Stanley A. Plotkin misses leading his own research lab, but, on the cusp of 89, he is still shaping vaccine advances.

“I’m glad I can still contribute,” he said Wednesday with characteristic but undue modesty.

Plotkin, nicknamed the “Godfather of Vaccines,” learned the ropes working on polio and anthrax immunizations in the 1950s, then invented the rubella (German measles) vaccine that is now used worldwide to prevent dreadful birth defects. During an illustrious career at the Wistar Institute, the University of Pennsylvania, and Children’s Hospital of Philadelphia, he had a hand in developing vaccines for rotavirus, rabies, Lyme disease, and cytomegalovirus.

Now, he is in demand because of the coronavirus pandemic. He is a consultant to COVID-19 vaccine makers, the Gates Foundation, and the World Health Organization, among others.

“Perhaps egotistically, I thought I could offer advice about what to develop and what strategies to use,” he said. “I have been extremely busy.”

Even before the winter rollout of the first COVID-19 vaccines, Plotkin joined the scientific race to figure out precisely what level of immune response protects against infection, and how long that protection lasts.

The still-emerging answers are important for understanding the rare cases of infection after vaccination, and of reinfection after recovery from COVID-19. But that’s not all. The answers are also vital to making COVID-19 vaccine development faster and simpler.

» READ MORE: What we know about ‘breakthrough’ COVID-19 infections in vaccinated people

If a certain concentration of antibodies in the blood prevents infection, then that level, or “titer,” could be used as a substitute for demonstrating vaccine effectiveness in clinical trials. A booster shot against emerging mutant strains of the coronavirus could be approved just by generating that threshold antibody titer, called a correlate of protection. That’s how the seasonal flu vaccine gets licensed every year.

In contrast, Pfizer, Moderna, and Johnson & Johnson — makers of the three vaccines authorized in the United States — each followed tens of thousands of volunteers in many countries for months to show the immunizations reduced the risk of infection compared with placebo. Volunteers also gave periodic blood samples for lab assessment of their immune responses.

Such clinical trials are becoming impractical because so many people have immunity through vaccination or infection. Besides, giving a placebo at this point would be unethical.

“With placebo-controlled trials becoming infeasible due to the roll out of licensed vaccines, a correlate of protection is urgently needed to provide a path for regulatory approval of novel vaccines,” Plotkin and seven colleagues wrote in a draft research paper shared on medRxiv in April.

Their study, led by Gates Foundation researcher Kristen Earle, crunched data from trials of seven vaccines that had demonstrated effectiveness ranging from 51% to 95%. The bottom line: The more effective the vaccine was at preventing infection, the higher the volunteers’ average peak antibody level.

Vaccine developers are now doing their own, more definitive analyses to identify a cutoff titer — how low a level is still protective.

“I do know,” Earle emailed this week, “that several … are coming very close to being able to submit manuscripts” on correlates of protection.

Not one-size-fits-all

Like almost everyone, Plotkin was amazed that COVID-19 vaccines arrived in record time, with excellent safety profiles, conferring even stronger immunity than natural infection.

“We have accomplished more than I would have imagined possible, and it’s been a global effort. It’s astounding. It’s thrilling,” he told the Washington Post in January.

But he has also been dismayed by the chaotic early rollout — he and his wife were not spared the anxious hunt for vaccine appointments — and by hesitation now that vaccines are readily available.

» READ MORE: COVID-19 vaccine hesitancy is understandable. But the risks vastly outweigh the benefits.

“Contrary to the early days, the distribution now is going very well,” he said. “Here in Doylestown, the local hospital has done an excellent job of setting up facilities for testing and vaccination. Regrettably, the demand has fallen off.”

While Americans have the luxury of dithering, the pandemic is decimating less affluent countries such as India where vaccine supply is scarce. Around the world, the virus continues to evolve in ways that thwart current vaccines. That’s why finding a shortcut to making booster shots and next-generation vaccines is crucial.

It is also uncertain. Researchers have never been able to define protective correlates for some vaccines, including rotavirus, mumps, and tuberculosis. Plotkin described some of the complexities. For one thing, protective correlates may differ, depending on whether the goal is to prevent infection, disease, or severe disease. For another, immune function declines with age, chronic illness, or immune-suppressing drugs, so a correlate is not one-size-fits-all.

And while antibodies are the first line of immune defense — able to repel the virus before it breaks into cells and replicates — there are more formidable lines of defense, such as B cells and T cells, which remember the virus and guard against reinfection.

“When I first started writing about this subject [of correlates], I guess I thought one could identify a correlate for every vaccine and that would be it,” Plotkin said. “I now realize that was naïve. The immune system is redundant. So it’s necessary to identify the most important immune response for preventing infection.”

For most vaccines, that means the antibody level.

Comparing antibodies

The earliest evidence that antibody levels are a reliable indicator of protection came from COVID-19 studies in Rhesus monkeys. Then circumstantial evidence began mounting. Last August, for example, a COVID-19 outbreak tore through the 122-member crew of a Seattle fishing vessel, but spared three sailors with something in common: Before the ship set sail, they were the only ones who tested positive for COVID-19 antibodies, indicating a past infection.

Recent studies have found natural infection generates weaker, shorter antibody responses than vaccination, but after recovery, COVID-19 patients may need only one dose of the two-dose vaccines for full protection.

Numerous studies around the world are now following big groups such as health-care workers to get a better handle on how quickly antibodies wane after natural infection or vaccination. And researchers at the University of Oxford are carefully but deliberately reinfecting volunteers to study the dynamics of reinfection and antibody response.

Meanwhile, the U.S. government is funding development of standardized biochemical tests, called “immunoassays,” that labs around the world can use to come up with comparable antibody measurements.

Plotkin is working on another crucial piece, an international conference where researchers and regulators could arrive at a consensus on a minimum protective antibody level.

Last fall, many of them gathered for a virtual workshop on correlates of protection, cohosted by the Coalition for Epidemic Preparedness Innovation, which Plotkin helped create in 2015.

“The Gates Foundation has been trying to achieve that” consensus conference, Plotkin said. “I’ve been communicating with the WHO about that as well. You always have some disagreement originally. That’s the way science works.

“But I’m pretty confident that a conclusion will be arrived at in a brief period of time, certainly before the end of the year.”