ARTICLES| VOLUME 22, ISSUE 4, P483-495, APRIL 01, 2022

Immunogenicity and safety of a third dose of CoronaVac, and immune persistence of a two-dose schedule, in healthy adults: interim results from two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials

Gang Zeng, Qianhui Wu, Hongxing Pan, et al

Lancet Infect Dis 2022; 22: 483-495

Summary

Background

Large-scale vaccination against COVID-19 is being implemented in many countries with CoronaVac, an inactivated vaccine. We aimed to assess the immune persistence of a two-dose schedule of CoronaVac, and the immunogenicity and safety of a third dose of CoronaVac, in healthy adults aged 18 years and older.

Methods

In the first of two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials, adults aged 18–59 years in Jiangsu, China, were initially allocated (1:1) into two vaccination schedule cohorts: a day 0 and day 14 vaccination cohort (cohort 1) and a day 0 and day 28 vaccination cohort (cohort 2); each cohort was randomly assigned (2:2:1) to either a 3 μg dose or 6 μg dose of CoronaVac or a placebo group. Following a protocol amendment on Dec 25, 2020, half of the participants in each cohort were allocated to receive an additional dose 28 days (window period 30 days) after the second dose, and the other half were allocated to receive a third dose 6 months (window period 60 days) after the second dose. In the other phase 2 trial, in Hebei, China, participants aged 60 years and older were assigned sequentially to receive three injections of either 1·5 μg, 3 μg, or 6 μg of vaccine or placebo, administered 28 days apart for the first two doses and 6 months (window period 90 days) apart for doses two and three. The main outcomes of the study were geometric mean titres (GMTs), geometric mean increases (GMIs), and seropositivity of neutralising antibody to SARS-CoV-2 (virus strain SARS-CoV-2/human/CHN/CN1/2020, GenBank accession number MT407649.1), as analysed in the per-protocol population (all participants who completed their assigned third dose). Our reporting is focused on the 3 μg groups, since 3 μg is the licensed formulation. The trials are registered with ClinicalTrials.gov, NCT04352608 and NCT04383574.

Findings

540 (90%) of 600 participants aged 18–59 years were eligible to receive a third dose, of whom 269 (50%) received the primary third dose 2 months after the second dose (cohorts 1a-14d-2m and 2a-28d-2m) and 271 (50%) received a booster dose 8 months after the second dose (cohorts 1b-14d-8m and 2b-28d-8m). In the 3 μg group, neutralising antibody titres induced by the first two doses declined after 6 months to near or below the seropositive cutoff (GMT of 8) for cohort 1b-14d-8m (n=53; GMT 3·9 [95% CI 3·1–5·0]) and for cohort 2b-28d-8m (n=49; 6·8 [5·2–8·8]). When a booster dose was given 8 months after a second dose, GMTs assessed 14 days later increased to 137·9 (95% CI 99·9–190·4) for cohort 1b-14d-8m and 143·1 (110·8–184·7) 28 days later for cohort 2b-28d-8m. GMTs moderately increased following a primary third dose, from 21·8 (95% CI 17·3–27·6) on day 28 after the second dose to 45·8 (35·7–58·9) on day 28 after the third dose in cohort 1a-14d-2m (n=54), and from 38·1 (28·4–51·1) to 49·7 (39·9–61·9) in cohort 2a-28d-2m (n=53). GMTs had decayed to near the positive threshold by 6 months after the third dose: GMT 9·2 (95% CI 7·1–12·0) in cohort 1a-14d-2m and 10·0 (7·3–13·7) in cohort 2a-28d-2m. Similarly, in adults aged 60 years and older who received booster doses (303 [87%] of 350 participants were eligible to receive a third dose), neutralising antibody titres had declined to near or below the seropositive threshold by 6 months after the primary two-dose series. A third dose given 8 months after the second dose significantly increased neutralising antibody concentrations: GMTs increased from 42·9 (95% CI 31·0–59·4) on day 28 after the second dose to 158·5 (96·6–259·2) on day 28 following the third dose (n=29). All adverse reactions reported within 28 days after a third dose were of grade 1 or 2 severity in all vaccination cohorts. There were three serious adverse events (2%) reported by the 150 participants in cohort 1a-14d-2m, four (3%) by 150 participants from cohort 1b-14d-8m, one (1%) by 150 participants in each of cohorts 2a-28d-2m and 2b-28d-8m, and 24 (7%) by 349 participants from cohort 3-28d-8m.

Interpretation

A third dose of CoronaVac in adults administered 8 months after a second dose effectively recalled specific immune responses to SARS-CoV-2, which had declined substantially 6 months after two doses of CoronaVac, resulting in a remarkable increase in the concentration of antibodies and indicating that a two-dose schedule generates good immune memory, and a primary third dose given 2 months after the second dose induced slightly higher antibody titres than the primary two doses.

Funding

National Key Research and Development Program, Beijing Science and Technology Program, and Key Program of the National Natural Science Foundation of China.

Translation

For the Mandarin translation of the abstract see Supplementary Materials section.

研究背景

全球多国正在使用新冠灭活疫苗 CoronaVac 开展大规模人群接种。本研究旨在评估 18 岁及以上的健康成年人接种两剂次 CoronaVac 的免疫持久性，以及接种第三剂次 CoronaVac 的免疫原性和安全性。

研究方法

本研究包括两个单中心、双盲、随机、安慰剂对照的二期临床试验。一项在中国江苏省 18-59 岁成年人中开展，受试者按照 1:1 的比例分入 0/14 天免疫程序队列(cohort 1)和 0/28 天免疫程序队列(cohort 2)，再按照 2:2:1 的比例随机分配至 3μg 剂量疫苗组、6μg 剂量疫苗组或安慰剂组。经 2020 年 12 月 25 日 修订研究方案后，上述各试验组的一半受试者在接种第二剂次后 28 天(窗口期 30 天)接种第三剂次，另一半在接种第二剂次后 6 个月(窗口期 60 天)接种第三剂次。另一项研究在中国河北省 60 岁及以上成年人中开展，受试者依次接种三剂次 1.5μg 疫苗、3μg 疫苗、6μg 疫苗或安慰剂;前两剂次接种间隔 28 天，第 二、三剂次接种间隔为 6 个月(窗口期 90 天)。研究的主要结局指标为针对新冠病毒(SARS-CoV-2/human/CHN/CN1/2020, GenBank number MT407649.1)的中和抗体几何平均滴度(GMTs)、几何平均增量(GMIs)和血清阳性率，按符合方案集进行分析(即完成接种第三剂次的受试者)。因为 3μg 是获批剂量，本研究主要报告该组的结果。研究已在 ClinicalTrials.gov 网站登记，注册号为 NCT04352608 和 NCT04383574。

研究结果

在 600 名 18 至 59 岁的受试者中，有 540 人(90%)接种了第三剂次，其中 269 人(50%)在接种第二剂次 2 个月后接种第三剂次(cohort 1a-14d-2m 和 cohort 2a-28d-2m)，271 人(50%)在接种第二剂次 8 个月后接种加强剂次(cohort 1b-14d-8m 和 cohort 2b-28d-8m)。在 3μg 组中，前两剂次诱导的中和抗体水平在 6 个月后下降至接近或低于血清阳性阈值(1:8):cohort 1b-14d-8m(n=53, GMT 3.9 [95%CI 3.1-5.0]);cohort 2b-28d-8m(n=49, 6.8 [95%CI 5.2-8.8])。在第二剂次 8 个月后接种加强针，cohort 1b-14d-8m 接种加强针 14 天后 GMT 增加至 137.9 (95%CI 99.9-190.4)，cohort 2b-28d-8m 接种加强针 28 天后 GMT 增加至 143.1 (95% CI 110.8-184.7)。在接种第二剂次 2 个月后接种第三剂次，可以轻度升高中和抗体水平:cohort 1a-14d-2m(n=54)GMT 从第二剂次后 28 天的 21.8(95%CI 17.3-27.6)增加至第三剂次后 28 天的 45.8(95%CI 35.7-58.9)，cohort 2a-28d-2m (n=53)GMT 从38.1(95%CI28.4-51.1)增加至49.7(95%CI39.9-61.9)。接种第三剂次 6 个月后，GMT 均衰减至接近阳性阈值(cohort 1a-14d-2m GMT 为 9.2 [95%CI 7.1-12.0];cohort 2a-28d-2m GMT 为 10.0 [95%CI 7.3-13.7])。在接种了加强针的 60 岁及以上人群中(n=303)，两剂次基础免疫 6 个月后中和抗体滴度下降到接近或低于血清阳性阈值。第二剂次 8 个月后接种第三剂次可以显著提高中和抗体水平(n=29):GMT 从第二剂次 28 天后的 42.9(95% CI 31.0-59.4)升高至第 三剂次 28 天后 158.5(95% CI 96.6-259.2)。在所有疫苗组中，第三剂次后 28 天内报告的不良反应严重程度均为 1 或 2 级。Cohort 1a-14d-2m 的 150 名受试者共 报告 3 起(2%)严重不良事件，cohort 1b-14d-8m 的 150 名 受试者 共 报 告 4 起 (3%)，cohort 2a-28d-2m 和 cohort 2b-28d-8m 的各 150 名受试者分别报告了 1 起(1%);cohort 3-28d-8m 的 349 名受试者报告了 24 起(7%)。

研究结论

接种 CoronaVac 第二剂次后 6 个月，疫苗诱导的中和抗体水平大幅下降，在 完成两剂次基础免疫 8 个月后接种第三剂次可以有效诱导特异性免疫反应，中和抗体水平显著升高，表明两剂次基础免疫能够产生良好的免疫记忆。和两剂次基础免疫方案相比，在完成基础免疫 2 个月后接种第三剂次可以使中和抗体水平轻度升高。