Last updated on September 9th, 2020 at 10:51 am
Donald Trump has recently pushed “Operation Warp Speed” that will speed the coronavirus vaccine race so that we can have a new COVID-19 vaccine by January 2021. This is could end up being a disaster.
This is like the hundredth article I’ve posted on coronavirus vaccines. I just joked with someone that if I wrote an article that conclusively established that aluminum adjuvants in vaccines actually cured cancer, erectile dysfunction, and the inability to hit an inside curveball, the first 30 comments posted at the end of that article would ask, “yeah that’s nice to know, old dinosaur. But does it cure COVID-19?”
Even Dr. Anthony Fauci, whose facial expressions in response to whatever lie that Donald Trump is saying during his daily coronavirus campaign events are meme-worthy, has also said that we might see a vaccine within 12-18 months. Now, Dr. Fauci is a billion times smarter than I ever will be about immunology, infectious diseases, and baseball, but I have numerous reservations about this aggressive timeline.
Maybe Dr. Fauci has some inside knowledge. Maybe he has seen some secret data only available only to him and Bill Gates. Maybe Trump has a gun pointed at him during these press briefings (really, campaign rallies).
I don’t know the real answer, but a lot of vaccine experts who have spent their lifetime studying vaccines are very skeptical of this aggressive timeline for a new COVID-19 vaccine. I consider myself a pharmaceutical development expert, and I am unconvinced that this coronavirus vaccine race can be done safely.
This is the normal timeline for vaccine development:
Month 0-24, Preclinical. This is the period of time where scientists attempt to determine if they can identify a part of the virus which stimulates the immune memory so that the immune system can quickly destroy the pathogen before it can do harm. They also need to isolate and culture a lot of viruses to be used in preclinical studies.
These steps will help scientists understand SARS-CoV-2 characteristics and pathophysiology in humans. Since it would be unethical to do these studies in actual humans, researchers need to develop an animal model that mimics a human. Also, researchers need to determine if the vaccine is safe and triggers an adaptive immune response in that animal model. For the SARS vaccine, ferrets were used, because their physiology and immune responses are similar to humans, so it might be used for a COVID-19 vaccine.
Month 24, IND application. The sponsoring organization (probably a Big Pharma company) must make an Investigational New Drug (IND) application to the FDA’s Center for Biologics Evaluation and Research (CBER) to begin clinical trials. CBER reviews the IND, which will include preclinical data, and the sponsor can proceed with the clinical trial within 30 days if the FDA does not find cause to stop it from moving forward. This is the process in the USA, but it’s much the same in most developed countries.
Month 24-60 (or more), clinical trials. Then the sponsoring organization must get Institutional Review Board (IRB) approval to proceed with clinical trials (see this article for more information about the process).
These clinical studies must go through three phases like all drugs, although the process could be shortened if the data is very clear and there is a public need (like the COVID-19 pandemic). The proposed clinical trials will be posted to a US government website that tracks all clinical trials worldwide (and must be posted there before a drug can get US FDA approval).
Phase 1 clinical trials usually include around 100 healthy patients (that is, they have no comorbidities and generally lack any chronic health conditions). This study is not randomized or blinded, as there is only one group, those that receive the vaccine. Phase 1 clinical trials rarely give any information about the safety and effectiveness of the vaccine – it really only tells the researchers if there are some significant safety signals.
Phase 2 clinical trials usually include around 200-300 patients. This study is a randomized, double-blind trial that is too small to observe small differences in effectiveness and safety. However, it helps researchers to determine if there is sufficient data to move forward.
Phase 3 clinical trials, sometimes called pivotal studies, include around 2-3 thousand patients. These studies must be randomized, double-blinded, placebo-controlled (or versus a standard of care control).
Phase 2 and 3 clinical trials are often published in peer-reviewed journals (unless they’ve failed to show anything, then the vaccine is shelved or reworked). Sometimes, the two phases are combined, but that’s rare.
Despite the really weird claims of the anti-vaccine crowd, phase 3 clinical trials are thorough and are statistically powerful. They truly allow us to know if a vaccine is safe and effective.
Month 60-78, regulatory review and approval. After all of the preclinical and clinical is completed, the sponsoring organization must make a Biologics License Application (BLA) to CBER. Although this process is what is done in the USA, it’s similar in most other countries (and some countries accept FDA review for their own country.
At the same time, a manufacturing plan has to be developed. People seem to think that a vaccine is simple to manufacture, but it really isn’t. There might be some excess capacity to make 200 million coronavirus vaccines across the world, but that’s not much. One choice would be to convert manufacturing from producing other important vaccines like MMR or Tdap, but that seems like a bad choice.
So, new manufacturing facilities will need to be built so we have more capacity. Of course, these facilities also need to be reviewed and approved by regulatory authorities.
The timeline I provided above is generally one that I would think is fairly optimistic. If someone asked me a year ago, before we knew anything about COVID-19, to tell them how long it would take to get a vaccine to market from scratch, I would have answered, “5-10 years.”
Why are we stuck with this timeline?
There are several answers to this, but I’ll list just a few.
- Setting up the clinical trials takes time. I know everyone thinks it is easy to find patients to volunteer, but they generally have to fit into certain demographic groups across the world. You just can’t recruit American patients who live in one small part of California, you need to have patients from numerous centers. You need patients that represent broad income, ethnic, and other groups. Then, the sponsor has to find investigators, has to get IRB approval (see above), has to get the vaccines and placebos to the sites, and so many other steps that I’d bore you silly writing about them. Then the data has to be analyzed in various ways to see if it is safe and effective.
- Getting results takes time. If the virus is not circulating widely at the time of the year that the trial starts, then there will probably be no statistical difference between the vaccinated and placebo groups, so the data will be essentially worthless, giving us no information about either its short- or long-term effectiveness. Moreover, what if the vaccine only works for six months? What if an adverse event only happens six months later (though this is mostly an anti-vaccine myth, it can happen)? There is no way to rush these steps, that’s why it takes four or five years. Some people are suggesting “challenge studies,” which places a few hundred young, healthy volunteers in an isolated location and intentionally expose them to the coronavirus. The ethical and scientific issues are difficult, and though many will volunteer for it, few scientists would support it.
- Sometimes vaccines need to be reworked. Frequently, after phase 2 or 3 clinical trials, the sponsor realizes that the vaccine is not very useful because they did something wrong. Maybe they need an adjuvant or a new adjuvant. Maybe the vaccine goes bad after a few weeks and needs different storage recommendations. Maybe the vaccine needs a higher concentration of antigens. Everyone seems to think that once a vaccine enters clinical trials, it must work, but clinical trials are a scientific experiment. We are asking whether the vaccine is safe and effective, and the clinical trial provides evidence to reject or support that hypothesis. And in real science, you gather data and then go back to the beginning. Again, if the vaccine doesn’t work very well, what can be done to improve it?
- Clinical trials fail the vast majority of the time. This is something that few people understand – clinical trials rarely work out for the drug companies. And it happens all of the time with vaccines. That’s why I keep writing this over and over – if everything goes perfectly, maybe we can have a coronavirus vaccine within 3-5 years. But it never goes perfectly, it’s science.
- Ramping up manufacturing. Those who think that we can have a vaccine broadly available in 12-18 months are simply overlooking the immense issues in building up vaccine production capacity across the world. It might take years to build, install, and certify new equipment. And the raw materials need for vaccines, everything from pharmaceutical glass to stoppers to adjuvants don’t just appear overnight – the production of these important materials are also capacity limited.
One more thing – ignore any words that come out of the mouths of anyone that is associated with any company that is developing a vaccine. Period. Just don’t do it. I’m not saying they’re lying, but what I am saying is that they have precisely one audience – their investors and shareholders.
They can boost their stock prices by over-exaggerating results or compacting timelines. Moderna, who is developing an mRNA COVID-19 vaccine, has recently claimed that they will have their vaccine available for healthcare workers by the end of 2020. Yeah, right.
The biotechs are being very aggressive in their press statements. What they’re doing is talking to their investors. I think you have to filter that away from what the FDA is thinking. A wishlist from the CEO of a biotech or a pharma company means nothing to me. It’s what the clinical trialists are finding in collaboration with the FDA that matters.
Moreover, Moderna’s mRNA vaccines have never shown to be effective (or safe for that matter) in humans. Again, Dr. Hotez says:
Without having the efficacy and safety data, I think you have to be really careful about bold statements like that. As I often like to say, these nucleic acid vaccines have been around for 30 years and they offer great promise, they work in laboratory animals, but, historically, they have not worked well in people. Maybe now there’s been modifications to improve that. Let’s wait and see.
These comments are not meant to be an indictment of Moderna, who has significant resources in the development of mRNA vaccines. It’s just that they need to be overoptimistic, assuming that everything will go 100% perfect. There will be no mistakes. Statistical analysis is easy and fast. There are zero safety signals. It is 100% effective after one or two shots.
When does that happen? Never.
I cannot stress this enough – nearly 84% of drugs (including vaccines) that enter clinical trials FAIL to get FDA approval. Not to be sarcastic, but if Big Pharma has the FDA in their back pocket, they need to do a better job.
It is expensive and incredibly difficult to get a new drug or vaccine to market – to me, only magical thinking would lead me to believe that a new vaccine will be available by January 2021. And we shouldn’t give up the absolute requirement for overwhelming evidence supporting the safety and effectiveness of the winners of the coronavirus vaccine race.
Cutting corners in the race
I think everyone is asking, or even demanding, that there must be some method to speed up the coronavirus vaccine race. Usually, they want to hit the gas pedal by:
- Speeding up clinical trials. There is no way to speed it up without sacrificing knowledge about its safety or effectiveness. We cannot reduce the number of patients, the methodology, or statistical analyses of clinical trials just to get a vaccine out to the world.
- Speeding up regulatory review. This is a slippery slope that right-wing governments would like to implement. Generally, FDA reviewers are not political appointments but are scientists themselves. They probably cannot be forced to overlook issues just to get a vaccine approved, but it’s possible they’ll move a coronavirus vaccine application to the top of the pile. But this isn’t the factor that slows down the process, it’s still clinical trials.
- Speeding up manufacturing. I don’t know how this can be done without the aforementioned magical thinking. One proposal I keep hearing is “let’s stop production of other vaccines while we vaccinate everyone against the coronavirus.” No, absolutely not. As scary as COVID-19 is, polio, measles, tetanus, diphtheria, and pertussis are extremely dangerous too. And scary.
- Release the vaccine to anyone who wants it regardless of clinical trials. I hate this one. Even some pro-vaccine people are pushing this because they have this odd belief that ALL vaccines that enter clinical trials are safe and effective. This seems to be the mirror image beliefs of anti-vaxxers who think ALL vaccines are unsafe and ineffective. Furthermore, that whole “right to try” nonsense needs to stop.
One more thing that Dr. Hotez said about the FDA:
…the branch of the FDA called the Center for Biologics Evaluation and Research has been around for a while and has some of the smartest vaccine scientists that I’ve ever worked with. I’m fairly confident they would not do anything that would jeopardize the health and safety of Americans.
Operation Warp Speed – Trump again
Donald Trump has invented “Operation Warp Speed” to deliver a COVID-19 vaccine by January, years ahead of any reasonable and legitimate vaccine development and manufacturing timeline. Like just about everything Trump has said about this pandemic, it’s hard to see how this is possible.
But Operation Warp Speed may not happen because, as the Washington Post recently wrote:
U.S. regulators are firm in that they will not sacrifice safety for speed, but some ethicists raise concerns about “pandemic research exceptionalism,” in which the demand to speed a vaccine to market could come at the expense of evidence and fuel the powerful anti-vaccine lobby.
Paul Offit, one of the leading experts on vaccine development in the world, stated:
The 26 years it took us to make the rotavirus vaccine is pretty typical. If it’s 12 to 18 months, you’re skipping steps. Is that a little risky? Yes, it is, but so is getting infected with the virus.
I think that what a lot of people are missing is that “designing” a vaccine is actually the easy part (and that’s not all that easy). I even think that many of my pro-vaccine readers think that once you have the design, everything else is a smoothing coronavirus vaccine race.
The really hard part is establishing that it is very safe and very effective. The New York Times, in an excellent article about how difficult it will be to get a new vaccine, posted this timeline IF we use every single method to speed up the coronavirus vaccine race:
If we do everything possible, it might not be until 2031, yes 2031, before a vaccine is widely available.
I’m now feeling like I’m the optimistic one by warning that it might take 4-5 years before we have a vaccine. The nonsense I’m reading about the University of Oxford vaccine, which some people are claiming will be available by the end of 2020, will probably not be shown to be safe and effective on such a compressed timeline. And there is no way that it will be manufactured in quantities that would actually end this pandemic.
Rushing development can lead to overlooking such serious adverse effects like antibody-dependent enhancement where the anti-SARS-CoV-2 antibody actually makes it easier for the virus to enter cells. This is one of the reasons that other coronavirus vaccines for SARS and MERS have not worked.
Finally, and many pro-vaccine people are ignoring this point, but we must have superior evidence supporting the safety and effectiveness of all vaccines. We have that for every single vaccine on the market now. Despite the lies of the anti-vaccine world, for example, we know that the HPV vaccine is extraordinarily safe and effective. That’s because there is an immense body of research that has shown it’s safe and effective.
We need the same thing for a potential coronavirus vaccine. We can’t have anti-vaxxers establish a narrative about this vaccine that will potentially put people at risk of COVID-19. We can’t have a vaccine that we can’t show is effective that gives us a false sense of protection instead of using more proven methods like mitigation.
I’m also concerned about my fellow pro-vaccine people saying that we should have this vaccine as fast as possible because we don’t care about the anti-vaxxers. Except if the vaccine doesn’t work, then we’re doing what the anti-vaxxers are trying to do – put those who cannot be vaccinated at risk of dying.
We need a COVID-19 vaccine that is safe and effective, just like every vaccine on the market right now, in case some ignorant anti-vaxxer takes my comments out of context.
The coronavirus vaccine race should be done correctly – Operation Warp Speed is just another lame effort by Donald Trump to pretend he’s doing something. Ignore him.
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- McNamee LM, Walsh MJ, Ledley FD. Timelines of translational science: From technology initiation to FDA approval. PLoS One. 2017;12(5):e0177371. doi: 10.1371/journal.pone.0177371. eCollection 2017. PubMed PMID: 28481922; PubMed Central PMCID: PMC5421779.