions for 8-3-2020

Aug 03, 2020

Greetings from an undisclosed location in my hotel room.

It has been 260 days since the first documented human case of COVID-19.

Housekeeping note:

Today’s in-depth piece is part two of the series on protective responses to vaccines in development. Headlines section is short today but covers an important story.

Glossary terms are bolded words with links to the running newsletter glossary.

If you like what you see—or what you might see in the future—tell others about it so the newsletter continues to grow:

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Now, let’s talk COVID.

High levels of virus RNA recovered from children

A research letter published in JAMA reports that children, especially young children, may have levels of SARS-CoV-2 RNA that are equal to those seen in adults, if not substantially higher: https://jamanetwork.com/journals/jamapediatrics/fullarticle/2768952

The work suggests that children under the age of 5 years may have 100 times as much recoverable virus RNA in their upper respiratory tract as adults.

Apoorva Mandavilli reports on this here, providing useful context: https://www.chicagotribune.com/coronavirus/ct-nw-nyt-coronavirus-children-lurie-childrens-hospital-study-20200731-enq5fjcjxzbtvceqombbuekfka-story.html

Something to keep in mind is that this study is very small and that it did not measure infectious virus, but only RNA genome amounts. This means that children might not necessarily be able to transmit the virus very effectively. So far, epidemiological studies have suggested that young children do not transmit the virus as effectively as adults, but this study suggests there may be reason to question those findings.

If anything, this means there should be caution displayed in the rush to reopen schools, daycares, and other child-centric businesses.

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

Vacation

We’re up in Ithaca NY for a socially-distanced vacation of hiking, enjoying the area’s lakes, and also some of the local restaurants and breweries. It’s a different sort of vacation than I’m used to—I like to see foreign cities and enjoy the local culture, generally—but it’s a much-needed break from confinement in our tiny apartment.

The pandemic requires creativity, including in finding ways to relax. We’ll see how this goes.

Vaccines protect…monkeys, Part 2

Last time, we walked through a recent paper that established that the ChAdOx1-nCov-19 vaccine is protective in rhesus monkeys. This gives us additional confidence that the vaccine may be protective in humans as well, and would normally have been one of the first steps on the road to a vaccine—were the schedule not so accelerated due to the global emergency.

At the same time, the Moderna vaccine (called mRNA-1273) had a similar paper come out. Today, we’ll walk through that. You can find the paper here: https://www.nejm.org/doi/full/10.1056/NEJMoa2024671

The mRNA-1273 rhesus macaque study was published in The New England Journal of Medicine (NEJM), and looked at two doses of vaccine—10 micrograms and 100 micrograms. The study explored antibody and T-cell responses, and also measured levels of virus upon a postvaccination challenge with SARS-CoV-2. This design was similar to the ChAdOx1 study.

Unlike the ChAdOx1 study, the mRNA-1273 study did not look at different dosing schedules. All of the subjects received 2 doses of vaccine, separated by 4 weeks. Control animals received a saline vaccine rather than an irrelevant RNA preparation, something that I consider a small flaw in the experimental design. It would have been better to choose an mRNA that would still act essentially like the active vaccine, but that would produce an irrelevant protein. One example would be the protein that produces egg whites, which is commonly used as a control in mammal immunity experiments. Unfortunately, that wasn’t done here. Still, I think that might be OK, because two very different doses of the mRNA-1273 vaccine were used, and that might form a sufficient comparator in this case.

Similarly to the ChAdOx1 study, this work used a subsequent challenge with SARS-CoV-2 infection to test the efficacy of the vaccine.

Let’s walk through the results. First, the researchers established that vaccination produced antibodies—though I’m going to focus on neutralizing antibodies.

Image is a box-and-whisker plot showing the control (PBS, grey), the two vaccine conditions (10 micrograms, blue and 100 micrograms, red), and serum from recovering human patients (“Conv,” for convalescent, purple). The two vaccine conditions have much higher neutralizing antibody titers than both the control and convalescent serum conditions. Image from NEJM.

This is an important figure because it shows that the 100 microgram dose produces better neutralizing antibody levels than even convalescent serum from human patients, as does the other vaccine condition. But you can see here that clearly the 100 microgram condition is superior. This is important because this is the dose that is going forward for Phase 3 trials in humans.

Also, I didn’t walk through it, but the two-dose system induced increasing levels of antibodies with each dose, and that the average antibody levels with the 100 microgram dose were higher overall than for the 10 microgram dose, even over time rather than in the snapshot shown in that figure. Neither of these things are surprising, but both are reassuring. If this vaccine works, then this is what we would expect to see, so it’s good that we’re seeing it.

The next set of experiments focused on the T-cell response. This was very involved and detailed, but I will summarize rather than belaboring it:

Both vaccine conditions induced T-cell responses; the 100-microgram dose was substantially superior to the 10 microgram dose
Not only did they detect T-cell responses, they showed that they types of T-cells that were elicited are the type that are expected in the response to virus infections—this is very important because they will better defend in the face of infection
Memory T-cell responses were also detected, indicating that the vaccine may produce a durable immunity

This is all well and good, of course, but it doesn’t tell us if the monkeys in the experiments are protected from the virus. For that, we turn to the challenge phase of the study.

Image is a box-and-whisker plot, with a logarithmic scale, of genome copies recovered from lung fluid for animals in three vaccination conditions: control (PBS, grey), 10 microgram (blue), and 100 microgram (red). Readings are taken on Day 2, 4, and 7 after challenge with SARS-CoV-2. The control animals have detectable virus genome copies at high levels, ranging from thousands to over millions, on Day 2, and many still have high, detectable levels on Day 4. Only one animal still has detectable genomes on Day 7. In the two vaccine conditions, only one animal ever shows detectable genome levels. With 10 micrograms, one animal has a detectable level on Day 2 and Day 4. With 100 micrograms, only one animal has a detectable level on Day 2. After that, all animals in the vaccinated conditions are negative. Image from NEJM.

Here we are looking at bronchoalveolar lavage fluid, ie, stuff rinsed out of the animals’ lungs. By looking at genome copies, we get a sense of how much the virus may be replicating in these animals. We can see clearly that the level of viral genome recoverable from the vaccinated animals is overall much lower, and any detection is much less long-lasting altogether. The 100 microgram condition appears to offer the best protection.

They also looked at upper respiratory nasal swabs, and saw a similar pattern, but to me in the lungs is where the real protection can be detected. This is not a virus that kills people by replicating in the nasal passage; it does it by replicating in the lungs, so I find that the most compelling. However, the authors make the point that by studying nasal passages, they may be showing evidence that their vaccine also reduces transmission of virus—and maybe it does. However, since we don’t have a great understanding of transmission of this virus I think that’s conjecture, even if it is an educated conjecture.

Now we have to ask the last question—does the virus damage the lungs of vaccinated animals?

I won’t show the pathology slides because pathology images are very complicated to look at even with a somewhat trained eye. That said, the authors indicate that they found control animals had substantial evidence of lung inflammation and damage that were also associated with the appearance of virus antigens. The vaccinated animals’ pathology slides did not have these features, indicating a level of protection.

That’s great news too. Overall, this research demonstrates in a reasonable way that a robust immune response is elicited by the mRNA-1273 vaccine, and that this immune response is protective against challenge with the virus. If monkeys and men turn out to be similar in this regard, then we might be in very good shape indeed, with two promising vaccines on the horizon.

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

Also, I welcome any feedback on structure and content. I want this to be as useful as possible, and I can only make that happen with constructive comments.

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