Characterization of Epitope-Specific Anti-Respiratory Syncytial Virus (Anti-RSV) Antibody Responses after Natural Infection and after Vaccination with Formalin-Inactivated RSV.
Antibodies against the fusion (F) protein of respiratory syncytial virus (RSV) play an important role in the protective immune response to this important respiratory virus. Little is known, however, about antibody levels against multiple F-specific epitopes induced by infection or after vaccination against RSV, while this is important to guide the evaluation of (novel) vaccines. In this study, we analyzed antibody levels against RSV proteins and F-specific epitopes in human sera and in sera of vaccinated and experimentally infected cotton rats and the correlation thereof with virus neutralization. Analysis of human sera revealed substantial diversity in antibody levels against F-, G (attachment)-, and F-specific epitopes between individuals. The highest correlation with virus neutralization was observed for antibodies recognizing prefusion-specific antigenic site Ø. Nevertheless, our results indicate that high levels of antibodies targeting other parts of the F protein can also mediate a potent antiviral antibody response. In agreement, sera of experimentally infected cotton rats contained high neutralizing activity despite lacking antigenic site Ø-specific antibodies. Strikingly, vaccination with formalin-inactivated RSV (FI-RSV) exclusively resulted in the induction of poorly neutralizing antibodies against postfusion-specific antigenic site I, although antigenic sites I, II, and IV were efficiently displayed in FI-RSV. The apparent immunodominance of antigenic site I in FI-RSV likely explains the low levels of neutralizing antibodies upon vaccination and challenge and may play a role in the vaccination-induced enhancement of disease observed with such preparations.



RSV is an importance cause of hospitalization of infants. The development of a vaccine against RSV has been hampered by the disastrous results obtained with FI-RSV vaccine preparations in the 1960s that resulted in vaccination-induced enhancement of disease. To get a better understanding of the antibody repertoire induced after infection or after vaccination against RSV, we investigated antibody levels against fusion (F) protein, attachment (G) protein, and F-specific epitopes in human and animal sera. The results indicate the importance of prefusion-specific antigenic site Ø antibodies as well as of antibodies targeting other epitopes in virus neutralization. However, vaccination of cotton rats with FI-RSV specifically resulted in the induction of weakly neutralizing, antigenic site I-specific antibodies, which may play a role in the enhancement of disease observed after vaccination with such preparations.
Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands i.widjaja@uu.nl c.a.m.dehaan@uu.nl.|Mucosis B.V., Meditech Center, Groningen, The Netherlands.
Ivy
I
Widjaja
Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Oliver
http://orcid.org/0000-0003-3266-8075
O
Wicht
Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
Willem
W
Luytjes
Mucosis B.V., Meditech Center, Groningen, The Netherlands.
Kees
K
Leenhouts
Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Peter J M
PJM
Rottier
Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Frank J M
FJM
van Kuppeveld
Mucosis B.V., Meditech Center, Groningen, The Netherlands.
Bert Jan
BJ
Haijema
Virology Division, Department of Infectious Diseases & Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands i.widjaja@uu.nl c.a.m.dehaan@uu.nl.
Cornelis A M
CAM
de Haan
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood* / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005557:Formaldehyde; D006801:Humans; D007113:Immunity, Innate; D016056:Immunodominant Epitopes / Q000097:blood / Q000276:immunology; D051381:Rats; D022261:Respiratory Syncytial Virus Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000276:immunology*; D018113:Respiratory Syncytial Virus, Human / Q000737:chemistry / Q000276:immunology*; D016205:Sigmodontinae; D014611:Vaccination / Q000009:adverse effects; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000009:adverse effects; D014759:Viral Envelope Proteins / Q000276:immunology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D016056:Immunodominant Epitopes; D022261:Respiratory Syncytial Virus Vaccines; D015164:Vaccines, Inactivated; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins; D014764:Viral Proteins; C116204:attachment protein G; D005557:Formaldehyde