A new nanoparticle-based system allows flu vaccines to be assembled in Lego-like fashion. Besides simplifying the construction of multivalent flu vaccines, the system also makes it possible to arrange diverse antigens in well-ordered arrays. Specifically, the distinct antigens—hemagglutinin (HA) glycoprotein trimers—may be displayed in defined ratios on a single nanoparticle.

In animal studies, well-ordered mosaic vaccines based on the new nanoparticle approach provided protection that was at least as broad as that provided by current quadrivalent flu vaccines. This encouraging finding represents progress toward a universal flu vaccine, suggested the nanoparticle-based system’s creators, a research team led by scientists at the University of Washington School of Medicine and the Vaccine Research Center, part of the National Institute of Allergy and Infectious Diseases.

Details about the nanoparticle-based system appeared March 24 in the journal Nature, in an article titled, “Quadrivalent influenza nanoparticle vaccines induce broad protection.” The article described vaccines that were built around a self-assembling, two-component nanoparticle core. Studding this core are HA trimers.

Four nanoparticles were assembled that each incorporated just one of four different HA trimers; that is, each of the four nanoparticles incorporated a different HA trimer. These nanoparticles were mixed together into a four-nanoparticle cocktail. Another nanoparticle was assembled that incorporated the four different HA trimers on a single nanoparticle, which was called a mosaic nanoparticle.

The nanoparticles incorporated 20 HA trimers. In the mosaic nanoparticles, in vitro assembly enabled the precisely controlled co-display of multiple distinct HA trimers in defined ratios.

Next, the article described experiments to assess the immunogenicity of the cocktail (qsCocktail-I53_dn5), the mosaic (qsMosaic-I53_dn5), and a commercial 2017–2018 quadrivalent influenza vaccine (QIV) in mice, ferrets, and nonhuman primates. In general, both nanoparticle immunogens elicited roughly equivalent or superior neutralizing activity to QIV, with the mosaic outperforming the cocktail against certain challenges.

The nanoparticle vaccines—but not the commercial vaccines—induced protective antibody responses to viruses not contained in the vaccine formulation. These include avian influenza viruses H5N1 and H7N9, which are considered pandemic threats.

“Nanoparticle immunogens that co-display the four haemagglutinins of licensed quadrivalent influenza vaccines elicited antibody responses in several animal models against vaccine-matched strains that were equivalent to or better than commercial quadrivalent influenza vaccines, and simultaneously induced broadly protective antibody responses to heterologous viruses by targeting the subdominant yet conserved haemagglutinin stem,” the article’s authors wrote. “The combination of potent receptor-blocking and cross-reactive stem-directed antibodies induced by the nanoparticle immunogens makes them attractive candidates for a supraseasonal influenza vaccine candidate with the potential to replace conventional seasonal vaccines.”

Essentially, the researchers developed experimental flu shots that protect animals from a wide variety of seasonal and pandemic influenza strains. The mosaic vaccine product is currently being advanced toward clinical testing. If proven safe and effective, the mosaic vaccine could inspire confidence that next-generation influenza vaccines could replace current seasonal options by providing protection against many more strains that current vaccines do not adequately cover.

“The responses that our vaccine gives against strain-matched viruses are really strong,” said Daniel Ellis, a research scientist at the University of Washington and one of the Nature article’s lead authors. “The additional coverage we saw against mismatched strains could lower the risk of a bad flu season.”

Influenza virus causes an estimated 290,000–650,000 deaths per year. Available flu vaccines, which need to be taken seasonally, often fail to protect against many circulating flu strains that cause illness, and the threat of another influenza pandemic looms.

“Most flu shots available today are quadrivalent, meaning they are made from four different flu strains,” noted Ellis, who is a member of the Neil P. King laboratory at the University of Washington. “Each year, the World Health Organization makes a bet on which four strains will be most prevalent, but those predictions can be more or less accurate. This is why we often end up with ‘mismatched’ flu shots that are still helpful but only partially effective.”

King, one of the Nature article’s senior authors, leads research that extends computational methods to design functional protein nanomaterials for applications in structure-based vaccine design and targeted delivery of biologics. In the current study, King and colleagues concluded that in addition to evaluating safety and reactogenicity, the upcoming trial should reveal “the effect of complex and individualized influenza exposure histories on the responses elicited by this nanoparticle immunogen and bring us one step closer to a universal influenza vaccine.”