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Clinical Research and Public HealthImmunologyVaccines
Open Access | 
10.1172/jci.insight.184128
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Bonduelle, O. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Delory, T. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
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1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
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1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
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1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
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1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Lenormand, M. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Petrier, M. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Rogeaux, O. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by de Bernard, S. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Alves, K. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
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1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Lina, B. in: JCI | PubMed | Google Scholar
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
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Combadiere, B.
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1Sorbonne Université, Institut National de Santé et de Recherche Médicale, Inserm U1135, Centre d’Immunologie et des Maladies Infectieuses, Cimi-Paris, Paris, France.
2Centre Hospitalier Annecy Genevois, Epagny Metz-Tessy, France.
3Centre Hospitalier Centre Hospitalier Métropole Savoie, Chambéry, France.
4Altrabio, Lyon, France.
5Centre International de Recherche en Infectiologie, Université Claude Bernard Lyon-1, INSERM U1111, CNRS, UMR5308, ENS Lyon, Université Jean Monnet de Saint-Etienne, Lyon, France.
6Laboratoire de Virologie, Institut des Agents Infectieux, Centre National de Référence des Virus des Infections Respiratoires, Hospices Civils de Lyon, Lyon, France.
7The INFLUOMICS Study group is detailed in Supplemental Acknowledgments.
Address correspondence to: Cécile Janssen, Centre Hospitalier Annecy Genevois, 74330, Epagny Metz-Tessy, France. Email: cjanssen@ch-annecygenevois.fr. Or to: Behazine Combadiere, Center for Immunology and Diseases (Cimi-Paris), Inserm, Sorbonne University, 91 Boulevard de l’Hôpital, 75013 Paris, France. Email: behazine.combadiere@inserm.fr.
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Find articles by Janssen, C. in: JCI | PubMed | Google Scholar
Authorship note: OB and TD contribtued equally to this work. BC and CJ contributed equally to this work.
Published March 4, 2025 - More info
Published in Volume 10, Issue 8 on April 22, 2025
Abstract
BACKGROUND. The high-dose quadrivalent influenza vaccine (QIV-HD) showed superior efficacy against laboratory-confirmed illness compared with the standard-dose quadrivalent influenza vaccine (QIV-SD) in randomized controlled trials with the elderly. However, specific underlying mechanism remains unclear.
METHODS. This phase IV randomized controlled trial compared early innate responses induced by QIV-HD and QIV-SD in 59 individuals aged > 65 years. Systemic innate cells and gene signatures at day 0 (D0) and D1 as well as hemagglutinin inhibition antibody (HIA) titers at D0 and D21 after vaccination were assessed.
RESULTS. QIV-HD elicited robust humoral response with significantly higher antibody titers and seroconversion rates than QIV-SD. At D1 after vaccination, QIV-HD recipients showed significant reduction in innate cells, including conventional DCs and NK cells, compared with QIV-SD, correlating with significantly increased HIA titers at D21. Blood transcriptomic analysis revealed greater amplitude of gene expression in the QIV-HD arm, encompassing genes related to innate immune response, IFNs, and antigen processing and presentation, and correlated with humoral responses. Interestingly, comparative analysis with a literature dataset from young adults vaccinated with influenza standard-dose vaccine highlighted strong similarities in gene expression patterns and biological pathways with the elderly vaccinated with QIV-HD.
CONCLUSION. QIV-HD induces higher HIA titers than QIV-SD, a youthful boost of the innate gene expression significantly associated with high HIA titers.
TRIAL REGISTRATION. EudraCT no. 2021-004573-32.
IntroductionInfluenza is a contagious disease due to respiratory RNA viruses (1, 2). Vaccination with the influenza vaccines is the foremost strategy for preventing influenza and its severe complications on a global scale. Extensive evidence supports the effectiveness of influenza vaccination in diminishing morbidity and mortality associated with influenza, particularly in high-risk groups, including neonates, young children, pregnant women, and individuals aged 50 years or older (3, 4).
Despite the overall efficacy of influenza vaccination campaigns, emerging evidence indicates that vaccines may elicit diverse responses, leading to suboptimal immunity in specific populations, particularly in the elderly. Hence, a significant public health challenge lies in developing a vaccine that effectively safeguards populations with diverse and comparatively weaker immune systems than the average. Given the high mutation rate and transmissibility, it is also suggested that the next pandemic is likely to be caused by a respiratory RNA virus, including influenza (5). Understanding biological pathways leading to optimal immunization is thereby essential in this perspective. Several factors are known to influence the immune response to influenza vaccines and should be encompassed in the design of vaccine strategies: (a) host genetic factors (i.e., genetic polymorphisms); (b) host-related factors such as age, comorbidities, physiological stress, and microbiome; and (c) vaccination strategies, including mode of vaccine administration, doses, and adjuvants. Based on the findings previous studies, we proposed that the early innate immune response triggered in the hours following vaccination plays a crucial role in shaping the magnitude and effectiveness of the adaptive immune response in the weeks following vaccination (6–8). This assumption was supported by the integration of biological data obtained during influenza vaccination clinical trials. These various studies have provided valuable insights into the effect of immunization methods and vaccine formulations on the innate signature, influencing the quality of immune responses (7, 9, 10). It could also contribute to epidemic and pandemic preparedness, giving guidance for industry to develop future vaccine candidates for emerging influenza strains, including mRNA strains.
Optimal targeted strategies to improve immune responses to the vaccine in the elderly population could stem influenza-associated morbidity and mortality (4). One way is to increase the dose of HA in inactivated vaccines (11, 12), such as Efluelda (Sanofi Pasteur high-dose quadrivalent influenza vaccine [QIV-HD], 60 μg hemagglutinin [HA] per strain) for elderly population. The QIV-HD stands out as the only vaccine that has shown superior efficacy against laboratory-confirmed illness in adults aged 65 years and older. This was demonstrated in a significant pivotal randomized controlled trial, comparing it with the standard-dose QIV (QIV-SD, 15 μg HA) (12), along with established and consistent performances over many consecutive influenza seasons (13).
In addition to the direct clinical benefits of QIV-HD vaccine, the immunological responses of high-dose versus standard-dose vaccines were documented in a recent systematic review (14). High-dose influenza vaccines have demonstrated the ability to elicit elevated hemagglutination inhibition antibody (HIA) titers, increased neutralization, and higher antineuraminidase titers. However, their effects on other facets of immunity remain unknown. Further studies delving into the contributions of various immune cells to this improved immune response could offer valuable insights, particularly regarding the vaccine’s application in special groups at risk of infection. To enhance vaccination strategies, particularly for elderly individuals, a deeper understanding of the intricate molecular mechanisms and interconnected networks regulating innate and adaptive immunity induced by high-dose vaccines is essential (15).
We advocate for holistic systems vaccinology approaches that concurrently consider both innate and adaptive immunity. This comprehensive perspective enables us to gain a global understanding of the response to an influenza vaccine. The foundation of systems vaccinology rests on 2 core objectives: first, unveiling new mechanisms involved in vaccination, and second, identifying novel biomarkers that can distinguish between responders and nonresponders to vaccines. Ultimately, these approaches will facilitate the identification of early molecular and cellular factors that may contribute to the enhanced clinical protection offered by high-dose vaccines in the days following vaccination. This knowledge will enable tailoring vaccination strategies to specific populations, ensuring the right dose, for the right population, and employing the right delivery strategy.
One of our approaches is based on measurement of variations in innate immune responses in the blood during the 24 hours following vaccination (7, 9, 10). We can leverage this data to assess the intensity of immune responses linked to key innate immune gene signatures and compare them to gene signatures documented in existing literature (7, 9, 10).
We hypothesize that the dose of QIV HA can affect the intensity and quality of innate immunity and, subsequently, the humoral responses. In this phase IV open-label randomized (1:1 ratio) versus active-controlled multicenter trial, we aim at comparing the effect of QIV-HD versus QIV-SD in patients aged 65 years or older, on the 2 components of immune response: early innate and adaptive immunity. The relative evolution of (a) the early blood molecular (transcriptome) and the cellular (blood phenotyping) signatures 1 day (D1) after vaccination, and (b) the late adaptive immunity D21 after vaccination with either QIV-HD or QIV-SD vaccinees during the 2021/2022 influenza season, were compared with baseline values.
ResultsStudy population and HIA titers. A total of 59 participants with a signed informed consent were included, randomized. Of them, 31 were assigned to QIV-HD arm and 28 to QIV-SD arm. The flowchart diagram is presented in Figure 1A and Supplemental Figure 1 (supplemental material available online with this article; https://doi.org/10.1172/jci.insight.184128DS1). Biological and clinical data were complete for all patients (Supplemental Figure 1). Participant characteristics were similar between both arms. The median age of the participants was 70 years, and females were 42% (n = 25) of the study participants (Supplemental Table 1). During the 2020/2021 winter season, 83% were vaccinated against influenza using 1 dose of QIV-SD, and 100% patients received 2 doses or more of SARS-CoV-2 vaccine in a median of 2 months prior trial participation (Supplemental Table 2). Safety between arms was similar, with 5 serious adverse events occurred in 4 patients. One of them was a suspected unexpected serious adverse reaction 120 days after QIV-HD vaccination, and 4 were considered not to be related to the vaccine or the study procedure by the investigators and the sponsor (Supplemental Table 3).
Figure 1Study protocol and immunogenicity of QIV-HD compared with QIV-SD in adults ≥ 65 years old. (A) Schematic overview of experiment with kinetics of biological sample collection including serum collection and whole blood cells for transcriptomic and innate cell phenotype analyses. (B) Dot plots present geometric mean titers (GMT) with 95% CI of anti–A H1N1 hemagglutination inhibition antibody (HIA) titers, anti–A H3N2 HIA titers, anti–B Victoria HIA titers, and anti–B Yamagata HIA titers at D0, D21, D90, and D210 after QIV-SD (green) or QIV-HD (violet) vaccination. The horizontal line represents the seroprotection cut off with HIA titers at 40. Wilcoxon tests and Fisher’s exact tests were performed to compare the characteristics of the 2 groups (**P <0.01).
We first compared the immunogenicity of QIV-HD versus QIV-SD by measurement of HIA titers in the study population. Results are displayed in Figure 1B and Supplemental Table 4. QIV-HD induced significantly higher geometric mean titers (GMTs), seroprotection, and seroconversion rates against influenza A strains (A/H1N1 and A/H3N2) D21 after vaccination (P < 0.01). However, HIA titers were not sustained until D210 after vaccination. The immune responses against influenza strain B were less effective in both study arms, yet higher seroconversion rate was observed against influenza B/Victoria strain when receiving QIV-HD compared with QIV-SD.
Our study validated elevated immunogenicity of QIV-HD compared with QIV-SD in elderly patients aged > 65 years.
Early whole blood gene expression following QIV-HD compared with QIV-SD vaccination in the elderly population. Our hypothesis posits that the robust humoral responses observed after QIV-HD administration could be attributed to modulation of innate responses at gene expression levels. Initially, we employed transcriptomic methods to assess the early innate immunity’s quality, irrespective of the outcomes in adaptive immunity. Through this, we identified a distinct “gene expression signature” after vaccination by comparing gene expression within the initial 24 hours following vaccination (from D1 to D0) across different trial arms.
Gene expression 7 days before (D–7) vaccination, and upon immunization (D0) was similar between treatment arms (data not shown). In the 24 hours following vaccination (D1), compared with D0, we observed strong modifications in the blood transcriptome with each vaccine, and we identified genes that were differentially expressed (D1/D0) with each vaccine, shown in Figure 2, A and B. The statistical analyses showed that modification in gene expression was induced by both vaccines, yet to a much greater and significant extent in patients vaccinated with QIV-HD. We did not detect significant differentially expressed genes (DEG) (adjusted P < 0.05 and with absolute fold-change [FC] of 1.41), at D1 in the QIV-SD arm, while we found 293 DEG in the QIV-HD arm, suggesting a higher intensity of innate signature in elderly patients vaccinated with high-dose influenza vaccine. The list of gens is reported in Supplemental Table 5. Genes were similarly up- or downregulated by vaccines, with higher intensity among patients receiving QIV-HD compared with QIV-SD (Figure 2B).
Figure 2Differential expression genes by transcriptomic analysis at D1 after vaccination in QIV-HD and QIV-SD arms. (A) Left panel: Volcano plot of differentially expressed genes (DEG) (D1/D0) of arm QIV-SD. Significance is defined by a FDR adjusted P < 0.05 and a FC > 1.41 (red; upregulated) or < –1.41 (blue; downregulated). Right panel: Volcano plot of DEG: (D1/D0) of arm QIV-HD. The vertical black lines delimit the 1.41-FC effects. (B) Differential FC (D1/D0) comparison of gene expression between QIV-SD and QIV-HD groups. The black square delimits the 1.41-FC effects. Significance is defined by an FDR adjusted P <0.05 and a FC > 1.41 (red; upregulated) or < –1.41 (blue; downregulated). (C) Biological processes enriched by the DEG in the QIV-HD. DEG were ranked by their value of FC (P <0.05), and the GSEA algorithm using Gene Ontology – Biological Processes was performed to extract functional information from gene expression data.
Although to different extents in terms of FC and P values, QIV-HD vaccines induced expression of genes involved in the same biological pathways, as observed in the enrichment analysis performed by Gene Set Enrichment Analysis (GSEA) algorithm using the Gene Ontology (GO) database (Figure 2C). Among the biological activated pathways, we observe those related to “innate immune response”, “responses to virus and to interferons (IFNs)”, and “antigen processing and presentation”. Indeed, among the top DEG (lowest P values and highest FC), many were known to be involved in these major biological pathways, such as UBE2L6 (Class I MHC antigen processing and presentation), GBP5 and GBP1 (IFN inducible GTPases), SERPING1 (regulation of complement cascade), and ANKRD22 (antiviral activity) (Supplemental Table 6).
Gene signature of H3N2 HIA titers following QIV-HD vaccination in elderly individuals. We sought to define an early innate gene signature associated with HIA titers following QIV-HD influenza immunization. Considering the intensity of humoral responses to A/H3N2 HIA titers in our dataset, and consistent with previous studies on the dominance of A/H3N2 HIA titers (16), we observed that the log2 FC of 213 genes correlated with the log2 FC of A/H3N2 HIA titers (Supplemental Table 7). We applied hierarchical clustering to the expression profile of these 213 genes for which the log2 FC was found significantly correlated (P < 0.05 and r > 0.4) with the log2 FC of A/H3N2 HIA titers. As shown in Figure 3A, we observed their expression among volunteers with increasing values of antibody response against H3N2 virus strain (Figure 3A and Supplemental Table 7). We found genes that are involved with antiviral and IFN signaling responses as well as other innate immunity pathways. In Figure 3B, we represented a few examples of genes (IFNA7, IFNG, CALM1, and CAMK2B) with the expression levels that are positively or negatively correlated with log2 FC of A/H3N2 HIA titers. STRING analysis (https://string-db.org/) showed their biological link (Figure 3C). CALM1 and CAMK2 belongs to the calmodulin pathway, as well as CAMK4, which was described by Nakaya et al. (17) and negatively correlated with Ab responses at D3 after vaccination.
Figure 3Early innate gene signature following QIV-HD vaccination in elderly. (A) Heatmap of the log2 FC values of the 213 genes correlated with the log2 FC of anti–A H3N2 HIA titers. The graph displays the values for each patient, ordered by increasing values in the log2 of antibody titers, which are displayed in the bar plot (Spearman correlation, P < 0.05 and r > 0.4). (B) Correlation plots of the log2 FC of H3N2 HIA titers (y axis) and the log2 FC of some of the top genes correlated with them (x axis). (C) STRING pathway analysis of genes correlated with the log2 FC of anti–A H3N2 HIA titers, without disconnected nodes in the network. Edges represent protein-protein associations with minimum required interaction score of 0.4 edge confidence (line thickness indicates the strength of data support).
Our study thereby validates previous findings on an early innate gene signature linked to HIA titers following QIV-HD with pronounced effect in elderly individuals.
Early whole blood cellular variation following QIV-HD compared with QIV-SD vaccination in the elderly population. We analyzed the abundance of different blood cell subpopulation at D1 after vaccination as indicated in the gating strategy (Supplemental Figure 2). The results are represented in percentage of CD45+ cells, excluding eosinophils. Different blood cell populations were identified using conventional surface markers: T and B cells; neutrophils; basophils; CD56bright early and CD56dim NK cells; classical, intermediate, and nonclassical monocytes; and plasmacytoid-, type 1 and 2 conventional-, and monocyte-derived DCs (pDC, cDC1, cDC2, and moDC, respectively). These blood cell populations remained were stable before (D–7) and upon randomization (D0) (Supplemental Figure 3). To compare the modulation of blood cell populations following vaccination (D1) by trial arm, we normalized and represented the FC differences (D1/D0) by arm using a radar chart (Figure 4A). Two main populations were significantly lowered in the QIV-HD arm 24 hours after vaccination, compared with the QIV-SD arm (Figure 4, A and B): cDC2 and early CD56bright NK cells (adjusted P = 0.03 and < 0.0001, respectively), whereas other circulating blood cell populations remained stable (Supplemental Figure 4). The percentages of cDC2 and CD56bright NK cells are more strongly decreased for the QIV-HD group compared with the QIV-
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