Chapter 12 : Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:
Zoom in

Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555817411/9781555817350_Chap12-1.gif /docserver/preview/fulltext/10.1128/9781555817411/9781555817350_Chap12-2.gif


Influenza hemagglutinin (HA) is the major glycoprotein on the surface of influenza virions. It mediates receptor binding and fusion. The surface glycoprotein neuraminidase (NA) is a receptor-destroying enzyme. Even though humoral immunity to NA and other proteins and cellular immunity to several viral proteins contribute to protection against influenza infection, neutralizing antibodies directed against influenza HA are sufficient to protect against disease. The H3 HA crystal structure was solved in 1981 at 3-Å resolution ( ). Since then, the crystal structures of HA molecules from H2, H5, H7, and several different H1 strains including the pandemic 1918 H1 and the pandemic 2009 H1 ( ) have been determined. In brief, HA is a trimeric type I membrane glycoprotein made of three identical subunits ( Fig. 1 ). Each subunit is synthesized as an HA0 precursor and cleaved proteolytically into an HA1 subunit that composes the membrane-distal globular head and part of the membrane-proximal stem region, and an HA2 subunit that only contributes to the stem region ( Fig. 1 ).

Citation: Krause J, Crowe J. 2015. Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head, p 209-219. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0021-2014
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Space-filling model of influenza hemagglutinin HA based on PDB 1RD8 ( ). The three protomers of the HA trimer are colored white, gray, or black.

Citation: Krause J, Crowe J. 2015. Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head, p 209-219. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0021-2014
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Wilson IA,, Skehel JJ,, Wiley DC . 1981. Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289 : 366 373.[PubMed] [CrossRef]
2. Xu R,, Ekiert DC,, Krause JC,, Hai R,, Crowe JEJ,, Wilson IA . 2010. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science 328 : 357 360.[PubMed] [CrossRef]
3. Corti D,, Voss J,, Gamblin SJ,, Codoni G,, Macagno A,, Jarrossay D,, Vachieri SG,, Pinna D,, Minola A,, Vanzetta F,, Silacci C,, Fernandez-Rodriguez BM,, Agatic G,, Bianchi S,, Giacchetto-Sasselli I,, Calder L,, Sallusto F,, Collins P,, Haire LF,, Temperton N,, Langedijk JP,, Skehel JJ,, Lanzavecchia A . 2011. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333 : 850 856.[PubMed] [CrossRef]
4. Ekiert DC,, Friesen RH,, Bhabha G,, Kwaks T,, Jongeneelen M,, Yu W,, Ophorst C,, Cox F,, Korse HJ,, Brandenburg B,, Vogels R,, Brakenhoff JP,, Kompier R,, Koldijk MH,, Cornelissen LA,, Poon LL,, Peiris M,, Koudstaal W,, Wilson IA,, Goudsmit J . 2011. A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 333 : 843 850.[PubMed] [CrossRef]
5. Okuno Y,, Isegawa Y,, Sasao F,, Ueda S . 1993. A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J Virol 67 : 2552 2558.[PubMed]
6. Wrammert J,, Koutsonanos D,, Li GM,, Edupuganti S,, Sui J,, Morrissey M,, McCausland M,, Skountzou I,, Hornig M,, Lipkin WI,, Mehta A,, Razavi B,, Del Rio C,, Zheng NY,, Lee JH,, Huang M,, Ali Z,, Kaur K,, Andrews S,, Amara RR,, Wang Y,, Das SR,, O’Donnell CD,, Yewdell JW,, Subbarao K,, Marasco WA,, Mulligan MJ,, Compans R,, Ahmed R,, Wilson PC . 2011. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208 : 181 193.[PubMed] [CrossRef]
7. Davenport FM,, Hennessy AV,, Francis T, Jr . 1953. Epidemiologic and immunologic significance of age distribution of antibody to antigenic variants of influenza virus. J Exp Med 98 : 641 656.[PubMed] [CrossRef]
8. Fish S,, Zenowich E,, Fleming M,, Manser T . 1989. Molecular analysis of original antigenic sin. I. Clonal selection, somatic mutation, and isotype switching during a memory B cell response. J Exp Med 170 : 1191 1209.[PubMed] [CrossRef]
9. Krause R . 2006. The swine flu episode and the fog of epidemics. Emerg Infect Dis 12 : 40 43.[PubMed] [CrossRef]
10. Wrammert J,, Smith K,, Miller J,, Langley WA,, Kokko K,, Larsen C,, Zheng NY,, Mays I,, Garman L,, Helms C,, James J,, Air GM,, Capra JD,, Ahmed R,, Wilson PC . 2008. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453 : 667 671.[PubMed] [CrossRef]
11. Palese P,, Wang TT . 30 August 2011. Why do influenza virus subtypes die out? A hypothesis. MBio doi:10.1128/mBio.00150-11. [PubMed] [CrossRef]
12. Wrammert J,, Onlamoon N,, Akondy RS,, Perng GC,, Polsrila K,, Chandele A,, Kwissa M,, Pulendran B,, Wilson PC,, Wittawatmongkol O,, Yoksan S,, Angkasekwinai N,, Pattanapanyasat K,, Chokephaibulkit K,, Ahmed R . 2012. Rapid and massive virus-specific plasmablast responses during acute dengue virus infection in humans. J Virol 86 : 2911 2918.[PubMed] [CrossRef]
13. Krause JC,, Tsibane T,, Tumpey TM,, Huffman CJ,, Basler CF,, Crowe JE . 2011. A broadly neutralizing human monoclonal antibody that recognizes a conserved, novel epitope on the globular head of the influenza H1N1 virus hemagglutinin. J Virol 85 : 10905 10908.[PubMed] [CrossRef]
14. Krause JC,, Tsibane T,, Tumpey TM,, Huffman CJ,, Briney BS,, Smith SA,, Basler CF,, Crowe JE, Jr . 2011. Epitope-specific human influenza antibody repertoires diversify by B cell intraclonal sequence divergence and interclonal convergence. J Immunol 187 : 3704 3711.[PubMed] [CrossRef]
15. Whittle JR,, Zhang R,, Khurana S,, King LR,, Manischewitz J,, Golding H,, Dormitzer PR,, Haynes BF,, Walter EB,, Moody MA,, Kepler TB,, Liao HX,, Harrison SC . 2011. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA 108 : 14216 14221.[PubMed] [CrossRef]
16. Krause JC,, Tsibane T,, Tumpey TM,, Huffman CJ,, Albrecht R,, Blum DL,, Ramos I,, Fernandez-Sesma A,, Edwards KM,, García-Sastre A,, Basler CF,, Crowe JE . 2012. Human monoclonal antibodies to pandemic 1957 H2N2 and pandemic 1968 H3N2 influenza viruses. J Virol 86 : 6334 6340.[PubMed] [CrossRef]
17. Xu R,, Krause JC,, McBride R,, Paulson JC,, Crowe JE,, Wilson IA . 2013. A recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin. Nat Struct Mol Biol 20 : 363 370.[PubMed] [CrossRef]
18. National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Food and Drug Administration . 2012. Universal Influenza Vaccines Meeting Summary. 19 to 20 June 2012.
19. Caton AJ,, Brownlee GG,, Yewdell JW,, Gerhard W . 1982. The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell 31 : 417 427.[PubMed] [CrossRef]
20. Krause JC,, Tumpey TM,, Huffman CJ,, McGraw PA,, Pearce MB,, Tsibane T,, Hai R,, Basler CF,, Crowe JE . 2010. Naturally occurring human monoclonal antibodies neutralize both 1918 and 2009 pandemic influenza A (H1N1) viruses. J Virol 84 : 3127 3130.[PubMed] [CrossRef]
21. Manicassamy B,, Medina RA,, Hai R,, Tsibane T,, Stertz S,, Nistal-Villan E,, Palese P,, Basler CF,, Garcia-Sastre A . 2010. Protection of mice against lethal challenge with 2009 H1N1 influenza A virus by 1918-like and classical swine H1N1 based vaccines. PLoS Pathog 6 : e1000745. doi: 10.1371/journal.ppat.1000745. [PubMed] [CrossRef]
22. Brownlee GG,, Fodor E . 2001. The predicted antigenicity of the haemagglutinin of the 1918 Spanish influenza pandemic suggests an avian origin. Philos Trans R Soc Lond B Biol Sci 356 : 1871 1876.[PubMed] [CrossRef]
23. Tsibane T,, Ekiert DC,, Krause JC,, Martinez O,, Crowe JE,, Wilson IA,, Basler CF . 2012. Influenza human monoclonal antibody 1F1 interacts with three major antigenic sites and residues mediating human receptor specificity in H1N1 viruses. PLoS Pathog 8 : e1003067. doi:10.1371/journal.ppat.1003067. [PubMed] [CrossRef]
24. Wiley DC,, Wilson IA,, Skehel JJ . 1981. Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289 : 373 378.[PubMed] [CrossRef]
25. Fleury D,, Wharton SA,, Skehel JJ,, Knossow M,, Bizebard T . 1998. Antigen distortion allows influenza virus to escape neutralization. Nat Struct Biol 5 : 119 123.[PubMed] [CrossRef]
26. Fleury D,, Barrere B,, Bizebard T,, Daniels RS,, Skehel JJ,, Knossow M . 1999. A complex of influenza hemagglutinin with a neutralizing antibody that binds outside the virus receptor binding site. Nat Struct Biol 6 : 530 534.[PubMed] [CrossRef]
27. Fleury D,, Daniels RS,, Skehel JJ,, Knossow M,, Bizebard T . 2000. Structural evidence for recognition of a single epitope by two distinct antibodies. Proteins 40 : 572 578.[PubMed] [CrossRef]
28. Barbey-Martin C,, Gigant B,, Bizebard T,, Calder LJ,, Wharton SA,, Skehel JJ,, Knossow M . 2002. An antibody that prevents the hemagglutinin low pH fusogenic transition. Virology 294 : 70 74.[PubMed] [CrossRef]
29. Knossow M,, Skehel JJ . 2006. Variation and infectivity neutralization in influenza. Immunology 119 : 1 7.[PubMed] [CrossRef]
30. Yamada A,, Brown LE,, Webster RG . 1984. Characterization of H2 influenza virus hemagglutinin with monoclonal antibodies: influence of receptor specificity. Virology 138 : 276 286.[PubMed] [CrossRef]
31. Connor RJ,, Kawaoka Y,, Webster RG,, Paulson JC . 1994. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Virology 205 : 17 23.[PubMed] [CrossRef]
32. Krause JC,, Ekiert DC,, Tumpey TM,, Smith PB,, Wilson IA,, Crowe JE Jr . 2011. An insertion mutation that distorts antibody binding site architecture enhances function of a human antibody. MBio 2 : e00345-10. doi:10.1128/mBio.00345-10. [PubMed] [CrossRef]
33. Yu X,, Tsibane T,, McGraw PA,, House FS,, Keefer CJ,, Hicar MD,, Tumpey TM,, Pappas C,, Perrone LA,, Martinez O,, Stevens J,, Wilson IA,, Aguilar PV,, Altschuler EL,, Basler CF,, Crowe JE, Jr . 2008. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 455 : 532 536.[PubMed] [CrossRef]
34. Shope RE . 1931. Swine influenza. I. Experimental transmission and pathology. J Exp Med 54 : 349 359.[PubMed] [CrossRef]
35. Wei CJ,, Boyington JC,, Dai K,, Houser KV,, Pearce MB,, Kong WP,, Yang ZY,, Tumpey TM,, Nabel GJ . 2010. Cross-neutralization of 1918 and 2009 influenza viruses: role of glycans in viral evolution and vaccine design. Sci Transl Med 2 : 24ra21. doi:10.1126/scitranslmed.3000799. [PubMed] [CrossRef]
36. Herzenberg LA,, Black SJ,, Tokuhisa T . 1980. Memory B cells at successive stages of differentiation. Affinity maturation and the role of IgD receptors. J Exp Med 151 : 1071 1087.[PubMed] [CrossRef]
37. Gamblin SJ,, Haire LF,, Russell RJ,, Stevens DJ,, Xiao B,, Ha Y,, Vasisht N,, Steinhauer DA,, Daniels RS,, Elliot A,, Wiley DC,, Skehel JJ . 2004. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303 : 1838 1842.[PubMed] [CrossRef]
38. Stevens J,, Corper AL,, Basler CF,, Taubenberger JK,, Palese P,, Wilson IA . 2004. Structure of the uncleaved human H1 hemagglutinin from the extinct 1918 influenza virus. Science 303 : 1866 1870.[PubMed] [CrossRef]
39. Glaser L,, Stevens J,, Zamarin D,, Wilson IA,, Garcia-Sastre A,, Tumpey TM,, Basler CF,, Taubenberger JK,, Palese P . 2005. A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. J Virol 79 : 11533 11536.[PubMed] [CrossRef]
40. Stevens J,, Blixt O,, Glaser L,, Taubenberger JK,, Palese P,, Paulson JC,, Wilson IA . 2006. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. J Mol Biol 355 : 1143 1155.[PubMed] [CrossRef]
41. Colman PM,, Tulip WR,, Varghese JN,, Tulloch PA,, Baker AT,, Laver WG,, Air GM,, Webster RG . 1989. Three-dimensional structures of influenza virus neuraminidase-antibody complexes. Philos Trans R Soc Lond B Biol Sci 323 : 511 518.[PubMed] [CrossRef]
42. Naeve CW,, Hinshaw VS,, Webster RG . 1984. Mutations in the hemagglutinin receptor-binding site can change the biological properties of an influenza virus. J Virol 51 : 567 569.[PubMed]
43. Daniels PS,, Jeffries S,, Yates P,, Schild GC,, Rogers GN,, Paulson JC,, Wharton SA,, Douglas AR,, Skehel JJ,, Wiley DC . 1987. The receptor-binding and membrane-fusion properties of influenza virus variants selected using anti-haemagglutinin monoclonal antibodies. EMBO J 6 : 1459 1465.[PubMed]
44. Schmidt AG,, Xu H,, Khan AR,, O’Donnell T,, Khurana S,, King LR,, Manischewitz J,, Golding H,, Suphaphiphat P,, Carfi A,, Settembre EC,, Dormitzer PR,, Kepler TB,, Zhang R,, Moody MA,, Haynes BF,, Liao H-X,, Shaw DE,, Harrison SC . 2013. Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc Natl Acad Sci USA 110 : 264 269.[PubMed] [CrossRef]
45. Hong M,, Lee PS,, Hoffman RMB,, Zhu X,, Krause JC,, Laursen NS,, Yoon S-I,, Song L,, Tussey L,, Crowe JE,, Ward AB,, Wilson IA . 2013. Antibody recognition of the pandemic H1N1 Influenza virus hemagglutinin receptor binding site. J Virol 87 : 12471 12480.[PubMed] [CrossRef]
46. Ohshima N,, Iba Y,, Kubota-Koketsu R,, Asano Y,, Okuno Y,, Kurosawa Y . 2011. Naturally occurring antibodies in humans can neutralize a variety of influenza virus strains, including H3, H1, H2, and H5. J Virol 85 : 11048 11057.[PubMed] [CrossRef]
47. Yoshida R,, Igarashi M,, Ozaki H,, Kishida N,, Tomabechi D,, Kida H,, Ito K,, Takada A . 2009. Cross-protective potential of a novel monoclonal antibody directed against antigenic site B of the hemagglutinin of influenza A viruses. PLoS Pathog 5 : e1000350. doi:10.1371/journal.ppat.1000350. [PubMed] [CrossRef]
48. Lee PS,, Yoshida R,, Ekiert DC,, Sakai N,, Suzuki Y,, Takada A,, Wilson IA . 2012. Heterosubtypic antibody recognition of the influenza virus hemagglutinin receptor binding site enhanced by avidity. Proc Natl Acad Sci USA 109 : 17040 17045.[PubMed] [CrossRef]
49. Ekiert DC,, Kashyap AK,, Steel J,, Rubrum A,, Bhabha G,, Khayat R,, Lee JH,, Dillon MA,, O’Neil RE,, Faynboym AM,, Horowitz M,, Horowitz L,, Ward AB,, Palese P,, Webby R,, Lerner RA,, Bhatt RR,, Wilson IA . 2012. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489 : 526 532.[PubMed] [CrossRef]
50. Thornburg NJ,, Nannemann DP,, Blum DL,, Belser JA,, Tumpey TM,, Desphande S,, Fritz GA,, Sapparapu G,, Krause JC,, Lee JH,, Warm AB,, Lee DE,, Li S,, Winarski KL,, Spiller BW,, Meiler J,, Crowe JE, Jr . 2013. Human antibodies that neutralize respiratory droplet transmissible H5N1 influenza viruses. J Clin Invest 123 : 4405 4409.[PubMed] [CrossRef]
51. Fleishman SJ,, Whitehead TA,, Ekiert DC,, Dreyfus C,, Corn JE,, Strauch EM,, Wilson IA,, Baker D . 2011. Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science 332 : 816 821.[PubMed] [CrossRef]
52. Whitehead TA,, Chevalier A,, Song Y,, Dreyfus C,, Fleishman SJ,, De Mattos C,, Myers CA,, Kamisetty H,, Blair P,, Wilson IA,, Baker D . 2012. Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nat Biotechnol 30 : 543 548.[PubMed] [CrossRef]
53. Wei C-J,, Yassine HM,, McTamney PM,, Gall JG,, Whittle JR,, Boyington JC,, Nabel GJ . 2012. Elicitation of broadly neutralizing influenza antibodies in animals with previous influenza exposure. Sci Transl Med 4 : 147ra114. doi:10.1126/scitranslmed.3004273. [PubMed] [CrossRef]
54. Khurana S,, Chearwae W,, Castellino F,, Manischewitz J,, King LR,, Honorkiewicz A,, Rock MT,, Edwards KM,, Del Giudice G,, Rappuoli R,, Golding H . 2010. Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Sci Transl Med 2 : 15ra5. doi:10.1126/scitranslmed.3000624. [PubMed] [CrossRef]
55. Haynes BF,, Kelsoe G,, Harrison SC,, Kepler TB . 2012. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol 30 : 423 433.[PubMed] [CrossRef]
56. Medina RA,, Stertz S,, Manicassamy B,, Zimmermann P,, Sun X,, Albrecht RA,, Uusi-Kerttula H,, Zagordi O,, Belshe RB,, Frey SE,, Tumpey TM,, Garcia-Sastre A . 2013. Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses. Sci Transl Med 5: 187ra70. doi:10.1126/scitranslmed.3005996. [PubMed] [CrossRef]


Generic image for table

Characteristics of globular head versus stem HA antibodies

Citation: Krause J, Crowe J. 2015. Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head, p 209-219. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0021-2014
Generic image for table

Select cross-reactive globular head HA antibodies

Citation: Krause J, Crowe J. 2015. Committing the Oldest Sins in the Newest Kind of Ways—Antibodies Targeting the Influenza Virus Type A Hemagglutinin Globular Head, p 209-219. In Crowe J, Boraschi D, Rappuoli R (ed), Antibodies for Infectious Diseases. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.AID-0021-2014

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error