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  • Review Article
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Advances in the development of influenza virus vaccines

Nature Reviews Drug Discovery volume 14, pages 167–182 (2015)Cite this article

Subjects

An Erratum to this article was published on 06 March 2015

This article has been updated

Key Points

  • Seasonal influenza virus vaccines are an effective countermeasure against influenza if the vaccine strains and the circulating viruses are well matched; vaccine efficacy drops sharply if mismatched viruses are circulating.

  • Viruses from the animal reservoir, including H3N2v, H5N1, H5N6, H6N1, H7N3, H7N9 and H10N8, have recently caused morbidity and mortality in humans. Although these viruses are unable to transmit efficiently among humans, the development of pre-pandemic vaccine candidates that could enhance pandemic preparedness is warranted.

  • Pandemic influenza virus vaccines must be produced in a timely manner to effectively reduce the impact of a novel pandemic virus on the global human population. Technological advances such as gene synthesis, reverse genetics and recombinant production systems will facilitate the production of vaccines more rapidly in response to future influenza pandemics.

  • Novel human monoclonal antibody technology has helped provide a better understanding of the humoral (crossreactive) immune responses against the influenza virus surface glycoproteins haemagglutinin and neuraminidase.

  • Glycosylation of haemagglutinin and neuraminidase has a role in the immunogenicity of influenza virus vaccines and vaccine candidates.

  • Broadly protective antibodies against the haemagglutinin stalk domain and neuraminidase guide the design of novel, broadly protective vaccines. Novel influenza virus vaccine candidates that induce broad or universal influenza virus coverage are currently in preclinical and clinical development.

  • Broadly protective or universal influenza virus vaccines could abolish the need for annual reformulation and re-administration of seasonal influenza virus vaccines and could improve our pandemic preparedness.

Abstract

Influenza virus infections are a major public health concern and cause significant morbidity and mortality worldwide. Current influenza virus vaccines are an effective countermeasure against infection but need to be reformulated almost every year owing to antigenic drift. Furthermore, these vaccines do not protect against novel pandemic strains, and the timely production of pandemic vaccines remains problematic because of the limitations of current technology. Several improvements have been made recently to enhance immune protection induced by seasonal and pandemic vaccines, and to speed up production in case of a pandemic. Importantly, vaccine constructs that induce broad or even universal influenza virus protection are currently in preclinical and clinical development.

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Figure 1: Advances in the pandemic influenza virus vaccine production process.
Figure 2: Mechanism of action of haemagglutinin-specific and neuraminidase-specific antibodies.
Figure 3: Glycosylated influenza virus haemagglutinin and neuraminidase molecules.
Figure 4: Chimeric haemagglutinin-based universal influenza virus vaccine strategies.
Figure 5: Strategies to enhance neuraminidase-based immunity.

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Change history

  • 06 March 2015

    The citation number for reference 41, a World Health Organization monthly risk asssesment summary, was missing in the article text and reference list. This has been corrected in the online version. The statement at the end of the legend for Figure 1, related to the permission to adapt a figure in reference 227, has also been modified.

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Acknowledgements

The authors thank T. J. Wohlbold for help with GlyProt and PyMOL. Research in the Krammer laboratory is supported by a US National Institutes of Health (NIH) Centres for Excellence in Influenza Research and Surveillance (CEIRS) contract (HHSN272201400008C). P.P. is supported by an NIH CEIRS contract (HHSN272201400008C) and by NIH grants (U19 AI109946 and P01 AI097092).

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Authors and Affiliations

  1. Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Florian Krammer & Peter Palese

  2. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, 10029, New York, USA

    Peter Palese

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  1. Florian Krammer
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  2. Peter Palese
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Corresponding authors

Correspondence to Florian Krammer or Peter Palese.

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Competing interests

The Icahn School of Medicine at Mount Sinai has filed several patents regarding influenza virus vaccine constructs.

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Glossary

Antigenic drift

A mechanism by which influenza viruses escape from human 'herd immunity'. The RNA-dependent RNA polymerase of influenza viruses is relatively error prone and has no proofreading mechanism, resulting in a high frequency of point mutations. Immunologic pressure in the human population then selects for mutants that can escape from this herd immunity. The globular head domain of haemagglutinin is — owing to its immuno-dominance and high plasticity — most affected by antigenic drift.

Haemagglutinin

(HA). A homotrimeric viral surface glycoprotein that mediates the attachment of influenza viruses to cells by binding to sialic acids on glycan structures of cellular receptors. Haemagglutinin also mediates the fusion of viral and endosomal membranes, which causes the release of the viral genome into the cytosol. Haemagglutinin is the major antigen of the virus.

Neuraminidase

(NA). A viral homotetrameric viral surface glycoprotein with sialidase activity. Neuraminidase helps transport the virus trough mucosal surfaces and mediates the release of budding viruses from the cell surface.

Whole-virus inactivated vaccines

Whole-virus inactivated vaccines are based on intact virions that have been chemically (for example, with formalin or β-propiolactone) or physically (for example, with ultraviolet light) inactivated. Treatment of these virions with detergent leads to split vaccines. Further (partial) purification of the haemagglutinin and neuraminidase of viruses results in subunit vaccines.

Haemagglutination inhibition

(HI). Haemagglutination activity is the standard correlate of protection used for influenza virus vaccines, and haemagglutination inhibition describes the ability of antibodies to block the binding of the haemagglutinin globular head domain to cellular receptors. Stalk-reactive antibodies are generally haemagglutination inhibition negative.

Neuraminidase inhibition

(NI). NI describes the ability of antibodies to block the sialidase function of neuraminidase.

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Krammer, F., Palese, P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov 14, 167–182 (2015). https://doi.org/10.1038/nrd4529

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