Phase 1 dose-escalation trial evaluating a group 2 influenza hemagglutinin stabilized stem nanoparticle vaccine

Abstract

The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22). Vaccination with H10ssF was safe and well tolerated with only mild systemic and local reactogenicity reported. No serious adverse events occurred. Vaccination significantly increased homologous H10 HA stem binding and neutralizing antibodies at 2 weeks after both first and second vaccinations, and these responses remained above baseline at 40 weeks. Heterologous H3 and H7 binding antibodies also significantly increased after each vaccination and remained elevated throughout the study. These data indicate that the group 2 HA stem nanoparticle vaccine is safe and induces stem-directed binding and neutralizing antibodies.

Fig. 1. Study CONSORT Diagram.

Twenty-five healthy adults aged 18–70 years old enrolled between 8 October 2020 and 22 April 2021 to receive 20 mcg H10ssF once (n = 3) or 60 mcg H10ssF twice (n = 22) with an interval of 16 weeks between vaccines. A total of 7 early terminations resulted from participant relocation (n = 4), early withdrawal due to time commitment (n = 1), or loss of participant to follow-up (n = 2). All participants were monitored for safety and immunogenicity until study completion or termination.

Fig. 2. The H10ssF vaccine elicited mild reactogenicity.

Percentage of participants (x-axis) reporting solicited reactogenicity symptoms (y-axis) in the seven days following each vaccination. For symptoms persisting more than 1 day, a single count per person at the maximum severity of the symptom was plotted. No injection site redness, pruritus, bruising, or fevers were reported. N/A indicates that no second vaccination was administered to the dose group.

Fig. 3. H10ssF vaccination elicited antibodies against homologous H10 HA antigens.

Binding antibodies were assayed using H10 stabilized stem (H10ss, a, c) or full-length (H10FL, b, d) antigens by ECLIA. The AU/mL GM of the 60 mcg recipients’ binding antibodies (a, b) or fold change compared to baseline (c, d) are shown in black with 95% CI. Individual participants’ AU/mL are shown in red or blue lines based on their age group. In (c) and (d), the dashed line represents no fold change from baseline. Symbols in (a) and (b) indicate where the AU/mL GM values at week 2, 16, 18, or 40 after vaccination were significantly different (p < 0.001) from the AU/mL GM at day 0 or week 16.

Fig. 4. H10ssF vaccination elicited neutralizing antibodies against H10N8 A/Jiangxi-Donghu/346/2013.

The geometric mean IC₅₀ neutralizing antibody titers (GMT) and 95% CI of all 60 mcg H10ssF recipients are shown in black, with individual participants’ values in red or blue based on their age group. The dotted line indicates the assay LOD. Brackets indicate two time points that are significantly different from each other with the p value noted above the line. When the significance between a timepoint and baseline is p ≤ 0.001, this is noted by a symbol above the later timepoint. When LOD imputation with zero produced a different p value than imputation with half LOD, results are reported as p ≤ x, where x is the least significant p value resulting from the two test methods.

Fig. 5. H10ssF vaccination elicited binding antibodies against heterologous group 2 influenza HAs.

Binding antibodies were assayed using the H7 stabilized stem (H7ss, a, b) or full-length (H7FL, c, d) antigens, or the H3ss antigen (e, f) by ECLIA. The GM of the 60 mcg recipients’ binding antibodies in AU/mL (a, c, e) or fold change (b, d, f) are shown with 95% CI in black, with individual participants’ AU/mL in red or blue based on their age group. In (b), (d), (f), the dashed line represents no change over baseline. Brackets indicate two time points that are significantly different from each other, with the p value noted above the line. When the significance between a timepoint and baseline is p < 0.001, this is noted by a symbol above the later timepoint.