Next-generation influenza vaccines: opportunities and challenges


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.

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Fig. 1: A spectrum of efficacy for influenza vaccines.
Fig. 2: Structural basis for the induction of broadly neutralizing antibodies against HA.
Fig. 3: Structural basis for the induction of neutralizing antibodies against NA.


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The authors thank Jeffrey C. Boyington (Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health) for generating the HA structural model and Stefan Köester (Sanofi) for the HA and NA phylogenetic trees and the NA model. They also thank Brian DelGiudice (Sanofi) for assistance in manuscript preparation.

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Correspondence to Gary J. Nabel.

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Competing interests

C.-J.W., J.S., and G.J.N. are employees and stock owners of Sanofi, whose subsidiary Sanofi-Pasteur is a major influenza vaccine producer and has issued patents and pending filed patent applications on various influenza vaccine technologies. C.-J.W and G.J.N. are inventors of gene-based and nanoparticle-based influenza vaccines that have been filed by either Sanofi or the US government. J.R.M. and B.S.G. are employees of the US government, which has issued patents and filed patent applications on various vaccines including ferritin nanoparticle-based influenza vaccines mentioned in this article. The other authors declare no competing interests.

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A contagious respiratory disease caused by influenza viruses.


(HA). A homotrimeric glycoprotein found on the surface of influenza virus particles responsible for the recognition of the host target cell through the binding of sialic acid-containing receptors.


(NA). A homotetrameric glycoprotein found on the surface of influenza virus particles that facilitates the virus’ release from the host cell.

Matrix protein 2

(M2). A homotetrameric protein that serves as a proton-selective channel essential for maintaining a pH gradient across the viral membrane during host cell entry and is vital for virus replication.


(NP). A viral structural protein that encapsidates negative-strand viral RNA to allow RNA transcription, replication and packaging.

Haemagglutination inhibition

(HAI). The haemagglutination inhibition assay is a method to quantify the relative titre of viruses or determine the concentration of antiserum or antibody required to prevent haemagglutination, a process in which influenza viruses bind and agglutinate red blood cells in cell culture.

Virus-like particle

A molecule that closely resembles viruses but lacks certain viral genetic materials to be infectious.

Vaccine adjuvant

An immunostimulant used with an antigen to improve its immunogenicity.

Pandemic influenza

An epidemic caused by worldwide spread of a new influenza virus that infects a large portion of the population globally.

Toll-like receptor

A family of type I transmembrane pattern recognition receptors that sense foreign pathogens or endogenous danger signals and play a central role in early innate immune response.

Antibody-dependent cellular cytotoxicity

An adaptive immune response by which specific antibodies bind to foreign antigens and, in turn, recruit effector cells to lyse target cells.

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Wei, C., Crank, M.C., Shiver, J. et al. Next-generation influenza vaccines: opportunities and challenges. Nat Rev Drug Discov (2020).

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