Influenza viruses pose a significant threat to the public and are a burden on global health systems. Each year, influenza vaccines must be rapidly produced to match circulating viruses, a process constrained by dated technology and vulnerable to unexpected strains emerging from humans and animal reservoirs. Here we use knowledge of protein structure to design self-assembling nanoparticles that elicit broader and more potent immunity than traditional influenza vaccines. The viral haemagglutinin was genetically fused to ferritin, a protein that naturally forms nanoparticles composed of 24 identical polypeptides. Haemagglutinin was inserted at the interface of adjacent subunits so that it spontaneously assembled and generated eight trimeric viral spikes on its surface. Immunization with this influenza nanoparticle vaccine elicited haemagglutination inhibition antibody titres more than tenfold higher than those from the licensed inactivated vaccine. Furthermore, it elicited neutralizing antibodies to two highly conserved vulnerable haemagglutinin structures that are targets of universal vaccines: the stem and the receptor binding site on the head. Antibodies elicited by a 1999 haemagglutinin-nanoparticle vaccine neutralized H1N1 viruses from 1934 to 2007 and protected ferrets from an unmatched 2007 H1N1 virus challenge. This structure-based, self-assembling synthetic nanoparticle vaccine improves the potency and breadth of influenza virus immunity, and it provides a foundation for building broader vaccine protection against emerging influenza viruses and other pathogens.

Background Waning of vaccine protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (Covid-19) is a concern. The persistence of BNT162b2 (Pfizer–BioNTech) vaccine effectiveness against infection and disease in Qatar, where the B.1.351 (or beta) and B.1.617.2 (or delta) variants have dominated incidence and polymerase-chain-reaction testing is done on a mass scale, is unclear. Methods We used a matched test-negative, case–control study design to estimate vaccine effectiveness against any SARS-CoV-2 infection and against any severe, critical, or fatal case of Covid-19, from January 1 to September 5, 2021. Results Estimated BNT162b2 effectiveness against any SARS-CoV-2 infection was negligible in the first 2 weeks after the first dose. It increased to 36.8% (95% confidence interval [CI], 33.2 to 40.2) in the third week after the first dose and reached its peak at 77.5% (95% CI, 76.4 to 78.6) in the first month after the second dose. Effectiveness declined gradually thereafter, with the decline accelerating after the fourth month to reach approximately 20% in months 5 through 7 after the second dose. Effectiveness against symptomatic infection was higher than effectiveness against asymptomatic infection but waned similarly. Variant-specific effectiveness waned in the same pattern. Effectiveness against any severe, critical, or fatal case of Covid-19 increased rapidly to 66.1% (95% CI, 56.8 to 73.5) by the third week after the first dose and reached 96% or higher in the first 2 months after the second dose; effectiveness persisted at approximately this level for 6 months. Conclusions BNT162b2-induced protection against SARS-CoV-2 infection appeared to wane rapidly following its peak after the second dose, but protection against hospitalization and death persisted at a robust level for 6 months after the second dose. (Funded by Weill Cornell Medicine–Qatar and others.)

HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease1 and is related to the zoonotic SARS2 and MERS3 betacoronaviruses that have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein4, which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 Å resolution structure of the trimeric HKU1 S protein determined using single-particle cryo-electron microscopy. In the prefusion conformation, the receptor-binding subunits, S1, rest atop the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known to bind protein receptors in other coronaviruses. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. Additionally, these studies should serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens.