Safety and Immunogenicity of a Live Oral Recombinant Cholera Vaccine VA1.4: A Randomized, Placebo Controlled Trial in Healthy Adults in a Cholera Endemic Area in Kolkata, India

BackgroundA live oral cholera vaccine VA 1.4 developed from a non-toxigenic Vibrio cholerae O1 El Tor strain using ctxB gene insertion was further developed into a clinical product following cGMP and was evaluated in a double-blind randomized placebo controlled parallel group two arm trial with allocation ratio of 1∶1 for safety and immunogenicity in men and women aged 18–60 years from Kolkata, India.MethodA lyophilized dose of 1.9×109 CFU (n = 44) or a placebo (n = 43) reconstituted with a diluent was administered within 5 minutes of drinking 100 ml of a buffer solution made of sodium bicarbonate and ascorbic acid and a second dose on day 14.ResultThe vaccine did not elicit any diarrhea related adverse events. Other adverse events were rare, mild and similar in two groups. One subject in the vaccine group excreted the vaccine strain on the second day after first dose. The proportion of participants who seroconverted (i.e. had 4-folds or higher rise in reciprocal titre) in the vaccine group were 65.9% (95% CI: 50.1%–79.5%) at both 7 days (i.e. after 1st dose) and 21 days (i.e. after 2nd dose). None of the placebo recipients seroconverted. Anti-cholera toxin antibody was detected in very few recipients of the vaccine.ConclusionThis study demonstrates that VA 1.4 at a single dose of 1.9×109 is safe and immunogenic in adults from a cholera endemic region. No additional benefit after two doses was seen.Trial RegistrationClinical Trials Registry-India, National Institute of Medical Statistics (Indian Council of Medical Research) CTRI/2012/04/002582

**背景**：本研究针对一株经霍乱毒素B亚基基因（ctxB gene）插入改造获得的无毒产毒株O1群埃尔托霍乱弧菌（Vibrio cholerae O1 El Tor），开发了口服活霍乱疫苗VA 1.4；该疫苗按照现行药品生产质量管理规范（current Good Manufacturing Practice，cGMP）进一步开发为临床产品，并于印度加尔各答招募18~60岁男女受试者，开展了一项分配比例为1:1的双盲、随机、安慰剂对照平行组双臂试验，以评估其安全性与免疫原性。

**方法**：受试者在饮用100ml碳酸氢钠-抗坏血酸缓冲液后的5分钟内，经稀释剂复溶后接受单剂冻干制剂（剂量为1.9×10^9 菌落形成单位（CFU），n=44）或安慰剂（n=43）接种，并于第14天接受第二剂接种。

**结果**：该疫苗未引发任何与腹泻相关的不良事件。其余不良事件发生率极低、程度轻微，且两组间无统计学差异。疫苗组仅1名受试者在首剂接种后第2天排出疫苗菌株。首剂接种后第7天及第2剂接种后第21天，疫苗组发生血清阳转（即抗体反向滴度升高4倍及以上）的受试者占比均为65.9%（95%置信区间（95% CI）：50.1%~79.5%）；安慰剂组无受试者发生血清阳转。仅极个别疫苗接种者检测到抗霍乱毒素抗体。

**结论**：本研究证实，剂量为1.9×10^9 CFU的单剂VA 1.4疫苗在霍乱流行区成人人群中具有良好的安全性与免疫原性，且第二剂接种未带来额外获益。

**试验注册**：印度临床试验注册库（Clinical Trials Registry-India），印度医学研究理事会国家医学统计研究所（National Institute of Medical Statistics, Indian Council of Medical Research），注册号：CTRI/2012/04/002582