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

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.

研究背景
儿童易罹患重症流感感染，并可促进社区流感传播。提升儿童对季节性流感疫苗免疫原性的潜在策略之一，是采用三价血凝素DNA初免-三价灭活流感疫苗（IIV3）加强免疫方案。
研究方法
研究机构先招募青少年受试者，随后纳入低龄儿童，受试者均通过无针喷射注射器（Biojector）肌内注射DNA初免疫苗（剂量为1mg或4mg），约18周后通过针头注射器接种分剂型2012/13季节性IIV3进行加强免疫。对照组受试者在相近间隔期内接受IIV3初免及加强免疫。本研究的主要研究目标为评估各疫苗免疫方案的安全性与耐受性，次要研究目标为在加强免疫后4周，通过血凝抑制试验（HAI）及中和试验检测抗体应答水平。
研究结果
共纳入75名6至17岁的儿童受试者。DNA初免后的局部不良反应发生率高于IIV3初免（疼痛/压痛、红斑或肿胀的P<0.001），但症状均为轻至中度。全身性不良反应发生率在两种疫苗间无显著差异。总体而言，各组间抗体应答水平相近，不过4mg DNA初免-IIV3加强组的HAI抗体应答呈高于IIV3初免-IIV3加强组的趋势。针对A/California/07/2009[A(H1N1)pdm09]的HAI抗体滴度增幅，4mg DNA初免-IIV3加强组（10.12倍，95%置信区间5.60~18.27）显著高于IIV3初免-IIV3加强组（3.86倍，95%置信区间2.32~6.44）。不同免疫方案的中和抗体滴度相近，但4mg DNA初免-IIV3加强组的应答阳性率呈升高趋势。不过，针对中和试验panel中的H1N1病毒株，几何平均折叠比增幅存在显著差异：A/New Caledonia/20/1999（1.41倍，95%置信区间1.10~1.81）及A/South Carolina/1/1918（1.55倍，95%置信区间1.27~1.89）。
研究结论
本项在美国开展的首个儿童DNA疫苗研究结果显示，DNA初免-IIV3加强免疫方案安全性良好且耐受性佳。在儿童群体中，4mg DNA初免-IIV3加强方案的抗体应答水平与IIV3初免-IIV3加强方案相当。