Next-generation influenza vaccines: opportunities and challenges

Abstract

Seasonal influenza vaccines lack efficacy against drifted or pandemic influenza strains. Developing improved vaccines that elicit broader immunity remains a public health priority. Immune responses to current vaccines focus on the haemagglutinin head domain, whereas next-generation vaccines target less variable virus structures, including the haemagglutinin stem. Strategies employed to improve vaccine efficacy involve using structure-based design and nanoparticle display to optimize the antigenicity and immunogenicity of target antigens; increasing the antigen dose; using novel adjuvants; stimulating cellular immunity; and targeting other viral proteins, including neuraminidase, matrix protein 2 or nucleoprotein. Improved understanding of influenza antigen structure and immunobiology is advancing novel vaccine candidates into human trials.

Fig. 1. A spectrum of efficacy for influenza vaccines.

a | Effectiveness of seasonal influenza vaccines from 2009 to 2019 (Data from ‘CDC: Past Seasons Vaccine Effectiveness Estimates’). The vaccine effectiveness is estimated from the US Flu Vaccine Effectiveness Network and measures the flu vaccine’s effectiveness in preventing outpatient medical visits due to laboratory-confirmed influenza. Adjusted overall vaccine effectiveness (%) and 95% confidence interval are shown. b | Phylogenetic tree of influenza A and influenza B haemagglutinin (HA). Eighteen influenza A HA subtypes have been detected in nature, and they can be further divided into group 1 and group 2 based on amino acid sequence composition, whereas influenza B HA subtypes have differentiated into two serologically distinct lineages (B/Victoria/2/87-like and B/Yamagata/16/88-like). Current licensed flu vaccines consist of one H1 strain, one H3 strain and one or two influenza B viruses. H2 virus also has the ability to infect humans and caused the pandemic in 1957. Occasionally, transmission of zoonotic influenza viruses, such as H5, H7 and H9, to humans has been reported. *H17 and H18 are from bat influenza. The scale bar indicates the numbers of amino acid substitutions per site. c | Incremental steps towards a ‘true’ universal influenza vaccine. Vaccine breadth against divergence of influenza strains, ranging from strain-specific (effective against a single, matched strain) to subtype-specific (effective against all or most strains within a given subtype), multi-subtype (effective against select subtype viruses), pan-group/lineage (effective against most subtype viruses within a group/lineage), type A (against all type A viruses), types A and B (against all type A and B viruses) and universal coverage (against most seasonal, drifted and pandemic strains for multiple years in a single product). Part c adapted from Erbelding et al..

Fig. 2. Structural basis for the induction of broadly neutralizing antibodies against HA.

a | Left: structure of influenza haemagglutinin (HA). The trimeric protein consists of a globular head that mediates attachment and a stem region that anchors the viral spike. Sequence variability among H1 HA subtypes is depicted in red (variable) and cyan (conserved). Conserved neutralizing antibody epitopes in the receptor binding site and stem are mapped onto the crystal structure of the HA ectodomain from A/South Carolina/1918 (H1N1) (PDB 1RUZ) and highlighted in yellow. Right: HA structural model showing a broadly neutralizing H1 subtype-specific (CH65) antibody bound to the receptor binding site and a pan-group 1 (CR6261) antibody targeting the stem (adapted from Nabel and Fauci). CH65 is isolated from an adult donor and neutralizes various H1N1 viruses by preventing viral attachment to its sialic acid-containing receptor. CR6261 also comes from a human subject and neutralizes a broad range of viruses within group 1 HA. It recognizes a highly conserved helical region in the HA stem and blocks viral entry by preventing membrane fusion. b | Structural models of novel immunogens that target the conserved HA stem region: stabilized stem HA–ferritin and trimeric mini-HA. Stabilized stem HA–ferritin is generated by fusion of the stem region of HA to a self-assembling ferritin nanoparticle. This immunogen lacks the immunodominant head domain and elicits only stem-specific immune responses. The mini-HA is another ‘headless’ antigen that preserves the structural and antigenic integrity of the HA stem and has been shown to provide heterosubtypic immunity. Part a adapted from ref., Springer Nature Limited. Part b (left) reprinted from ref., Springer Nature Limited. Part b (right) adapted with permission from ref., AAAS.

Fig. 3. Structural basis for the induction of neutralizing antibodies against NA.

a | Phylogenetic tree of influenza A and influenza B neuraminidase (NA) subtypes. Influenza A NA can be divided into three genetically distinct subgroups: group 1 consists of N1, N4, N5 and N8; group 2 consists of N2, N3, N6, N7 and N9; and group 3 has two NA subtypes from fruit bats (*N10 and *N11). The scale bar indicates the numbers of amino acid substitutions per site. b | Structure of influenza NA. Top and bottom views of NA tetramers are shown. Sequence conservation from select NAs from 1977 to 2018 depicted in red (variable) and cyan (conserved) and mapped onto the crystal structure of the NA ectodomain from A/California/04/2009 (H1N1) (PDB 3TI6).