COMMENTARY

The COVID Vaccine Derby: A Guide to the Top Contenders

F. Perry Wilson, MD, MSCE

Disclosures

September 16, 2020

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This transcript has been edited for clarity.

Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I'm Dr F. Perry Wilson from the Yale School of Medicine.

The vaccines are coming. That statement can be said with only a modest amount of uncertainty; with more than 200 vaccine candidates in the pipeline and seven in phase 3 trials, we are in good shape to have a vaccine to help us in the fight against COVID-19.

But when are they coming?

The CDC has asked localities to prepare for COVID-19 vaccination to begin by November 1. That's about 45 days away from now and just 2 days before election day. This despite the fact that we haven't even seen interim results from any of the ongoing trials.

Which led me to ask the question: If we are going to be vaccinating people before 2021, which vaccine will it be? So, without further ado, I am going to give you a whirlwind tour of the seven vaccines currently in phase 3 trials. If there's going to be a winner, here are the horses to bet on.

RNA Vaccines

Let's start with the shiny objects. Two companies, Pfizer and Moderna, are betting on something different — an RNA vaccine.

Vaccines work by teaching your body how to recognize the foreign invader, usually by introducing pieces of that invader in the form of viral proteins, inactivated virus, or attenuated virus.

But RNA vaccines are different. RNA is injected, your cells take it up, and they make the protein on their own. The vaccine is produced inside your body.

The pros of the RNA approach are clear: rapid scalability. You can make RNA by the vatload and you don't need complicated bioreactors to do it.

The downside of RNA vaccines? We don't know much about them yet. Preliminary data suggest good antibody responses — that's a plus, but what might the side effects be? Concerns about generating autoimmunity (after all, it's your cells producing those viral proteins) have been raised, but I haven't seen compelling data showing a high risk here.

So, RNA vaccines are the new, young horses in this race. They've got a lot of speed, but this is their first Kentucky Derby.


 

The Pfizer mRNA vaccine encodes the receptor binding domain of SARS-CoV-2, albeit with some modifications to make it a bit more immunogenic. You'll need two doses for this one. Pfizer's trial was supposed to recruit 30,000 people; they apparently hit that target last week. They have expanded to 44,000 people to increase diversity. The CEO says they'll have efficacy data in October, but safety data takes longer, and remember that you need both for approval (at least, if the U.S. Food and Drug Administration [FDA] works the way it's supposed to). ClinicalTrials.gov lists the study end date as April 2021.


 

The Moderna mRNA vaccine encodes the spike protein. Other than that, it's pretty darn similar to the Pfizer approach, with two doses being standard. Best I can tell, Moderna is somewhere past halfway through recruiting a 30,000-patient clinical trial.

Inactivated Vaccines

If RNA vaccines are the young bucks, inactivated virus vaccines are the older champions — a storied pedigree, but maybe not up to the current task, particularly because of the difficulty of manufacturing them on a truly global scale.


 

Two companies, Sinovac and Sinopharm, both from China, have inactivated virus vaccines in clinical trials.

The Sinovac trial is the lone phase 3 trial targeting a high-risk population: 8870 healthcare workers. Given the higher anticipated rate of COVID-19 in this crowd, that's a smart approach, letting them do a smaller study with adequate power, which might be a decent advantage. Data on recruitment are hard to come by, though.


 

The Sinopharm vaccine has already been approved for use by the Chinese military, and according to press reports has actually completed a 50,000-person clinical trial in the Middle East. If that's the case, great. But where are the data? It was like pulling teeth to find information on the Chinese vaccines, and I still don't even have a name for the Sinopharm vaccine. It is continually referred to as "an inactivated SARS-CoV-2 vaccine." More info, please.


 

Adenovirus Vector Vaccines

Maybe the happy medium here are the adenovirus vector vaccines.

You know adenovirus, of common cold and pink eye fame. Vector vaccines use an existing virus, modified to express a SARS-CoV-2 protein as a Trojan horse, to rev up the immune response. The pros of this approach? The vehicle is a live attenuated virus; it might engender a more robust immune response. But that is the con as well. If you have existing antibodies to the adenovirus in the vaccine, it may get broken down before the new protein gets a chance to generate its own antibody response.


 

We have three vector vaccines in phase 3 trials right now. CanSinoBio, another Chinese firm, is using adenovirus 5 vector to introduce spike protein. Adenovirus 5 is the workhorse of vector-based technology. But there's a problem: A lot of us have had it already. A 2004 study found that 37% of individuals in the United States have neutralizing antibodies to adenovirus 5.


 

AstraZeneca is using a chimpanzee adenovirus as their vector. That should help avoid the "already immune" problem. They were up to 20,000 of their 30,000-patient target for the trial when, as widely publicized, a case of transverse myelitis led the study to be halted. It has since been restarted. Is there a protein on that chimp adenovirus that could lead to cross-reactivity with some human protein? We'll see.


 

Finally, Gamaleya — the Russian team. They are using a combination of adenoviruses 5 and 26, but otherwise have a similar approach. Russia famously approved the use of this vaccine before the phase 3 study was completed. As of September 4, only 3000 of the target 40,000 individuals in their Phase 3 study have been recruited. And concerns about the data quality of their phase 1/2 study, published in the Lancet, may temper enthusiasm for this particular vaccine.


 

Running through these, there does not seem to be a clear winner. Preliminary data on antibody titers are pretty similar for all of these vaccines (assuming the data can be trusted, Russia).

But the pace of recruitment is encouraging.

The big question: A vaccine before the new year? Maybe. But we need to look out for a few things.

First, it's likely that the FDA will consider an emergency use authorization (EUA) for one or more of these agents. That's not necessarily bad; it doesn't necessarily mean that the government has put its thumb on the scale. The key is to know whether the Vaccines and Related Biological Products Advisory Committee, a group staffed by completely independent scientists, has vetted the data, and what the vote for approval was.

I'll say it now so it's out there before this happens: An EUA without the endorsement of the vaccine advisory committee is a huge red flag. An EUA with their approval may be the best way to get people vaccinated quickly.

But remember, vaccine approval is only step one. Our patients want to know when they will be able to get a vaccine. That is a much more complex question and depends more on logistics than scientific success. That is almost certainly in 2021.

And perhaps the biggest milestone of all: When will enough people be vaccinated so that we can get back to normal?

That depends not only on the logistical capacity to get the vaccines to those who need it, but to ensure that people take them. And that means clear, honest, transparent reporting. Put the results of these trials out in public. Be open about controversies and disagreements. Tell us what side effects we need to watch out for, and show us a clear path to keep track of unexpected events.

I've said it before, but the key to beating this pandemic is coming together around the science. We've missed that ball a few times already. This may be our last chance before we strike out.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and director of Yale's Program of Applied Translational Research. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @methodsmanmd and hosts a repository of his communication work at www.methodsman.com.

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