Collect More Data or Begin Widespread Distribution? An Historical Perspective on the Vaccine Test Dilemma

David M. Warmflash, MD


December 08, 2022

Poliomyelitis is on the radar screen once again, but it's not only because of the recent case of paralytic polio striking in Rockland County, New York, and the related findings of vaccine-derived poliovirus type 2 in city sewage systems. It also dovetails with recent experience testing vaccines against SARS-CoV-2 and administering them quickly through populations to get the COVID-19 pandemic under control.

Two years ago, as the first COVID-19 vaccines were just weeks away from their anticipated rollout, the pandemic was just 1 year old. And so it was clear that the government-industry effort to advance vaccines, diagnostics, and therapeutics that the US was calling "Operation Warp Speed" was certainly earning its name. This was true, even though the programs in the US and other countries had yet to distribute the vaccines within the framework of emergency use authorization (EUA).

Given the relative slowness of previous vaccine programs, vaccines ready for distribution just a year after the virus had first emerged evoked excitement and hope for many, but also safety concerns for a good number of people. But this was against a backdrop of the extensive spread of SARS-CoV-2, a lack of effective therapies, overwhelmed intensive care units, and a high case-fatality rate. The stakes were high, and with the clinical trials showing good initial efficacy and no major safety signals, remaining risks and unknowns were weighed against the cost of delaying the transition from clinical trials to widespread distribution.

That's not a comfortable dilemma, but it's also not a new phenomenon in public health. Such dilemmas have been around for as long as there have been vaccines, and even prior to that. In America, we could look all the way back to 1721 — 75 years prior to Edward Jenner's invention of vaccination — when two Bostonians, the physician Zabdiel Boylston and the clergyman Cotton Mather, promoted a much cruder method: inoculation. This meant controlled exposure to variola, the smallpox virus itself, which was dangerous, yet less dangerous than facing a smallpox outbreak unimmunized. More in line with scientific vaccine development and the question of how much clinical study is enough, however, we can look to the dilemma that emerged in the 1950s over the first polio vaccine. This was the inactivated polio vaccine (IPV) that Jonas Salk developed and began testing in the early 1950s.

Polio starts when a poliovirus infects through the gastrointestinal tract, usually asymptomatically, but it spreads to other people. In a small fraction of infected people, retrograde transport takes the virus to the anterior horns of the spinal cord, containing cell bodies of lower motor neurons. This leads to flaccid paralysis, with severity varying from mild, temporary disability to severe sequelae that can include permanent paralysis of voluntary muscles, respiratory paralysis, or death.

Victims in the early 20th century were mostly children, so the disease was called infantile paralysis, yet its most famous victim, President Franklin D. Roosevelt, had been diagnosed with infantile paralysis in 1921 at the age of 39. Analysis of FDR's presenting symptoms and signs suggest that he actually had Guillain–Barré syndrome (GBS). Known to medicine since 1916, GBS results from an autoimmune attack on the peripheral nervous system, triggered usually by an acute infectious disease. It is differentiated from polio today on the basis of cerebrospinal fluid analysis, electromyography, nerve conduction studies, and the clinical presentation. With only the clinical presentation to guide physicians, however, in a time when GBS was a brand-new phenomenon, FDR's personal struggle with what was taken for polio would have a major impact on the disease. In 1938, it led FDR to found the National Foundation for Infantile Paralysis (NFIP), later called the "March of Dimes." In 1949, the NFIP would begin funding Dr Jonas Salk to develop the first polio vaccine at the University of Pittsburgh.

Going against a common assumption of his era — that vaccines had to be "live" in order to immunize —Salk produced an inactivated ("killed") polio vaccine to be administered by intramuscular injection. The IPV's early selling point was that it could be developed faster than a live attenuated vaccine, the strategy that Salk's rival, Dr Albert Sabin, received NFIP funds to pursue in 1952. So at the midpoint of the last century, polio vaccine research was advancing with a kind of warp speed vs play-it-safe dilemma somewhat analogous to the first year of the COVID-19 pandemic.

And polio was indeed an epidemic illness. Though not on the public health radar screen before the late 19th century, polio is hypothesized to have surged owing to improvements in public hygiene, including water hygiene, that came with industrialization.

Previously, the constant, low-level presence of polioviruses would keep most people at least partially immunized. This included pregnant women, and thus their newborn infants through passive immunity. With the advent of clean water and other hygienic measures, however, a generation came to life with virtually no polio immunity, so when infected people arrived in population centers from elsewhere, polio outbreaks occurred.

Exacerbated by expanded overseas immigration at the turn of the 20th century, infantile paralysis emerged as one of the most devastating and feared communicable diseases. One particularly notorious outbreak hit immigrant neighborhoods in Brooklyn in 1916 and spread through New York City and the northeastern US, leaving 27,000 people paralyzed and 6000 dead, most of them under the age of 5. Another major outbreak struck 58,000 people across the US in 1952, by which time Salk had not only produced his inactivated vaccine but had also shown it to be safe and effective in monkeys and had adjusted it for human testing.

Salk first tested the IPV in polio survivors, thus minimizing the risk but still providing him something useful to measure: neutralizing antibodies. In 1953, he published the results of this trial, showing that the vaccine was indeed immunogenic. Having also tested the vaccine on himself and his family, Salk was confident enough to run another trial of the vaccine, this time on about 700 children in the Pittsburgh area. The resulting data were enough for Salk to declare his vaccine to be safe and effective, so he wanted to begin widespread vaccine distribution. He argued that waiting for additional, larger trials would only put more people at risk for polio, and Salk was not the only one with this mindset. Parents of the 700 immunized children in Pittsburgh had been thrilled to get their children into the trial, and many more throughout the nation were eager for the vaccine.

As the main funder of Salk's research and the public face of the project, however, the NFIP wanted a more cautious approach. They wanted a larger trial, and not only that, a placebo-controlled trial. That's the gold standard for clinical research in our time, of course, but, knowing that the placebo group would be in danger from poliovirus, Salk resisted the idea and pushed for a field study in which everybody would receive the actual vaccine. But the NFIP worried that an unexpected safety issue emerging in the setting of widespread vaccine administration would devastate not only Salk's IPV program, but also Sabin's live attenuated oral polio vaccine (OPV) program, which they were now funding too. Though taking longer to develop, OPV had its own selling points: It could immunize against gastrointestinal spread; it could spread to others through stool shedding and immunize them; and, swallowed as a sugar cube, it could be administered in populations without nurses trained to give injections.

Given the NFIP's insistance on placebo control, Salk reluctantly agreed to a trial in which some 440,000 children received the vaccine, while approximately 210,000 received placebo shots. Though corroborating Salk's earlier findings that the vaccine was potent and safe, the trial also showed that Salk's concern about the placebo group was right on target. That's because 16 of the children died of polio, all of them in the placebo group, and 36 became paralyzed, 34 of them in the placebo group. Here was a case in which playing things safe actually hurt and killed children.

What happened in the following years amounts to a still bigger story. This would include success with yet larger trials and also a major tragedy — the Cutter incident — in which a batch of IPV from a particular company was not adequately inactivated. This resulted in roughly 40,000 polio cases, but it merits a story of its own. So does the polio dilemma that we now face: what to do about the fact that OPV, though cheap and easy to administer and thus still in use in the developing world, reverts to a less attenuated form that can cause vaccine-derived polio, as it did in the unvaccinated Rockland County victim, who apparently contracted it while traveling in eastern Europe.

The lesson of today's story, the relevance of Salk's resistance to the placebo-controlled, more cautious approach, is that research is a double-edged sword. Safety is of the utmost importance, but being too safe can also be dangerous, as it would have been 2 years ago, when nobody was yet vaccinated against SARS-CoV-2 and the illness struck with great severity.

But what about now, in a world in which immunity, at least against severe COVID-19, is actually good, towing to many people having received vaccine doses, plus widespread natural infection and circulating viral variants that may be less lethal than what we faced in 2020? Does the rationale for additional, updated boosters really warrant the EUA approach that we welcomed 2 years ago for the initial vaccines, or does it now make sense to adjust to the situation, as we adjusted to the changing realities of diseases and immunity in the past?

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