Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study

Lancet Microbe. 2024 Jul;5(7):645-654. doi: 10.1016/S2666-5247(24)00024-7. Epub 2024 May 7.

Abstract

Background: Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients.

Methods: In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113.

Findings: Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported.

Interpretation: The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults.

Funding: Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase II

MeSH terms

  • Adolescent
  • Adult
  • Antibodies, Viral / blood
  • Belgium / epidemiology
  • CD8-Positive T-Lymphocytes* / immunology
  • Double-Blind Method
  • Female
  • Humans
  • Immunity, Cellular
  • Influenza A Virus, H3N2 Subtype* / immunology
  • Influenza Vaccines* / administration & dosage
  • Influenza Vaccines* / immunology
  • Influenza, Human* / immunology
  • Influenza, Human* / prevention & control
  • Male
  • Middle Aged
  • Nucleocapsid Proteins / immunology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / immunology
  • Vaccines, DNA / administration & dosage
  • Vaccines, DNA / immunology
  • Viral Core Proteins / immunology
  • Viral Load*
  • Viral Matrix Proteins / immunology
  • Young Adult

Substances

  • Influenza Vaccines
  • Viral Matrix Proteins
  • M1 protein, Influenza A virus
  • Viral Core Proteins
  • NP protein, Influenza A virus
  • RNA-Binding Proteins
  • Vaccines, DNA
  • Nucleocapsid Proteins
  • Antibodies, Viral

Associated data

  • ClinicalTrials.gov/NCT03883113