Like millions of people in the United States last year, Stanley Plotkin and his wife got vaccinated against influenza at the start of the Northern Hemisphere’s flu season, in early October. Plotkin, a physician and emeritus professor at the University of Pennsylvania, knew well the value of the shot: He is one of the world’s most renowned vaccinologists, having had a hand in several vaccines on the market, including the one for rubella. He’s even the co-author of the standard medical textbook, Vaccines.

In January, just 3 months later, the couple got a second flu shot.

That was an unusual choice, one not recommended by the U.S. Advisory Committee on Immunization Practices (ACIP), which guides the country’s vaccine usage. But a growing body of evidence that the protective immune responses triggered by flu vaccines wane in a matter of weeks persuaded Plotkin to return to the clinic. “The time and cost was trivial compared to the importance of influenza at my age,” says Plotkin, 86. “With flu, we’re not talking about getting a case of the sniffles.”

It’s not just flu. Recent studies show vaccines for mumps, pertussis, meningococcal disease, and yellow fever also lose their effectiveness faster than official immunization recommendations suggest. Vaccines have been a crucial public health tool for decades, so it may seem strange that their durability isn’t well understood. But vaccines are approved and come to market years before it’s clear how long protection lasts. Later, fading protection can go unnoticed because a vaccine in wide use has largely eliminated transmission of the microbes it protects against, making “breakthrough” infections rare. Even if viruses or bacteria are still in circulation, people vaccinated against them will sometimes receive natural boosting of their immunity. And declining vaccine immunity is not an all-or-nothing phenomenon: A breakthrough infection often leads to much less severe symptoms of the disease.

Researchers are ramping up efforts to figure out why some vaccines protect for mere weeks but others work for life. “We simply don’t know what the rules are to inducing long-lasting immunity,” says Plotkin, who began to research vaccines in 1957. “For years, we were making vaccines without a really deep knowledge of immunology. Everything of course depends on immunologic memory, and we have not systematically measured it.”

Bali Pulendran, an immunologist at Stanford University in Palo Alto, California, has reached the same frustrating conclusion about vaccine durability. “I keep saying, ‘It’s not well understood, it’s not well understood.’ This is one of the major issues in vaccines.” Deepening the confusion, two essential vaccines, against diphtheria and tetanus, appear to have better durability than widely presumed.

Yet some clues are surfacing from unusually successful vaccines that drive the immune system to mount effective responses for decades, if not an entire human life. One comes from the vaccine against the cancer-causing, sexually transmitted human papillomavirus (HPV), which has proved remarkably durable since it debuted about a decade ago, spotlighting a novel mechanism of long-lasting protection. New insights about durability are also leading researchers to more intensively scrutinize the vaccine booster recommendations by ACIP and similar oversight bodies.

Still, Wayne Koff, an immunologist who heads the nonprofit Human Vaccines Project in New York City, says vaccine durability deserves far more attention than it has received. “If you could understand this,” Koff says, “you could make all vaccines better.”

Mimicking natural immunity

More than 150 years ago, a natural experiment on a rocky, volcanic archipelago between Scandinavia and Iceland proved that an infection can trigger lifelong immunologic memory. Measles raced through residents of the Faroe Islands in 1781. The disease did not reappear on the isolated island group for 65 years, when a visitor brought it back. A thorough study found that no one alive during the first outbreak became ill again. Their elderly immune systems remembered and fought off the virus.

Vaccinemakers aim to duplicate such spectacular feats of immune memory. They create harmless mimics of disease-causing viruses or bacteria, or their toxins, designed to teach immune systems to recognize the real thing and quickly mount robust immune responses. Immunologists believe that for many infectious diseases, long-lived memory B cells are key to that response. When confronted by known enemies, those cells quickly expand and produce hordes of antibodies that latch onto the invaders, preventing infections. Vaccines also can train “killer” T cells, which mop up when antibodies fail, eliminating infected cells.

“For a lot of the things we have vaccines against, antibodies are probably the protective mechanism,” says Mark Slifka, an immunologist who specializes in vaccine studies at the Oregon National Primate Research Center in Beaverton. “For the hard ones to vaccinate against—TB [tuberculosis], malaria, HIV—antibodies play some role, but you need T cells.”

Vaccine designers debate the best way to trigger those responses. Some designers hold fast to the idea that a live but weakened pathogen—or genes from it stitched into a harmless virus that acts as a Trojan horse—induces the longest-lasting, most robust responses. Just such a weakened virus is the basis of the measles vaccine, for example, which protects for life. But Pulendran calls this notion simpleminded. He and others argue that a killed pathogen or a genetically engineered variant of it can work equally well.

For the flu, both killed (also known as inactivated) and live virus vaccines exist—and neither offers sturdy protection. Even when they closely match the circulating strains of influenza viruses, both types protect only about 60% of vaccinated people. And those modest immune responses rapidly wane.

If you could understand [durability], you could make all vaccines better.

In a 2018 review of 11 recent studies on the durability of influenza vaccines, researchers concluded that effectiveness can vanish as soon as 90 days after vaccination. The article, published in Clinical Infectious Diseases, further noted that 20% of Americans received their flu vaccines for a given season by the end of September—which means the vaccine may do nothing come peak flu spread in January and February. “The further away you get from your vaccine, the higher the risk that you’ll contract influenza,” says study co-author Kunal Rambhia, a drug delivery specialist working on a Ph.D. at the University of Michigan in Ann Arbor. “This has huge implications.”

Rambhia says ACIP has good reason to urge people to get vaccinated early, given the challenge of immunizing more than 100 million Americans each year. “They’re making the best decision they can,” he says. “They acknowledge that the vaccine might be less effective toward the end of the flu season.”

He and others also note that a vaccine can offer a benefit even if it “fails.” In people who receive the flu vaccine but become ill, the disease often is markedly less severe. Such partial protection was first recognized more than a century ago with the smallpox vaccine, which fully prevents disease for only a few decades, but powerfully shields people from severe illness and death for life.

Resurgence of mumps

Before the mumps vaccine came to market in 1967, more than 90% of U.S. children suffered from the viral disease, which swells the salivary glands and causes a puffy face and fever. By the 2000s, the country had only a few hundred cases per year. But then in 2006, mumps surged on college campuses in the Midwest, with 6500 cases tallied before the year’s end. Nearly 85% of the college-age people who became ill had received the recommended two doses of the mumps vaccine. Despite wide use of the vaccine, mumps outbreaks continue in the United States on college campuses and in tightly knit religious communities.

Some researchers speculate that the vaccine fails because mutations in the virus allow it to evade the immunity generated by the vaccine. But epidemiologist Joseph Lewnard of the University of California, Berkeley, and immunologist Yonatan Grad of the Harvard T.H. Chan School of Public Health in Boston recently analyzed data on the outbreaks—which have also occurred in Europe, Asia, and Canada. They reported last year in Science Translational Medicine that the disease disproportionately strikes people between 18 and 29. That pattern, Lewnard and Grad conclude, implies the vaccine itself loses effectiveness, because a new mumps strain that has genetically “escaped” should strike other age groups just as often. In a dozen other studies of mumps outbreaks around the world, researchers have also found signs of waning protection.

Lewnard and Grad’s modeling indicates that adding a third dose of mumps vaccine around age 18 and then booster shots every 10 years could dramatically decrease the likelihood of outbreaks. The researchers note that since 1991 the U.S. military has given all its recruits a mumps vaccine booster and not had a single outbreak, even though troops live in close quarters.

Sorting out waning immunity from other factors that influence a vaccine’s success isn’t straightforward, as a mumps outbreak that began in Arkansas in August 2016 shows. More than half the cases were in school-aged children, 92% of whom had been fully vaccinated. “At first, I thought the data had to be wrong because they didn’t fit our model,” Grad says.

The outbreak, which continued until September 2017 and afflicted nearly 3000 people, was concentrated in people from the Marshall Islands. They have a large community in rural Arkansas that attends the same churches and lives in jam-packed houses. According to a February report in The Lancet Infectious Diseases, 92% of affected children had received both doses of the mumps vaccine. Intense exposure to mumps in the close-knit community apparently overwhelmed what should have been robust protection. “Protection from a vaccine is not all or nothing,” Grad says. “The more exposed you are, the likelier you are to get infected.”

Last year, ACIP recommended a third dose of the mumps vaccine—but only for people who are “part of a group or population at increased risk” because of an outbreak.

Needing a boost?

The growing understanding of the speed at which vaccine-trained immune systems can lose their muscle has raised concerns about some recent public health decisions. In 2016, the World Health Organization (WHO) in Geneva, Switzerland, changed its legally binding regulations about use of the yellow fever vaccine, an attenuated form of the virus, which went into wide use in the 1940s and has spared untold millions from disease and death. Three years earlier, an expert committee had found a mere 12 cases of yellow fever among the more than 540 million people worldwide vaccinated against the disease over nearly 70 years. So WHO shifted from requiring booster shots every 10 years to a single, lifetime shot.

That was a mistake, says Slifka, who, along with his work at the primate lab, is president of Najít Technologies, a Beaverton-based company making a new yellow fever vaccine. In the December 2016 issue of the Expert Review of Vaccines, he and his Najít colleague Ian Amanna argue that what looked like near-perfect protection to the expert committee reflects the fact that many vaccinated people are never exposed to yellow fever. The authors also point to a Brazilian study that came out after the expert committee’s analysis, which reported 459 cases of the disease in vaccinated people in that country alone over 35 years. In 52% of those cases, 10 years or more had passed since the person’s vaccination. “The yellow fever vaccine–induced immunity is long-lived, but only in 80% of people,” Slifka says.

Antibody data back that argument. Slifka and Amanna point to a Centers for Disease Control and Prevention (CDC) review of nine studies that analyzed blood levels of yellow fever antibodies that can “neutralize” the virus, a test tube measure of potency that is key to a vaccine’s effectiveness. Four of the studies were done in people from areas where yellow fever virus circulates, finding that 97.6% of them had detectable neutralizing antibodies 10 years after vaccination. But in the other five studies, from areas with little or no yellow fever, only 83.7% of vaccinated people had those signs of immunity. To Slifka, that finding indicates that without periodic exposure to the pathogen, people gradually lose protection. “We need at least one booster,” he says.

Plotkin says he strongly agrees that WHO should reconsider its recommendation to drop booster shots. “There’s no doubt there’s a problem,” he says.

A WHO spokesperson for the expert committee that evaluates vaccines says it continues to review new data on breakthrough cases of yellow fever, closely monitoring the duration of immunity in people who received a single dose. “The evidence provided does not support the need for [a] booster dose,” the spokesperson says, noting that WHO cautions against “overinterpretation” of antibody data.

Combo confusion

Some vaccinologists are also questioning a 1991 switch to a putatively safer vaccine against pertussis, which causes whooping cough. For decades, the United States and other countries enjoyed great success with a vaccine made from killed Bordetella pertussis, the bacterium that causes the disease. But that “whole cell” vaccine became the centerpiece of an antivaccine movement some 40 years ago because of a much-debated claim that in rare cases it caused serious neurological damage. So an acellular vaccine, containing an inactivated version of the pertussis toxin that causes the disease as well as pieces of B. pertussis, replaced it.

The vaccine is given with two others, against diphtheria and tetanus. ACIP calls for six doses of the triple-combo vaccine between infancy and age 12. It then recommends tetanus and diphtheria boosters every 10 years for adults. Despite the rigorous vaccination schedule, in 2010–11 and 2014–15 California experienced about 20,000 pertussis cases in two massive outbreaks.

To find out whether waning protection was to blame, Kaiser Permanente in Northern California, a health care system that has detailed medical records for its millions of long-term patients, examined more than 4000 children from 2006 to 2015. The team concluded that protection waned 27% per year after children’s fifth dose of the acellular vaccine, which is given between ages 4 and 6. “We will be increasingly vulnerable to pertussis outbreaks until vaccines which provide more enduring protection are developed,” the researchers concluded in their analysis in the 8 June 2017 issue of Vaccine.

Slifka says the replacement of the whole cellular vaccine with the acellular one was unnecessary and a mistake. “Acellular starts with 80% to 90% protection but crashes over the next few years,” he says, which leaves many children dangerously susceptible between their fifth dose and sixth given at 11 or 12 years of age. (B. pertussis causes relatively mild symptoms, if any, in teens and adults but can be deadly in younger children.)

Ironically, the two other components of the triple vaccine have surprising staying power. The primate center where Slifka works draws blood from its employees to monitor potential infections to and from monkeys and other nonhuman primates. Slifka, Amanna, and colleagues obtained blood samples collected over a 26-year period and assessed how quickly antibodies to the tetanus and diphtheria bacteria decayed after vaccination. It would take more than 40 years for people to begin to lose protective immunity against those two pathogens, they reported last year in PLOS Biology. “We have a much higher level of immunity than previously realized,” Slifka says.

WHO, Slifka notes, already does not recommend tetanus and diphtheria boosters for adults who have received their complete childhood shots. He says ACIP, a rotating group of vaccine experts that meets three times a year and regularly revises recommendations, should also consider withdrawing its recommendation for boosters. He estimates eliminating those shots would save the United States about $1 billion per year.

Durability clues

Just why one vaccine in the trio fades while the others work for almost a lifetime underscores the broader mystery of how to make vaccines more durable. But clues are coming from an unusual vaccine against HPV.

Concerned that an attenuated or an inactivated HPV vaccine might still contain viral components that can cause cancer, researchers genetically engineered another virus to manufacture copies of a harmless HPV surface protein that self-assembles into what’s called a viruslike particle (VLP). Trials have shown that nearly everyone vaccinated with that noninfectious VLP develops high levels of HPV-neutralizing antibodies. Those levels decline moderately after 2 years but then remain stable for at least a decade. “Until we did the human studies with the vaccine, we really weren’t aware we were going to get such consistent and durable antibody responses,” says John Schiller, an oncologist at the National Cancer Institute in Bethesda, Maryland, who in the 1990s pioneered development of the vaccine, which protects against genital cancers and warts

VLPs challenge the widely held notion that durability depends primarily on memory B cells waking and expanding when an infection occurs. Schiller notes that the HPV vaccine leads to consistent blood levels of neutralizing antibodies for years on end. “If it were memory B cells, you should see spikes, blips up and down,” he says.

Schiller and others contend that VLPs trigger production of a different set of B cells called long-lived plasma cells (LLPCs), which reside in the bone marrow and continually produce antibodies specific to different foreign antigens. “Viruslike particles are clearly the best way to make LLPCs,” Schiller says.

In the wake of the HPV vaccine’s success, VLPs have become a trendy vaccine strategy. A hepatitis E vaccine on the market in China uses VLPs, and experimental influenza, norovirus, chikungunya, encephalitis, malaria, and dengue VLP vaccines are in development.

Yet no one knows precisely how VLPs prod the immune system to make LLPCs. Schiller points to the work of Nobel Prize winner Rolf Zinkernagel of the University of Zurich in Switzerland and his then–graduate student Martin Bachmann. They reported 25 years ago that dense, highly repetitive proteins on the surfaces of viruses trigger the strongest antibody responses. A VLP is just such a structure. In theory, that allows the viral antigens to “cross-link” to many receptors on the surface of B cells. That, in turn, triggers a cascade of signals in immune cells that lead to strong, durable antibodies. How? “That’s the million-dollar question,” Slifka says.

Such unknowns frustrate him, he says. He also laments what he sees as a disconnect between epidemiologists who investigate vaccine breakthrough infections during outbreaks and the type of laboratory studies he and other researchers conduct about immune mechanisms of protection and their durability. “How do we sort out this mess?” he asks. “We need to have the epidemiologists and the immunologists discuss their findings. Both sides could learn so much.”

The flu season in North America is ending. CDC estimates that the virus sickened nearly 40 million people, hospitalized half a million, and killed up to 50,000. Neither Stanley Plotkin nor his wife developed the disease.