Two vaccines, two viruses, two different problems

COVID-19 and monkeypox require different strategies

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

On August 19th (today) in 1991, hardline communist elements in the USSR government tried to oust Mikhail Gorbachev. Their attempt failed in the long run, ending by the 23rd of August. This event precipitated the eventual total dissolution of the USSR by December of 1991. What followed included an international effort to make sure that Soviet weapons of mass destruction were accounted for. As part of this, Soviet sources divulged that their government had stockpiled, secretly, hundreds of tons of dried variola virus, which causes smallpox, as part of an illegal bioweapons program. Those stockpiles were subsequently destroyed, but their existence is relevant to one of our topics for today.

We’ll discuss, today, the ongoing vaccination campaigns against monkeypox and COVID-19, which involve different challenges that relate to the nature of these two diseases and the vaccines against them.

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As a reminder, links that look like this go to the glossary I maintain for this newsletter.

Now, let’s talk viruses.

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COVID-19: The era of Omicron-specific vaccines begins

I’d like to get the shorter of our two stories out of the way first. For quite some time, global vaccine makers have been interested in updating their COVID-19 vaccines to account for drifting in the sequence of virus proteins. We do this every year with influenza vaccines, and for COVID-19 vaccines it makes some amount of sense—depending on the goals of your vaccination program.

Something that I have long maintained is that what the press frequently referred to as vaccine “waning” was a combination of a small amount of actual immune waning plus something else that was going unappreciated; the escape of the virus from immune pressure through mutation. Since the rise of the Omicron variant, however, it seems that popular media have started to appreciate that the virus has changed substantially and the original COVID-19 vaccines are not optimized to target what is currently circulating.

There have been efforts, therefore, to make new vaccines that include sequences of more current SARS-CoV-2, such as the BA.4 and BA.5 Omicron sublineages. These have been endorsed, back in June, by the FDA, but not yet approved to come to the US market (that is expected in the fall of 2022): https://www.fiercepharma.com/pharma/fda-recommends-updated-vaccine-boosters-include-omicron-variants-manufactures-say-they-could

What brings this topic up for me now is that Moderna’s updated vaccine booster was just approved in the UK, a first-of-its-kind approval: https://www.reuters.com/world/uk/variant-adapted-covid-vaccine-wins-first-approval-britain-2022-08-15/

That approval is for a “bivalent” booster vaccination in adults, so the scope is somewhat limited for the time being. Bivalent means that it targets both the Omicron lineage as well as the original SARS-CoV-2 virus. Multivalent vaccines are very common—the seasonal influenza vaccine typically targets 4 different virus variants, and is thus “quadrivalent.”¹ At any rate, I am excited about the prospects of these updated vaccines and am eager to learn more about how well they work--I am convinced they are no worse than the existing vaccine, but unsure how much better they might be.

This does not mean, however, that the COVID-19 vaccines that we have right now are “bad.” We need to get away from this kind of dichotomous attitude. The existing COVID-19 vaccines work well to keep people out of the hospital the large majority of the time, especially if individuals stay “up to date” with their schedule of boosters.² They prevent deaths and to some extent they prevent the onset of long COVID. Their effectiveness against the spread of COVID-19, however, leaves something to be desired compared to the pre-Omicron days. At best, there is about a 20% protective effect against transmission.

It’s great to be able to prevent severe disease, and a lot of the progress that has been made against the COVID-19 pandemic is because of the vaccines that we have now. But, it has been speculated that a more specific vaccine would yield improvements in all measurements of vaccine effectiveness, and I have to agree that this possibility is enticing.

There are those who disagree, and feel that the entire point of vaccination was to prevent severe disease, and since we can do that, they do not think it is important to update the vaccines right now. Individuals in this camp include some very respected vaccinologists—but certainly not all vaccinologists—and I think it is important to present their viewpoint respectfully. I also happen to disagree with it.

I think it’s important to recognize that there are times when a purely scientific approach to health is actually harmful. We saw this in the early days of the COVID-19 pandemic, when conventional wisdom based on existing data from other viruses drove reliable authorities to recommend against good practices like masking, or to deny the possibility that asymptomatic infected individuals could spread COVID-19. These errors were direct contributors to the rapid global spread of the virus, in my opinion.

In the case of these multivalent COVID-19 vaccine boosters, I think their detractors argue that we have only information on neutralizing antibodies to guide us about their effects. We do not know how much impact they really have on outcomes in the real world, and so, it is argued, it is premature to approve them when the vaccine already improves outcomes.

I find this short-sighted. To wait for outcomes data to become apparent means waiting for deaths and hospitalizations to take place. From the data that I have seen, the updated vaccine is at least as good as the original version in terms of every measurement we can make. I believe it generates an immune response that is at least equivalent, if not possibly better.

In light of that, I think we have very little to lose by deploying this updated booster in lieu of the out-dated older booster vaccination. In fact I think we might have more to lose by not doing it, frankly. It is no longer 2020 and we are not entirely naive about COVID-19 vaccinology. We know what a good immune response to a COVID-19 vaccine looks like, and I think it is fair to say that we can expect this new type of booster to give us at least the same amount of protection that we had before, if not more. It could also possibly restore protections against transmission.

We don’t know precisely yet, and I don’t wish to pretend that we do. But I think that waiting to know for certain puts more people at risk, without preventing any greater harm that I am aware of. It seems that 19 of the 21 advisors to the FDA on this matter agreed with me on this, back in June. But I won’t pretend the sentiment is unanimous.

MPXV: Jynneos and ACAM2000

I’ve written before about the availability of two vaccines for monkeypox virus (MPXV). As it happens, both of these are really orthopoxvirus vaccines, meaning they are not specific to MPXV so much as the wider genus that includes MPXV, variola virus (which causes smallpox), vaccinia virus (which is what we use to make vaccines against this genus), and camelpox, among others. With monkeypox becoming an increasingly concerning public health emergency, we need to revisit these vaccines.

ACAM2000 is an older-technology vaccine, but we do have supplies of it. Why? Well, there’s a lot of concern about the use of variola virus as a bioweapon. So many countries have kept stockpiles of vaccines like ACAM2000—but usually just enough to protect the victims of a terror attack or the members of their military. Before 2022, the main thought for application of this stockpile was biodefense, not monkeypox prevention.

ACAM2000 is a vaccinia virus-based vaccine, and it is actually a “second generation” orthopoxvirus vaccine. It was licensed in 2007—many decades after smallpox was eradicated—because, again, there are biodefense applications. I think we have gotten very lucky here in that regard—but I must caution that our data with ACAM2000 are limited in the monkeypox context, something that complicates the argument for its use.

Also, ACAM2000 is pretty unpleasant to receive. It contains replication-competent vaccinia virus, and must be delivered to the skin via a bifurcated needle. After it is scratched into the skin, it causes a lesion and that lesion can shed virus for some days after vaccination. That can endanger people who are immunocompromised who encounter the vaccinee, so it is not really an ideal way to vaccinate against orthopoxviruses. It can also cause myocarditis or pericarditis much more frequently than anyone would like—for 1 in every couple of hundred vaccinees. In light of this, the US government has instead been trying to favor the live attenuated Jynneos vaccine, from a company called Bavarian Nordic.

Image shows the packaging for Jynneos. Credit: Bavarian Nordic.

Jynneos is also based on vaccinia, but it is not replication competent—it uses an attenuated virus called “modified vaccinia Ankara,” or MVA. As designed, it is supposed to be an under-the-skin (subcutaneous) injection, into the layer of fat that is beneath the skin. It does not cause lesions and vaccinees do not shed virus.

Unfortunately, there is a lot less of the Jynneos vaccine around the world than of ACAM2000, and that situation is going to remain unchanged until at least the end of this year. So, what are we to do?

One option comes to us from a 2015 study, and you may have heard about this technique. It is being referred to as “dose-sparing,” but I prefer to call it what it is: intradermal administration of a smaller dose of the Jynneos vaccine. Intradermal means into the skin rather than beneath it. In the 2015 study of this technique, it was compared directly to subcutaneous injection and found to be noninferior to that route: https://www.sciencedirect.com/science/article/pii/S0264410X15008762?via%3Dihu

Why did they do this study? Well, it’s pretty simple:

The ID route may increase the number of available doses in an emergency situation.

Back in 2015, these vaccinologists were thinking that there could be a major orthopoxvirus outbreak and that we might need to stretch vaccine supplies, so they tested this approach for just that eventuality. I bet they weren’t thinking about monkeypox though! Even so, we are lucky that we have this history of people worrying about bioterror or accidents with bioweapons, because it’s helping us now.

This intradermal, dose-sparing approach is now being recommended in the US by the CDC and FDA to make our Jynneos supplies last longer—by using one-fifth doses for each vaccination, that lets us vaccinate five times as many people. However, Bavarian Nordic, the makers of Jynneos, have cautioned against this approach—on the argument primarily that data are limited. CIDRAP provides their full position here: https://www.cidrap.umn.edu/news-perspective/2022/08/fractional-monkeypox-vaccine-dosing-comes-under-scrutiny

This is one situation where I do think it’s worth getting more data, and I think CDC and FDA should try to work with Bavarian Nordic to get data in a bigger population. I would be OK with this being real-world data from field use, though, since we are in an emergency scenario. But, this isn’t the only option.

There is another option, though—we could be making ACAM2000 more widely available. There are also those who think this vaccine doesn’t have enough data to be used against monkeypox, such as Dr. Caitlin Rivers and Dr. Tom Inglesby: https://www.statnews.com/2022/08/11/acam2000-full-fda-review-before-widespread-use-against-monkeypox/

Both of these approaches—dose-sparing with Jynneos or expansion of the use of ACAM2000—come with potential risk-benefit issues. But they are responses to a severely limited supply of vaccines that we cannot quickly remedy. I do not think that I know enough at this time to choose between these options or to propose that both be used. Part of the reason is I don’t think we know the full extent of the severity of the monkeypox situation, even still. In this information vacuum, all I can say is that I’m glad we have these options, but I don’t know which I would bet on.

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Recently, my wife and I joined the American Museum of Natural History on a family membership! For $150 we can take ourselves and our daughter there whenever we like. Which is great, because we live only about a half mile away from it. On our last trip, we bought our daughter a baby outfit that looks like a NASA shuttle commander uniform. I don’t usually like to buy things on museum trips, but I couldn’t resist that.

Today’s discussion of the Jynneos and ACAM2000 vaccines, and the dose-sparing Jynneos strategy, was reader-requested. If you’re interested in hearing about something, let me know in the comments, and I’ll write about it.

As I’ve said throughout, I want to hear from you, too, with your questions about monkeypox, or COVID-19, or just updates about your lives. This newsletter is a community. Reach out!

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I have a commitment to accuracy, but I’m still human and I get things wrong. Sometimes, very wrong. If you catch an error, let me know—you can email me directly or leave a comment.

Thanks for reading today. It’s great to be writing to you again. Have a wonderful weekend!

Always,

JS

1. Sometimes—rarely for flu—”tetravalent” is used. No, I don’t know why some use the “quadri” prefix and some use the “tetra” prefix, but apparently one of my professors in grad school felt strongly about this, because when I referred to the influenza vaccine as tetravalent on an exam once, I got to see some red ink.

2. How many boosters you need, and when, is a conversation to have with your physician.