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Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.
Nat Struct Mol Biol. 2009 Mar; 16(3):265-73
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11 Mar 2009
Peter Colman
F1000 Structural Biology
The Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, Australia.
F1000 Structural Biology
The Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, Australia.
Douglas Fairlie
F1000 Structural Biology
The Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, Australia.
F1000 Structural Biology
The Walter and Eliza Hall Institute of Medical Research,
Parkville, VIC, Australia.
New Finding
DOI: 10.3410/f.1157030.617114
These authors show that certain antibodies to the influenza virus haemagglutinin (HA), selected from a phage display library, are more broadly neutralising than the typical antibodies raised during an influenza virus infection. This is due to their recognition of a relatively conserved feature near...Continue reading
These authors show that certain antibodies to the influenza virus haemagglutinin (HA), selected from a phage display library, are more broadly neutralising than the typical antibodies raised during an influenza virus infection. This is due to their recognition of a relatively conserved feature near the base of the HA spike.
Antigenic variation in the surface glycoproteins of influenza virus hampers the quest for a broadly effective vaccine. Here, broadly neutralising antibodies selected from a phage library are shown to have prophylactic and therapeutic efficacy in mice against two different clades of H5 virus. The three-dimensional structure of the complex between H5 HA and a representative scFv fragment shows that the antibody binds to a site adjacent to the fusion-peptide-binding pocket on trimeric cleaved HA. Comparison with the structure of the fusion-active form of HA shows that the amino acids contacting the antibody make important intramolecular interactions in that structure, suggesting a plausible rationale for their conservation. Critically, the antibodies in question did not select variants in 72 hours of tissue culture, whilst an antibody directed at the head of HA readily selected an escape variant, suggesting, at least, that a higher barrier exists for escape variants of these antibodies. Nevertheless, more extensive culturing of the virus with a similar antibody did generate escape variants {1}. Comparison of structures of HA from other subtypes explains why these antibodies bind H1, H5 and H9 viruses, but not H3 and H7 viruses.
Antigenic variation in the surface glycoproteins of influenza virus hampers the quest for a broadly effective vaccine. Here, broadly neutralising antibodies selected from a phage library are shown to have prophylactic and therapeutic efficacy in mice against two different clades of H5 virus. The three-dimensional structure of the complex between H5 HA and a representative scFv fragment shows that the antibody binds to a site adjacent to the fusion-peptide-binding pocket on trimeric cleaved HA. Comparison with the structure of the fusion-active form of HA shows that the amino acids contacting the antibody make important intramolecular interactions in that structure, suggesting a plausible rationale for their conservation. Critically, the antibodies in question did not select variants in 72 hours of tissue culture, whilst an antibody directed at the head of HA readily selected an escape variant, suggesting, at least, that a higher barrier exists for escape variants of these antibodies. Nevertheless, more extensive culturing of the virus with a similar antibody did generate escape variants {1}. Comparison of structures of HA from other subtypes explains why these antibodies bind H1, H5 and H9 viruses, but not H3 and H7 viruses.
References
1.
Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells.
PLoS ONE 2008; 12(3):e3942
PMID: 19079604
Disclosures
None declared
Add Comment
Colman P and Fairlie D: F1000Prime Recommendation of [Sui J et al., Nat Struct Mol Biol 2009, 16(3):265-73]. In F1000Prime, 11 Mar 2009; DOI: 10.3410/f.1157030.617114. F1000Prime.com/1157030#eval617114
11 Mar 2009
New Finding
DOI: 10.3410/f.1157030.617622
This paper identifies a highly conserved epitope in the stalk region of the influenza hemagglutinin (HA) that is recognized by recently identified human antibodies isolated from phage display libraries. The antibodies were encoded by a canonical VH gene segment (VH1-69) that specifies several residues...Continue reading
This paper identifies a highly conserved epitope in the stalk region of the influenza hemagglutinin (HA) that is recognized by recently identified human antibodies isolated from phage display libraries. The antibodies were encoded by a canonical VH gene segment (VH1-69) that specifies several residues in the germline that mediate binding into a pocket on the HA stalk.
Neutralizing antibodies to influenza HA generally bind hypervariable protein loops on the head of the HA molecule. Point mutations in these regions confer antigenic drift and escape from neutralization, while a new subtype of HA can be introduced by reassortment causing wholesale changes in the sequence of the HA. Generally it has been thought difficult or impossible to find a completely conserved epitope and, thus, challenging to design a universal vaccine against a wide variety of strains. This paper shows that there is an important epitope on the stalk of HA that can be recognized by human antibodies, raising the possibility that a more universal vaccine could be developed. In addition, the antibodies themselves have promise as prophylactic agents for a wide variety of flu strains. Questions remain about how common such antibodies are in nature. First, these antibodies were derived from phage display libraries, which randomly pair heavy and light chains. Second, very few individuals exhibit serum-neutralizing antibody titers against the wide array of flu viruses with which these antibodies should be reactive. A similar paper was published nearly concurrently {1}.
Neutralizing antibodies to influenza HA generally bind hypervariable protein loops on the head of the HA molecule. Point mutations in these regions confer antigenic drift and escape from neutralization, while a new subtype of HA can be introduced by reassortment causing wholesale changes in the sequence of the HA. Generally it has been thought difficult or impossible to find a completely conserved epitope and, thus, challenging to design a universal vaccine against a wide variety of strains. This paper shows that there is an important epitope on the stalk of HA that can be recognized by human antibodies, raising the possibility that a more universal vaccine could be developed. In addition, the antibodies themselves have promise as prophylactic agents for a wide variety of flu strains. Questions remain about how common such antibodies are in nature. First, these antibodies were derived from phage display libraries, which randomly pair heavy and light chains. Second, very few individuals exhibit serum-neutralizing antibody titers against the wide array of flu viruses with which these antibodies should be reactive. A similar paper was published nearly concurrently {1}.
References
1.
Antibody recognition of a highly conserved influenza virus epitope.
Science 2009 Apr 10; 5924(324):246-51
PMID: 19251591
Disclosures
None declared
Crowe J: F1000Prime Recommendation of [Sui J et al., Nat Struct Mol Biol 2009, 16(3):265-73]. In F1000Prime, 11 Mar 2009; DOI: 10.3410/f.1157030.617622. F1000Prime.com/1157030#eval617622
12 Mar 2009
New Finding, Technical Advance
DOI: 10.3410/f.1157030.617618
This is an extraordinary finding, which shows that a very highly conserved domain exists and has been identified for a broad spectrum of avian and influenza A viruses yet responds to appropriate neutralizing antibodies (nAB). A convincing crystal structure of such an antibody - H5 domain binding - effectively...Continue reading
This is an extraordinary finding, which shows that a very highly conserved domain exists and has been identified for a broad spectrum of avian and influenza A viruses yet responds to appropriate neutralizing antibodies (nAB). A convincing crystal structure of such an antibody - H5 domain binding - effectively demonstrates that inhibition of infection may be ocurring by the insertion of a heavy chain into a highly conserved stem region domain, thus inhibiting membrane fusion.
It is well known that human influenza remains a very serious public threat in spite of the annual vaccines that are produced and distributed to protect the population. Human influenza A viruses possess the unique ability to avoid immuno-interception by engaging in rapid genetic drift and resortment of viral surface domains that have been targeted with traditional vaccines. A more serious threat from highly pathogenic avian influenza (HPAI) looms over the global population and could present a pandemic threat by such a similar genetic drift or rapid reassortment. Using a phage-display antibody library, a category of high affinity nABs have been identified and shown to be potent inhibitors of H5N1 viral infection both in vitro and in vivo. Based on crystallographic and functional studies, it has been shown that these nABs bind to a highly conserved common epitope residing in the hemagglutinin stem region. These domains are associated with fusion peptide dynamics. It appears that inhibition may involve their ability to block membrane fusion as opposed to cell attachment.
This breakthrough study clearly offers considerable optimism for developing new broad spectrum vaccines suitable for neutralizing serious avian and human influenza A viral pathogens that may not be vulnerable to genetic drift and reassortment. For further reading, please note related work {1}.
It is well known that human influenza remains a very serious public threat in spite of the annual vaccines that are produced and distributed to protect the population. Human influenza A viruses possess the unique ability to avoid immuno-interception by engaging in rapid genetic drift and resortment of viral surface domains that have been targeted with traditional vaccines. A more serious threat from highly pathogenic avian influenza (HPAI) looms over the global population and could present a pandemic threat by such a similar genetic drift or rapid reassortment. Using a phage-display antibody library, a category of high affinity nABs have been identified and shown to be potent inhibitors of H5N1 viral infection both in vitro and in vivo. Based on crystallographic and functional studies, it has been shown that these nABs bind to a highly conserved common epitope residing in the hemagglutinin stem region. These domains are associated with fusion peptide dynamics. It appears that inhibition may involve their ability to block membrane fusion as opposed to cell attachment.
This breakthrough study clearly offers considerable optimism for developing new broad spectrum vaccines suitable for neutralizing serious avian and human influenza A viral pathogens that may not be vulnerable to genetic drift and reassortment. For further reading, please note related work {1}.
References
1.
Antibody recognition of a highly conserved influenza virus epitope.
Science 2009 Apr 10; 5924(324):246-51
PMID: 19251591
Disclosures
None declared
Tomalia D: F1000Prime Recommendation of [Sui J et al., Nat Struct Mol Biol 2009, 16(3):265-73]. In F1000Prime, 12 Mar 2009; DOI: 10.3410/f.1157030.617618. F1000Prime.com/1157030#eval617618
21 Jul 2011
New Finding, Novel Drug Target
DOI: 10.3410/f.1157030.13260055
This is one of two papers published in 2009 (the other being Ekiert et al. {1}) that describe the crystal structure of phage-display antibodies that bound to a region of the hemagglutinin protein on the surface of influenza. This region is highly conserved on many divergent influenza strains and is...Continue reading
This is one of two papers published in 2009 (the other being Ekiert et al. {1}) that describe the crystal structure of phage-display antibodies that bound to a region of the hemagglutinin protein on the surface of influenza. This region is highly conserved on many divergent influenza strains and is critical for viral function, and thus can be targeted by antibodies to neutralize the virus.
This finding demonstrated that at least some critical influenza epitopes are evolutionarily conserved and can be targets for therapeutics, including monoclonal antibody drugs, as well as targets to improve influenza vaccines with broader protection across many influenza strains.
To view the context in which this article was evaluated, see its citation in F1000 Biology Reports: Harnessing the immune system's arsenal: producing human monoclonal antibodies for therapeutics and investigating immune responses by Patrick C. Wilson et al (2011).
This finding demonstrated that at least some critical influenza epitopes are evolutionarily conserved and can be targets for therapeutics, including monoclonal antibody drugs, as well as targets to improve influenza vaccines with broader protection across many influenza strains.
To view the context in which this article was evaluated, see its citation in F1000 Biology Reports: Harnessing the immune system's arsenal: producing human monoclonal antibodies for therapeutics and investigating immune responses by Patrick C. Wilson et al (2011).
References
1.
Antibody recognition of a highly conserved influenza virus epitope.
Science 2009 Apr 10; 5924(324):246-51
PMID: 19251591
Acknowledgments
Meghan Sullivan, Kaval Kaur and Noel Pauli helped with the writing of this evaluation.
Disclosures
None declared
Wilson P: F1000Prime Recommendation of [Sui J et al., Nat Struct Mol Biol 2009, 16(3):265-73]. In F1000Prime, 21 Jul 2011; DOI: 10.3410/f.1157030.13260055. F1000Prime.com/1157030#eval13260055
F1000Prime Recommendations, Dissents and Comments for [Sui J et al., Nat Struct Mol Biol 2009, 16(3):265-73]. In F1000Prime, 22 May 2013; F1000Prime.com/1157030
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Influenza virus remains a serious health threat, owing to its ability to evade immune surveillance through rapid genetic drift and reassortment. Here we used a human non-immune antibody phage-display library and the H5 hemagglutinin ectodomain to select ten neutralizing antibodies (nAbs) that were effective against all group 1 influenza viruses tested, including H5N1 'bird flu' and the H1N1 'Spanish flu'. The crystal structure of one such nAb bound to H5 shows that it blocks infection by inserting its heavy chain into a conserved pocket in the stem region, thus preventing membrane fusion. Nine of the nAbs employ the germline gene VH1-69, and all seem to use the same neutralizing mechanism. Our data further suggest that this region is recalcitrant to neutralization escape and that nAb-based immunotherapy is a promising strategy for broad-spectrum protection against seasonal and pandemic influenza viruses.
DOI: 10.1038/nsmb.1566
PMID: 19234466
