NIAID Now | May 06, 2021
Wouldn’t it be great to get a flu vaccine once and then feel confident that you’d be well protected from influenza for years to come? That’s the dream of designers who are working to develop so-called universal flu vaccines. They envision a vaccine that would prompt a robust, long-lasting immune response in the form of antibodies capable of recognizing most of the ever-evolving strains of influenza virus.
Recently, scientists at NIAID’s Vaccine Research Center (VRC) and their NIAID-supported colleagues at the University of Washington School of Medicine’s Institute for Protein Design (IPD) used small particles to make a huge leap towards the goal of a universal flu vaccine. The team was led by Barney Graham, M.D., and Masaru Kanekiyo, D.V.M., Ph.D., and Seyhan Boyoglu-Barnum, Ph.D., from the VRC, and IPD’s Neil King, Ph.D., and Daniel Ellis, Ph.D., and included NIAID-funded investigator David Veesler, Ph.D., of University of Washington. The research was published online in Nature in March, 2021.
We must be re-vaccinated against flu every year because the influenza virus is constantly mutating, especially in its hemagglutinin (HA) surface protein. The HA surface protein is recognized by the immune system, which develops virus-fighting antibodies matched to its latest configuration. Most commercially available seasonal flu vaccines are quadrivalent, meaning they contain the four virus strains that global health authorities predict will be most prominent in the coming flu season. Inaccurate predictions can lead to a seasonal flu vaccine that is “mismatched” to the circulating strains and the HA-targeting antibodies generated by such a mismatched vaccine may be less than fully effective at preventing infection.
Like standard flu vaccines, the experimental one made by the VRC and University of Washington investigators is designed to elicit antibodies targeted to HA proteins from four seasonal flu virus strains. It differs from current, commercial flu vaccines, however, because the HA antigen components are displayed in a repeating pattern on scaffolds made of self-assembling nanometer-sized particles. At one-billionth of a meter, a nanoparticle is truly tiny—a human hair is about 90,000 nanometers wide. The scientists created four separate types of nanoparticles, each displaying a single HA, as well as mosaic nanoparticles that contained all four HAs. Importantly, and unlike any currently available flu vaccine, the nanoparticle vaccines display 20 HA antigens arranged in repeated patterns; such repeated antigenic patterns send a strong “danger” signal to the immune system and prompt vigorous antibody responses.
Next, the investigators tested the nanoparticle vaccines in mice, ferrets, and nonhuman primates and compared the immune responses to those generated by a commercially available seasonal quadrivalent flu vaccine. Both vaccines contained the same four human flu virus strains from the 2017-18 season (two influenza type A strains of subtypes H1 and H3 and two influenza type B strains.) The nanoparticle vaccine performed as well as or slightly better than the commercial vaccine in eliciting antibodies matched to the vaccine HA components.
Where this nanoparticle vaccine far outperformed standard flu vaccine, however, was in its ability to elicit protective antibodies to influenza type A subtypes H5 and H7. These are flu virus subtypes (examples include H5N1 and H7N9) that usually infect birds, but that have the potential to spark a human influenza pandemic should they acquire the ability to infect and spread easily between people. In their new research, the scientists determined that a vaccine mixture of the four HA nanoparticles conferred 73% protection against H5 and H7 viruses when tested in mice, while the mosaic nanoparticle vaccine conferred an impressive 92% protection against those subtypes. In contrast, the commercial flu vaccine conferred very little (12%) protection against viral subtypes not represented in the vaccine.
Subsequently, the investigators used electron microscopy to examine the interactions between HA and the vaccine-elicited antibodies. Antibodies that recognized H1 subtype virus did so primarily via interaction with a part of HA within its globular head (the receptor-binding domain) that varies greatly from strain to strain and undergoes continual change. In comparison, antibodies recognizing H5 and H7 subtypes could bind to HA’s stem region, which does not vary as much among subtypes. Scientists believe that a long-lasting and broadly protective flu vaccine would likely need to elicit stem-directed antibodies.
A version of the nanoparticle flu vaccine has been manufactured with the aim of launching a first-in-humans, Phase 1 clinical trial at the NIH Clinical Center in Bethesda, Maryland, in the coming weeks. Eventually, if this or another of the several universal flu candidate vaccines now being developed proves to be safe and effective, we may one day have to roll up our sleeves just once to gain years of protection from many flu strains.
Reference: S Boyoglu-Barnum et al. Quadrivalent influenza nanoparticle vaccines induce broad protection. Nature DOI: 10.1038/s41586-021-03365-x (2021).