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

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.

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Respiratory and systemic cellular and humoral immune responses to influenza virus vaccine administered parenterally or by nose drops

Cellular Immunology ◽

10.1016/0008-8749(72)90168-2 ◽

1972 ◽

Vol 3 (2) ◽

pp. 294-300 ◽

Cited By ~ 55

Author(s):

R.H. Waldman ◽

C.S. Spencer ◽

J.E. Johnson

Keyword(s):

Influenza Virus ◽

Immune Responses ◽

Virus Vaccine ◽

Influenza Virus Vaccine ◽

Humoral Immune ◽

Humoral Immune Responses

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Critical Role of TLR7 Signaling in the Priming of Cross-Protective Cytotoxic T Lymphocyte Responses by a Whole Inactivated Influenza Virus Vaccine

PLoS ONE ◽

10.1371/journal.pone.0063163 ◽

2013 ◽

Vol 8 (5) ◽

pp. e63163 ◽

Cited By ~ 22

Author(s):

Natalija Budimir ◽

Aalzen de Haan ◽

Tjarko Meijerhof ◽

Simke Waijer ◽

Louis Boon ◽

...

Keyword(s):

Influenza Virus ◽

T Lymphocyte ◽

Virus Vaccine ◽

Cytotoxic T Lymphocyte ◽

Critical Role ◽

Influenza Virus Vaccine ◽

Lymphocyte Responses

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IMMUNOGENICITY AND SAFETY OF INACTIVATED INFLUENZA VIRUS VACCINE IN YOUNG CHILDREN IN 2003???2004

The Pediatric Infectious Disease Journal ◽

10.1097/01.inf.0000180978.66362.d9 ◽

2005 ◽

Vol 24 (10) ◽

pp. 925-927 ◽

Cited By ~ 17

Author(s):

Douglas K. Mitchell ◽

Frederick L. Ruben ◽

Stefan Gravenstein

Keyword(s):

Influenza Virus ◽

Young Children ◽

Virus Vaccine ◽

Influenza Virus Vaccine

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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

Journal of Hygiene ◽

10.1017/s0022172400023251 ◽

1974 ◽

Vol 72 (1) ◽

pp. 91-100 ◽

Cited By ~ 20

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.

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

Journal of Virology ◽

10.1128/jvi.03099-14 ◽

2015 ◽

Vol 89 (7) ◽

pp. 3610-3618 ◽

Cited By ~ 50

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.

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

Scientific Reports ◽

10.1038/s41598-021-01780-8 ◽

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.

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