Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans

Abstract

Background: The novel influenza vaccine MVA-NP+M1 is designed to boost cross-reactive T-cell responses to internal antigens of the influenza A virus that are conserved across all subtypes, providing protection against both influenza disease and virus shedding against all influenza A viruses. Following a phase 1 clinical study that demonstrated vaccine safety and immunogenicity, a phase 2a vaccination and influenza challenge study has been conducted in healthy adult volunteers.

Methods: Volunteers with no measurable serum antibodies to influenza A/Wisconsin/67/2005 received either a single vaccination with MVA-NP+M1 or no vaccination. T-cell responses to the vaccine antigens were measured at enrollment and again prior to virus challenge. All volunteers underwent intranasal administration of influenza A/Wisconsin/67/2005 while in a quarantine unit and were monitored for symptoms of influenza disease and virus shedding.

Results: Volunteers had a significantly increased T-cell response to the vaccine antigens following a single dose of the vaccine, with an increase in cytolytic effector molecules. Intranasal influenza challenge was undertaken without safety issues. Two of 11 vaccinees and 5 of 11 control subjects developed laboratory-confirmed influenza (symptoms plus virus shedding). Symptoms of influenza were less pronounced in the vaccinees and there was a significant reduction in the number of days of virus shedding in those vaccinees who developed influenza (mean, 1.09 days in controls, 0.45 days in vaccinees, P = .036).

Conclusions: This study provides the first demonstration of clinical efficacy of a T-cell-based influenza vaccine and indicates that further clinical development should be undertaken.

Clinical trials registration: NCT00993083.

Figures

Figure 1.

Ex vivo interferon γ enzyme-linked immunosorbent spot assay responses to nucleoprotein (NP) and matrix protein 1 (M1). The graph represents the summed response to NP and M1 antigens in vaccinees (circles) and controls (squares) at the relevant time points; lines represent the median per group and open symbols represent subjects who developed laboratory-confirmed influenza. Control subjects were not assayed at day 0 or day 21. Vaccination took place on day 0 and influenza challenge on day 30. Data were analyzed with a Kruskal-Wallis 1-way analysis of variance with selected pairs of data analyzed with a Dunn positive test. No significant difference between the median response in the vaccinated and control group was observed at time of screening (day 0 for vaccinees, day 29 for controls). A significant increase in the response was observed in vaccinees between days 0 and 21 and days 0 and 29 (P < .001,P < .05, respectively). A significant difference between vaccinees and controls was observed at day 29 (P < .05). Abbreviations: PBMC, peripheral blood mononuclear cell; SFU, spot-forming units.

Figure 2.

Responses to M158–66 in human leukocyte antigen A2–positive volunteers. Whole blood drawn 1 day prior to virus challenge was labeled for tetramer (A*0201/GILGFVFTL) followed by perforin or granzyme A staining. Values shown are the percentage of CD8+ T cells or Tet+ cells; individuals are shown as a single point with lines representing the median per group. Open symbols represent samples from volunteers who subsequently developed laboratory-confirmed influenza. For each marker the data were analyzed with an unpaired t test; P values are shown for statistically significant differences between vaccinees and controls.

Figure 3.

Total of symptom scores at each time point following challenge (A) or total grade 2 and 3 symptom and examination scores (B) for vaccinees (circles) and controls (squares), with the group mean indicated by a line. Open symbols denote subjects who developed laboratory-confirmed influenza after challenge.