Vaccine Pandemic Preparedness Through Airway Immunology Characterization (VAXXAIR)

In-depth Immunological Analysis of Airway Immunity Following Nasal Live Attenuated and Intramuscular Influenza Vaccine

The study aims to compare the effectiveness of live attenuated influenza vaccines (LAIV) and intramuscular-inactivated vaccines (IIV) in healthy individuals aged 18-49. It will investigate cellular and humoral responses, identify immunological markers for targeted vaccine improvement, and establish a collaborative platform for accelerated immunological and clinical vaccine research.

Study Overview

• Status: Not yet recruiting
• Conditions: Influenza, Human
• Intervention / Treatment: Biological: Vaxigripetra; Biological: Flumist

Detailed Description

There are several types of vaccines and the focus on the important role of vaccines in health has increased after the SARS-CoV-2 pandemic. Therefore, it is desired to investigate whether so-called 'live attenuated influenza vaccines' (LAIV) can prove more effective than the most frequently used 'intramuscular-inactivated vaccines' (IIV).

Several studies have previously compared the humoral and cellular response to LAIV and IIV and some of these have shown that LAIV elicits a more robust cellular response than intramuscularly administered vaccines.

In the study, the immunological differences in cellular and humoral response following vaccination either intramuscularly or nasally will be characterized. The patient group will consist of healthy individuals between 18-49 years of age. It is further desired to identify immunological markers that vaccines can be directed against in order to improve the immunological response. Finally, a platform for collaboration on accelerated immunological and clinical vaccine research will be established.

The study is a randomized, double-blind, placebo-controlled study. It is carried out in several locations and is Good Clinical Practice monitored.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Pradeesh Sivapalan, MD, PhD; Phone Number: 45 29880601; Email: pradeesh.sivapalan.02@regionh.dk
• Study Contact Backup: Name: Jens-Ulrik Stæhr Jensen, MD, PhD; Phone Number: 45 38673057; Email: jens.ulrik.jensen@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Copenhagen Hospital Biobank Unit, Department of Clinical Immunology, Rigshospitalet, Denmark
    • Contact: Sisse Rye Ostrowski, MD,PhD, DMSc
    • Contact: Erik Sørensen, MD, PhD
  • Copenhagen, Denmark, 2100
    • Diagnostic Immunology, Department of Clinical Immunology, Rigshospitalet, Denmark
    • Contact: Hanne Vibeke Hansen Marquart, MD, PhD
    • Contact: Signe Modvig, MD, PhD
  • Copenhagen, Denmark, 2100
    • Institute for Immunology and Microbiology (ISIM), Panum Institute, University of Copenhagen
    • Contact: Henrik Kløverpris, PhD
  • Copenhagen, Denmark, 2300
    • National Influenza Center for WHO at Statens Serum Institut (SSI)
  • Kongens Lyngby, Denmark, 2800
    • Technical University of Denmark (DTU)
  • Copenhagen
    • Gentofte, Copenhagen, Denmark, 2900
      • Department of Medicine, Section of Respiratory Medicine, Herlev and Gentofte Hospital
      • Contact: Pradeesh Sivapalan, MD, PhD; Phone Number: 45 29880601; Email: pradeesh.sivapalan.02@regionh.dk
      • Contact: Jens-Ulrik Stæhr Jensen, MD, PhD; Phone Number: 45 38673057; Email: jens.ulrik.jensen@regionh.dk
• United Kingdom
  • London, United Kingdom, W12 0NN
    • Imperial College

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy individuals (Charlson´s co-morbidity index :0, and investigator judged as healthy)
2. Age: 18-49 years
3. Total IgG levels in normal range (discretion of investigator according to local lab)
4. Total IgA levels (discretion of investigator according to local lab)
5. Undetectable HAI titres to the H3N2 component of the vaccines*
6. Normal CD4+ and CD8+ T-cell and normal B-cell counts

7. Reference levels from ISO-15189 accredited T-, B- and NK-cell count routine analyses will be applied.

   • If <20% of the first 100 screened persons apply to this criterion, this will be changed to a specific cut off based on the lowest quartile level of HAI titres to the H3N2 component of these 100 screened persons.

Exclusion Criteria:

1. Laboratory-confirmed influenza infection during the past year documented by a positive PCR test in the Danish Microbiological database or anamnestic reported influenza infection in the same period
2. Active smoker
3. BMI > 35 kg/m2
4. Women of childbearing potential not using safe contraception, or who are pregnant, or breast-feeding
5. Any allergies to components of or contraindication for Vaxigriptetra® or Flumist® incl. previous severe adverse reactions to influenza vaccinations or components of the vaccines
6. Use of immunosuppressive drugs* within the past 6 months or who are currently using them
7. HIV, HBV, HCV laboratory confirmed active infection at screening visit
8. Have an acute illness, including an oral temperature ≥ 38°C, within 3 days prior to vaccination
9. Have received any vaccines, including live-attenuated vaccines within 4 weeks before inclusion, or plan receipt of such vaccines within 30 days following the inclusion
10. Any known malignant neoplasm within 5 years (except basal carcinoma of the skin).
11. Severe mental illness or linguistic issues which significantly impedes cooperation

12. Inability to provide written informed consent

    • defined as: Azathioprin, methotrexate, cyclophosphamide, basiliximab, belimumab, anifrolumab, alemtuzumab, rituximab, mycophenolat, calcineurin inhibitors (ciclosporin, voclosporin and tacrolimus), mTOR inhibitors (everolimus and sirolimus), prednisolone (or any corticosteroid in doses above the equivalent of 5 mg prednisolone), TNF-α inhibitors (such as infliximab), anti-thymocyte globulin.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vaxigripetra; This arm will receive 1 dose of 0.5 mL Vaxigripetra (intra-muscular injection) and 1 dose of 0.2 mL placebo (nasal, 1 spray in each nostril).	Biological: Vaxigripetra; Tetravalent intramuscular vaccine. Mechanism of action: The vaccine induces an immune reaction involving antibody production.
Experimental: Flumist; 1 dose of 0.2 mL Flumist (nasal, 1 spray in each nostril) and 1 dose of 0.5 mL placebo (intra-muscular injection).	Biological: Flumist; Tetravalent live attenuated influenza vaccine administered as a nasal spray. Mechanism of action: Not fully understood according to the prescribing information, but may involve influenza-specific T-cells and antibodies (serum and mucosal).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 28, mucosal immunity in nasopharynx (humoral)	Time point: Comparison between day -14 (baseline) [+/-5 days] vs. day +28 [+/-5 days]. Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2) haemagglutinin vaccine-specific IgA in nasopharyngeal secretions will be characterized as outcome 1. All other individuals will be characterized as outcome 0. Material: Nasopharyngeal secretions Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2) haemagglutinin vaccine-specific IgA in nasal secretions will be characterized as outcome 1. All other individuals will be characterized as outcome 0. Material: nasopharyngeal secretion.	Day -14 (baseline) [+/-5 days] vs. day +28 [+/-5 days]

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Day 7, mucosal immunity in nasopharynx (humoral)	Time point: Comparison between day -14 (baseline) [+/-5 days] vs. day +7 [+/-1 days]. Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2) haemagglutinin vaccine-specific IgA in nasopharyngeal secretions will be characterized as outcome 1. All other individuals will be characterized as outcome 0. Material: Nasopharyngeal secretions Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2) haemagglutinin vaccine-specific IgA in nasopharyngeal secretions will be characterized as outcome 1. All other individuals will be characterized as outcome 0. Material: Nasopharyngeal secretions Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2)) haemagglutinin vaccine-specific IgA in nasal secretions will be characterized as outcome 1. All other individuals will be characterized as outcome 0. Material: nasopharyngeal secretion.	Day -14 (baseline) [+/-5 days] vs. day +7 [+/-1 days]
Day 28, mucosal immunity in Lower Airways (BALF) (humoral)	Time point: Comparison between day -14 (baseline) [+/-5 days] vs. day +28 [+/-5 days]. Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2) haemagglutinin vaccine-specific IgA in nasopharyngeal secretions will be characterized as outcome 1. All other will be characterized as outcome 0.	Day -14 (baseline) [+/-5 days] vs. day +28 [+/-5 days]
Day 7, mucosal immunity in Lower Airways (BALF) (humoral)	Time point: Comparison between day -14 (baseline) [+/-5 days] vs. day +7 [+/-1 days]. Explanation: all individuals who have a ≥-4-fold rise in (A (H3N2) haemagglutinin vaccine-specific IgA in BALF will be characterized as outcome 1. All other individuals will be characterized as outcome 0.	Day -14 (baseline) [+/-5 days] vs. day +7 [+/-1 days]
Rise in mucosal antibody titre (humoral)	Hypothesis: Intranasally administered LAIV influenza vaccine will more often produce a ≥-4-fold rise in mucosal antibody titre against each of the remaining (non-H3N2) vaccine virus haemagglutinin antigens vaccine-specific antibody (IgG (when BALF) and IgA (when nasopharyngeal)) titres in respiratory secretions compared to intramuscular IIV tetravalent influenza vaccine. Time points: Day -14 (baseline), and i) day 28 [+/-5 days] ii) and day 7 [+/-1 day] after vaccination. Antigens: 1) A (H1N1) ; 2) B/Austria/1359417/2021 ; 3) B/Phuket/3073/2013 Material: BALF and nasopharyngeal secretion	Day +28 [+/- 5 days]
Lower airways mucosal immunity, CD4+ (cellular)	Hypothesis: Intranasally administered LAIV influenza vaccine will lead to a higher number of Antigen activated* CD4+ T-lymphocytes in BALF measured at day -14 (baseline) vs. day +7 as compared to intramuscular IIV tetravalent influenza vaccine. Explanation: Fractions of CD4+ T-lymphocytes, that are antigen activated against an antigen pool composed of the antigens in the two utilized vaccines, will be measured at day -14 (baseline) and day +7. Fold changes will be compared between vaccine arms. Material: BALF. * A (H1N1) - A (H3N2) • B/Austria/1359417/2021 • B/Phuket/3073/2013	Day -14 (baseline) vs. day +7
Systemic immunity (blood) (cellular)	Hypothesis: Intranasally administered LAIV influenza vaccine will lead to a higher number of Antigen activated* CD4+ T-lymphocytes in blood measured at day -14 (baseline) vs. day +7 as compared to intramuscular IIV tetravalent influenza vaccine. Explanation: Fractions of CD4+ T-lymphocytes, that are antigen activated against an antigen pool composed of the antigens in the two utilized vaccines, will be measured at day -14 (baseline) and day +7. Fold changes will be compared between vaccine arms. Material: Blood * A (H1N1) - A (H3N2) • B/Austria/1359417/2021 • B/Phuket/3073/2013	Day -14 (baseline) vs. day +7

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Early changes in local immune profiles (cellular)	Hypothesis and explanation: Airway-delivered LAIV vaccine (Flumist) will induce early antigen specific T- lymphocytes as well as resident memory T- and B-cells locally in the respiratory tract that is characterized by activated TRM and TFH in BALF and mediastinal lymph nodes, and with higher levels of CXCR3pos-B-cells and BRM in BALF and respiratory mucosal tissue and mediatinal lymph nodes compared to that of intramuscular delivered trivalent flu vaccine. Material: BALF	Day -14 (baseline) vs. day +7
Upper airways lymph node (Tonsil) immunity (cellular)	Hypothesis: Intranasally administered LAIV influenza vaccine will lead to a higher number of Antigen activated* CD4+ T-lymphocytes in lymphoid tissue from tonsils measured at day -14 (baseline) vs. day +7 as compared to intramuscular IIV tetravalent influenza vaccine. Explanation: Fractions of CD4+ and CD8+ T-lymphocytes, that are antigen activated against an antigen pool composed of the antigens in the two utilized vaccines, will be compared between day -14 (baseline) and day +7. Material: Lymphoid tissue from tonsils. Analysis of this hypothesis depends on feasibility (enough material) * A (H1N1) - A (H3N2) • B/Austria/1359417/2021 • B/Phuket/3073/2013	Day -14 (baseline) vs. day +7
Lower airways mucosal immunity, CD8+ (cellular)	Hypothesis: Intranasally administered LAIV influenza vaccine will lead to a higher number of Antigen activated* CD8+ T-lymphocytes in BALF measured at day -14 (baseline) vs. day +7 as compared to intramuscular IIV tetravalent influenza vaccine. Explanation: Fractions of CD8+ T-lymphocytes, that are antigen activated against an antigen pool composed of the antigens in the two utilized vaccines, will be measured at day -14 (baseline) and day +7. Fold changes will be compared between vaccine arms. Material: BALF. * A (H1N1) - A (H3N2) • B/Austria/1359417/2021 • B/Phuket/3073/2013	Day -14 (baseline) vs. day +7
Further exploratory humoral characterization	Haemagglutinin antigens vaccine-specific antibody (IgG) titres in serum (HAI). This will be analysed in the following analyses: A. Number of participants with ≥-4-fold rise in serum antibody titres against each vaccine virus* B. Categorical and scalar associations between vaccine virus shedding (measured at days +1, +3, and +7 post-vaccination) and cellular and humoral immune responses. C. Proportion of study enrolled subjects achieving a HAI titre of ≥1:40 measured using antibody titre measured at -14 (baseline), day +7 day +28 [+/-5 days], day +90 and day 180 [+/-5 days] after vaccination. * A (H1N1) - A (H3N2) • B/Austria/1359417/2021 • B/Phuket/3073/2013	Day -14 (baseline), day +7 day +28 [+/-5 days], day +90 and day 180 [+/-5 days]

Collaborators and Investigators

• Sponsor: Chronic Obstructive Pulmonary Disease Trial Network, Denmark
• Collaborators: The Novo Nordic Foundation
• Investigators: Principal Investigator: Jens-Ulrik Stæhr Jensen, MD, PhD, Chronic Obstructive Pulmonary Disease Trial Network, Denmark

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: June 18, 2023
• First Submitted That Met QC Criteria: June 18, 2023
• First Posted (Actual): June 27, 2023

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 20, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Orthomyxoviridae Infections; Influenza, Human
• Other Study ID Numbers: VAXXAIR

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This has not yet been decided.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No