When developing influenza vaccines, researchers are forced to predict the genetic makeup of the virus some months in advance, and mismatches occur relatively frequently as strains become antigenically diverse. This makes it more difficult to match strains to vaccines. In a pandemic setting, vaccine matching and development could take up to six months, during which time the population is vulnerable. Therefore, the development of a universal influenza virus vaccine is desirable.

There are four classes of influenza viruses (A-D), with influenza A and B causing most seasonal epidemics. The serotype of influenza A virus is determined by the hemagglutinin (HA) and neuraminidase (NA) proteins present on its surface, and there are at least 18 subtypes of HA in influenza A.

Most current influenza vaccines target the immunodominant head domain of the viral HA and therefore antibodies produced by these vaccines are strain specific. HA are homotrimeric glycoproteins found on the surface of influenza viruses. The membrane-proximal stalk domain of the HA tends to be more conserved compared to the head. However, it has been traditionally difficult to induce a potent antibody response against the stalk region of the HA.

"Unfortunately, the virus is able to escape neutralization by mutating this part of hemagglutinin through a process known as antigenic drift," explained co-author Peter Palese, PhD, professor and chair of the department of microbiology at the Icahn School of Medicine at Mount Sinai. "This genetic change, or shift, in the virus results in immunity to only specific strains of the influenza virus, requiring frequent re-formulation and re-administration of seasonal vaccines. Our chimeric HA vaccine, by contrast, is directed at the proximal part of the HA protein -- the stalk domain -- which has been shown to broadly neutralize diverse influenza virus strains in both animal models and humans."

To redirect immune responses from the head to the stalk, researchers from Mount Sinai have developed a sequential chimeric HA (cHA) vaccine. The vaccine consists of group 1 or group 2 stalk domains in combination with head domains from avian influenza virus subtypes.

"An influenza virus vaccine that results in broad immunity would likely protect against any emerging influenza virus subtype or strain and would significantly enhance our pandemic preparedness, avoiding future problems with influenza pandemics as we see them now with COVID-19," said author Florian Krammer, PhD, professor of microbiology at the Icahn School of Medicine at Mount Sinai, in a statement. "Our chimeric hemagglutinin vaccine is a major advance over conventional vaccines which are often mismatched to the circulating strains of virus, impacting their effectiveness. In addition, revaccinating individuals annually is a huge and expensive undertaking."

The researchers conducted a randomized, multicenter, observer-blind, placebo-controlled phase I clinical trial to evaluate the safety and immunogenicity of the group 1 cHA-based vaccine (a live attenuated or inactive influenza virus vaccine expressing a cH8/1 HA and an N1 NA with a backbone from a master donor stain) in 65 participants in the U.S.

The team found that a single vaccination with adjuvanted, inactivated cHA vaccines induced remarkably high anti-stalk antibody titers. They also found that immunoglobulin G (IgG) serum antibody titers were long-lived. While titers decreased after vaccination, they stabilized over baseline at six months after a booster dose and remained constant even after 18 months.

In previous animal studies, the researchers determined that the Fc-FcR (immunoglobulin receptors)-mediated effector functions were important mechanisms of protection of anti-stalk antibodies. Antibodies induced in the trial showed strong activity in both antibody dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis reporter bioassays. Therefore, the anti-stalk monoclonal antibodies showed multifunctionality in terms of antiviral activity.

"The beauty part of this vaccine is that it's not only broad, but multifunctional with stalk-specific antibodies that can neutralize many kinds of influenza viruses," said co-author Dr. Adolfo García-Sastre, director of the Global Health and Emerging Pathogens Institute and professor of microbiology at the Icahn School of Medicine at Mount Sinai. "This universal vaccine could be particularly beneficial to low and middle income countries that don't have the resources or the logistics to vaccinate their populations each year against influenza."

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