scholarly journals Broadly Neutralizing Anti-Influenza Virus Antibodies: Enhancement of Neutralizing Potency in Polyclonal Mixtures and IgA Backbones

2015 ◽  
Vol 89 (7) ◽  
pp. 3610-3618 ◽  
Author(s):  
Wenqian He ◽  
Caitlin E. Mullarkey ◽  
J. Andrew Duty ◽  
Thomas M. Moran ◽  
Peter Palese ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Monoclonal Antibodies ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Human Peripheral Blood ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Broadly Neutralizing Antibodies ◽  
Variable Regions

ABSTRACTCurrent influenza virus vaccines rely upon the accurate prediction of circulating virus strains months in advance of the actual influenza season in order to allow time for vaccine manufacture. Unfortunately, mismatches occur frequently, and even when perfect matches are achieved, suboptimal vaccine efficacy leaves several high-risk populations vulnerable to infection. However, the recent discovery of broadly neutralizing antibodies that target the hemagglutinin (HA) stalk domain has renewed hope that the development of “universal” influenza virus vaccines may be within reach. Here, we examine the functions of influenza A virus hemagglutinin stalk-binding antibodies in an endogenous setting, i.e., as polyclonal preparations isolated from human sera. Relative to monoclonal antibodies that bind to the HA head domain, the neutralization potency of monoclonal stalk-binding antibodies was vastly inferiorin vitrobut was enhanced by several orders of magnitude in the polyclonal context. Furthermore, we demonstrated a surprising enhancement in IgA-mediated HA stalk neutralization relative to that achieved by antibodies of IgG isotypes. Mechanistically, this could be explained in two ways. Identical variable regions consistently neutralized virus more potently when in an IgA backbone compared to an IgG backbone. In addition, HA-specific memory B cells isolated from human peripheral blood were more likely to be stalk specific when secreting antibodies of IgA isotypes compared to those secreting IgG. Taken together, our data provide strong evidence that HA stalk-binding antibodies perform optimally when in a polyclonal context and that the targeted elicitation of HA stalk-specific IgA should be an important consideration during “universal” influenza virus vaccine design.IMPORTANCEInfluenza viruses remain one of the most worrisome global public health threats due to their capacity to cause pandemics. While seasonal vaccines fail to protect against the emergence of pandemic strains, a new class of broadly neutralizing antibodies has been recently discovered and may be the key to developing a “universal” influenza virus vaccine. While much has been learned about the biology of these antibodies, most studies have focused only on monoclonal antibodies of IgG subtypes. However, the study of monoclonal antibodies often fails to capture the complexity of antibody functions that occur during natural polyclonal responses. Here, we provide the first detailed analyses of the biological activity of these antibodies in polyclonal contexts, comparing both IgG and IgA isotypes isolated from human donors. The striking differences observed in the functional properties of broadly neutralizing antibodies in polyclonal contexts will be essential for guiding design of “universal” influenza virus vaccines and therapeutics.

scholarly journals A public broadly neutralizing antibody class targets a membrane-proximal anchor epitope of influenza virus hemagglutinin

2021 ◽  
Author(s):  
Jenna J. Guthmiller ◽  
Julianna Han ◽  
Henry A. Utset ◽  
Lei Li ◽  
Linda Yu-Ling Lan ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Memory ◽  
Influenza Virus Vaccine ◽  
Virus Infections ◽  
Broadly Neutralizing Antibodies ◽  
Cell Repertoire ◽  
Influenza Virus Hemagglutinin

SummaryBroadly neutralizing antibodies against influenza virus hemagglutinin (HA) have the potential to provide universal protection against influenza virus infections. Here, we report a distinct class of broadly neutralizing antibodies targeting an epitope toward the bottom of the HA stalk domain where HA is “anchored” to the viral membrane. Antibodies targeting this membrane-proximal anchor epitope utilized a highly restricted repertoire, which encode for two conserved motifs responsible for HA binding. Anchor targeting B cells were common in the human memory B cell repertoire across subjects, indicating pre-existing immunity against this epitope. Antibodies against the anchor epitope at both the serological and monoclonal antibody levels were potently induced in humans by a chimeric HA vaccine, a potential universal influenza virus vaccine. Altogether, this study reveals an underappreciated class of broadly neutralizing antibodies against H1-expressing viruses that can be robustly recalled by a candidate universal influenza virus vaccine.

scholarly journals Interferon mediated prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine lacking non-structural protein 1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Raveen Rathnasinghe ◽  
Mirella Salvatore ◽  
Hongyong Zheng ◽  
Sonia Jangra ◽  
Thomas Kehrer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Type I ◽  
Respiratory Pathogens ◽  
Structural Protein ◽  
Human Influenza Virus

AbstractThe influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

scholarly journals Prophylactic protection against respiratory viruses conferred by a prototype live attenuated influenza virus vaccine

2021 ◽  
Author(s):  
Raveen Rathnasinghe ◽  
Mirella Salvatore ◽  
Hongyong Zheng ◽  
Sonia Jangra ◽  
Thomas Kehrer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Type I ◽  
Respiratory Pathogens ◽  
Structural Protein ◽  
Human Influenza Virus

AbstractThe influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

scholarly journals Prophylactic Protection Against Respiratory Viruses Conferred by a Prototype Live Attenuated Influenza Virus Vaccine

2021 ◽  
Author(s):  
Raveen Rathnasinghe ◽  
Mirella Salvatore ◽  
Hongyong Zheng ◽  
Sonia Jangra ◽  
Thomas Kehrer ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Infection ◽  
Influenza Virus Vaccine ◽  
Influenza Viruses ◽  
Type I ◽  
Respiratory Pathogens ◽  
Structural Protein ◽  
Human Influenza Virus

Abstract The influenza A non-structural protein 1 (NS1) is known for its ability to hinder the synthesis of type I interferon (IFN) during viral infection. Influenza viruses lacking NS1 (ΔNS1) are under clinical development as live attenuated human influenza virus vaccines and induce potent influenza virus-specific humoral and cellular adaptive immune responses. Attenuation of ΔNS1 influenza viruses is due to their high IFN inducing properties, that limit their replication in vivo. This study demonstrates that pre-treatment with a ΔNS1 virus results in an immediate antiviral state which prevents subsequent replication of homologous and heterologous viruses, preventing disease from virus respiratory pathogens, including SARS-CoV-2. Our studies suggest that ΔNS1 influenza viruses could be used for the prophylaxis of influenza, SARS-CoV-2 and other human respiratory viral infections, and that an influenza virus vaccine based on ΔNS1 live attenuated viruses would confer broad protection against influenza virus infection from the moment of administration, first by non-specific innate immune induction, followed by specific adaptive immunity.

scholarly journals A Host-Restricted Self-Attenuated Influenza Virus Provides Broad Pan-Influenza A Protection in a Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Minjin Kim ◽  
Yucheol Cheong ◽  
Jinhee Lee ◽  
Jongkwan Lim ◽  
Sanguine Byun ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Mouse Model ◽  
Neutralizing Antibodies ◽  
Influenza A ◽  
Protective Efficacy ◽  
Influenza Viruses ◽  
Cross Protection ◽  
Infection Model ◽  
Wild Type ◽  
Group 1

Influenza virus infections can cause a broad range of symptoms, form mild respiratory problems to severe and fatal complications. While influenza virus poses a global health threat, the frequent antigenic change often significantly compromises the protective efficacy of seasonal vaccines, further increasing the vulnerability to viral infection. Therefore, it is in great need to employ strategies for the development of universal influenza vaccines (UIVs) which can elicit broad protection against diverse influenza viruses. Using a mouse infection model, we examined the breadth of protection of the caspase-triggered live attenuated influenza vaccine (ctLAIV), which was self-attenuated by the host caspase-dependent cleavage of internal viral proteins. A single vaccination in mice induced a broad reactive antibody response against four different influenza viruses, H1 and rH5 (HA group 1) and H3 and rH7 subtypes (HA group 2). Notably, despite the lack of detectable neutralizing antibodies, the vaccination provided heterosubtypic protection against the lethal challenge with the viruses. Sterile protection was confirmed by the complete absence of viral titers in the lungs and nasal turbinates after the challenge. Antibody-dependent cellular cytotoxicity (ADCC) activities of non-neutralizing antibodies contributed to cross-protection. The cross-protection remained robust even after in vivo depletion of T cells or NK cells, reflecting the strength and breadth of the antibody-dependent effector function. The robust mucosal secretion of sIgA reflects an additional level of cross-protection. Our data show that the host-restricted designer vaccine serves an option for developing a UIV, providing pan-influenza A protection against both group 1 and 2 influenza viruses. The present results of potency and breadth of protection from wild type and reassortant viruses addressed in the mouse model by single immunization merits further confirmation and validation, preferably in clinically relevant ferret models with wild type challenges.

scholarly journals Correlation of Cellular Immune Responses with Protection against Culture-Confirmed Influenza Virus in Young Children

2008 ◽  
Vol 15 (7) ◽  
pp. 1042-1053 ◽  
Author(s):  
Bruce D. Forrest ◽  
Michael W. Pride ◽  
Andrew J. Dunning ◽  
Maria Rosario Z. Capeding ◽  
Tawee Chotpitayasunondh ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Young Children ◽  
Immune Responses ◽  
Virus Vaccine ◽  
Elispot Assay ◽  
Influenza Virus Vaccine ◽  
The Philippines ◽  
Influenza Viruses ◽  
Ifn Γ

ABSTRACT The highly sensitive gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 107 fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.

scholarly journals A Lipid/DNA Adjuvant–Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge

2018 ◽  
Vol 218 (6) ◽  
pp. 856-867 ◽  
Author(s):  
Timothy D Carroll ◽  
Sinthujan Jegaskanda ◽  
Shannon R Matzinger ◽  
Linda Fritts ◽  
Michael B McChesney ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Virus Replication ◽  
Virus Vaccine ◽  
Influenza A ◽  
Rhesus Macaques ◽  
Influenza Virus Vaccine ◽  
Virus Challenge

scholarly journals Immunity to influenza in ferrets: VII. Effect of previous infection with heterotypic and heterologous influenza viruses on the response of ferrets to inactivated influenza virus vaccines

1974 ◽  
Vol 72 (1) ◽  
pp. 91-100 ◽  
Author(s):  
C. McLaren ◽  
C. W. Potter
Keyword(s):  
Influenza Virus ◽  
Hong Kong ◽  
Virus Vaccine ◽  
Serum Antibody ◽  
Influenza Virus Vaccine ◽  
Challenge Infection ◽  
Influenza Viruses ◽  
Subsequent Challenge ◽  
Ann Arbor ◽  
Previous Infection

SUMMARYNormal ferrets did not produce serum antibody following immunization with 200 i.u. of inactivated A/Hong Kong/68 influenza virus vaccine and were found to be susceptible to subsequent challenge infection with A/Hong Kong/68 virus. High titres of virus were recovered from nasal washings collected 3 days after infection, serum antibody was produced, increased nasal protein was detected and HI antibody was detected in nasal washings. Ferrets infected with influenza virus A/PR/8/34 7 weeks before immunization with inactivated A/HK/68 virus did, however, produce serum HI antibody to A/HK/68 virus. This antibody conferred partial immunity to challenge infection with A/HK/68 virus, as shown by decreased titres of virus in nasal washings and reduced levels of nasal protein. Previous infection of ferrets with influenza virus B/Ann Arbor/66 did not result in the production of serum antibody to A/HK/68 virus following immunization with A/HK/68 vaccine and the animals were completely susceptible to subsequent challenge infection with A/HK/68 virus. Differences in the amount of nasal protein and nasal antibody produced after A/HK/68 infection were also found in ferrets previously infected with either A/PR/8/34 or B/AA/66 virus, compared with normal ferrets.

scholarly journals WHO recommendations for influenza virus vaccine 2002/03

2002 ◽  
Vol 6 (6) ◽  
Author(s):  
J Watson ◽  
M Zambon
Keyword(s):  
Influenza Virus ◽  
General Population ◽  
Influenza A Virus ◽  
Virus Vaccine ◽  
Influenza A ◽  
Influenza Virus Vaccine ◽  
Good Level

The new subtype of the influenza A virus, A(H1N2), is a combination of components present in the strains of the two influenza A subtypes (H1N1 and H3N2) currently contained in the vaccine, and so people who have received the vaccine should have a good level of immunity to the new subtype. People in the general population who have not been vaccinated should also have some immunity due to the circulation of the H1N1 and H3N2 subtypes over the last two decades.

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