The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants
The effect of azithromycin on the immunogenicity of oral poliovirus vaccine: a double-blind randomised placebo-controlled trial in seronegative Indian infants
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DOI：
10.1016/s1473-3099(16)30023-8
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发表时间：
2016-08-01
影响因子：
56.3
通讯作者：
Kang, Gagandeep
中科院分区：
文献类型：
--
作者：
Grassly, Nicholas C.;Praharaj, Ira;Kang, Gagandeep
背景与其他口服疫苗类似，口服脊髓灰质炎病毒疫苗在低收入国家的免疫原性和有效性低于高收入国家。肠道病原体和相关环境肠病的高患病率已被提出来解释这个问题。由于管理的抗生素有可能解决环境肠病和明确的细菌病原体，我们的目的是评估抗生素是否会提高口服脊髓灰质炎病毒疫苗immunogenicity.Methods我们做了一个双盲，随机，安慰剂对照试验阿奇霉素对血清型3单价口服脊髓灰质炎病毒疫苗的免疫原性的影响，给予健康的婴儿生活在14个街区的韦洛雷区，印度。如果婴儿年龄为6-11个月，在研究期间可供使用，并且缺乏血清3型脊髓灰质炎病毒的血清中和抗体，则有资格参与研究。婴儿在入组时被随机分配（1：1）接受口服10 mg/kg阿奇霉素或安慰剂，每日一次，持续3天，然后在第14天接受血清3型单价口服脊髓灰质炎病毒疫苗。主要结局是在第35天检测到稀释度为1/8或以上的血清3型脊髓灰质炎病毒中和抗体，并在符合方案人群中进行评估（即，所有接受阿奇霉素或安慰剂、口服脊髓灰质炎病毒疫苗并根据研究方案提供血液样本的患者）。在所有入组研究的婴儿中评估了安全性结局。该试验在印度临床试验注册处注册，编号CTRI/2014/05/004588。结果在2014年8月5日至2015年3月21日期间，754名婴儿被随机分配：376名接受阿奇霉素，378名接受安慰剂。其中，阿奇霉素组376名婴儿中的348名（93%）和安慰剂组378名婴儿中的357名（94%）按照方案完成了研究。在阿奇霉素组中，175例（50%）血清转化为血清3型脊髓灰质炎病毒，而安慰剂组为192例（54%）（风险比0.94，95% CI 0.81-1.08; p=0.366）。阿奇霉素降低了环境肠病的粪便生物标志物（钙卫蛋白、髓过氧化物酶、α 1-抗胰蛋白酶）和细菌而非病毒或真核病原体的患病率。病毒病原体与较低的血清转化率。报道了三起严重不良事件（阿奇霉素组两起，安慰剂组一起），但均不认为与研究干预措施有关。解释阿奇霉素并没有改善口服脊髓灰质炎病毒疫苗的免疫原性，尽管减少了环境肠病的生物标志物和致病性肠道细菌的患病率。病毒干扰和先天性抗病毒免疫机制可能是口服活病毒疫苗免疫原性的更重要决定因素。
Background Oral poliovirus vaccine is less immunogenic and effective in low-income countries than in high-income countries, similarly to other oral vaccines. The high prevalence of intestinal pathogens and associated environmental enteropathy has been proposed to explain this problem. Because administration of an antibiotic has the potential to resolve environmental enteropathy and clear bacterial pathogens, we aimed to assess whether antibiotics would improve oral poliovirus vaccine immunogenicity.Methods We did a double-blind, randomised, placebo-controlled trial of the effect of azithromycin on the immunogenicity of serotype-3 monovalent oral poliovirus vaccine given to healthy infants living in 14 blocks of Vellore district, India. Infants were eligible to participate if they were 6-11 months old, available for the study duration, and lacked serum neutralising antibodies to serotype-3 poliovirus. Infants were randomly assigned (1:1) at enrolment to receive oral 10 mg/kg azithromycin or placebo once daily for 3 days, followed by serotype-3 monovalent oral poliovirus vaccine on day 14. The primary outcome was detection of serum neutralising antibodies to serotype-3 poliovirus at a dilution of one in eight or more on day 35 and was assessed in the per-protocol population (ie, all those who received azithromycin or placebo, oral poliovirus vaccine, and provided a blood sample according to the study protocol). Safety outcomes were assessed in all infants enrolled in the study. The trial is registered with the Clinical Trials Registry India, number CTRI/2014/05/004588.Findings Between Aug 5, 2014, and March 21, 2015, 754 infants were randomly assigned:376 to receive azithromycin and 378 to placebo. Of these, 348 (93%) of 376 in the azithromycin group and 357 (94%) of 378 infants in the placebo group completed the study per protocol. In the azithromycin group, 175 (50%) seroconverted to serotype-3 poliovirus compared with 192 (54%) in the placebo group (risk ratio 0.94, 95% CI 0.81-1.08; p=0.366). Azithromycin reduced faecal biomarkers of environmental enteropathy (calprotectin, myeloperoxidase, alpha 1-antitrypsin) and the prevalence of bacterial but not viral or eukaryotic pathogens. Viral pathogens were associated with lower seroconversion. Three serious adverse events were reported (two in the azithromycin group and one in the placebo group), but none was considered related to the study interventions.Interpretation Azithromycin did not improve the immunogenicity of oral poliovirus vaccine despite reducing biomarkers of environmental enteropathy and the prevalence of pathogenic intestinal bacteria. Viral interference and innate antiviral immune mechanisms might be more important determinants of the immunogenicity of live-virus oral vaccines.