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    Flu Fighters: In Search of a Universal Vaccine


    One hundred years after the 1918 influenza pandemic killed more than 50 million people, the flu remains a major health threat. In fact, the 2017-2018 U.S. flu season was among the worst in a decade, hospitalizing over 28,000 people and taking the lives of 165 children.

    This deadly season highlights the need for a universal flu vaccine that offers protection against multiple influenza strains, experts say. In fact, the Bill and Melinda Gates Foundation and Larry and Linda Page recently established a $12 million fund to support work on such a vaccine. And scientists across the globe, including researchers at several U.S. academic medical institutions, are edging ever closer to reaching this major goal.

    “There’s no doubt that we have to do better than we are doing currently.”

    Anthony Fauci, MD
    National Institute of Allergy and Infectious Diseases

    Currently, scientists design each year’s seasonal vaccine based on the previous year’s virus and on predictions about the strain most likely to surface the following year. The approach takes some guesswork, and it isn't always successful.

    “There really is an important need for a universal influenza vaccine,” says Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID). “There’s no doubt that we have to do better than we are doing currently—the way we approach seasonal flu vaccine and our very clear lack of complete preparedness.”

    In 2017, the NIAID convened scientists from academia, industry, and government to discuss knowledge gaps, identify research strategies, and develop criteria for a universal influenza vaccine. The resulting strategic plan, published in the Feb. 28 Journal of Infectious Diseases, points to key targets for influenza research such as immunity, transmission methods, and vaccine design.

    “We’re making significant progress,” notes Fauci. “Bottom line is, [we’re] learning a lot about the fundamental basic science questions that need to be answered if we are going to be on a pathway to a universal flu vaccine.”

    Unlocking answers from the body

    To design the most effective vaccine, researchers must understand how the immune system responds to influenza, says James Crowe, MD, director of the Vanderbilt Vaccine Center at Vanderbilt University Medical Center.

    Crowe leads the Universal Influenza Vaccine Initiative, a new effort from the Human Vaccines Project (HVP). HVP is a multidisciplinary consortium of academic research centers, pharmaceutical companies, government agencies, and nonprofits dedicated to accelerating the development of vaccines and immunotherapies against major infectious diseases.

    Researchers with the initiative are studying 750 people of all ages to determine how their first flu infection and initial seasonal vaccine impact their bodies over time.

    “One of the fundamental questions in the field is: How does your prior exposure to flu vaccine or infection influence how your body responds to new ones?” Crowe says. “It’s become clear that if you’re infected or vaccinated, you develop an immune response that changes the way [your body] will recognize new viruses in the future.”

    In the last year, initiative researchers identified which previously exposed people generated high concentrations of antibodies and studied the B cells responsible for unleashing those antibodies. The efforts paid off, revealing a whole new class of flu antibodies.

    Crowe now looks ahead to the initiative’s next steps. “Researchers are now planning to harness this knowledge to design and engineer improved vaccines . . . that induce the most broad and potent protective responses,” he says.

    Latching on to what’s constant

    For Deborah Fuller, PhD, professor of microbiology at the University of Washington School of Medicine, a key step in creating a universal vaccine is identifying how best to trigger virus-killing T cells.

    Fuller’s team has designed a DNA-based vaccine using components of influenza virus that always remain the same—the conserved areas. By targeting the conserved parts of the virus, vaccines could offer broader protection.

    “One type of T cell that can see the conserved parts [of a virus] is a killer T cell,” explains Fuller. “Whether you get infected with one flu strain or another, the killer T cell induced by our vaccine will recognize it and be able to eliminate it from the body.”

    In fact, Fuller and her team succeeded in increasing flu resistance in monkeys, a recent paper in PLOS One notes.

    “We were able to show that when we immunized monkeys with this vaccine, they developed really strong killer T cell responses,” Fuller says. “When we challenged the monkeys [with H1N1 flu], we showed that our monkeys had more rapid clearance of the virus when compared to the control monkeys, and they were completely protected from any symptoms of influenza disease.”

    Interferon interference

    Another source of hope for a universal vaccine lies in unraveling the flu’s own genome to build up human immunity.

    Scientists at the David Geffen School of Medicine of the University of California, Los Angeles (UCLA) have engineered a vaccine using interferons, a key component of the immune system. Interferons play multiple roles, including serving as first responders to viruses and helping coordinate the responses of other virus-fighting cells.

    In their quest to bolster interferons, UCLA researchers spent four years sequencing the entire influenza genome to pinpoint which parts inhibited interferons, says Ren Sun, PhD, professor of molecular and medical pharmacology at UCLA. The team then produced a strain that weakened the flu’s interferon-impairing parts and used it to create their vaccine.

    When injected with the vaccine, mice and ferrets generated potent immune responses, a sign that the vaccine successfully stimulated interferons, according to research published in the journal Science.

    “We expected the virus would induce [a] response, but we were surprised by the level of the response,” says Sun. What’s more, although the vaccine was derived from an H1N1 strain, animals that were exposed to the H3N2 strain also showed an effective immune response, suggesting the potential for broad coverage.

    Moving forward, the team plans to test the vaccine on humans as well as explore the vaccine’s effectiveness in fighting other influenza strains.

    “This is a step closer to a universal vaccine,” says Sun.