Comparative antibody and cell-mediated immune responses, reactogenicity, and efficacy of homologous and heterologous boosting with CoronaVac and BNT162b2 (Cobovax): an open-label, randomised trial

Abstract

<h3>Background</h3><p>Few trials have compared homologous and heterologous third doses of COVID-19 vaccination with inactivated vaccines and mRNA vaccines. The aim of this study was to assess immune responses, safety, and efficacy against SARS-CoV-2 infection following homologous or heterologous third-dose COVID-19 vaccination with either one dose of CoronaVac (Sinovac Biotech; inactivated vaccine) or BNT162b2 (Fosun Pharma–BioNTech; mRNA vaccine).</p><h3>Methods</h3><p>This is an ongoing, randomised, allocation-concealed, open-label, comparator-controlled trial in adults aged 18 years or older enrolled from the community in Hong Kong, who had received two doses of CoronaVac or BNT162b2 at least 6 months earlier. Participants were randomly assigned, using a computer-generated sequence, in a 1:1 ratio with allocation concealment to receive a (third) dose of CoronaVac or BNT162b2 (ancestral virus strain), stratified by types of previous COVID-19 vaccination (homologous two doses of CoronaVac or BNT162b2). Participants were unmasked to group allocation after vaccination. The primary endpoint was serum neutralising antibodies against the ancestral virus at day 28 after vaccination in each group, measured as plaque reduction neutralisation test (PRNT₅₀) geometric mean titre (GMT). Surrogate virus neutralisation test (sVNT) mean inhibition percentage and PRNT₅₀ titres against omicron BA.1 and BA.2 subvariants were also measured. Secondary endpoints included geometric mean fold rise (GMFR) in antibody titres; incidence of solicited local and systemic adverse events; IFNγ⁺ CD4⁺ and IFNγ⁺ CD8⁺ T-cell responses at days 7 and 28; and incidence of COVID-19. Within-group comparisons of boost in immunogenicity from baseline and between-group comparisons were done according to intervention received (ie, per protocol) by paired and unpaired <em>t</em> test, respectively, and cumulative incidence of infection was compared using Kaplan-Meier curves and a proportional hazards model to estimate hazard ratio. The trial is registered with <a href="https://clinicaltrials.gov/">ClinicalTrials.gov</a>, NCT05057169.</p><h3>Findings</h3><p>We enrolled participants from Nov 12, 2021, to Jan 27, 2022. We vaccinated 219 participants who previously received two doses of CoronaVac, including 101 randomly assigned to receive CoronaVac (CC-C) and 118 randomly assigned to receive BNT162b2 (CC-B) as their third dose; and 232 participants who previously received two doses of BNT162b2, including 118 randomly assigned to receive CoronaVac (BB-C) and 114 randomly assigned to receive BNT162b2 (BB-B) as their third dose. The PRNT₅₀ GMTs on day 28 against ancestral virus were 109, 905, 92, and 816; against omicron BA.1 were 9, 75, 8, and 86; and against omicron BA.2 were 6, 80, 6, and 67 in the CC-C, CC-B, BB-C, and BB-B groups, respectively. Mean sVNT inhibition percentages on day 28 against ancestral virus were 83%, 96%, 87%, and 96%; against omicron BA.1 were 15%, 58%, 19%, and 69%; and against omicron BA.2 were 43%, 85%, 50%, and 90%, in the CC-C, CC-B, BB-C, and BB-B groups, respectively. Participants who had previously received two doses of CoronaVac and a BNT162b2 third dose had a GMFR of 12 (p<0·0001) compared with those who received a CoronaVac third dose; similarly, those who had received two doses of BNT162b2 and a BNT162b2 third dose had a GMFR of 8 (p<0·0001). No differences in CD4⁺ and CD8⁺ T-cell responses were observed between groups. We did not identify any vaccination-related hospitalisation within 1 month after vaccination. We identified 58 infections when omicron BA.2 was predominantly circulating, with cumulative incidence of 15·3% and 15·4% in the CC-C and CC-B groups, respectively (p=0·93), and 16·7% and 14·0% in the BB-C and BB-B groups, respectively (p=0·56).</p><h3>Interpretation</h3><p>Similar levels of incidence of, presumably, omicron BA.2 infections were observed in each group despite very weak antibody responses to BA.2 in the recipients of a CoronaVac third dose. Further research is warranted to identify appropriate correlates of protection for inactivated COVID-19 vaccines.</p><h3>Funding</h3><p>Health and Medical Research Fund, Hong Kong.</p><h3>Translation</h3><p>For the Chinese translation of the abstract see Supplementary Materials section.</p>

背景： 就2019冠狀病毒病(COVID-19/新冠)，現今只有少數臨床試驗比較同類(同源)和混合(異源)滅活疫苗或mRNA疫苗加強劑接種方案。本研究旨在評估同源或異源接種第三劑克爾來福(CoronaVac；科興控股；滅活疫苗)或復必泰(BNT162b2；復星醫藥-BioNTech；mRNA疫苗)新冠疫苗後的免疫原性、安全性和減低新冠病毒(SARS-CoV-2)感染效用。 方法： 本研究是一項進行中的隨機、隱蔽分組、開放標籤、活性對照試驗，在香港招募年齡18歲或以上、來自社區、並於至少6個月前已接種兩劑克爾來福(C)或復必泰(B)疫苗的成年人參與。參加者按早前已接種新冠疫苗類型(同源接種兩劑克爾來福或復必泰)分成兩組，分別按由電腦隨機生成順序以1:1比例及隱蔽分組被隨機分配接種第三劑克爾來福或復必泰疫苗(原始病毒株)。接種疫苗後，參加者解盲被分配疫苗名稱。主要終點包括接種疫苗後第28天血清中針對原始病毒株蝕斑減少50%中和抗體幾何平均滴度(PRNT50 GMT)，另測量替代病毒中和抗體平均抑制率(sVNT mean inhibition percentage)、及針對變異株Omicron亞型BA.1和BA.2 PRNT50。次要終點包括抗體幾何平均增加倍數(GMFR)；局部和全身不良反應發生率；第7和28天IFNγ+CD4+和IFNγ+CD8+T細胞反應；及COVID-19感染率。在符合方案組(per-protocol)，即按已接種第三劑疫苗分類，通過配對樣本t檢驗進行組內免疫原性與基線比較，通過獨立樣本t檢驗分析兩組間免疫原性差異，通過Kaplan-Meier曲線估算感染率及比例風險模型估算兩組間風險比(hazard ratio)。本試驗已在clinicaltrials.gov註冊(登記號：NCT05057169)。 結果： 2021年11月12日至2022年1月27日期間招募參加者。已接種兩劑克爾來福疫苗組入組219名參加者，其中101名被隨機分配接種第三劑克爾來福疫苗(CC-C組)，另118名分配接種復必泰疫苗(CC-B組)；已接種兩劑復必泰疫苗組入組232名參加者，其中118名被隨機分配接種第三劑克爾來福疫苗(BB-C組)，另114名分配接種復必泰疫苗(BB-B組)。第28天PRNT50 GMT，對原始病毒株分別是CC-C組：109，CC-B組：905，BB-C組：92，BB-B組：816；對Omicro