The Fallacy of the “Make It So” Mentality to Rush a COVID-19 Vaccine

Taking a meatloaf out of the oven too soon is an inconvenience, easily corrected by shoving it back in until it’s ready.

Marketing a vaccine for COVID-19 too soon could be a disaster, with massive, far-reaching consequences. But that’s what the U.S. government’s Operation Warp Speed might make happen, with the goal of having a vaccine ready for distribution by year’s end.

The problem is that vaccines aren’t “found” or “discovered,” like pretty shells on a beach, and if you just look enough, you’ll find one. Vaccines are invented, developed, and tested, tested, tested, and that takes time. Biological factors could even make a vaccine impossible.

Measures are already in place to speed things along.

The FDA is collapsing protocols normally conducted in tandem into overlapping or parallel designs. They’re allowing clinical trials to begin sooner following preclinical (non-human animal and cell-based) studies, expediting formation of institutional review boards to speed set-up of clinical trials, shifting reviewers from non-COVID projects to COVID ones, and enrolling thousands of people into clinical trials rather than the typical hundreds.

But will these measures be enough to roll out a vaccine six months from now? I don’t think so.

Buzzwords Versus Reality

Operation Warp Speed’s timetable is a little like condensing four years of high school into one, which isn’t far off the mark considering the chronology of vaccine development. It typically takes years. A vaccine against yellow fever took 5; against Ebola more than two decades, with approval just days before the first cases of COVID-19 appeared in Wuhan at the end of 2019.

“It’s hard for me to see that we’d have a vaccine on this side of January. The process is designed to be slow, reflective, peer-reviewed and evidence-based. It takes a long time, not the science part nor to build the vaccine, but to conduct safety testing in enough people across enough time,” said Gregory A. Poland, MD, Director of the Mayo Clinic’s Vaccine Research Group and Editor-in-Chief of the journal Vaccine at a JAMA webinar at the end of March. That was just before the years-end goal started to gain traction.

Clinicaltrials.gov lists details of COVID-19 vaccine efforts. In general, after the first two phases of a clinical trial assess safety and efficacy in a small number of individuals, a larger phase 3 trial confirms that the vaccine (or drug) works, with sufficient numbers and time for adverse effects to emerge. But even after phase 3, accruing data can reveal a glitch, or something can go wrong with vaccine production.

“Just because we’ve tested a vaccine in phase 1 and 2 doesn’t mean it is effective. Should we take what you think is a vaccine and give it to people? That’s dangerous. Our first mandate in medicine is to do no harm. There is no vaccine in the immediate future, which tells us we need to rely on public health measures,” Dr. Fauci said at another JAMA webinar before Operation Warp Drive was declared. He meant masks and social distancing, not taking hydroxychloroquine or chugging clorox.

Ironically, the COVID-19 vaccine timeline could be extended, not contracted, because a leading candidate, from Moderna Therapeutics, uses a novel technology, based on messenger RNA (I explained the approach here). To continue the culinary metaphor, it would take me longer to sculpt a variation on the beef meatloaf theme from broccoli than from ground turkey. Perhaps the president, when conjuring up Operation Warp Speed, needed to channel Mr. Spock’s trademark logic rather than Captain Picard’s proclamation.

Pay Attention to Precedents

What might go wrong if we rush a vaccine to market? A new Viewpoint in JAMA, from Brit Trogen, David Oshinsky, and Arthur Caplan of NYU Langone Health, revisits vaccine history to offer advice.

In 1955, Jonas Salk’s killed polio vaccine was successfully tested in more than a million children, and orders were promptly given to five manufacturers. But one company’s vaccine contained enough live virus to kill 10 children, paralyze 164, and leave about 70,000 with weak muscles.

Then in 1976, a new strain of swine influenza emerged that was similar to the one that killed millions in 1918. To prevent another pandemic, President Gerald Ford met quickly with an expert panel and pushed a live vaccine into development, production, and distribution, with disastrous consequences.

Some vaccines had the wrong influenza strains. Some kids spiked high fevers, while others had no immune response at all. And a slight uptick in the number of cases of a neurological condition, Guillain-Barré syndrome, may have been due to the vaccine – the numbers were too small to really tell. But some people trace the origin of the anti-vaccine movement to the 1976 swine flu incident.

For some other infectious diseases, like SARS and HIV/AIDS, a vaccine just might not be in the cards.

The half-year SARS epidemic that straddled 2002 to 2003 ebbed before a vaccine could be developed. The quick decline in cases could have been due to a lucky natural attenuation of a changeling virus. But Brian Doberstyn, Director of the Division for Combating Communicable Disease in the WHO Regional Office for the Western Pacific, attributed it to “unprecedented collaboration among scientists and laboratories around the world working together to identify the causative agent, map its genome, and develop reliable diagnostic tests,” in the book SARS: How a Global Epidemic Was Stopped, from 2007.

SARS was a terror: a 10% mortality rate, reinfection possible, severe inflammation a complication, and natural immunity waning in months. And obstacles arose in designing SARS vaccines.

In animal studies vaccines ramped up the immune response against parasites and dampened the part against viruses. Experimental SARS vaccines also shifted the proportion of white blood cells to favor eosinophils, which provoke inflammation and accumulate in the lungs. “Eosinophilia” had sickened people in trials of vaccines for other infectious diseases, causing “vaccine-enhanced disease.”

Coronavirus vaccine developer Nikolai Petrovsky, of  Vaccine Pty Limited and a professor at Flinders University in Adelaide, South Australia, emailed me about the eosinophilia complication after I posted “COVID-19 Vaccine Will Close in on the Spikes” here at DNA Science on February 20, which seems another age already. “Vaccine-enhanced disease is a very real issue – we saw it with original trials of RSV (respiratory syncytial virus) vaccines in children 50 years ago, then more recently with the dengue vaccines in children, and in SARS vaccines in animal models.”

Several vaccines against SARS didn’t work: Recombinant and monoclonal antibodies against the spike protein, a SARS gene carried in a flu vaccine squirted up monkeys’ noses, a vaccine made in insect cells. Because they all caused an outpouring of eosinophils, the challenge seemed to lie with the coronavirus, not in the vaccine designs. Researchers are closely monitoring the role of eosinophils in COVID-19 and in developing a vaccine against the novel coronavirus.

HIV/AIDS is another infectious disease that has eluded efforts to create a vaccine. In fact, it’s possible to find an article addressing why an HIV/AIDS vaccine doesn’t yet exist for nearly every year since the beginning of the pandemic in the early 1980s. Here’s one from 2020.

A vaccine against HIV has been challenging to develop for three reasons. The virus changes, through mutation and recombination, too fast for vaccine developers to keep up. AIDS impairs the very cells required to mount an immune defense in response to a vaccine, and HIV hides in the body, able to emerge and resurge if the person isn’t taking anti-retrovirals.

How does SARS-CoV-2 compare to the recalcitrant HIV? The novel coronavirus doesn’t seem to be changing unusually rapidly, and it overstimulates the immune response rather than dampening it. We don’t yet know whether the virus can hide, other than a PCR throat swab snaked up a nostril failing to sop it up.

Stick to the Science

In the best-case scenario, a vaccine against SARS-CoV-2 will be possible. But the consequences of pushing warp speed development could be diverse and dire, including:

• Failure to maintain production of neutralizing antibodies, slowing acquisition of herd immunity
• Adverse effects like eosinophilia
• People thinking they’re protected before a vaccine has been evaluated for long enough, which may prompt some individuals to prematurely abandon public health measures. Cases will return and spike.

If any of these outcomes happen, then the longest-lasting disaster will be ignited: fueling vaccine hesitancy, which the WHO named one of the 10 threats to global health in 2019. More people refusing vaccines will lead to the return of other infectious diseases: measles, mumps, rubella, diphtheria, pertussis, chickenpox, polio. Avoidable doom.

Experimental controls, repetition, building numbers to statistical significance, data analysis, and looking to successes and errors of the past, taken together, form a strategy for vanquishing an infectious disease that has stood the test of time. These requirements should prevail over the commandments and unrealistic deadlines set by leaders who are neither physicians nor scientists – nor even respect what these professionals do.

We have so much to lose if vaccine development is accelerated beyond scientific reason.