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The human antibody response to influenza A virus infection and vaccination

Abstract

The adaptive immune response to influenza virus infection is multifaceted and complex, involving antibody and cellular responses at both systemic and mucosal levels. Immune responses to natural infection with influenza virus in humans are relatively broad and long-lived, but influenza viruses can escape from these responses over time owing to their high mutation rates and antigenic flexibility. Vaccines are the best available countermeasure against infection, but vaccine effectiveness is low compared with other viral vaccines, and the induced immune response is narrow and short-lived. Furthermore, inactivated influenza virus vaccines focus on the induction of systemic IgG responses but do not effectively induce mucosal IgA responses. Here, I review the differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection. A better understanding of how natural infection induces broad and long-lived immune responses will be key to developing next-generation influenza virus vaccines.

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Acknowledgements

The author thanks P. Wilson, A. Ellebedy and R. Nachbagauer for providing helpful comments and suggestions and J. Bragg for editing the manuscript. The author apologizes to all the colleagues whose great studies could not be cited here owing to space limitations. Work on influenza virus immunology and vaccines in the laboratory of F.K. is funded by the US National Institute of Allergy and Infectious Diseases (NIAID), the US Department of Defense, the Bill and Melinda Gates Foundation, PATH and GlaxoSmithKline. In particular, the author highlights support from the NIAID through the Centers of Excellence for Influenza Research and Surveillance (CEIRS), which has catalysed many of the recent significant advancements in the field.

Author information

Competing interests

The Icahn School of Medicine at Mount Sinai has filed patent applications regarding influenza virus vaccines that name F.K. as inventor. The laboratory of F.K. has received funding for a research programme from GlaxoSmithKline.

Correspondence to Florian Krammer.

Glossary

Zoonotic infections

Infections caused by an agent with an animal reservoir that can be transmitted from an animal to a human — for example, H5N1 or H7N9 influenza A viruses.

Antigenic shift

Describes marked changes in the antigenicity of influenza viruses that are caused by the exchange of genomic segments encoding surface glycoproteins, usually involving a change from one virus subtype to another.

Pandemics

Infections caused by a new influenza virus subtype that spreads throughout the human population worldwide.

Influenza virus epidemics

Seasonal outbreaks of influenza virus infection that typically occur during winter months.

Population immunity

Also known as community immunity or herd immunity. Describes a situation in which a large proportion of the population is immune to a virus, thus limiting or completely inhibiting its spread, even to naive individuals.

Correlate of protection

A measurable parameter that correlates with protection of an individual from infection and/or disease.

Antigenic drift

Describes small changes in the antigenicity of influenza viruses that are usually caused by mutations in their surface glycoproteins, mostly in haemagglutinin (HA), leading to immune escape.

Vaccine effectiveness

The ability of a vaccine to reduce disease and/or infection in the field, under non-optimal conditions.

Immunodominance

Describes a phenomenon in which an antigen or epitope is preferentially targeted by the immune system compared with other antigens or epitopes.

Haemagglutination inhibition assay

An assay that measures the ability of serum to block haemagglutination, which is the aggregation (agglutination) of red blood cells caused by influenza virus. The resulting haemagglutination inhibition titre is a correlate of protection for influenza virus that is accepted by many regulatory agencies.

Seroconversion

A measurable increase (typically fourfold) in the titre of specific antibodies that is induced by vaccination or infection.

Enzyme-linked immunosorbent assay

(ELISA). An assay that is used to detect the binding of antibody to antigens.

Microneutralization assay

An assay that measures the ability of serum or antibodies to neutralize influenza virus.

Imprinting

Describes a phenomenon in which the first exposure to influenza virus during childhood leaves an immunological ‘imprint’, whereby subsequent exposures to antigenically different influenza virus strains boost responses to those epitopes that are shared between the two virus strains.

Group 1 HA proteins

A phylogenetic cluster of influenza A virus haemagglutinin (HA) subtypes that includes H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17 and H18.

Glycan shielding

Shielding of epitopes from B cell receptors or antibodies by N-linked glycans.

Group 2 HA proteins

A phylogenetic cluster of influenza A virus haemagglutinin (HA) subtypes that includes H3, H4, H7, H10, H14 and H15.

Neuraminidase inhibition assays

Assays that measure the ability of antiserum to block the sialidase activity of neuraminidase (NA).

Group 1 NA proteins

A phylogenetic cluster of influenza A virus neuraminidase (NA) subtypes that includes N1, N4, N5 and N8.

Group 2 NA proteins

A phylogenetic cluster of influenza A virus neuraminidase (NA) subtypes that includes N2, N3, N6, N7 and N9.

Fc receptor

(FcR). A receptor expressed on immune cells to which antibodies can bind via their crystallizable fragment (Fc) region. These receptors are important for antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis.

Vaccine efficacy

The ability of a vaccine to reduce disease and/or infection in an ideal setting.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). The killing of infected cells by effector cells (for example, natural killer cells) via bound antibody.

Antibody-dependent cellular phagocytosis

(ADCP). The phagocytosis of infected cells or virus by effector cells (for example, macrophages) via bound antibody.

Complement-dependent lysis

The lysis of cells or viruses by complement via bound antibody.

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Fig. 1: The life cycle of influenza virus and its antibody targets.
Fig. 2: Mechanism of action of antibodies against influenza virus.