Developing a safe and effective new vaccine normally takes five to 15 years at a cost of $500 million to $1 billion, with less than a one in 10 chance of success. A recent front page headline in this newspaper and many others across the country announced “Fauci hopeful for a vaccine by late 2020, early 2021.” With worldwide cases totaling over 11 million, confirmed deaths over 500,000 and unrelenting grim news, this pronouncement in nationally televised congressional testimony from the only consistently credible federal health official sounded like the much-anticipated game changer we had all been waiting for. 

“We feel cautiously optimistic, based on the concerted effort and the fact we are taking financial risks — not risks to safety, not risks to the integrity of the science, but financial risk to be able to be ahead of the game — so that when, and I believe it will be when and not if, we get favorable candidates with good results, we will be able to make them available to the American public," Dr. Fauci testified. “It would put us at the end of this calendar year and the beginning of 2021.”

This is somewhat misleading. Dr. Fauci’s choice of words is worth noting: predicting the availability of “favorable candidates with good results” in six months does not mean that they will be safe and effective in the way we usually perceive newly approved vaccines. In a subsequent interview with Elizabeth Cohen, CNN’s senior medical correspondent, Dr. Fauci also acknowledged that he had based his comments on reports from manufacturers and not directly assessed any available data himself. At this time, with some of the more than 140 vaccines under development already in the second phase of clinical trials, there are no published peer reviewed data for any studies involving humans.

Most scientists and physicians of Dr. Fauci’s caliber are loath to juggle serious work with politics and public relations. For the good of the nation, I believe, he has managed to maintain his well-earned scientific credibility while cognizant of the psychological needs of a population suffering through a pandemic that has caused global economic collapse and social upheaval with no quick solution in sight. A good doctor worth his salt offers his patients hope. However, I would characterize his year-end timeline more as overly optimistic rather than “cautiously optimistic."

In mid-May, President Trump, not wearing a mask, unveiled “Operation Warp Speed,” a $10 billion public-private partnership tasked with expediting the testing, manufacture and distribution of hundreds of millions of doses of COVID-19 vaccine by year end, an unprecedented timeline in the history of vaccine development. Fans of science fiction and Star Trek are familiar with warp speed as faster-than-light velocity — fascinating and entertaining but technically impossible. While our government has the means and ability to accelerate galactic spending of money on unproven vaccine candidates, it cannot safely rush clinical trials.

Establishing the safety and effectiveness of a vaccine requires multiple steps that are simply unattainable in a 6- to 12-month time frame. In the first two phases of clinical trials, usually after animal studies, first dozens and then hundreds of healthy volunteers receive the vaccine to look for early side effects as well as the ability of the body to mount an immune response. Each step normally requires many months of scrutiny before proceeding to the next phase.

In a pivotal or final “Phase 3” stage, thousands of individuals are immunized in randomized controlled trials conducted under strictly regulated ideal conditions. This involves close monitoring for side effects as well as studying the ability of the vaccine to prevent infection after study subjects are naturally exposed to disease in the community during their everyday lives. About half the volunteers receive the test vaccine and the rest a harmless placebo. To prevent bias, doses are assigned randomly with both subject and investigator unaware.

This is the gold standard for clinical testing and normally takes a couple of years to generate enough reliable data. An independent Data Safety Monitoring Board that is not blinded keeps a constant eye on results in order to halt the study early in case serious adverse effects occur more often in people receiving the test vaccine. If all goes well, the FDA and a multidisciplinary panel of experts on its vaccine advisory committee analyze the entire dossier submitted by the manufacturer, including public scrutiny of its deliberations in open hearings.

A major shortcut taken by companies testing their COVID vaccines is to skip this normal chronology and run phases of testing in parallel in an attempt to save time. The enormity and intensity of the pandemic has created frenzy amongst them akin to the run-up to the Kentucky Derby, with both historic prestige and a monumental payoff for the first to cross the finish line. Indeed, they have made large unprecedented investments in late-stage activities while still in the early laps of this race. Typically, expenditures for manufacture occur during the final phase when safety and efficacy are verified. To enable pandemic if not warp speed, the government is underwriting this risk for the most promising candidates to potentially stockpile millions of vaccine doses even before safety and efficacy are established.

There are many reasons why circumventing the normal clinical development process is a slippery slope in determining both safety and effectiveness for new vaccines. Assurance of safety is the prime concern. While the occurrence of major adverse effects is usually detected early and effectively ends a trial, many potentially disqualifying side effects can only be observed when thousands of recipients have been studied. Significant injurious reactions may occur in a small percentage of individuals that can only be detected after tens of thousands are immunized over a longer period of time.

While the scientific knowledge of the COVID-19 virus is evolving rapidly, it is well known that severe disease in symptomatic patients involves an intense and complex immune response involving not only the lungs but also other organs. By the same token, we hope that a successful vaccine stimulates a robust immune response to prevent infection while not harming its recipient. Vaccines may actually result in a greater susceptibility or even cause more serious disease after infection, a phenomenon called “vaccine induced enhancement” that was observed in dengue vaccine development.

Another safety concern involves the possibility of serious adverse effects in individuals based on their genetic makeup. The public is familiar with the widely reported severe pediatric multisystem inflammatory syndrome that appears to be linked to COVID-19 infection and has similarities with Kawasaki disease, thought to be an inflammatory response to an infectious agent like a virus in genetically predisposed children. The possibility that a vaccine could cause a similar reaction exists and would require long-term safety data to determine, due to apparently low incidence of the disease in children.

Turning to the question of vaccine efficacy, there are numerous issues besides its ability to prevent infection. We need to know how often it fails, what level of protection it provides, how long it lasts, whether boosters will be required or could the virus possibly mutate and require annual modification like the flu vaccine. There will be a multitude of gaps in our knowledge of these and other factors well into 2021 and beyond.

It is helpful to understand the difference between efficacy and effectiveness in assessing the ability of a vaccine to make a significant difference in populations. Efficacy is a measurement of protection generated by the carefully controlled late stage trial conducted under optimal conditions in healthy volunteers and supervised by investigators who adhere to a strict study protocol. However, effectiveness of a vaccine is quite different and refers to observation of long term effects after approval in a broad spectrum of recipients vaccinated by health care providers in everyday “real world conditions” not enrolled in studies: will it be effective for people with multiple underlying medical conditions, the immune compromised, the very old, the very young, pregnant women and others?

The influenza vaccine was only 39 percent effective in the 2019-2020 flu season. It is hoped that a COVID-19 vaccine would be at least 60 to 70 percent effective. Recent polls of Americans reveal that only 50 to 60 percent would elect to receive it. If these statistics are accurate, it will be difficult to achieve the “herd immunity” or collective resistance to eradicate the contagion.

I will be an eager recipient of any COVID-19 vaccine that has been properly vetted for safety and efficacy before licensure. Meanwhile, it is vital that health authorities work to establish public trust in the ongoing regulatory process. Top federal officials have already eroded their credibility by foolishly endorsing and promoting unproven treatments like hydroxychloroquine. If “Operation Warp Speed” criteria are used to evaluate the “favorable candidates with good results” that Dr. Fauci mentioned to Congress, it is likely that vaccine approval will come with an Emergency Use Authorization based on limited evidence. It behooves the FDA to remain uninfluenced by politics and mindfully base licensure of a COVID-19 vaccine on its normal review process to reassure the American public that the benefits outweigh the risks.

Vijay K. Sikand, M.D., practices family medicine and pediatrics at Yale New Haven Health/Lawrence & Memorial Hospital.