Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model

ABSTRACT The immunogenicity of current influenza virus vaccines is assessed by measuring an increase of influenza virus-specific antibodies in a hemagglutination inhibition assay. This method exclusively measures antibodies against the hemagglutinin head domain. While this domain is immunodominant,...

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Autores principales:	Henning Jacobsen, Madhusudan Rajendran, Angela Choi, Haakon Sjursen, Karl A. Brokstad, Rebecca J. Cox, Peter Palese, Florian Krammer, Raffael Nachbagauer
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	ADCC ELISA correlate of protection hemagglutinin hemagglutinin stalk influenza Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d709eec0ace54c98a0b1c220de07b37d
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spelling	oai:doaj.org-article:d709eec0ace54c98a0b1c220de07b37d2021-11-15T15:51:51ZInfluenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model10.1128/mBio.01463-172150-7511https://doaj.org/article/d709eec0ace54c98a0b1c220de07b37d2017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01463-17https://doaj.org/toc/2150-7511ABSTRACT The immunogenicity of current influenza virus vaccines is assessed by measuring an increase of influenza virus-specific antibodies in a hemagglutination inhibition assay. This method exclusively measures antibodies against the hemagglutinin head domain. While this domain is immunodominant, it has been shown that hemagglutination inhibition titers do not always accurately predict protection from disease. In addition, several novel influenza virus vaccines that are currently under development do not target the hemagglutinin head domain, but rather more conserved sites, including the hemagglutinin stalk. Importantly, antibodies against the hemagglutinin stalk do not show activity in hemagglutination inhibition assays and will require different methods for quantification. In this study, we tested human serum samples from a seasonal influenza virus vaccination trial and an avian H5N1 virus vaccination trial for antibody activities in multiple types of assays, including binding assays and also functional assays. We then performed serum transfer experiments in mice which then received an H1N1 virus challenge to assess the in vivo protective effects of the antibodies. We found that hemagglutinin-specific antibody levels measured in an enzyme-linked immunosorbent assay (ELISA) correlated well with protection from weight loss in mice. In addition, we found that weight loss was also inversely correlated with the level of serum antibody-dependent cellular cytotoxicity (ADCC) as measured in a reporter assay. These findings indicate that protection is in part conferred by Fc-dependent mechanisms. In conclusion, ELISAs can be used to measure hemagglutinin-specific antibody levels that could serve as a surrogate marker of protection for universal influenza virus vaccines. IMPORTANCE Influenza viruses are a serious concern for public health and cause a large number of deaths worldwide every year. Current influenza virus vaccines can confer protection from disease, but they often show low efficacy due to the ever-changing nature of the viruses. Novel vaccination approaches target conserved epitopes of the virus, including the hemagglutinin stalk domain, to elicit universally protective antibodies that also bind to mutated viruses or new subtypes of viruses. Importantly, the hemagglutination inhibition assay—the only assay that has been accepted as a correlate of protection by regulatory authorities—cannot measure antibodies against the hemagglutinin stalk domain. Therefore, novel correlates of protection and assays to measure vaccine immunogenicity need to be developed. In this study, we correlated the results from multiple assays with protection in mice after transfer of human serum and a lethal virus challenge to investigate potential novel serological surrogate markers for protection.Henning JacobsenMadhusudan RajendranAngela ChoiHaakon SjursenKarl A. BrokstadRebecca J. CoxPeter PaleseFlorian KrammerRaffael NachbagauerAmerican Society for MicrobiologyarticleADCCELISAcorrelate of protectionhemagglutininhemagglutinin stalkinfluenzaMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	ADCC ELISA correlate of protection hemagglutinin hemagglutinin stalk influenza Microbiology QR1-502
spellingShingle	ADCC ELISA correlate of protection hemagglutinin hemagglutinin stalk influenza Microbiology QR1-502 Henning Jacobsen Madhusudan Rajendran Angela Choi Haakon Sjursen Karl A. Brokstad Rebecca J. Cox Peter Palese Florian Krammer Raffael Nachbagauer Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model
description	ABSTRACT The immunogenicity of current influenza virus vaccines is assessed by measuring an increase of influenza virus-specific antibodies in a hemagglutination inhibition assay. This method exclusively measures antibodies against the hemagglutinin head domain. While this domain is immunodominant, it has been shown that hemagglutination inhibition titers do not always accurately predict protection from disease. In addition, several novel influenza virus vaccines that are currently under development do not target the hemagglutinin head domain, but rather more conserved sites, including the hemagglutinin stalk. Importantly, antibodies against the hemagglutinin stalk do not show activity in hemagglutination inhibition assays and will require different methods for quantification. In this study, we tested human serum samples from a seasonal influenza virus vaccination trial and an avian H5N1 virus vaccination trial for antibody activities in multiple types of assays, including binding assays and also functional assays. We then performed serum transfer experiments in mice which then received an H1N1 virus challenge to assess the in vivo protective effects of the antibodies. We found that hemagglutinin-specific antibody levels measured in an enzyme-linked immunosorbent assay (ELISA) correlated well with protection from weight loss in mice. In addition, we found that weight loss was also inversely correlated with the level of serum antibody-dependent cellular cytotoxicity (ADCC) as measured in a reporter assay. These findings indicate that protection is in part conferred by Fc-dependent mechanisms. In conclusion, ELISAs can be used to measure hemagglutinin-specific antibody levels that could serve as a surrogate marker of protection for universal influenza virus vaccines. IMPORTANCE Influenza viruses are a serious concern for public health and cause a large number of deaths worldwide every year. Current influenza virus vaccines can confer protection from disease, but they often show low efficacy due to the ever-changing nature of the viruses. Novel vaccination approaches target conserved epitopes of the virus, including the hemagglutinin stalk domain, to elicit universally protective antibodies that also bind to mutated viruses or new subtypes of viruses. Importantly, the hemagglutination inhibition assay—the only assay that has been accepted as a correlate of protection by regulatory authorities—cannot measure antibodies against the hemagglutinin stalk domain. Therefore, novel correlates of protection and assays to measure vaccine immunogenicity need to be developed. In this study, we correlated the results from multiple assays with protection in mice after transfer of human serum and a lethal virus challenge to investigate potential novel serological surrogate markers for protection.
format	article
author	Henning Jacobsen Madhusudan Rajendran Angela Choi Haakon Sjursen Karl A. Brokstad Rebecca J. Cox Peter Palese Florian Krammer Raffael Nachbagauer
author_facet	Henning Jacobsen Madhusudan Rajendran Angela Choi Haakon Sjursen Karl A. Brokstad Rebecca J. Cox Peter Palese Florian Krammer Raffael Nachbagauer
author_sort	Henning Jacobsen
title	Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model
title_short	Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model
title_full	Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model
title_fullStr	Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model
title_full_unstemmed	Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model
title_sort	influenza virus hemagglutinin stalk-specific antibodies in human serum are a surrogate marker for <italic toggle="yes">in vivo</italic> protection in a serum transfer mouse challenge model
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/d709eec0ace54c98a0b1c220de07b37d
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Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for <italic toggle="yes">In Vivo</italic> Protection in a Serum Transfer Mouse Challenge Model

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