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Just over a century ago, a calamitous influenza outbreak swept across the globe, infecting a fifth of the world’s population and killing between 50 million and 100 million people in the space of a year.
It’s easy to assume that modern medicine protects humankind from the likes of 1918’s devastating Spanish flu. But experts warn that the world’s much larger population—increasingly connected both geographically and economically—is more vulnerable now than ever.
“In those days we didn’t have airplane flights happening a thousand times a day with stocks being traded electronically around the world,” said Martin Friede, PhD, who leads the World Health Organization (WHO) Initiative for Vaccine Research in Geneva, Switzerland.
It’s only a matter of time before the next global flu outbreak hits. Three other pandemics occurred in the past century, in 1957, 1968, and most recently in 2009, when the “swine flu” caused by a novel H1N1 virus killed an estimated 284 000 people worldwide. As Bruce Gellin, MD, MPH, of the Washington, DC–based nonprofit Sabin Vaccine Institute, put it, “It’s going to happen—we just don’t know when.”
Today’s seasonal flu vaccines protect against viral strains already circulating in people, but pandemic influenza usually originates in birds or pigs. Flu viruses that mutate and jump to humans pose the greatest public health risk when they also acquire the ability to spread efficiently among people, as was the case with the avian and swine H1N1 strains that were behind the 1918 and 2009 pandemics, respectively. Without prior exposure to similar strains through natural infection or vaccination, humans are largely unprotected.
The last 3 pandemic strains weren’t as virulent as their 1918 predecessor, so the world got off relatively easily. But a more lethal outbreak could be just a mutation away. Two influenza A virus subtypes found in poultry, H5N1 and H7N9, have caused sporadic, deadly human infections since the late 1990s but haven’t acquired the ability to circulate easily among people. If they do, the results could be catastrophic.
Recent modeling suggests that a strain like the Spanish flu could kill 33 million people within the first 6 months, roughly the amount of time it takes to produce an influenza vaccine. Millions more would likely die before most of the global population could be immunized. “The impact of a severe pandemic now would leave us crippled for ages,” Friede said.
Along with the ever-looming threat of a global flu outbreak, there’s also increasing recognition that the seasonal flu vaccine, while far better than nothing, isn’t nearly as effective as it should be. In good years, the vaccine’s estimated effectiveness has been 60%; in bad years that’s fallen to 10%. Last season’s vaccine was only 29% effective. It’s no wonder then that about half of people the National Foundation for Infectious Diseases surveyed in a recent poll said they wouldn’t bother to get a flu shot this season.
Many people underappreciate the toll of seasonal epidemics. In the United States alone, an estimated 49 million people came down with the flu during the 2017-2018 season, 960 000 were hospitalized, and 79 000 died, according to the Centers for Disease Control and Prevention. Globally, the WHO estimates that the flu kills as many as 650 000 people every year.
“We need to do much better, and the way we can do much better is to be able to get a very potent vaccine,” said Anthony S. Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health.
Scientists have talked about a “universal” flu vaccine for decades, but in the past 10 years, innovations in structure-based vaccine design, along with other advancements, have brought the goal into sharper focus. Using newer techniques like cryoelectron microscopy, researchers are designing modified influenza proteins that substitute specific molecules, amino acids, or chemical interactions. The goal: to confer advantageous characteristics that could result in more successful universal flu vaccine candidates.
The perfect vaccine would provide lifelong protection against all current and future strains of seasonal and pandemic flu. Short of this holy grail, which Fauci said is “more aspirational than realistic,” more broadly protective flu vaccines might be a reality within a few years.
A recent NIAID strategic plan aims for a vaccine that protects people of all ages against all possible permutations of the influenza A virus for at least a year, and ideally much longer. An improvement like this would be vastly better than the current vaccines. The most common version is the inactivated flu shot, which can be used by more groups than the live attenuated nasal spray. But all flu vaccines cover only 3 or 4 circulating influenza A and B strains.
Selected anew every year, those strains are a best guess based on previous season global surveillance and can sometimes miss the mark. Even when the right strains are chosen, the virus undergoes constant small mutations, a process known as antigenic drift. Manufacturing in eggs—still the primary method—is time-consuming and can exacerbate the problem, by occasionally promoting mutations in vaccine virus strains that make them somewhat off-target. All of these factors add up to a less-than-optimal vaccine.
Although new approaches like egg-free recombinant vaccines have been introduced, they haven’t been widely adopted. And none of the seasonal flu vaccines on the market offer protection from pandemic strains, new viruses that result from more significant, abrupt mutations called antigenic shifts.
A vaccine that protects against seasonal and pandemic flu has the unenviable task of covering all the innumerable bases. To get there, researchers are focusing on virus regions that are highly stable, or “conserved.” These common antigenic regions, or epitopes, elicit an immune response but also tend to stay the same across strains and over time.
The universal flu vaccine candidate that’s farthest along in clinical trials, BiondVax Pharmaceuticals’ M-001, is a recombinant protein incorporating 9 common surface and internal peptides that are broadly conserved across influenza A and B strains. The prototype is currently being tested in a NIAID-sponsored phase 2 trial, with results from a European phase 3 study expected by the end of next year. The viral common denominators in M-001 elicit both B-cell and T-cell responses, and the latter is a growing area of interest for the field. There’s evidence that, thanks to the vaccine’s T-cell priming, elderly adults immunized in a 2011 trial were protected from a new strain that emerged 3 years later.
Several teams are also looking at developing vaccines based on the conserved stem, or stalk, portion of the hemagglutinin protein, the influenza surface antigen that binds to host cell receptors and induces the primary antibody response. Hemagglutinin can be likened to a broccoli floret, with a large, highly exposed head and a smaller, less-visible stalk. Current vaccine strategies focus on the immunodominant but ever-changing head. But the more stable stalk also induces an immune response, albeit less pronounced.
Researchers at the Icahn School of Medicine at Mount Sinai in New York City and colleagues recently published the first clinical trial results involving a stalk-based approach. The team is conducting a phase 1 study of chimeric hemagglutinin-based vaccines that combine stalks from the same human influenza virus with heads from different animal influenza strains to which humans haven’t been exposed. Vaccinating with 2 of these candidates in sequence—the first live attenuated and the second inactivated—induced antibodies that strongly cross-reacted with the stalks of human, avian, and bat influenza virus subtypes in the recent interim analysis.
Another prototype, the NIAID-developed H1ssF_3928, eschews the hemagglutinin head altogether. The candidate, which entered phase 1 trials this year, is composed of lab-grown hemagglutinin stalks studding a self-assembling ferritin nanoparticle derived from Helicobacter pylori bacteria. “Instead of showing the body the entire virus, you’re showing it only that part of the virus that you want [it] to make a response against,” Fauci said.
Theoretically, without the immune distraction from hemagglutinin heads, the stalks will elicit a substantial response against all group 1 influenza A viruses. A similar prototype against group 2 influenza A viruses is also being developed, and in the future the candidates might be combined into a single universal influenza A vaccine. A broadly protective influenza B vaccine would potentially be administered in separate shot, Fauci said.
Indeed, achieving a universal flu vaccine will almost certainly be an incremental process, according to Robert Atmar, MD, an infectious disease expert at the Baylor College of Medicine in Houston and principal investigator of the M-001 phase 2 trial: “We’ll end up taking small steps—hopefully not baby steps.”
In Fauci’s view, the first key milestone is a vaccine that protects against all possible versions of a particular flu subtype, like H1N1 or H3N2. “I think we’re probably just a few years away from that,” he said.
A broader flu vaccine also could help to address the issue of immunologic imprinting, more colorfully referred to as the “original antigenic sin.” There’s increasing evidence that the first influenza strain a person encounters, either through natural exposure or vaccination, “imprints” on the immune system. Because the body is trained to mount a defense against those original antigens, imprinting may impact—and potentially hinder—a custom-built response to different strains. “For the rest of your life, whenever you get exposed to an influenza virus, you will continue to make some response against the first influenza [virus] that you ever saw,” Fauci said.
To gain more insight into how imprinting affects immunity, NIAID is funding large epidemiological studies on the relationship between a child’s first influenza infection or vaccination and their subsequent response to different flu strains. Although people of all ages would benefit from a universal flu vaccine, it would best be administered to children, “so that the first flu they see is the universal one,” Fauci said.
But there’s a harsh reality: developing countries focus their limited vaccination resources on childhood diseases. Seasonal flu epidemics primarily kill seniors, so influenza ranks low on the list compared with scourges like measles, typhoid, or polio. For many of these poorer nations, the vaccine would be a hedge against a pandemic rather than a routine childhood immunization, Friede said. In the event of a worldwide outbreak, universal flu vaccine stockpiles could mitigate the impact, a key goal of the WHO’s recently announced Global Influenza Strategy.
Collaboration has long been a missing piece of the universal flu vaccine puzzle. But spurred by scientific advances and factors like the 2009 pandemic, the WHO and other groups are coming together to accelerate progress. Chief among the new initiatives is the Global Funders Consortium for Universal Influenza Vaccine Development, an information-sharing collaboration between 20 major international groups including the WHO, the Sabin Vaccine Institute, the Bill and Melinda Gates Foundation, the United Kingdom–based Wellcome Trust, and several US Department of Health and Human Services entities.
This summer, the Gates Foundation and another Consortium member, the philanthropic Flu Lab, announced funding for 7 innovative universal influenza vaccine development projects selected from a pool of 236 international applicants. One team is focusing on neuraminidase, an influenza virus surface antigen that’s gotten less attention than hemagglutinin. Another is pursuing a T-cell approach based on landmark HIV vaccine research. Yet another will combine structural modeling, atom-based simulations, and machine learning to develop stable hemagglutinin analogues.
A separate Flu Lab collaboration is taking a different tack. Working with the Center for Open Science and the Public Library of Science, the group will help fund and publish null and negative influenza research findings and replication studies. “We are concerned that publication bias could be limiting our worldview and negatively shaping what we know about influenza,” said Casey Wright, Flu Lab’s chief executive officer.
In fact, some basic knowledge gaps are still thwarting development of a nimble flu vaccine. Scientists want to know more about how the virus is transmitted, for example, and they’re interested in what makes some people more susceptible to severe infection. Plus, to winnow down novel vaccine candidates in quick-and-dirty human challenge trials, researchers will have to find new efficacy surrogates, biomarkers known as immune correlates of protection.
“As we improve our understanding of the immune response we get and the immune response we need, that’s going to help us to design the vaccines that are going to solve this problem,” Gellin said of the overall field.
Reflecting the growing sense of urgency, NIAID recently allocated up to $51 million in first-year funding for a new network of US research centers devoted to developing and testing a universal flu vaccine. Ultimately, a highly effective flu shot that’s needed just once in a lifetime, or even every 10 years, might overcome perhaps the most stubborn obstacle—flu vaccine hesitancy. “If you get a really good universal flu vaccine, everybody would want it,” Fauci said. And if that prediction comes anywhere close to bearing out, a flu shot that engenders public trust could change the course of human history.
Influenza A and B: The main influenza virus types that infect humans. Influenza A viruses mutate frequently and are responsible for most seasonal and all pandemic outbreaks. Seasonal vaccines currently include 2 influenza A subtypes (H1N1 and H3N2) and 1 or 2 influenza B lineages (Yamagata and Victoria).
Hemagglutinin (HA) andneuraminidase(NA): Influenza A virus surface proteins. Researchers have identified 18 HA and 11 NA subtypes circulating among birds and mammals, and their combinations are used to name influenza A subtypes.
Influenza A group 1 and group 2: Subtypes that express different HA proteins on their surface.
Abbasi J. The Search for a Universal Flu Vaccine Heats Up. JAMA. Published online November 06, 2019. doi:https://doi.org/10.1001/jama.2019.16816
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