Center for Clinical Epidemiology & Population Health, Marshfield Clinic Research Institute, Marshfield, WI, United States.
Influenza Division, Centers for Disease Control and Prevention, Atlanta, GA, United States.
Vaccine. 2020 Mar 30;38(15):3121-3128. doi: 10.1016/j.vaccine.2020.02.055. Epub 2020 Mar 4.
Licensed inactivated influenza vaccines (IIV) are recommended for persons aged ≥65 years, including trivalent high-dose IIV (HD-IIV3) and adjuvanted IIV (aIIV3); both are manufactured in eggs. Quadrivalent recombinant vaccine (RIV4) is produced without eggs. We conducted an exploratory study to compare immunogenicity of HD-IIV3, aIIV3 and RIV4 against cell-grown vaccine and circulating A(H3N2) viruses in 2017-18.
Eighty-nine adults aged 65-74 years participating in a 2-year, open-label immunogenicity trial (ClinicalTrails.gov: NCT02872311) were randomized 1:1:1 to receive HD-IIV3, aIIV3, or RIV4 after receipt of standard dose IIV3 in 2016-17. Serum was obtained at baseline and day 28 post vaccination. Microneutralization titers were determined using four cell-propagated A(H3N2) viruses: 2017-18 vaccine strain (clade 3C.2a), circulating viruses from clades 3C.2a1 and 3C.2a2, and 'antigenically advanced' clade 3C.3a (2019-20 vaccine strain). Active surveillance was conducted to identify influenza illnesses.
Post vaccination geometric mean titer (GMT) against the vaccine strain was <1:60 in each group and <15% seroconverted. RIV4 generated a greater fold-rise (2.0, 95% CI 1.7-2.5) compared to HD-IIV3 (1.6, 95% CI 1.3-1.8). RIV4 generated higher post vaccination titers against 3C.2a1 and 3C.2a2 viruses, and the mean fold-rise after RIV4 was twice as high (3.3 and 3.5, respectively) relative to HD-IIV3 (1.4 and 1.6) and aIIV3 (1.7 and 1.6). Against the antigenically advanced 3C.3a virus, RIV4 generated a greater mean fold-rise (2.9, 95% CI 2.0-4.3) vs HD-IIV3 (1.3, 95% CI 1.1-1.6) and aIIV3 (1.7, 95% CI 1.3-2.1). Postvaccination titers against 3C.2a2 were ≥1:40 in 5 of 7 participants with PCR-confirmed A(H3N2) infection during the ensuing influenza season.
High-dose, adjuvanted, and recombinant vaccines generated suboptimal neutralizing antibody responses to the cell-grown vaccine strain, but RIV4 generated a greater cross-protective response against circulating and antigenically advanced viruses. Recombinant technology may contribute to more broadly protective influenza vaccines, and comparative effectiveness studies are needed.
已许可的灭活流感疫苗（IIV）推荐用于≥65 岁人群，包括三价高剂量 IIV（HD-IIV3）和佐剂 IIV（aIIV3）；两者均在鸡蛋中生产。四价重组疫苗（RIV4）是在没有鸡蛋的情况下生产的。我们进行了一项探索性研究，比较了 2017-18 年 HD-IIV3、aIIV3 和 RIV4 对细胞生长疫苗和循环 A(H3N2)病毒的免疫原性。
89 名年龄在 65-74 岁的成年人参加了一项为期 2 年、开放标签的免疫原性试验（ClinicalTrails.gov：NCT02872311），他们在 2016-17 年接受标准剂量 IIV3 后，按 1:1:1 的比例随机接受 HD-IIV3、aIIV3 或 RIV4。在基线和接种后第 28 天采集血清。使用四种细胞培养的 A(H3N2)病毒确定微量中和滴度：2017-18 年疫苗株（谱系 3C.2a）、来自谱系 3C.2a1 和 3C.2a2 的循环病毒以及“抗原先进”谱系 3C.3a（2019-20 年疫苗株）。进行主动监测以确定流感病例。
接种疫苗后，每组针对疫苗株的几何平均滴度（GMT）均<1:60，<15%的人发生血清转化。与 HD-IIV3（1.6，95%CI 1.3-1.8）相比，RIV4 产生的倍数增长（2.0，95%CI 1.7-2.5）更大。RIV4 对 3C.2a1 和 3C.2a2 病毒产生的接种后滴度更高，接种 RIV4 后的平均倍数增长（分别为 3.3 和 3.5）是 HD-IIV3（1.4 和 1.6）和 aIIV3（1.7 和 1.6）的两倍。对于抗原先进的 3C.3a 病毒，RIV4 产生的平均倍数增长（2.9，95%CI 2.0-4.3）大于 HD-IIV3（1.3，95%CI 1.1-1.6）和 aIIV3（1.7，95%CI 1.3-2.1）。在接下来的流感季节中，有 7 名 PCR 确诊的 A(H3N2)感染患者中有 5 名接种后针对 3C.2a2 的血清滴度≥1:40。
高剂量、佐剂和重组疫苗对细胞生长疫苗株产生了不理想的中和抗体反应，但 RIV4 对循环和抗原先进的病毒产生了更大的交叉保护反应。重组技术可能有助于更广泛的保护性流感疫苗，需要进行比较有效性研究。
