Assessment of Human Immune Responses to H7 Avian Influenza Virus of Pandemic Potential: Results from a Placebo–Controlled, Randomized Double–Blind Phase I Study of Live Attenuated H7N3 Influenza Vaccine

IntroductionLive attenuated influenza vaccines (LAIVs) are being developed to protect humans against future epidemics and pandemics. This study describes the results of a double–blinded randomized placebo–controlled phase I clinical trial of cold–adapted and temperature sensitive H7N3 live attenuated influenza vaccine candidate in healthy seronegative adults.ObjectiveThe goal of the study was to evaluate the safety, tolerability, immunogenicity and potential shedding and transmission of H7N3 LAIV against H7 avian influenza virus of pandemic potential.Methods and FindingsTwo doses of H7N3 LAIV or placebo were administered to 40 randomly divided subjects (30 received vaccine and 10 placebo). The presence of influenza A virus RNA in nasal swabs was detected in 60.0% and 51.7% of subjects after the first and second vaccination, respectively. In addition, vaccine virus was not detected among placebo recipients demonstrating the absence of person–to–person transmission. The H7N3 live attenuated influenza vaccine demonstrated a good safety profile and was well tolerated. The two–dose immunization resulted in measurable serum and local antibody production and in generation of antigen–specific CD4+ and CD8+ memory T cells. Composite analysis of the immune response which included hemagglutinin inhibition assay, microneutralization tests, and measures of IgG and IgA and virus–specific T cells showed that the majority (86.2%) of vaccine recipients developed serum and/or local antibodies responses and generated CD4+ and CD8+ memory T cells.ConclusionsThe H7N3 LAIV was safe and well tolerated, immunogenic in healthy seronegative adults and elicited production of antibodies broadly reactive against the newly emerged H7N9 avian influenza virus.Trial registrationClinicalTrials.gov NCT01511419引言 减毒活流感疫苗（Live Attenuated Influenza Vaccines, LAIVs）目前正处于研发阶段，旨在保护人类抵御未来的流感疫情及大流行。本研究报告了冷适应减毒、温度敏感型H7N3候选减毒活流感疫苗在健康血清阴性成人中开展的双盲随机安慰剂对照I期临床试验结果。 研究目的 本研究旨在评估H7N3减毒活流感疫苗针对具备大流行潜力的H7亚型禽流感病毒的安全性、耐受性、免疫原性，以及潜在的病毒脱落与传播能力。 方法与结果 本研究将40名受试者随机分为两组（30名接种疫苗，10名接种安慰剂），分别给予两剂H7N3减毒活流感疫苗或安慰剂。首剂接种后，60.0%的受试者鼻拭子中检测到甲型流感病毒RNA；第二剂接种后，该比例为51.7%。此外，安慰剂组受试者未检出疫苗病毒，证实不存在人际传播。H7N3减毒活流感疫苗表现出良好的安全性与耐受性。两剂免疫程序可诱导可检测的血清及局部抗体产生，并生成抗原特异性CD4+及CD8+记忆T细胞。对免疫应答的综合分析（包括血凝抑制试验、微量中和试验，以及IgG、IgA与病毒特异性T细胞检测）显示，86.2%的疫苗接种者产生了血清和/或局部抗体应答，并生成了CD4+及CD8+记忆T细胞。 结论 H7N3减毒活流感疫苗在健康血清阴性成人中具有良好的安全性与耐受性，且具备免疫原性，可诱导产生对新型出现的H7N9禽流感病毒具有广泛反应性的抗体。 试验注册 ClinicalTrials.gov NCT01511419