Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Epidemiology and Biostatistics, Temple University College of Public Health, Philadelphia, PA, USA.
Division of Infectious Diseases, Massachusetts General Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
Lancet Microbe. 2023 Apr;4(4):e228-e235. doi: 10.1016/S2666-5247(22)00391-3. Epub 2023 Mar 9.
Vibriocidal antibodies are currently the best characterised correlate of protection against cholera and are used to gauge immunogenicity in vaccine trials. Although other circulating antibody responses have been associated with a decreased risk of infection, the correlates of protection against cholera have not been comprehensively compared. We aimed to analyse antibody-mediated correlates of protection from both V cholerae infection and cholera-related diarrhoea.
We conducted a systems serology study that analysed 58 serum antibody biomarkers as correlates of protection against V cholerae O1 infection or diarrhoea. We used serum samples from two cohorts: household contacts of people with confirmed cholera in Dhaka, Bangladesh, and cholera-naive volunteers who were recruited at three centres in the USA, vaccinated with a single dose of CVD 103-HgR live oral cholera vaccine, and then challenged with V cholerae O1 El Tor Inaba strain N16961. We measured antigen-specific immunoglobulin responses against antigens using a customised Luminex assay and used conditional random forest models to examine which baseline biomarkers were most important for classifying individuals who went on to develop infection versus those who remained uninfected or asymptomatic. V cholerae infection was defined as having a positive stool culture result on days 2-7 or day 30 after enrolment of the household's index cholera case and, in the vaccine challenge cohort, was the development of symptomatic diarrhoea (defined as two or more loose stools of ≥200 mL each, or a single loose stool of ≥300 mL over a 48-h period).
In the household contact cohort (261 participants from 180 households), 20 (34%) of the 58 studied biomarkers were associated with protection against V cholerae infection. We identified serum antibody-dependent complement deposition targeting the O1 antigen as the most predictive correlate of protection from infection in the household contacts, whereas vibriocidal antibody titres ranked lower. A five-biomarker model predicted protection from V cholerae infection with a cross-validated area under the curve (cvAUC) of 79% (95% CI 73-85). This model also predicted protection against diarrhoea in unvaccinated volunteers challenged with V cholerae O1 after vaccination (n=67; area under the curve [AUC] 77%, 95% CI 64-90). Although a different five-biomarker model best predicted protection from the development of cholera diarrhoea in the challenged vaccinees (cvAUC 78%, 95% CI 66-91), this model did poorly at predicting protection against infection in the household contacts (AUC 60%, 52-67).
Several biomarkers predict protection better than vibriocidal titres. A model based on protection against infection among household contacts was predictive of protection against both infection and diarrhoeal illness in challenged vaccinees, suggesting that models based on observed conditions in a cholera-endemic population might be more likely to identify broadly applicable correlates of protection than models trained on single experimental settings.
National Institute of Allergy and Infectious Diseases and National Institute of Child Health and Human Development, National Institutes of Health.
杀弧菌抗体是目前对抗霍乱的最佳保护相关因素，用于评估疫苗试验中的免疫原性。虽然其他循环抗体反应与感染风险降低有关，但针对霍乱的保护相关因素尚未得到全面比较。我们旨在分析来自霍乱弧菌 O1 感染和霍乱相关腹泻的抗体介导的保护相关因素。
我们进行了一项系统血清学研究，分析了 58 种血清抗体生物标志物作为预防霍乱弧菌 O1 感染或腹泻的保护相关因素。我们使用了来自两个队列的血清样本：孟加拉国达卡确诊霍乱患者的家庭接触者，以及在美国三个中心招募的未感染霍乱的志愿者，他们接种了一剂 CVD 103-HgR 口服霍乱活疫苗，然后用霍乱弧菌 O1 El Tor Inaba 菌株 N16961 进行了挑战。我们使用定制的 Luminex 测定法测量针对抗原的抗原特异性免疫球蛋白反应，并使用条件随机森林模型来检查哪些基线生物标志物对于将发生感染的个体与未感染或无症状的个体进行分类最为重要。霍乱弧菌感染定义为家庭索引病例确诊后第 2-7 天或第 30 天粪便培养阳性，在疫苗挑战队列中，定义为出现症状性腹泻（定义为每天 2 次或以上≥200 毫升的稀便，或在 48 小时内 1 次稀便≥300 毫升）。
在家庭接触者队列（来自 180 个家庭的 261 名参与者）中，58 种研究的生物标志物中有 20 种（34%）与预防霍乱弧菌感染有关。我们发现针对 O1 抗原的血清抗体依赖性补体沉积是家庭接触者预防感染的最具预测性的保护相关因素，而杀弧菌抗体滴度的排名较低。一个由 5 种生物标志物组成的模型对预防霍乱弧菌感染的预测具有 79%的交叉验证曲线下面积（cvAUC）（73-85）。该模型还预测了接种疫苗后用霍乱弧菌 O1 对未接种疫苗的志愿者进行挑战时预防腹泻的情况（AUC 为 77%，95%CI 为 64-90）。尽管最佳的五个生物标志物模型预测了在接受挑战的疫苗接种者中预防霍乱性腹泻的情况（cvAUC 为 78%，95%CI 为 66-91），但该模型在预测家庭接触者的感染保护方面表现不佳（AUC 为 60%，52-67）。
有几种生物标志物比杀弧菌抗体滴度更好地预测保护作用。基于家庭接触者感染保护的模型可以预测接种疫苗的接受者的感染和腹泻疾病的保护作用，这表明基于霍乱流行地区观察到的情况的模型可能比基于单一实验环境训练的模型更有可能确定广泛适用的保护相关因素。
美国国立过敏和传染病研究所和儿童健康与人类发展研究所，美国国立卫生研究院。
