Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

Abstract

Influenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in a highly immunogenic array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited hemagglutination inhibition and neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to commercial QIV in mice, ferrets, and nonhuman primates. The nanoparticle immunogens—but not QIV—simultaneously induced broadly protective antibody responses to heterologous viruses, including H5N1 and H7N9, by targeting the subdominant yet conserved HA stem. Unlike previously reported influenza vaccine candidates, our nanoparticle immunogens can alter the intrinsic immunodominance hierarchy of HA to induce both potent receptor-blocking and broadly cross-reactive stem-directed antibody responses and are attractive candidates for a next-generation influenza vaccine that could replace current seasonal vaccines.One Sentence SummaryNanoparticle immunogens displaying four seasonal influenza hemagglutinins elicit neutralizing antibodies directed at both the immunodominant head and the conserved stem and confer broad protective immunity.

Construction, characterization, and immunization of nanoparticles that display a diverse array of influenza HA trimers

“…In addition, the HA head monomers that were coupled to ferritin were restricted to the H1N1 subfamily [16], whereas our study involved HA trimers derived from group 1 and group 2 influenza strains. Consistent with our results, a recent study using designed nanoparticles to present trimeric HAs from influenza A and B strains also reported no increased breadth of antibody responses against mosaic particles compared with admixtures [33]. The HA2 ectodomain is followed by a foldon trimerization domain from T4 fibritin, a 13-residue SpyTag, and a 6x-His tag.…”

Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens

“…This capability is noteworthy as it enables production of each component independently, even from different host systems, which provides more flexibility in nanoparticle manufacturing. In vitro assembly also confers more control over nanoparticle assembly and composition, for example by assembling with a mixture of components fused to different antigens ( Boyoglu-Barnum et al, 2020 ).…”

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2

“…The RBD nanoparticle vaccines described here are not expected to provide protection against distantly related coronaviruses (e.g., MERS-CoV) due to substantial sequence variation among the RBDs of coronavirus S glycoproteins. However, the potent neutralizing Ab responses elicited by the nanoparticle immunogens combined with recent work demonstrating that co-displaying multiple antigens on the same nanoparticle can improve the breadth of vaccine-elicited immune responses ( Boyoglu-Barnum et al, 2020 ; Kanekiyo et al, 2019b ) suggests a potential route to broader coronavirus vaccines. Alternatively, optimizing the expression, stability, and multivalent display of prefusion S ectodomain trimers may lead to elicitation of even broader Ab responses based on the greater sequence and structural conservation of the S 2 subunit (i.e., the fusion machinery) among coronaviruses and the fact that it contains conserved epitopes that are targeted by neutralizing Abs such as the fusion peptide ( Poh et al, 2020 ).…”

“…A new development in this area has been the emergence of computationally designed protein nanoparticles as a robust and versatile platform for multivalent antigen presentation ( Bale et al, 2016 ; Hsia et al, 2016 ; King et al, 2012 ; Ueda et al, 2020 ). In preclinical studies, vaccine candidates based on designed protein nanoparticles have significantly improved the potency or breadth of antibody responses against numerous antigens, including prefusion RSV F ( Marcandalli et al, 2019 ), HIV envelope ( Brouwer et al, 2019 ), influenza hemagglutinin ( Boyoglu-Barnum et al, 2020 ), and P. falciparum CyRPA ( Bruun et al, 2018 ), relative to either soluble antigen or commercial vaccine comparators.…”