Department of Infectious Disease Epidemiology, Imperial College London, London, UK; Christian Medical College, Vellore, Tamil Nadu, India.
Christian Medical College, Vellore, Tamil Nadu, India.
Lancet Infect Dis. 2016 Aug;16(8):905-14. doi: 10.1016/S1473-3099(16)30023-8. Epub 2016 May 4.
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.
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.
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, α1-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.
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.
Bill & Melinda Gates Foundation.
与其他口服疫苗类似，口服脊髓灰质炎疫苗在低收入国家的免疫原性和有效性不如高收入国家。有人提出，肠道病原体的高流行率和相关的环境肠病解释了这一问题。由于抗生素的使用有可能解决环境肠病并清除细菌病原体，我们旨在评估抗生素是否会提高口服脊髓灰质炎疫苗的免疫原性。
我们在印度维洛尔区的 14 个街区进行了一项双盲、随机、安慰剂对照试验，评估阿奇霉素对健康婴儿口服三价脊髓灰质炎疫苗免疫原性的影响。如果婴儿年龄在 6-11 个月之间、可参加研究全程且缺乏血清中和抗体 3 型脊髓灰质炎病毒，则有资格参加。婴儿在登记时以 1:1 的比例随机分配（随机分配）接受口服 10mg/kg 阿奇霉素或安慰剂，每天一次，连续 3 天，然后在第 14 天接种三价口服脊髓灰质炎疫苗。主要结局是在第 35 天检测血清中和抗体 3 型脊髓灰质炎病毒的滴度为 1:8 或更高，并在方案人群中进行评估（即，所有接受阿奇霉素或安慰剂、口服脊髓灰质炎疫苗且按照研究方案提供血样的人）。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中心注册，注册号为 CTRI/2014/05/004588。
2014 年 8 月 5 日至 2015 年 3 月 21 日，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 名中的 348 名（93%）和安慰剂组 378 名中的 357 名（94%）按方案完成了研究。阿奇霉素组中有 175 名（50%）发生血清型 3 脊髓灰质炎病毒血清转化，而安慰剂组中有 192 名（54%）（风险比 0.94，95%CI 0.81-1.08；p=0.366）。阿奇霉素降低了粪便环境肠病的生物标志物（钙卫蛋白、髓过氧化物酶、α1-抗胰蛋白酶）和细菌但不是病毒或真核病原体的流行率。病毒病原体与较低的血清转化率相关。报告了 3 例严重不良事件（阿奇霉素组 2 例，安慰剂组 1 例），但均认为与研究干预无关。
尽管阿奇霉素降低了环境肠病的生物标志物和致病性肠道细菌的流行率，但并未提高口服脊髓灰质炎疫苗的免疫原性。病毒干扰和先天抗病毒免疫机制可能是影响活病毒口服疫苗免疫原性的更重要决定因素。
比尔和梅琳达·盖茨基金会。
