The Causative Agent, vol 9
Special edition: The Food and Drug Administration approved an Emergency Use Authorization for an Omicron-specific booster shot.... without human clinical trials. And I have questions.
Today, August 31, the FDA approved Emergency Use Authorizations for both Pfizer and Moderna to release their updated Omicron-specific booster vaccines. Neither of these vaccines has yet to be tested on people. Here are the details:
What is in the updated vaccines?
The original vaccines are MONOVALENT (meaning they only protect against one type of COVID-19 virus). They were: Comirnaty (an mRNA vaccine by Pfizer, given FDA approval in August 2021); Spikevax (an mRNA vaccine by Moderna, given FDA approval in January of 2022); and Jcovden (a vector vaccine by Johnson and Johnson, given EUA on February of 2021, it has not received full FDA approval).
The updated vaccines are BIVALENT (meaning they protect against two different viruses). Both Pfizer and Moderna are very similar and their updated vaccines contain the original mRNA from the monovalent vaccine plus a new mRNA from an Omicron variant, BA.4/5.
So, these weren’t tested in people?
Not exactly. In June, both Pfizer and Moderna presented data to the FDA about a different bivalent vaccine: one containing the original vaccine’s mRNA plus an Omicron variant BA.1 (going forward, I’ll call this one “Bivalent BA.1”). These were tested in both mice and humans. However by June, Omicron BA.1 had pretty much disappeared from circulation and had been replaced by new Omicron variants: BA.4 and BA.5 (both of which are actually pretty similar). They tested the Bivalent BA.1 vaccine against the new variants, but found that it didn’t protect against BA.4/5 as well as it did against BA.1 (no surprise there). The FDA did not grant approval for this Bivalent BA.1 vaccine and wanted to hold off for a more relevent “Bivalent BA.4/5” vaccine. Pfizer and Moderna got to work on that update, and that’s what we have now. They basically just swapped out the BA.1 mRNA, and replaced it with mRNA from the BA.4/5 variant.
This new vaccine, Bivalent BA.4/5, has been tested in a small number of mice, but has not directly been tested in humans.
So, how did the Bivalent BA.1 vaccine do in humans?
Pretty good. The safety data was fine… it had similar side effects to Comirnaty and Spikevax. The Bivalent BA.1 vaccine from Pfizer gives you 1.56 times more antibodies to Omicron BA.1 variant when used as the 4th dose (after 3 previous Comirnaty vaccines) than if you just get 4 doses of Comirnaty. So, yeah. You get more Omicron-specific antibodies with the Bivalent vaccine versus the monovalent vaccine, but its not extraordinary.
With Moderna, it was very similar. Similar rates of side effects to the monovalent Spikevax and their bivalent BA.1 booster gave you 1.75 times more antibodies to Omicron BA.1 than if you used Spikevax as a booster.
But still, the Omicron BA.1 variant doesn’t really exist anymore so all of this is kind of moot. Unfortunately, when they tested these bivalent BA.1 boosters against the new Omicron BA.4/5 variants, they didn’t perform as well.
How did the Bivalent BA.4/5 vaccine do in mice?
Surprisingly well. These data are very preliminary and they have only released a study on 8 mice, so we’re not talking huge amounts of data here. The Bivalent BA.4/5 vaccine gave mice 2.6 times more neutralizing antibodies to the Omicron BA.4/5 variant than the original monovalent vaccine. Also, the mice antibodies were able to neutralize a whole list of variants about equally well: The original 2019 variant, BA.1, BA.2, BA.2.1 and BA.4/5.
Here’s the catch though. Mice are mice, and people are people. Studies in mice can give us useful information but they are not always 100% predictive of what will happen in a human body. It’s very possible that the Bivalent BA.4/5 vaccine will not work this well in humans (I guess its also possible that it will work better in humans than it did in mice…)
Has any vaccine ever been FDA approved without being tested on humans?
Yes, but I’m not sure it directly applies here. There are two different kinds of flu vaccines: inactivated (shot in the arm) and live attenuated (spray up the nose). Companies that bring a new flu vaccine to market have to get FDA approval (after extensive animal and human testing, clinical trials, factory inspections, etc). However, the flu vaccine needs to be updated each year with the new circulating strains. Companies that make the inactivated flu shot do not need to submit new clinical trial data each year (although there is still quality control testing for purity) when they make the seasonal updates. Companies that make the live nasal spray do need to complete abbreviated human trials of several hundred people each year to make sure the updates are safe (the live vaccine has more risks than the inactivated).
So, in a way, this is following the same process that the seasonal flu shot gets updated every year. They use the same approved factories, procedures and ingredients, they just swap out the old virus for the new. I think, though, this might be comparing apples to oranges. Or maybe, comparing Granny Smiths to Red Delicious. Deliciouses?
The flu shot platforms have been around for decades and are well established. Comirnaty and Spikevax have been FDA approved for only a year, so I’m not sure we can really treat it like the flu shot. Another isssue is that for flu, last year’s vaccine will not work against this year’s flu strains… so we really have no other choice but to make new vaccines each year. And a rapid rollout system is needed to make sure that happens in time for flu season. But with COVID, we already have boosters that work against Omicron. Sure, the Bivalent BA.1 (and maybe the BA.4/5) give you a little extra, but the old Comirnaty and Spikevax boosters give you decent protection against Omicron too (see image below). So, again, not directly comparable to the flu situation in that we do have other options here.
What problems do you predict?
Firstly, I do not think that the bivalent vaccines are unsafe. There is no scientific reason to think that this small addition will change the safety profile of this vaccine. Plus, a Bivalent BA.1 vaccine was proven to be safe in human studies, so that’s a good indicator that a Bivalent BA.4/5 vaccine might be safe too. But, I follow the data. And right now there is no data in humans on Bivalent BA.4/5…. So we cannot say for sure until it starts going into someone’s arm.
The biggest problem I predict is this: We have no idea how effective this Bivalent vaccine is. Mouse studies show the 2.6 fold increase in antibody production, but there’s no telling if that will hold true in humans. I worry that this vaccine will get rolled out, hyped up as a sure-fire protection against Omicron, and then be underwhelming. People are already getting fed up with vaccines and boosters as it is. Another disappointment might be really demoralizing.
Also, a lot of people are already really distrustful of the COVID vaccines. Rolling out yet another COVID vaccine, this time with no human trials, does not ease anyones fears. I’m afraid that people are really going to start with the “too fast” “not enough data” arguments, and this time, they’ll actually have a point. Truly, there is a line between getting a product out fast and getting it out confidently. I’m not sure we are on the right side of that line here.
What do the experts say?
There are people on both sides here. Many experts, including those on the Vaccines And Related Biological Products Advisory Committee (the VRBPAC advises the FDA on what to do about vaccines), think that this is a good approach to getting updated COVID vaccines to market safely and on time. They think that if we do clinical trials, then by the time the data come in, that variant will be long gone and the vaccine would already be out-of-date before its even approved (pretty much what happened to Bivalent BA.1). Other experts, like Dr. Paul Offit, are taking a more conservative approach. Offit, who is one of the nation’s leading vaccinologists and one of the two VRBPAC members who voted ‘no’ on this vaccine, thinks that we should wait until we have at least some clinical trial data. We could do a small abbreviated trial, like the ones they do on the live flu vaccine, and data analysis might only take a few extra weeks. It would go a long way to gaining the public’s trust.
Dr. Offit says about the Bivalent vaccines: “If you have some evidence that this is likely to be of value, sure. But if you don’t have evidence, and you know that the current vaccine does offer protection against severe disease, I don’t think it’s fair to ask people to take risks.”
Can I still get the old vaccine as a booster instead of the Bivalent?
Um. I found this language in today’s Pfizer’s press release “With today’s authorization, the monovalent mRNA COVID-19 vaccines are not authorized as booster doses for individuals 12 years of age and older.”
It looks like they are going to pull Comirnaty and Spikevax and no longer give them as boosters. You can still get them as a primary series (your first two shots) but if you want to get a third or fourth booster, it seems as if you are stuck with the Bivalent BA.4/5. I can’t imagine that they have shipped all these new vaccines yet, so maybe for a short time you could still get the old vaccines as a booster, but for how long, I have no idea.
For kids under 12 (or under 18 for Moderna’s vaccines) you can still get the monovalent boosters since they are doing separate approvals for the children’s Bivalent BA.4/5 booster. That will be coming soon.
Remember that this announcement today was an Emergency Use Authorization, not full FDA approval. Full FDA approval will not be given until the human clinical trial data has been submitted (those trials are about to begin). This creates a conundrum for vaccine mandates (schools, federal agencies, etc). Usually you cannot mandate a vaccine unless its been FDA approved, so it will be interesting to see how that all shakes out.
Pfizer-BioNTech COVID-19 Omicron Modified Vaccine Options
mRNA1273.214 Moderna COVID-19 Investigational Bivalent Vaccine (Original+Omicron)
Faust Files: Paul Offit on His Vote Against Bivalent COVID Boosters
Latest COVID Boosters are Set to Roll Out Before Human Testing is Completed
COVID-19 Vaccine Effectiveness Against the Omicron (B.1.1.529) Variant