Pre-fusion F is absent on the surface of formalin-inactivated respiratory syncytial virus.
The lack of a licensed vaccine for respiratory syncytial virus (RSV) can be partly attributed to regulatory hurdles resulting from vaccine enhanced respiratory disease (ERD) subsequent to natural RSV infection that was observed in clinical trials of formalin-inactivated RSV (FI-RSV) in antigen-naïve infants. To develop an effective vaccine that does not enhance RSV illness, it is important to understand how formalin and heat inactivation affected the antigenicity and immunogenicity of FI-RSV compared to native virus. Informed by atomic structures of RSV fusion (F) glycoprotein in prefusion (pre-F) and postfusion (post-F) conformations, we demonstrate that FI-RSV predominately presents post-F on the virion surface, whereas infectious RSV presents both pre-F and post-F conformations. This significant antigenic distinction has not been previously appreciated. Thus, a stabilized pre-F antigen is more representative of live RSV than F in its post-F conformation, as displayed on the surface of FI-RSV. This finding has major implications for discriminating current pre-F-based immunogens from FI-RSV used in historical vaccine trials.
Vaccine Research Center, National Institute of Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
April M
AM
Killikelly
Vaccine Research Center, National Institute of Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Masaru
M
Kanekiyo
Vaccine Research Center, National Institute of Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, United States.
Barney S
BS
Graham
Nat Commun. 2015 Sep 03;6:8143
26333350
Am J Epidemiol. 1969 Apr;89(4):422-34
4305198
CMAJ. 1995 Feb 1;152(3):343-8
7828098
J Clin Microbiol. 1986 Nov;24(5):894-8
3771779
Am J Epidemiol. 1969 Apr;89(4):405-21
4305197
Am J Epidemiol. 1969 Apr;89(4):449-63
4305200
J Clin Microbiol. 1988 Aug;26(8):1595-7
2459154
Curr Opin Virol. 2015 Apr;11:70-5
25819327
Nat Med. 2006 Aug;12(8):905-7
16862151
Am J Epidemiol. 1969 Apr;89(4):435-48
4305199
J Infect Dis. 1982 Mar;145(3):311-9
7037983
J Immunol Methods. 2010 Oct 31;362(1-2):180-4
20727896
PLoS Pathog. 2014 Apr 24;10(4):e1004016
24763387
J Infect Dis. 1995 Mar;171 Suppl 1:S44-9
7876648
Curr Top Microbiol Immunol. 2013;372:391-404
24362701
J Virol. 2011 Aug;85(15):7788-96
21613394
J Exp Med. 2002 Sep 16;196(6):859-65
12235218
Science. 2015 Jul 10;349(6244):aac4223
26089353
Sci Transl Med. 2015 Oct 14;7(309):309ra162
26468324
Vaccine. 2007 Oct 16;25(42):7372-8
17868959
PLoS Pathog. 2015 Mar 13;11(3):e1004757
25769044
J Virol Methods. 2000 Feb;84(2):175-9
10680967
Science. 2013 Nov 1;342(6158):592-8
24179220
J Virol. 2014 Oct;88(20):11955-64
25100844
PLoS Pathog. 2015 Jul 10;11(7):e1005035
26161532