DNA vaccine priming for seasonal influenza vaccine in children and adolescents 6 to 17 years of age: A phase 1 randomized clinical trial

Abstract

Background: Children are susceptible to severe influenza infections and facilitate community transmission. One potential strategy to improve vaccine immunogenicity in children against seasonal influenza involves a trivalent hemagglutinin DNA prime-trivalent inactivated influenza vaccine (IIV3) boost regimen.

Methods: Sites enrolled adolescents, followed by younger children, to receive DNA prime (1 mg or 4 mg) intramuscularly by needle-free jet injector (Biojector), followed by split virus 2012/13 seasonal IIV3 boost by needle and syringe approximately 18 weeks later. A comparator group received IIV3 prime and boost at similar intervals. Primary study objectives included evaluation of the safety and tolerability of the vaccine regimens, with secondary objectives of measuring antibody responses at four weeks post boost by hemagglutination inhibition (HAI) and neutralization assays.

Results: Seventy-five children ≥6 to ≤17 years old enrolled. Local reactogenicity was higher after DNA prime compared to IIV3 prime (p<0.001 for pain/tenderness, redness, or swelling), but symptoms were mild to moderate in severity. Systemic reactogenicity was similar between vaccines. Overall, antibody responses were similar among groups, although HAI antibodies revealed a trend towards higher responses following 4 mg DNA-IIV3 compared to IIV3-IIV3. The fold increase of HAI antibodies to A/California/07/2009 [A(H1N1)pdm09] was significantly greater following 4 mg DNA-IIV3 (10.12 fold, 5.60-18.27 95%CI) compared to IIV3-IIV3 (3.86 fold, 2.32-6.44 95%CI). Similar neutralizing titers were observed between regimens, with a trend towards increased response frequencies in 4 mg DNA-IIV3. However, significant differences in fold increase, reported as geometric mean fold ratios, were detected against the H1N1 viruses within the neutralization panel: A/New Caledonia/20/1999 (1.41 fold, 1.10-1.81 95%CI) and A/South Carolina/1/1918 (1.55 fold, 1.27-1.89 95%CI).

Conclusions: In this first pediatric DNA vaccine study conducted in the U.S., the DNA prime-IIV3 boost regimen was safe and well tolerated. In children, the 4 mg DNA-IIV3 regimen resulted in antibody responses comparable to the IIV3-IIV3 regimen.

Fig 1. CONSORT diagram of study participants.

All 75 study participants completed the scheduled vaccinations and 74 subjects completed the scheduled visits and were included in the analysis. The remaining subject withdrew after completing the vaccination schedule but prior to the four week post boost time point. This subject was analyzed for safety but was not included in the immunological end point analysis.

Fig 2. Overall pain perception following administration of vaccines.

(A) The Wong-Baker Faces Pain Rating Scale for evaluation of pain perception following vaccination was shown to participants the same day (within an hour) and again at seven days post vaccination. (B) Overall pain perception of participants following both prime and boost. Age groups are combined and pain scores of 0 are not displayed.

Fig 3. Antibody responses to the vaccine strains by age and group, as determined by HAI.

The antibody responses for the 4 mg DNA-IIV3 and the IIV3-IIV3 regimens are displayed as group means based on the (A) magnitude of response at 4 weeks post boost, (B) geometric mean fold increase of titers from baseline at both 4 and 24 weeks post boost, and (C) seroconversion rates at 4 weeks post boost. DNA-IIV3 values shown in black, and IIV3-IIV3 in grey. Comparisons were made between the DNA-IIV3 and IIV3-IIV3 groups using Fisher’s exact test for serconversion rates, and t-test for response magnitude using log-transformed HAI titers.