The vaccines for SARS-CoV-2/COVID-19 weren’t rushed

The short version: Even though the vaccines for SARS-CoV-2/COVID-19 were made at an unbelievably fast rate, we have no basis to believe that there were corners cut from the perspective of the science or the efficacy. The cutting of the time in research and development is the result of two things: the existence of an extensive body of research that indicated which strategies for a vaccine and targets were viable and inviable (as well as considerations for which kinds of vaccines could be made rapidly, given the pandemic), financial limitations that are normally present for pharmaceutical research were not applicable, there was an enormous pool of willing subjects for the vaccines, and there was extensive streamlining of the regulatory process on the part of the FDA. If these vaccine candidates make it through EUA and then licensure, we should have every reason to believe that these are safe and effective vaccines and should not be worried about getting them.

The timeline of approval for some vaccines in routine use. Plotkin SA, Orenstein W, Offit DPA, Edwards KM. 2017. Plotkin’s Vaccines. 7th ed. Elsevier Table 4.3

I’m seeing a lot of people very concerned about the pace at which the vaccines for COVID-19 have been produced, which I get. We were told it could take years, we were told vaccines normally take decades of research and development to work out all the kinks and make it to licensure, and now in less than a year, it looks as though we will have effective vaccines being distributed in the US and licensed some time thereafter. Even the mumps vaccine, in an era with far more lax regulations, took 4 years to make. Surely some chicanery is afoot? This could not have been done without cutting some corners! And my answer to that is: Yes, but actually no.

Yes, the vaccines were expedited, in that it was made a huge priority to get out an effective vaccine as quickly as possible and every reasonable step was taken to make that happen. But no, this does not in any way mean that corners were cut in the process of getting us there.

Let’s talk about the process of making a vaccine and why it takes so long. Also the WHO has a really nice document on the subject if you want a detailed look.

At this point most people have at least heard of the phases of the clinical trial process, but they are worth going over. Under normal, non-pandemic circumstances it goes something like this:

It’s also worth noting that vaccines are treated with substantially MORE rigor than prescription drugs are as far as their clinical development goes. Because they are given to healthy people (often babies and young children in particular, and society places an especially high value on their life compared with other members) to prevent disease, the risk-benefit gradient margin of tolerability is much narrower than for therapeutics. In other words, vaccines are judged much more harshly in terms of how safe they are than prescription medications are because vaccines are given to healthy people with the promise of preventing a disease, as opposed to sick people with the hopes of treating their disease.

So, given how things are in normal times, how can I claim that corners have not been cut in the production of COVID-19 vaccines when it’s taken less than a year? Simple.

One thing that doesn’t get discussed enough is how risky vaccine development is, in the financial sense. It is extraordinarily costly, easily billions of dollars, for a vaccine to be taken from the preclinical setting to be put into effect in a vaccination program. More than that, only 1 in 15 vaccines that pass Phase II clinical trials actually make it to licensure. There are a few reasons for that (I have a post that explains in greater depth why it’s hard to make an effective vaccine here):

This was circumvented by the infusion of cash into vaccine manufacturers’ endeavors to produce a COVID-19 vaccine. The manufacturers had already begun producing vaccine before they knew it worked (at risk) because it was not THEIR money that was to be lost should the vaccine fail to meet its endpoints (note that some vaccine manufacturers did not accept money from the US government for this endeavor e.g. Pfizer). This Viewpoint in JAMA summarizes the role of Operation Warp Speed (still an utterly horrific name). It’s notable however that production of a vaccine will always occur at-risk because it usually begins while under review for BLA approval, and purchase agreements are put in place to protect the assets in the event that the BLA is rejected.

However, resources other than money played a role here. For this part, I am going to quote my friend Andrea Bailey (her qualifications to comment on this are stated at the end of the article):

It can take a considerable amount of planning to run a single small-scale clinical trial. There are a number of critical and time-consuming processes involved to set up a trial. This includes scheduling biolot production (and associated quality control), signing agreements and contracts, obtaining import/export permits to ship unlicensed product across borders, protocol development, agency approval, CRO scheduling, etc. A simple small-scale study can take months to arrange. Much of this time has been cut by prioritizing staff and resources

Basically every single project that needed the FDA’s attention was put on the back burner as everything to do with a vaccine for COVID-19 was pushed immediately to the front of the line. On top of this, the FDA allowed for seamless trials, meaning that if a vaccine met its phase I or II endpoints, it was permitted to immediately proceed to phase III, rather than deal with the regulatory rigamarole and paperwork required for normal progression.

There’s also another more subtle factor directly relating to the pandemic that allowed for expedited research and development. Normally, the regulatory process would require in-person meetings which can only occur if everyone can be present at a given time, and that’s tough with how busy these people are. The pandemic meant that people did not physically have to be in the same place for this: it could be done virtually. Furthermore, it can be very difficult to assemble a subject pool for these vaccine trials, but the exigency of the situation created circumstances in which there were a huge number of volunteers willing to

Earlier I said that phase II trials tend to be fairly redundant with Phase I trials. Phase II examines the vaccine for safety in a larger group but formally, it’s not adding new information, per se, beyond that the vaccine is safe in that larger group (you would get to see some of the rarer side effects but even then the sample size here doesn’t allow you to see the very rare ones), and thus more likely to be safe in the general population. The point is to increase the confidence of the vaccine manufacturer in the product so that they are willing to spend the millions of dollars on the production and approval. As Professor Paul Offit (an inventor of the rotavirus vaccine and member of VRBPAC, a regulatory agency associated with the FDA that will also evaluate the data of the vaccine candidates that are seeking licensure) stated in an interview about the subject:

As you move forward with these kinds of trials, you go from phase I to phase II to phase III, you just try to reduce uncertainty. That’s the goal. How much uncertainty do you need to reduce? Do we need to wait, for example, to see what the 1-year follow-up is, knowing that during that time hundreds of thousands of people may die? Should we wait 2 years, which William Haseltine, PhD, actually reasons: Why don’t we wait 2 years and get all the data as we would do for a typical vaccine? The answer is because with the rotavirus trials, 60 children died per year [as opposed to the 225,000 Americans who had died at the time of the interview from COVID-19]; that’s a little different from this.

Basically, from the perspective of the science and only the science, you could plug a vaccine into phase I and go straight to phase III after determining it isn’t acutely toxic. Or you could even go directly to a large Phase III trial (assuming you could recruit people for it).

Many pharmaceutical companies did a combined Phase 1 and 2 study e.g. Sanofi and GSK, which is an excellent compromise to accelerate production.

Another critical point that is worth mentioning is that the preclinical work of identifying leads for a vaccine normally takes a huge amount of time. This time it didn’t. Why? We knew from the past what strategies were likely to work with a vaccine against a coronavirus, what risks were probable, and what targets should be included in the vaccine. For instance, we knew that the spike protein was probably the best target for a vaccine (I imagine anyone who has taken a first course in immunology could have told you that), but we also knew from research on MERS-CoV that a double proline substitution locks the spike protein in a prefusion conformation. What this means is that the antigen that the immune system is intended to target, the pre-fusion form of the spike protein, is exposed for much longer, and indeed, this double proline substitution is used in the design of every vaccine candidate I could find data on.

It’s also worth noting that not all vaccine platforms are going to be suitable to respond to a pandemic. The platforms have to be rapidly scalable to meet production demands for example, and it was known in advance what type of vaccines would be effective for this and what kind weren’t practical. For example, setting aside the risks of a live attenuated vaccine for a coronavirus for a moment, it takes a long time to generate an attenuated strain. On the other hand in vitro transcribed RNA can be generated extremely quickly. There was some regulatory expediting at this stage too. Andrea told me:

To further expedite the development process the FDA allowed manufacturers to cross-reference to past BLAs for data that also supported their COVID vaccine development. For example, the manufacturer was permitted to cross-reference (by linking to the specific documents on file with the FDA) submitted safety data or proof of concept data to the FDA for another vaccine that used a similar platform, or any pre-developement data on new vaccine platforms that the agency had already reviewed. This means that they could avoid repeating studies that had already been conducted and reviewed.

So yes, the vaccines were rushed in that they are getting here much faster than anyone anticipated and via a different path, but there weren’t corners cut from the perspective of the science nor the safety. In fact, in the trial protocols for the phase 3 trials of the candidates currently in them, patients are being followed for 2 years after the receipt of the vaccine to confirm long-term safety (though I should point out this really isn’t the the risk people are making it).

So, we will have COVID-19 vaccines in record time, and we have every reason to believe that they will be effective (though for how long isn’t entirely clear yet) and safe.

I’d also like to include this short clip from the Oxford Vaccine Group:

Acknowledgements

I would like to credit and extend my sincerest gratitude to my dear friend, Andrea Bailey PhD, Senior Regulatory Affairs Specialist, for her thorough vetting of the content of this blog post for accuracy, and insightful suggestions for how to improve it. It would not have been possible without her.

I also need to thank Magdalen Rose Wind-Mozley for her immeasurably valuable insights on this process outside of the US context and valuable edits. The US accounts for < 5% of the world’s population, but this is a vaccine that everyone needs, which means it’s important that confidence be high across the entire world.

References

--

--

Get the Medium app

A button that says 'Download on the App Store', and if clicked it will lead you to the iOS App store
A button that says 'Get it on, Google Play', and if clicked it will lead you to the Google Play store
Edward Nirenberg

I write about vaccines here. You can find me on Twitter @enirenberg and at deplatformdisease.com (where I publish the same content without a paywall)