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

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.

Conflict of interest statement

Competing Interests: This study was partly funded by hVIVO Group PLC., ID Biomedical Corporation of Québec, Analytical Solutions Group, Inc. and ID Biomedical Corporation of Maryland, the respective employers of: Rob Lambkin-Williams, Anthony S. Gilbert, Alex Mann, Richard Broughton, Corey P. Mallett, David Burt, and David He. Patent details: Proteosome influenza vaccine US 6743900 B2. Abstract - Improved forms of vaccines which comprise proteosomes and protein antigens are described. Vaccines which contain influenza HA as the antigen are used for illustration as to demonstrate efficacy. Improvements in the preparation of the vaccines themselves and the proteosome component are also included. Publication number - US6743900 B2. Publication type - Grant Application number - US 09/788,280. Publication date - Jun 1, 2004. Filing date - Feb 15, 2001. Priority date - Feb 15, 2000. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. CONSORT Flowchart for Study 1 (Study Protocol 13004)

Fig 2. CONSORT Flowchart for Study 2 (Study Protocol 13005)

Fig 3. Summary of Study Design for both studies

Fig 4. Percentage vaccine efficacy by treatment group

Fig 5. Mean (± SE) Tissue count and tissue weight for all treatment groups in Study 2

Fig 6. Correlation of serum IgG (HAI) and mucosal sIgA levels at Day 39±3 and rates of any influenza symptoms and seroconversion following viral challenge