For the Covid vaccines, the fundamental goal was not to prevent mild infections but to prevent deaths, hospitalizations, and transmission. Despite this, the randomized controlled trials evaluated short-term reduction in symptomatic Covid infections while failing to address important public health issues. This result was due to badly designed trials. Despite lacking key data, public health agencies made unsubstantiated vaccine claims, published unscientific vaccine recommendations, and imposed unethical vaccine mandates. As a result, vaccine hesitance has increased while the trust in public health has deteriorated.

After contrasting them with the polio vaccine trials in the 1950s, this article outlines the fundamental design flaws in the Covid vaccine trials and describes how they could and should have been designed to generate the critical public health information on their ability to reduce hospitalizations, mortality and transmission.

Keywords: Covid vaccine, Polio vaccine, Vaccine randomized trials, Trial design

Disclosures, Funding & Conflicts of Interest:

We are grateful for helpful discussions with the Florida Public Health Integrity Committee and with Prof. Sunetra Gupta. Neither of us have any conflicts of interests to report and no funding sources for our work on this paper. 

Affiliations:

Jay Bhattacharya, MD, PhD, Department of Health Policy, Stanford University School of Medicine, Stanford, CA, USA

Martin Kulldorff, PhD, Ashford, CT, USA

Correspondence:

[email protected].

Prof. Jay Bhattacharya, 117 Encina Commons, Stanford University, Stanford, CA 94305-6019

 

Submitted 10/14/2024

The warp-speed development of the Covid vaccines was a remarkable achievement in the history of medicine. After less than a year, the vaccines had been developed and evaluated in a vaccine efficacy trial where tens of thousands of patients were randomized either to the Covid vaccine or a placebo. The trials measured the effectiveness of the Covid vaccine by comparing the number of symptomatic Covid infections in the vaccine versus placebo arms. The results showed that the Pfizer and Moderna vaccines both had 95% efficacy in reducing symptomatic infection during the few months after the second dose.^1,2,3 

Public health officials were ecstatic, launching a mass vaccination program. They promised that the vaccine would provide long-lasting protection against getting, spreading, and dying from Covid. Governments, corporations, and universities imposed vaccine mandates for students and employees.

But the vaccine rollout in the months after the vaccine's introduction struck a discordant note. The vaccine failed to live up to this promise after it was widely deployed in the population. Despite substantial uptake of the vaccine in the United States and many other countries, as well as subsequent boosters, Covid continued to circulate in substantial numbers⁴. Covid waves came and went in both 2021 and 2022, and eventually, almost everyone got infected Covid.⁵ Consequently, trust in vaccines has plummeted.⁶

What went wrong? In this paper, we argue that one fundamental problem was a failure in the design of the vaccine trials with a mismatch between the clinical trial endpoints and the public health needs. A second problem was a failure in the interpretation of the trials, with a mismatch between what public health officials claimed and recommended and what the trials actually showed. 

It is illustrative to compare the Covid vaccine trials to the 1954 Salk polio vaccine trial during a deadly polio pandemic that paralyzed and killed thousands of children.⁷ In 1952 alone, there were over 3,000 polio deaths in the United States. To survive, many children were put on iron lungs.

The development and announcement of the Salk vaccine generated much hope and excitement, but did it work? Similarly to Covid, only a small fraction of polio-infected children develop severe disease (paralysis) or die. That posed a significant challenge when evaluating the vaccine. If investigators recruited only a few thousand children for the randomized clinical trials (RCTs), there would be very few paralyzed or dead children in the placebo arm. No matter how good the vaccine was, the difference between the vaccine and placebo would be slight, even if there were no paralyses or deaths in the vaccine arm of the trial. So, to know whether the vaccine worked or not, the sample size had to be enormous.⁸

The vaccine developers and public health scientists of the time understood the need for solid proof that the vaccine addressed the actual public health problem, which was to prevent polio from paralyzing and killing children. Hence, the primary clinical endpoint was paralytic polio. For such a serious but rare endpoint, the scientists enrolled over 400,000 children in a landmark double-blinded randomized controlled trial, with 200,745 children receiving the polio vaccine and 201,229 receiving a placebo injection. In the placebo group, there were 115 cases of paralysis, at a rate of 57 per 100,000 children.⁹ In the vaccine group, there were only 33 cases, at the much lower rate of 16 cases per 100,000. That provided solid proof that the vaccine worked, with 71% vaccine efficacy (p<0.001).

After this successful trial, mass vaccinations followed. Polio is now eradicated in the United States and most of the world.

Without this trial, public health officials would have been shooting in the dark, giving advice to parents about the efficacy of the product without real data underlying it. It is easy to imagine the frustration that parents faced when their child would get polio while the trial was running. While public health officials were under tremendous pressure to deploy the vaccines more rapidly, they were right to take the time to evaluate the vaccines with this large randomized trial that lasted over a year. Had they not done so, there would have been valid concerns about the vaccine, creating vaccine hesitancy among the public. That is especially true in light of some manufacturing problems that arose when the vaccine was delivered at scale after the trial.¹⁰

The Covid vaccine RCTs did not provide public health professionals, physicians, or the public with the needed information that would have allowed them to address public health needs credibly. For evaluating vaccine efficacy, the primary failures of the Covid vaccine trials were (i) the lack of clinically meaningful outcomes such as prevention of hospitalization and death, (ii) the failure to evaluate disease transmission, (iii) the short follow-up time, and (iv) the lack of data on those with prior natural immunity.

Clinically Important Outcomes

As with polio, most people infected with the SARS-CoV-2 virus do not die from it.¹¹ Nor do they need hospitalization. The purpose of a vaccine is to prevent serious outcomes such as death or hospitalizations. This can either be done directly, if the vaccine protects the vaccinated person, or indirectly, if the vaccine prevents the spread of the virus to others. The Covid randomized trials evaluated neither of these outcomes. Instead, the clinical endpoint for the vaccine trials was the short-term prevention of symptomatic infection.

Was this flaw unavoidable? The answer is no. By recruiting many young and middle-aged adults, who are at low risk of death whether or not they take the vaccine, the pharmaceutical companies ensured that there would be very few hospitalizations or deaths in both the vaccine and placebo arms. This, in turn, made it impossible to know whether the vaccine prevented these serious outcomes from the individual trials.¹²

How could this have been avoided? One option would have been to greatly increase the sample size, just as for the 1954 polio RCT. That would have delayed the vaccine's approval, which would have negative consequences for public health.

The better solution would have been to recruit mostly older people to the trial.^13,14 While anyone can get infected, there is more than a thousand-fold difference in mortality between older and younger people, so it is primarily older people who stand to benefit from the vaccine.¹⁵ If the trials had enrolled more older people, we would have known from each trial if the evaluated vaccine prevented deaths. That is critical information that public health and medical authorities needed to confidently inform the general public about vaccine efficacy and to trust the vaccines.

To overcome the flaws in the trial designs, Benn et al. (2023) pooled data from all the trials for the mRNA vaccines (Pfizer and Moderna) as well as from the adenovirus vaccines (J&J, Astra-Zeneca, and Sputnik). Since the vaccines in each group use similar mechanisms of action, pooling increases the sample size enough to generate sufficient statistical power regarding vaccine efficacy from randomized studies. The authors found that the mRNA vaccines did not reduce all-cause mortality (RR=1.03, 95%CI 0.63-1.71), while the adenovirus vaccines did (RR=0.37, 95%CI: 0.19-0.70). Note, though, that these results are primarily for young and middle-aged adults, not for the much higher-risk older adults who may have benefitted more from the vaccines.

 

Transmission

The appropriate trial design also depends on the public health goal of the vaccine in the midst of a pandemic. The distinction between the public and private goals of the vaccine informs the answer. Consider, for instance, a randomized trial for a drug that treats a non-infectious disease. Typically, such a drug confers primarily a private benefit for patients who take it, with little to no direct benefit for others who do not. The only real question for a randomized trial is whether the drug makes the patient better. While there may be some controversy about whether to have a clinically meaningful endpoint (such as curing the disease the patient has or ameliorating symptoms) versus an intermediate endpoint (like improvement in a biomarker that correlates with good patient outcomes) as the primary endpoint of the trial, the critical outcome focuses on patients who take the drug themselves, not on the effect on other people.

In the context of the Covid vaccines, of course, there were both the private problems caused by Covid disease, especially in older people and other high-risk people, as well as the public problems caused by the spread of Covid from one person to another via respiratory droplets or aerosols. So, in the case of the Covid vaccine, there was a vital decision to be made in the design of the RCTs. If the Covid vaccines were aimed at producing a private benefit for patients by preventing severe Covid disease upon infection, well, that would suggest one kind of randomized trial with patient outcomes like hospitalizations and death as the primary endpoints. On the other hand, if the Covid vaccines were also envisioned as a means to stop the spread of the SARS-CoV-2 virus, reducing the prevalence of the disease in the population at large, and perhaps even eliminating or eradicating Covid, then the randomized trials would need to have a very different endpoint focused on whether the vaccines were capable of limiting the spread of the disease.

The Covid vaccine trials did not evaluate this endpoint at all.

Would it have been challenging to do so? The answer is no. Instead of recruiting individuals to the trial, the pharmaceutical companies could have recruited married couples or other pairs of cohabitating persons. In every couple, the first one would be randomized to receive either the vaccine or a placebo injection, while the second one would receive neither. The effect of the vaccine on the recipient would then be evaluated based on the first group, while the impact on transmission would be evaluated using the second group. If, for instance, the vaccinated patient's family members had lower rates of Covid infection than the family members of the placebo recipients, we can infer that the vaccine prevents disease transmission.

Since Covid infection is so common in the population, such a trial would not need a lot of patients enrolled, such as were enrolled in the Salk polio vaccine trial. A relatively small trial would suffice. The one extra thing required is the testing of household co-residents to check for asymptomatic disease. While we know that at least one of the vaccine companies contemplated this type of design to evaluate transmission-blocking (personal communication), we do not know why all the vaccine developers ultimately decided against it.

Some public health officials assumed that since the Covid vaccines reduce symptomatic infections for a short while, they would also reduce transmission and infection of others. That is not a logical conclusion, though, and it could potentially do the opposite. If the vaccines reduce symptoms but not infections, the vaccinated individuals could be more likely to spread the disease to others as they will be out and about while infected rather than sick in bed. Since the trials did not evaluate transmission, we do not know whether the vaccines reduce or increase viral transmission.

 

Lasting Immunity

For most diseases and people, a vaccine is only worthwhile if it provides lasting immunity.

The Covid vaccines were FDA-approved for emergency use authorization based on only a few months' follow-up. Such a short follow-up is appropriate when a vaccine is urgently needed during a pandemic, but it is also essential to know about long-term protection before final approval. It was, therefore, unethical and wrong to end the vaccine trials early. Since a vaccine that provides only short-run protection against disease is considerably less useful, the proper trial must run sufficiently long. If one vaccine provides longer protection than its competitors, that is essential public health knowledge, but that is impossible to know with only a few months of follow-up.

In the actual Covid vaccine trials, pharmaceutical companies only tracked patients between two to four months after completion of the vaccination sequence. That was not enough time to understand whether the vaccine provided long-lasting protection, which left public health officials to inappropriately extrapolate the efficacy of the vaccines against infection to a time period not covered by the trials.¹⁶

 

Vaccines for Covid-Recovered People With Natural Immunity

At the urging of public health officials, the Covid vaccines were mandated for people who had already had Covid.¹⁷ From a historical perspective, that was surprising since vaccines are supposed to mimic the natural immunity developed after being sick but without getting sick. It would, therefore, be astonishing if a vaccine provided better protection than recovery from the disease.

To scientifically justify such mandates, the randomized trials would have needed to evaluate patients who had recovered from Covid infection before enrollment. That information was available to the trial investigators, but the few participants with a prior Covid infection were excluded from the efficacy analyses.^1,2 From the point of view of both public health and the pharmaceutical companies, that was the right decision since Covid-recovered individuals with natural immunity are unlikely to benefit from the vaccine. Including such patients in the analysis would have attenuated the vaccine's measured effect size and efficacy for the population that could benefit the most from a vaccine.

Because the Covid-recovered were excluded, the trials could not measure the vaccine's marginal benefit by prior immunity status. If the effect size is much lower for Covid recovered patients than for immune naïve patients, which one would expect and which the pharmaceutical companies clearly expected since those individuals were excluded, then such a trial would have required an enormous sample size. On the other hand, if public health officials and pharmaceutical companies thought the vaccine would be highly beneficial for those with natural immunity, a separate trial with the same sample size would have sufficed to prove that if true. It was unscientific to recommend the vaccine for Covid-recovered patients without such a trial.

 

Vaccine Safety

Unlike efficacy, randomized clinical trials are insufficient to determine whether a vaccine or drug is sufficiently safe to administer. Adverse reactions are tallied and evaluated in all trials, and if there are many serious adverse reactions, the drug or vaccine is never approved. A trial cannot rule out rare but serious adverse reactions, though, nor adverse reactions in populations not included in the trial, such as pregnant women. Post-market safety surveillance is needed for that, using observational rather than randomized data.

So, there is unavoidable uncertainty about the safety of a new vaccine when it is first approved, an uncertainty that it is essential to be honest about with the public. That uncertainty should also be reflected in public health recommendations. For older people who are at high risk of death from Covid, a small potential risk from the vaccine is worth taking. For young health people who are at very low risk for Covid death, even a small risk from the vaccine can tip the balance of the risk/benefit ratio against the vaccine. 

When public health officials rolled out the vaccine campaign in December 2020 and January 2021, key communicators told the public that the vaccine would prevent all Covid infections and transmission, perhaps even allowing the eradication of Covid disease from general circulation.¹⁸ Officials made these claims even though the Covid vaccine trials did not include infection prevention or transmission-blocking as measured endpoints, and observational data were not yet available.

For instance, the CDC director, Rochelle Walensky, claimed that "vaccinated people do not carry the virus — they don't get sick." In a retrospective interview, she said that she based her public statements about the effectiveness of the vaccines in preventing people from getting infected on hope rather than on any result in the randomized trial.¹⁹

In 2020, Tony Fauci told the public that herd immunity would arrive when 60% of the population was vaccinated. Later, he upped the required fraction to successively higher numbers, 70% and 80% of the population, justifying the initially low number because he thought the public was not yet ready to hear the higher required percentages.²⁰ In January 2021, he told a Baltimore resident that the vaccine stops infection.²¹ However, in the context of herd immunity, this statement makes sense if the vaccine prevents disease transmission permanently or for years.

Policies like vaccine mandates and vaccine passports, widely adopted by governments worldwide, were premised on the ability of the vaccine to prevent disease transmission. The idea was that, compared to the unvaccinated, vaccinated individuals were clean and safe to be around, or at least safer to be around as far as Covid infection is concerned. Of course, that is only true if the vaccine prevents somebody from becoming infected and spreading the disease to others.

Even as late as fall 2021, the United States federal government told the US Supreme Court that Covid vaccination prevented infection. Hence, they claimed that the vaccine mandates were necessary for healthcare workers to protect patients from Covid. In court, the government defended its OSHA vaccine mandate, which required firms with more than 100 employees to have their employees vaccinated. OSHA defended in court this requirement, saying that the vaccine mandate was needed because it provided essential protection to workers against being infected with Covid disease, which was not evaluated in the randomized trial.²²

By the summer of 2021, evidence from observational data had emerged from several countries that showed that infection-acquired immunity was much stronger than vaccine-acquired immunity, as expected, and by two to three months, the vaccine's efficacy against symptomatic infection had dropped precipitously. Multiple epidemiological studies from Qatar, Denmark, Sweden, Israel, Sweden and the Kaiser Health System in California all had similar findings.^{23,24,25,26,27} Despite this, vaccine mandates for people with superior infection-acquired immunity persisted. For example, many nurses and physicians got infected while caring for Covid patients in 2020 but were subsequently fired for not taking the Covid vaccine despite having superior immunity.²⁸

The consequence of the mismatch between what the randomized trials examined and what prominent public health officials said during the vaccine rollout is enormous.

Since the randomized trials showed the vaccines prevented symptomatic infection, and since symptomatic infection is a precondition to severe disease and death, it was likely that the Covid vaccines also prevented severe illness and death. While it should not have been required (the trial should have been designed to test this hypothesis), this was a legitimate and logical extrapolation of the limited results available from the randomized trial data available at the time. Careful observational studies, such as the previously mentioned Qatari and Swedish studies, later verified both the efficacy against severe disease among the old and the waning of vaccine efficacy against infection.²⁴

The potential benefit of a vaccine is highest in those with the highest risk of hospitalization and death, and for Covid, that is the old. By mandating vaccines for students and working-age adults, low-risk individuals were forced to take the vaccine before many older high-risk people in America and abroad had received it. The randomized clinical trials did not properly evaluate the vaccine's benefit to older people, but subsequent observational studies showed decreased mortality. If that is so, then the vaccine mandates led to many unnecessary deaths among older people worldwide as younger Americans and Europeans were clamoring to get vaccinated to fulfill educational, work, or travel mandates, making the vaccine mandates unethical    

Was there an alternative strategy that might have produced better results? Yes – a strategy of focused vaccination aimed at high uptake among populations most vulnerable to severe outcomes from Covid could have saved lives. In December 2020, one of the authors of this article called for prioritizing the elderly for early vaccination because they were at the highest risk of dying from Covid infection.²⁹ In March 2021, at the request of the government-funded Virality Project at Stanford University, the other author of this article was censored by Twitter for stating that "Thinking that everyone must be vaccinated is as scientifically flawed as thinking that nobody should. COVID vaccines are important for older high-risk people and their caretakers. Those with prior natural infection do not need it. Nor children."

Had the focused vaccination strategy been adopted, we might have also avoided the needless direction of the vaccines to younger healthcare workers on the false premise that vaccinated healthcare workers would pose no danger of passing Covid disease to their patients. Of course, the vaccines do not have that property. The result of this misdirection is that many older people in the winter and spring of 2021 faced Covid disease unvaccinated. Shortages of Covid vaccines worldwide ensured there would be insufficient doses for many high-risk people.

Misrepresentation of the vaccine data has led to an understandable distrust in public health authorities. When the public contrasted the waning efficacy of the vaccine, plainly visible to almost everybody who took the vaccine and then later became infected, against public statements by public health officials, public trust in public health about the Covid vaccine collapsed.

This distrust generalized to deteriorating trust in non-Covid vaccines. If public health was wrong about the Covid vaccine, maybe they are wrong about all vaccines, many members of the public may have reasoned.³⁰ Estimates from CDC surveys demonstrate sharp declines in public confidence in basic childhood vaccines, such as the MMR vaccine, since the Covid vaccine rollout, leading to fears that there will be surges of these other infectious diseases that are preventable by vaccines that prevent disease transmission and infection.^31,32

The Covid booster campaign of 2022 demonstrates the fruits of this distrust. Despite relentless public service messaging, news reporting, and advertising by pharmaceutical companies, by May 2023, only 20 percent of the American population got the bivalent booster.³³

When the bivalent booster was developed in 2022, pharmaceutical companies did not conduct proper randomized control trials. Instead, Pfizer and Moderna ran trials that had the immunogenicity of the bivalent boosters as the primary clinical endpoint. The trial designers, rather than looking at the prevention of infection, prevention of symptomatic illness, or prevention of severe disease and death, looked only at whether the vaccine could produce antibodies in the patient population.

The companies ran trials for the bivalent boosters for a very short period of time, a matter of weeks, so the studies provided no information about the waning of the booster. The studies also did not provide any data about the relative efficacy of the vaccines for people who had previously recovered from Covid versus people who had not. The Pfizer trial for their bivalent booster did not include any humans at all. Their study looked only at immunogenicity in mice.

Surprisingly, the US FDA accepted this study of the booster in mice as a sufficient basis to approve the bivalent booster for emergency use. They reasoned that the boosters and the regulation of the boosters should be treated the same way that annual flu vaccine updates are treated in the regulatory process.

For flu vaccines, immunogenicity is not an unreasonable endpoint. The update process for the flu vaccine has a long history.^34,35 Safety profiles of the flu vaccines are generally excellent. The influenza virus mutates in ways such that prior vaccination and prior infection provide limited benefit against new strains of the flu. This contrasts with Covid, where previous infection offers substantial protection against severe disease even against new Covid strains.²⁷

So, for the Covid booster, the considerations that would lead regulators and the public to accept a limited study of short duration focused on immunogenicity rather than clinically meaningful outcomes do not apply. Without a rigorous randomized trial with human participants and a clinically significant endpoint such as protection against severe disease and death, it is not surprising that booster uptake is so low.

There are at least two primary lessons to be learned from this sorry episode in the history of medicine. First, regulators like the FDA must require pharmaceutical companies to conduct trials with clinically and epidemiologically meaningful endpoints. If the trials do not inform the key decisions that public health officials must make, they are not useful. They may cause harm by putting public health officials in a position where they are tempted to extrapolate their public communications beyond the evidence.

Second, public health officials must be scrupulous in not extrapolating far beyond what the randomized trial data say. The public's perception of public health officials' integrity depends on the accuracy of their statements. Since the public health officials did not have adequate randomized evidence to back up their claims about the Covid vaccine, it is no surprise that reality surprised them. The public has perceived this disconnect between public health officials' statements and reality as evidence of incompetence or worse. And now, it will take many years of honesty and hard work for public health officials to regain the public's trust, ultimately to the detriment of the public's health.

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