Garrett Nigel, Reddy Tarylee, Yende-Zuma Nonhlanhla, Takalani Azwidhwi, Woeber Kubashni, Bodenstein Annie, Jonas Phumeza, Engelbrecht Imke, Jassat Waasila, Moultrie Harry, Bradshaw Debbie, Seocharan Ishen, Odhiambo Jackline, Khuto Kentse, Richardson Simone I, Omondi Millicent A, Nesamari Rofhiwa, Keeton Roanne S, Riou Catherine, Moyo-Gwete Thandeka, Innes Craig, Zwane Zwelethu, Mngadi Kathy, Brumskine William, Naicker Nivashnee, Potloane Disebo, Badal-Faesen Sharlaa, Innes Steve, Barnabas Shaun, Lombaard Johan, Gill Katherine, Nchabeleng Maphoshane, Snyman Elizma, Petrick Friedrich, Spooner Elizabeth, Naidoo Logashvari, Kalonji Dishiki, Naicker Vimla, Singh Nishanta, Maboa Rebone, Mda Pamela, Malan Daniel, Nana Anusha, Malahleha Mookho, Kotze Philip, Allagappen Jon J, Diacon Andreas H, Kruger Gertruida M, Patel Faeezah, Moore Penny L, Burgers Wendy A, Anteyi Kate, Leav Brett, Bekker Linda-Gail, Gray Glenda E, Goga Ameena
Centre for the AIDS Programme of Research in South Africa, Durban, South Africa.
Discipline of Public Health Medicine, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa.
PLOS Glob Public Health. 2024 Dec 5;4(12):e0003260. doi: 10.1371/journal.pgph.0003260. eCollection 2024.
Limited studies have been conducted on the safety and effectiveness of heterologous COVID-19 vaccine boosting in lower income settings, especially those with high-HIV prevalence., The Sisonke Heterologous mRNA-1273 boost after prime with Ad26.COV2.S (SHERPA) trial evaluated a mRNA-1273 boost after Ad26.COV2.S priming in South Africa. SHERPA was a single-arm, open-label, phase 3 study nested in the Sisonke implementation trial of 500000 healthcare workers (HCWs). Sisonke participants were offered mRNA-1273 boosters between May and November 2022, when Omicron sub-lineages were circulating. Adverse events (AE) were self-reported, and co-primary endpoints (SARS-CoV-2 infections and COVID-19 hospitalizations or deaths) were collected through national databases. We used Cox regression models with booster status as a time-varying covariate to determine the relative vaccine effectiveness (rVE) of the mRNA-1273 booster among SHERPA versus unboosted Sisonke participants. Of 11248 SHERPA participants in the rVE analysis cohort (79.3% female, median age 41), 45.4% had received one and 54.6% two Ad26.COV2.S doses. Self-reported comorbidities included HIV (18.7%), hypertension (12.9%) and diabetes (4.6%). In multivariable analysis including 413161 unboosted Sisonke participants, rVE of the booster was 59% (95%CI 29-76%) against SARS-CoV-2 infection: 77% (95%CI 9-94%) in the one-Ad26.COV2.S dose group and 52% (95%CI 13-73%) in the two-dose group. Severe COVID-19 was identified in 148 unboosted Sisonke participants, and only one SHERPA participant with severe HIV-related immunosuppression. Of 11798 participants in the safety analysis, 228 (1.9%) participants reported 575 reactogenicity events within 7 days of the booster (most commonly injection site pain, malaise, myalgia, swelling, induration and fever). More reactogenicity events were reported among those with prior SARS-CoV-2 infections (adjusted odds ratio [aOR] 2.03, 95%CI 1.59-2.59) and less among people living with HIV (PLWH) (aOR 0.49, 95%CI 0.34-0.69). There were 115 unsolicited adverse events (AEs) within 28 days of vaccination. No related serious AEs were reported. In an immunogenicity sub-study, mRNA-1273 increased binding and neutralizing antibody titres and spike-specific T-cell responses 4 weeks after boosting regardless of the number of prior Ad26.COV2.S doses, or HIV status, and generated Omicron spike-specific cross-reactive responses. mRNA-1273 boosters after one or two Ad26.COV2.S doses were well-tolerated, safe and effective against Omicron SARS-CoV-2 infections among HCWs and PLWH. Trial registration: The SHERPA study is registered in the Pan African Clinical Trials Registry (PACTR): PACTR202310615330649 and the South African National Clinical Trial Registry (SANCTR): DOH-27-052022-5778.
关于异源新型冠状病毒疫苗加强针在低收入环境中的安全性和有效性的研究有限，尤其是在艾滋病毒高流行率地区。西松克（Sisonke）在以Ad26.COV2.S为基础免疫后接种异源mRNA-1273加强针（SHERPA）试验，评估了在南非以Ad26.COV2.S为基础免疫后接种mRNA-1273加强针的情况。SHERPA是一项单臂、开放标签的3期研究，嵌套在针对500000名医护人员的西松克实施试验中。西松克试验的参与者在2022年5月至11月期间接种了mRNA-1273加强针，当时奥密克戎亚谱系正在传播。不良事件（AE）通过自我报告，共同主要终点（严重急性呼吸综合征冠状病毒2感染以及新型冠状病毒肺炎住院或死亡）通过国家数据库收集。我们使用以加强针接种状态作为时变协变量的Cox回归模型，来确定SHERPA试验中接种mRNA-1273加强针的参与者相对于未接种加强针的西松克试验参与者的相对疫苗效力（rVE）。在rVE分析队列中的11248名SHERPA试验参与者中（79.3%为女性，中位年龄41岁），45.4%的人接种了一剂Ad26.COV2.S，54.6%的人接种了两剂。自我报告的合并症包括艾滋病毒感染（18.7%）、高血压（12.9%）和糖尿病（4.6%）。在纳入413161名未接种加强针的西松克试验参与者的多变量分析中，加强针针对严重急性呼吸综合征冠状病毒2感染的rVE为59%（95%置信区间29 - 76%）：在接种一剂Ad26.COV2.S的组中为77%（95%置信区间9 - 94%），在接种两剂的组中为52%（95%置信区间13 - 73%）。在148名未接种加强针的西松克试验参与者中发现了严重的新型冠状病毒肺炎病例；在SHERPA试验参与者中，只有一名患有严重艾滋病毒相关免疫抑制的患者。在11798名参与安全性分析的参与者中，228名（1.9%）参与者在接种加强针后7天内报告了575起反应原性事件（最常见的是注射部位疼痛、不适、肌痛、肿胀、硬结和发热）。在既往有严重急性呼吸综合征冠状病毒2感染的人群中报告了更多的反应原性事件（调整后的优势比[aOR]为2.03，95%置信区间1.59 - 2.59），而在艾滋病毒感染者（PLWH）中报告的较少（aOR为0.49，95%置信区间0.34 - 0.69）。在接种疫苗后28天内有115起非预期不良事件（AE）。未报告相关的严重AE。在一项免疫原性亚研究中，无论之前接种Ad26.COV2.S的剂量数量或艾滋病毒感染状况如何，mRNA-1273在加强针接种4周后均增加了结合抗体和中和抗体滴度以及刺突特异性T细胞反应，并产生了奥密克戎刺突特异性交叉反应。在接种一剂或两剂Ad26.COV2.S后接种mRNA-1273加强针，在医护人员和艾滋病毒感染者中对奥密克戎严重急性呼吸综合征冠状病毒2感染具有良好的耐受性、安全性和有效性。试验注册：SHERPA研究已在泛非临床试验注册中心（PACTR）注册：PACTR202310615330649以及南非国家临床试验注册中心（SANCTR）注册：DOH-27-052022-5778。
