Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies

Abstract

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.

Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza

“…For example, some studies [39][40][41] suggest a key role is having different HA heads in the prime vaccination and subsequent boosts, whereas other studies successfully boosted cross-reactive stem-specific antibodies using a homologous HA boost [37,38]. Our models predict that using the same or different HA head is not a critical factor in the boosting of stem-specific antibodies following immunization with HA (compare right panels in electronic supplementary material, figure S3), and we have identified the two key parameters (pre-existing immunity and the antigen dose) for boosting cross-reactive stem-specific immunity.…”

“…Immune sera from these mice also neutralized other group 1 influenza viruses such as H2N2 and H5N1 [37]. A second approach used immunization of HA-nanoparticles containing HA from H1N1 and generated much higher responses to both matched and unmatched H1N1 strains than immunization with TIV; this approach also showed greater control of viral load following challenge in ferrets [38]. A third strategy was to use sequential vaccinations with chimeric HA that have a conserved stem region but head regions from different subtypes [39][40][41].…”

Chimeric Pneumoviridae fusion proteins as immunogens to induce cross‐neutralizing antibody responses

“…In some cases, such as influenza virus (Kanekiyo et al , 2013; Krammer & Palese, 2014; Yassine et al , 2015) or human immunodeficiency virus (HIV) (Kwong et al , 2013), a universal vaccine is sought to overcome strain variability so that a single immunogen designed to reorient the antibody response toward relatively conserved antigenic regions would protect against infections with highly divergent antigenic variants. In other cases, the aim is to develop vaccines that will cross‐protect against related viruses from the same family, such as the Flaviviridae Zika and dengue viruses (Barba‐Spaeth et al , 2016).…”

Apoferritin: protein nanocarrier for targeted delivery

“…This can create particles with immunisation properties to use as more gentle vaccination agents [138].…”