Scientific barriers to developing vaccines against avian influenza viruses

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Key Points

  • The increasing number of reports of direct transmission of avian influenza viruses to humans in the past few years and the ongoing outbreak of H5N1 influenza virus infections in birds and humans highlight the pandemic threat posed by avian influenza viruses.

  • Although vaccination is the key strategy for the prevention of severe illness and death from pandemic influenza viruses and despite the long-term experience with vaccines against human influenza viruses, researchers face several obstacles in developing successful vaccines against avian influenza viruses.

  • The haemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza viruses are the main targets of the protective immune response. Licensed influenza virus vaccines are designed to induce HA-specific antibody responses to protect the host from infection. However, the presence of 16 subtypes of HA and 9 subtypes of NA glycoproteins among avian influenza viruses and the genetic and antigenic diversity among each subtype in nature present several unique challenges for the generation of broadly cross-protective vaccines.

  • Inactivated virus and live attenuated virus vaccines against pandemic influenza are being developed on the basis of plasmid-based reverse-genetics technology. Vaccines based on various other platforms, including live virus vectors and DNA vaccines, are also being developed and show promise in preclinical studies.

  • The available data indicate that inactivated avian influenza virus vaccines are poorly immunogenic and require a high concentration of HA glycoprotein or co-administration with an adjuvant to achieve the desired antibody response in humans. The biological basis for the poor immunogenicity of avian HA glycoproteins is not well understood.

  • Assays to measure the immune response to avian influenza viruses, in particular cell-mediated immune responses, are not available and the immune correlates of protection are not well understood. The choice of assay(s) for assessment of the immune response to pandemic influenza vaccines is a practical challenge in the evaluation of candidate vaccines.

  • As it is difficult to predict which avian influenza virus will cross the species barrier and cause a future pandemic, a library of candidate vaccines of different subtypes must be generated and evaluated in animal models and humans.

  • Although an ideal vaccine would prevent infection, a more realistic goal for a pandemic influenza vaccine might be to prevent severe illness and death.


The increasing number of reports of direct transmission of avian influenza viruses to humans underscores the need for control strategies to prevent an influenza pandemic. Vaccination is the key strategy to prevent severe illness and death from pandemic influenza. Despite long-term experience with vaccines against human influenza viruses, researchers face several additional challenges in developing human vaccines against avian influenza viruses. In this Review, we discuss the features of avian influenza viruses, the gaps in our understanding of infections caused by these viruses in humans and of the immune response to them that distinguishes them from human influenza viruses, and the current status of vaccine development.

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Figure 1: Schematic of an influenza A virus.
Figure 2: The adaptive immune response during infection with influenza virus.
Figure 3: The eight-plasmid reverse-genetics system.


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This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA.

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Correspondence to Kanta Subbarao.

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Competing interests

Kanta Subbarao and Tomy Joseph

Scientific barriers to developing vaccines against avian influenza viruses. Nature Reviews Immunology, published online 16 March 2007; doi: 10.1038/nri2054.

The laboratory of Dr Subbarao has a cooperative research and development agreement with MedImmune Vaccines to develop vaccines against potential pandemic strains of influenza.


Pandemic influenza virus

An influenza virus of a new subtype to which the general population has little or no immunity that causes disease in humans and spreads efficiently from person to person, causing community-wide outbreaks and resulting in a global outbreak of influenza.


A type I integral membrane glycoprotein that binds to cell-surface receptors and facilitates fusion between the viral envelope and endosomal membrane. It is the main target antigen of the humoral immune response to influenza viruses.


A type II integral membrane glycoprotein that facilitates virus release from cells by removing sialic acid from sialyloligosaccharides on the cell and viral surfaces. It is also a target of the protective immune response.

Antigenic drift

A process by which circulating influenza viruses are constantly changing, which allows the virus to cause annual epidemics of illness. Antigenic drift occurs when mutations accumulate in the haemagglutinin and neuraminidase genes that alter the antigenicity of these proteins such that the 'drifted' strains are no longer neutralized by antibodies that were specific for previously circulating strains.

Antigenic shift

A process by which a new influenza A virus haemagglutinin subtype (with or without an accompanying new neuraminidase subtype) is introduced into the human population, which lacks prior experience of and immunity to the subtype. Antigenic shift can occur as a result of the direct introduction of an influenza virus from an animal or avian host into humans or by the exchange or reassortment of gene segments between human and non-human influenza viruses when they co-infect animals or humans.

Matrix protein

The most abundant structural protein of influenza virus, which lies beneath the virus envelope.


Encapsidates viral genomic RNA and forms a ribonucleoprotein complex in association with viral polymerase proteins.

Positive immune selection

This is usually defined as a significant excess of non-silent over silent nucleotide substitutions in a gene, and occurs when natural selection favours a particular genetic variation and therefore the frequency of the genetic variation shifts.

Vaccine seed virus

A virus that is used for the large-scale production of vaccines.

PR8 H1N1 influenza virus (A/Puerto Rico/8/34)

A well-characterized laboratory strain of influenza virus that confers high growth in eggs and is used as the genetic backbone for viruses from which inactivated influenza virus vaccines are generated.


An agent mixed with an antigen that increases the immune response to that antigen after immunization.

Subvirion vaccine

In a subvirion vaccine, the virions are disrupted or split by detergent treatment and the surface glycoproteins are then partially purified.

Cold-adapted virus

A virus that replicates efficiently at low temperatures, which can be generated by serial passage of a wild-type virus at successively lower temperatures.

Haemagglutination-inhibition assay

An assay used to measure the concentration of antibodies that inhibit the agglutination of erythrocytes by a standard amount of influenza virus. Serum haemagglutination-inhibition antibody titres correlate with protection from infection with human influenza viruses.

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Subbarao, K., Joseph, T. Scientific barriers to developing vaccines against avian influenza viruses. Nat Rev Immunol 7, 267–278 (2007) doi:10.1038/nri2054

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