An Intranasal Proteosome-Adjuvanted Trivalent Influenza Vaccine Is Safe, Immunogenic & Efficacious in the Human Viral Influenza Challenge Model. Serum IgG & Mucosal IgA Are Important Correlates of Protection against Illness Associated with Infection

PLoS One. 2016 Dec 22;11(12):e0163089. doi: 10.1371/journal.pone.0163089. eCollection 2016.

Abstract

Introduction: A Proteosome-adjuvanted trivalent inactivated influenza vaccine (P-TIV) administered intra-nasally was shown to be safe, well tolerated and immunogenic in both systemic and mucosal compartments, and effective at preventing illness associated with evidence of influenza infection.

Methods: In two separate studies using the human viral challenge model, subjects were selected to be immunologically naive to A/Panama/2007/1999 (H3N2) virus and then dosed via nasal spray with one of three regimens of P-TIV or placebo. One or two doses, 15 μg or 30 μg, were given either once only or twice 14 days apart (1 x 30 μg, 2 x 30 μg, 2 x 15 μg) and subjects were challenged with A/Panama/2007/1999 (H3N2) virus. Immune responses to the vaccine antigens were measured by haemagglutination inhibition assay (HAI) and nasal wash secretory IgA (sIgA) antibodies.

Results: Vaccine reactogenicity was mild, predictable and generally consistent with earlier Phase I studies with this vaccine. Seroconversion to A/Panama/2007/1999 (H3N2), following vaccination but prior to challenge, occurred in 57% to 77% of subjects in active dosing groups and 2% of placebo subjects. The greatest relative rise in sIgA, following vaccination but prior to challenge, was observed in groups that received 2 doses.

Conclusion: Intranasal vaccination significantly protected against influenza (as defined by influenza symptoms combined with A/Panama seroconversion) following challenge with A/Panama/2007/1999 (H3N2). When data were pooled from both studies, efficacy ranged from 58% to 82% in active dosing groups for any influenza symptoms with seroconversion, 67% to 85% for systemic or lower respiratory illness and seroconversion, and 65% to 100% for febrile illness and seroconversion. The two dose regimen was found to be superior to the single dose regimen. In this study, protection against illness associated with evidence of influenza infection (evidence determined by seroconversion) following challenge with virus, significantly correlated with pre-challenge HAI titres (p = 0.0003) and mucosal sIgA (p≤0.0001) individually, and HAI (p = 0.028) and sIgA (p = 0.0014) together. HAI and sIgA levels were inversely related to rates of illness.

Trial registration: ClinicalTrials.gov NCT02522754.

Publication types

  • Clinical Trial

MeSH terms

  • Adjuvants, Immunologic
  • Administration, Intranasal
  • Adult
  • Antibodies, Viral / blood
  • Antibody Formation
  • Female
  • Hemagglutination Inhibition Tests
  • Humans
  • Immunoglobulin A, Secretory / analysis*
  • Immunoglobulin G / blood*
  • Influenza A Virus, H3N2 Subtype / immunology*
  • Influenza Vaccines / administration & dosage
  • Influenza Vaccines / immunology*
  • Influenza, Human / prevention & control*
  • Male
  • Placebo Effect
  • Vaccines, Inactivated / administration & dosage
  • Vaccines, Inactivated / immunology
  • Young Adult

Substances

  • Adjuvants, Immunologic
  • Antibodies, Viral
  • Immunoglobulin A, Secretory
  • Immunoglobulin G
  • Influenza Vaccines
  • Vaccines, Inactivated

Associated data

  • ClinicalTrials.gov/NCT02522754

Grants and funding

This study was funded by the authors' affiliations, i.e. hVIVO Group PLC., University Hospitals Coventry & Warwickshire NHS Trust, ID Biomedical Corporation of Québec, Analytical Solutions Group, Inc. Queen Mary’s School of Medicine and Dentistry and ID Biomedical Corporation of Maryland. hVIVO Group PLC., Analytical Solutions Group, Inc., ID Biomedical Corporation of Québec and ID Biomedical Corporation of Maryland provided support in the form of salaries for authors RLW, ASG, AM, RB, CPM, DB, and DH, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.