A Vaccine Big Shot

In February 1940, a mysterious respiratory disease began spreading through a facility near New York City that cared for children with heart damage from rheumatic fever. Virologist Thomas Francis Jr., then at New York University College of Medicine, heard about the outbreak and began to investigate. He suspected influenza, but all the lab tests for that disease were negative. Blood from children recovering from the illness did not appear to harbor antibodies against the known type of influenza virus, for instance.

Further research on samples from the kids and on experimental animals convinced Francis that he had stumbled on a second type of influenza caused by a distinctive virus. “By a brilliant piece of thinking, we called that influenza B,” he quipped. Analyzing stored blood samples, he learned that the new virus had also triggered a much larger outbreak in the southeastern United States in 1936.

The discovery of a second flu virus proved useful almost immediately. In 1941, the U.S. Army made Francis head of its new Commission on Influenza and Vaccine Development and tasked him with producing a flu vaccine to protect soldiers. At the time, scientists had made only a few vaccines, and nobody had developed one effective for flu. But by fall 1942, the experimental vaccine that Francis and colleagues created against influenza B and the other type of flu, influenza A, was going into the arms of test subjects. It worked, and in 1945 it received approval for widespread use. That achievement earned Francis, who had moved to the University of Michigan, the Albert Lasker Clinical Medical Research Award in 1947, the second year the prize was given.

Francis “was a global leader in the field of influenza and respiratory infections,” says epidemiologist Arnold Monto of the University of Michigan. Today’s flu vaccine arsenal—nine options are available in the United States—is one legacy of his work. “The vaccines we have now are very useful, and they save lives,” says vaccinologist Florian Krammer of the Icahn School of Medicine at Mount Sinai. Over the last 80 years, flu vaccines have prevented 154 million deaths, a 2024 study estimated.

Francis made an impact on the vaccine field in other ways. He helped design and run the 1954 field tests that confirmed the effectiveness of the first polio vaccine, developed by his protégé Jonas Salk, a Lasker winner in 1956. Francis also discovered an immune system quirk that he called “original antigenic sin” that limits the body’s response to flu vaccines.

Despite the success of flu vaccines, researchers “are still chasing the viruses,” Krammer says. The pathogens evolve rapidly, allowing them to elude vaccine-induced immune system defenses. As a result, flu vaccines give only a few months of protection and must be revised every year to protect against the latest viral varieties. But Krammer and other researchers are working to devise universal flu vaccines that would offer long-term protection. A few of those vaccines have reached clinical trials, and others are under development.

Catching the Influenza Bug
Francis was born in 1900 and grew up in a small town in Pennsylvania, where his father worked in the steel industry and as a minister. After finishing his undergraduate degree at Allegheny College, Francis took his brother-in-law’s advice and applied to medical school at Yale University. The decision was risky, according to Yale virologist John Paul, who wrote a biographical memoir of Francis’s life. Because the university had just revamped its medical school, Francis and his classmates would be the guinea pigs for a new teaching approach. “He was taking a chance not to have chosen one of the established and better-known medical schools,” Paul wrote. But the new system was a boon for Francis’s career, Paul argued, because it “opened up a vista of new paths and new opportunities which he eagerly followed.”

One of those paths led him to what is now Rockefeller University in New York City, where he took a job in 1928. Francis began working in the lab of microbiologist Oswald Avery, who was studying the pneumonia-causing bacterium Streptococcus pneumoniae. The bug came in two forms—a smooth variety that triggered illness and a rough variety that was innocuous—and Avery and colleagues were trying to determine how it could switch from one type to the other. “I would spend the mornings in the laboratory learning of these phenomena and the afternoons in the library and on the tennis court developing a model of the double fault,” Francis wrote.

He soon switched his research to influenza, which captivated him for the rest of his life. Long after Francis moved on, Avery and his team performed a landmark experiment showing that DNA was the genetic molecule—research that earned Avery a Lasker award in 1947, the same year in which Francis won.

As a person, Francis was “a bit of a character,” recalls Monto, his colleague at the University of Michigan in the 1960s. “He was very formal. He only referred to you by your last name—unless he was annoyed with you.” As a scientist, Francis had a reputation as a stickler who demanded solid evidence and rigorous laboratory confirmation of results. When brought in to help design the polio vaccine trial, for example, he insisted on including a control group of children who would receive a placebo injection. That decision was controversial because some of those children would develop polio. But had the trial “not been carried out under such carefully controlled conditions, it probably would not have succeeded,” Paul wrote.

Another characteristic that made Francis an excellent scientist, Monto says, was that “he was innovative. He was very open” to new approaches. Francis showed that quality in his first major study on influenza in 1934. U.K. researchers had identified the influenza A virus the year before. Francis wanted to test whether the same virus was causing flu in the United States, but the only outbreak of the disease at the time was in Puerto Rico. Colleagues on the island had agreed to send him samples from patients, but any viruses they contained would break down before arriving in New York. Francis recommended shipping the samples in the chemical glycerin. Sure enough, when the material arrived, the flu viruses were intact. As Paul noted, the technique of stabilizing viruses in clinical samples by using glycerin “had only been introduced a few weeks previously.”

Declaring War on Flu
By the time Francis started working for the U.S. Army in 1941, he and other researchers had crafted several experimental flu vaccines. Tests in patients were unimpressive, however. As Francis concluded, “none of these studies gave evidence that the vaccination had any significant effect against the natural disease.” He suggested three possible explanations: the vaccines did not include enough virus to induce immunity, did not include the right virus to fight the type of influenza spreading at the time, or were given when there was no flu outbreak.

Collaborating with Salk, who played a crucial role in the project, and other researchers, Francis developed a strategy to overcome all three problems. To obtain large quantities of the viruses, the scientists grew them in chicken eggs, a method other researchers had also tried (and is still used to produce some flu vaccines). But Francis and Salk had recently improved the procedure for isolating flu viruses from eggs, and they used their approach to prepare most doses of the vaccine.

The researchers inactivated the viruses with formaldehyde to make sure they wouldn’t cause the flu. To ensure protection against influenza A and B, they included both types of viruses in their preparations. They also took care to test the vaccine at the right time. In temperate climates, flu epidemics occur during most winters, and the researchers expected that one would start late in 1942. So that fall, they injected their vaccine into 5,000 subjects and gave another 5,000 placebo shots. “We then sat down to await the epidemic,” Francis wrote.

But it never came. Hoping to gather at least some evidence about the vaccine’s effectiveness, Francis and colleagues exposed a few subjects to influenza A or B by having them inhale preparations containing the viruses. The vaccine appeared to be effective. For example, in the group exposed to the influenza B virus, 40% of control patients developed flu, versus only 10% of people who had received the vaccine. Still, the results were not definitive because of the small number of subjects.

Francis and his team got a second chance in fall 1943. An epidemic of influenza A began just two weeks after they delivered their vaccine or a placebo to more than 12,000 subjects. The recipients who got the vaccine fared better. At the University of Michigan, for instance, 8.1% of the control group ended up in the hospital for influenza, whereas only 2.3% of subjects in the active vaccine group did—a 70% reduction in the risk of hospitalization.

Once the researchers showed that the vaccine worked, the Army planned to vaccinate every soldier. The war ended before that program began in late 1945, but 8 million military personnel received the injections that year, and civilians began getting them as well.

After the war, Francis continued to make major contributions to researchers’ understanding of flu viruses and vaccines. In the 1950s, he and colleagues discovered a surprising phenomenon that he called original antigenic sin—researchers now prefer the term “imprinting”—in which the immune system generates the strongest response the first time a person encounters a flu virus, either through vaccination or natural infection. Imprinting hampers the immune system’s ability to respond to fast-evolving viruses such as the flu viruses, says virologist Kanta Subbarao of Laval University. “If a pathogen changes over time, you don’t want to be stuck” with the old response.

Moreover, imprinting is “an obstacle” for flu vaccine development, says vaccinologist Ted Ross of the Cleveland Clinic’s Lerner Research Institute. Researchers are now trying to devise strategies to circumvent it. One possible approach, Ross says, would involve tailoring flu vaccines for each age group. People born in the 1990s and the 2000s might get different shots, for instance.

The Battle Goes On
Many people still receive flu vaccines made from inactivated viruses grown in eggs, the direct descendants of Francis’s formulations. But flu vaccines are no longer one-size-fits-all, Subbarao says. Today’s repertoire includes nasal sprays for people afraid of needles, egg-free shots made through genetic engineering, and supercharged vaccines for elderly people with weak immune systems.

Francis might be impressed by the range of approaches, but he also “might ask why we haven’t solved all those issues” that he had to struggle with, Krammer says. The biggest of those problems is the rapid evolution of flu viruses. The disease results from “a swarm of genetically related but distinct viruses,” says immunologist Jonah Sacha of Oregon Health & Science University. They are continually mutating, reshaping the surface proteins that the immune system recognizes. “As soon as a virus starts changing its outer surface, it wreaks havoc with our vaccines,” he says.

Vaccine makers combat viral evolution by updating their products annually, though the process is expensive, cumbersome, and can miss the mark. The World Health Organization’s global influenza program monitors circulating influenza viruses. Twice a year, scientists meet to assess whether the current vaccine needs to be updated to include a new variant. Because manufacturers need six months to prepare the shots, the viral mix can be out of date by the time the flu epidemic begins, and the vaccines may furnish little protection. Annual shots also don’t work against pandemic flu, the more dangerous form of the disease that results when the influenza A virus undergoes dramatic changes. The 1918–1919 pandemic killed up to 100 million people globally, but less severe pandemics also occurred in 1957, 1968, and 2009.

Those limitations explain the current push to develop universal vaccines that wouldn’t require annual updates and would guard against pandemic flu. The Collaborative Influenza Vaccine Innovation Centers (CIVICs) program from the National Institute of Allergy and Infectious Diseases has been funding research into various longer-lasting vaccines since 2019. The U.S. government also recently funneled an additional $300 million into one universal vaccine approach.

Current flu vaccines induce immune defenses that target hemagglutinin, one of the proteins jutting from the surface of a flu virus. However, the outer portion of hemagglutinin changes quickly. Researchers are trying several strategies to zero in on more stable parts of the viruses. By analyzing multiple virus variants, Ross and his team identified sections of hemagglutinin that stay constant and then combined them to make vaccines. In their 2025 study, vaccines created with that approach protected lab animals from the flu. Taking a different approach, Krammer and colleagues are looking to create vaccines that target the viral protein neuraminidase, which evolves more slowly than hemagglutinin.

Five universal flu vaccine candidates are set to begin initial clinical trials in 2026 and 2027—if funding for the CIVICs program is renewed. Such approaches won’t confer lifelong immunity, Ross says, but “even a vaccine that produces a protective immune response that lasts for five years would be a big improvement.” With those new options on the horizon, Francis’s optimism about the future of flu vaccination rings true today: “The outlook for increasingly broad and effective prophylactic immunization against the range of influenza viruses is extremely promising.”

By Mitchell Leslie