Drennan Philip G, Provine Nicholas M, Harris Stephanie A, Otter Ashley, Hollett Kate, Cooper Cushla, De Maeyer Roel P H, Nassanga Beatrice, Ateere Alberta, Pudjohartono Maria Fransiska, Peng Yanchun, Chen Ji-Li, Jones Scott, Fadzillah Nurul Huda Mohamad, Grifoni Alba, Sette Allessandro, Satti Iman, Murray Sam M, Rowe Cathy, Mandal Sema, Hallis Bassam, Klenerman Paul, Dong Tao, Richards Duncan, Fullerton James, McShane Helen, Coles Mark
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Pandemic Sciences Institute, University of Oxford, Oxford, UK; Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Lancet Microbe. 2025 Jun;6(6):101045. doi: 10.1016/j.lanmic.2024.101045. Epub 2025 Apr 23.
Since 2022, mpox has emerged as a global health threat, with two clades (I and II) causing outbreaks of international public health concern. The third generation smallpox vaccine modified vaccinia Ankara, manufactured by Bavarian Nordic (MVA-BN), has emerged as a key component of mpox prevention. To date, the immunogenicity of this vaccine, including determinants of response, has been incompletely described, especially when MVA-BN has been administered intradermally at a fifth of the registered dose (so-called fractionated dosing), as recommended as a dose-sparing strategy. The aim of this study was to explore the immunogenicity of MVA-BN and baseline determinants of vaccine response in an observational public-health response setting.
We conducted a prospective cohort study and immunological analysis of responses to MVA-BN in patients attending a sexual health vaccination clinic in Oxford, UK. Blood samples were taken at baseline, day 14, and day 28 after first vaccine, and 28 and 90 days following a second vaccine. A subcohort had additional blood samples collected day 1 following their first vaccine (optional timepoint). We assessed IgG responses to mpox and vaccinia antigens using Luminex assay (MpoxPlex) using generalised linear mixed modelling, and T-cell responses using IFN-γ enzyme-linked immunospot and activation-induced marker assay. Associations between blood transcriptomic signatures (baseline, day 1) and immunogenicity were assessed using differential expression analysis and gene set enrichment methods.
We recruited 34 participants between Dec 1, 2022 and May 3, 2023 of whom 33 received fractionated dosing. Of the 30 without previous smallpox vaccination, 14 (47%) seroconverted by day 28, increasing to 25 (89%) 90 days after second vaccination. However, individuals seronegative on day 28 had persistently lower responses compared with individuals seropositive on day 28 (numerically lower antibody responses to six of seven dynamic antigens in the MPoxPlex assay, p<0·05). Serological response on day 28 was positively associated with type I and II interferon signatures 1 day after vaccination (n=18; median module score 0·13 vs 0·06; p=1·1 × 10⁶), but negatively associated with these signatures at baseline (normalised enrichment score -2·81 and -2·86, respectively).
Baseline inflammatory states might inhibit MVA-BN serological immunogenicity by inhibiting the upregulation of MVA-induced innate immune signalling. If confirmed mechanistically, these insights could inform improved vaccination strategies against mpox in diverse geographic and demographic settings. Given the likelihood of vaccine supply limitations presently and in future outbreak settings, the utility of dose-sparing vaccine strategies as a general approach to maximising population benefit warrants further study.
UKRI via the UK Monkeypox Research Consortium, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, the Kennedy Trust for Rheumatology Research, the John Climax Donation, the Medical Research Council (UK), the Wellcome Trust, the Center for Cooperative Human Immunology (National Institutes of Health), and the National Institute for Health and Care Research Oxford Biomedical Research Centre.
自2022年以来，猴痘已成为全球健康威胁，两个分支（I和II）引发了国际关注的公共卫生疫情。由巴伐利亚北欧公司生产的第三代天花疫苗改良安卡拉痘苗（MVA-BN）已成为猴痘预防的关键组成部分。迄今为止，这种疫苗的免疫原性，包括反应的决定因素，尚未得到充分描述，特别是当MVA-BN按照作为剂量节省策略推荐的已注册剂量的五分之一进行皮内注射（所谓的分剂量给药）时。本研究的目的是在观察性公共卫生应对环境中探索MVA-BN的免疫原性和疫苗反应的基线决定因素。
我们在英国牛津的一家性健康疫苗接种诊所对接受MVA-BN治疗的患者进行了一项前瞻性队列研究和免疫反应分析。在首次接种疫苗后的基线、第14天和第28天，以及第二次接种疫苗后的第28天和第90天采集血样。一个亚队列在首次接种疫苗后的第1天（可选时间点）额外采集了血样。我们使用Luminex检测法（MpoxPlex）通过广义线性混合模型评估对猴痘和痘苗抗原的IgG反应，并使用IFN-γ酶联免疫斑点试验和激活诱导标记试验评估T细胞反应。使用差异表达分析和基因集富集方法评估血液转录组特征（基线、第1天）与免疫原性之间的关联。
我们在2022年12月1日至2023年5月3日期间招募了34名参与者，其中33人接受了分剂量给药。在30名既往未接种过天花疫苗的参与者中，14人（47%）在第28天血清转化，第二次接种疫苗90天后增至25人（89%）。然而，与第28天血清阳性的个体相比，第28天血清阴性的个体反应持续较低（在MPoxPlex检测中，对七种动态抗原中的六种的抗体反应在数值上较低，p<0·05）。第28天的血清学反应与接种疫苗1天后的I型和II型干扰素特征呈正相关（n=18；中位模块评分0·13对0·06；p=1·1×10⁶），但在基线时与这些特征呈负相关（标准化富集评分分别为-2·81和-2·86）。
基线炎症状态可能通过抑制MVA诱导的先天免疫信号上调来抑制MVA-BN的血清学免疫原性。如果从机制上得到证实，这些见解可为不同地理和人口环境下改进猴痘疫苗接种策略提供信息。鉴于目前以及未来疫情环境下疫苗供应受限的可能性，作为使人群效益最大化的一般方法，剂量节省疫苗策略的效用值得进一步研究。
英国研究与创新署通过英国猴痘研究联盟、中国医学科学院医学科学创新基金、肯尼迪风湿病研究信托基金、约翰·克莱马克斯捐赠基金、医学研究理事会（英国）、惠康信托基金会、合作人类免疫学中心（美国国立卫生研究院）以及牛津国家卫生与保健研究所生物医学研究中心提供资助。
