Broadly Protective Monoclonal Antibodies against H3 Influenza Viruses following Sequential Immunization with Different Hemagglutinins

English version České info

As targets of adaptive immunity, influenza viruses are characterized by the fluidity with which they respond to the selective pressure applied by neutralizing antibodies. This mutability of structural determinants of protective immunity is the obstacle in developing universal influenza vaccines. Towards the development of such vaccines and other immune therapies, our studies are designed to identify regions of influenza viruses that are conserved and that mediate virus neutralization. We have specifically focused on viruses of the H3N2 subtype, which have persisted as a principal source of influenza-related morbidity and mortality in humans since the pandemic of 1968. Three monoclonal antibodies have been identified that are broadly-neutralizing against H3 influenza viruses spanning 40 years. The antibodies react with the hemagglutinin glycoprotein and appear to bind in regions that are refractory to the structural variation required for viral escape from neutralization. The antibodies demonstrate therapeutic efficacy in mice against H3N2 virus infection and have potential for use in the treatment of human influenza disease. By mapping the binding region of one antibody, 12D1, we have identified a continuous region of the hemagglutinin that may act as an immunogen to elicit broadly protective immunity to H3 viruses. The anti-H3 monoclonal antibodies were identified after immunization of mice with the hemagglutinin of four different viruses (A/Hong Kong/1/1968, A/Alabama/1/1981, A/Beijing/47/1992, A/Wyoming/3/2003). This immunization schedule was designed to boost B cells specific for conserved regions of the hemagglutinin from distinct antigenic clusters. Importantly, our antibodies are of naturally occurring specificity rather than selected from cloned libraries, demonstrating that broad-spectrum humoral immunity to influenza viruses can be elicited in vivo.

Vyšlo v časopise: Broadly Protective Monoclonal Antibodies against H3 Influenza Viruses following Sequential Immunization with Different Hemagglutinins. PLoS Pathog 6(2): e32767. doi:10.1371/journal.ppat.1000796
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000796

Souhrn

Zdroje

1. WHO April, 2009 Influenza (Seasonal) Fact sheet 211

2. PiotP

BartosM

GhysPD

WalkerN

SchwartlanderB

2001 The global impact of HIV/AIDS. Nature 410 968 973

3. AhmedR

OldstoneMB

PaleseP

2007 Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nat Immunol 8 1188 1193

4. ChowellG

BertozziSM

ColcheroMA

Lopez-GatellH

Alpuche-ArandaC

2009 Severe Respiratory Disease Concurrent with the Circulation of H1N1 Influenza. N Engl J Med

5. CDC Seasonal flu; United States Surveillance Data

6. CouchRB

KaselJA

1983 Immunity to influenza in man. Annu Rev Microbiol 37 529 549

7. MartinezO

TsibaneT

BaslerCF

2009 Neutralizing anti-influenza virus monoclonal antibodies: therapeutics and tools for discovery. Int Rev Immunol 28 69 92

8. SkehelJJ

WileyDC

2000 Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69 531 569

9. WileyDC

WilsonIA

SkehelJJ

1981 Structural identification of the antibody-binding sites of Hong Kong influenza haemagglutinin and their involvement in antigenic variation. Nature 289 373 378

10. VareckovaE

MuchaV

WhartonSA

KostolanskyF

2003 Inhibition of fusion activity of influenza A haemagglutinin mediated by HA2-specific monoclonal antibodies. Arch Virol 148 469 486

11. SuiJ

HwangWC

PerezS

WeiG

AirdD

2009 Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16 265 273

12. EkiertDC

BhabhaG

ElsligerMA

FriesenRH

JongeneelenM

2009 Antibody recognition of a highly conserved influenza virus epitope. Science 324 246 251

13. RussellRJ

KerryPS

StevensDJ

SteinhauerDA

MartinSR

2008 Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion. Proc Natl Acad Sci U S A 105 17736 17741

14. OkunoY

IsegawaY

SasaoF

UedaS

1993 A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J Virol 67 2552 2558

15. KashyapAK

SteelJ

OnerAF

DillonMA

SwaleRE

2008 Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci U S A 105 5986 5991

16. ThrosbyM

van den BrinkE

JongeneelenM

PoonLL

AlardP

2008 Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS ONE 3 e3942 doi:10.1371/journal.pone.0003942

17. SmithDJ

LapedesAS

de JongJC

BestebroerTM

RimmelzwaanGF

2004 Mapping the antigenic and genetic evolution of influenza virus. Science 305 371 376

18. MoranTM

MonestierM

LaiAC

NortonG

RealeMA

1987 Characterization of variable-region genes and shared crossreactive idiotypes of antibodies specific for antigens of various influenza viruses. Viral Immunol 1 1 12

19. BowleyDR

JonesTM

BurtonDR

LernerRA

2009 Libraries against libraries for combinatorial selection of replicating antigen-antibody pairs. Proc Natl Acad Sci U S A 106 1380 1385

20. MarascoWA

SuiJ

2007 The growth and potential of human antiviral monoclonal antibody therapeutics. Nat Biotechnol 25 1421 1434

21. WilsonIA

SkehelJJ

WileyDC

1981 Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289 366 373

22. GravesPN

SchulmanJL

YoungJF

PaleseP

1983 Preparation of influenza virus subviral particles lacking the HA1 subunit of hemagglutinin: unmasking of cross-reactive HA2 determinants. Virology 126 106 116

23. JordanWSJr

OseasohnRO

1954 The use of RDE to improve the sensitivity of the hemagglutination-inhibition test for the serologic diagnosis of influenza. J Immunol 72 229 235

24. HarlowE

LaneD

1988 Antibodies: a laboratory manual Cold Spring Harbor, NY Cold Spring Harbor Laboratory xiii, 726

25. BaslerCF

ReidAH

DybingJK

JanczewskiTA

FanningTG

2001 Sequence of the 1918 pandemic influenza virus nonstructural gene (NS) segment and characterization of recombinant viruses bearing the 1918 NS genes. Proc Natl Acad Sci U S A 98 2746 2751

26. de StGrothSF

ScheideggerD

1980 Production of monoclonal antibodies: strategy and tactics. J Immunol Methods 35 1 21

27. KohlerG

MilsteinC

1975 Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256 495 497

28. TowbinH

StaehelinT

GordonJ

1979 Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 76 4350 4354

29. CohenA

NewlandSE

Biddlef

1963 Inhibition of Influenza Virus Haemagglutination: a Difference of Behavior in Sera from a Single Species. Virology 20 518 529