Data from: First-in-human randomized controlled trial of an oral, replicating Adenovirus 26 vector vaccine for HIV-1

Background: Live, attenuated viral vectors that express HIV-1 antigens are
being investigated as an approach to generating durable immune responses
against HIV-1 in humans. We recently developed a replication-competent,
highly attenuated Ad26 vector that expresses mosaic HIV-1 Env
(rcAd26.MOS1.HIV-Env, “rcAd26”). Here we present the results of a
first-in-human, placebo-controlled clinical trial to test the safety,
immunogenicity and mucosal shedding of rcAd26 given orally. Methods:
Healthy adults were randomly assigned to receive a single oral dose of
vaccine or placebo at 5:1 ratio in a dosage escalation of 10^8 to 10^11
rcAd26 VP (nominal doses) at University of Rochester Medical Center,
Rochester, NY, USA. Participants were isolated and monitored for
reactogenicity for 10 days post-vaccination, and adverse events were
recorded up to day 112. Rectal and oropharyngeal secretions were evaluated
for shedding of the vaccine. Humoral and cellular immune responses were
measured. Household contacts were monitored for secondary vaccine
transmission. Results: We enrolled 22 participants and 11 household
contacts between February 7 and June 24, 2015. 18 participants received
one dose of HIV-1 vaccine and 4 participants received placebo. The vaccine
caused only mild to moderate adverse events. No vaccine-related SAEs were
observed. No infectious rcAd26 viral particles were detected in rectal or
oropharyngeal secretions from any participant. Env-specific ELISA and
ELISPOT responses were undetectable. No household contacts developed
vaccine-induced HIV-1 seropositivity or vaccine-associated illness.
Conclusions: The highly attenuated rcAd26.MOS1.HIV-Env vaccine was well
tolerated up to 10^11 VP in healthy, HIV-1-uninfected adults, though the
single dose was poorly immunogenic suggesting the replicative capacity of
the vector was too attenuated. There was no evidence of shedding of
infectious virus or secondary vaccine transmission following the isolation
period. These data suggest the use of less attenuated viral vectors in
future studies of live, oral HIV-1 vaccines. Clinical Trials Registration:
NCT02366013

背景：表达HIV-1抗原的减毒活病毒载体（live, attenuated viral vectors）是目前被研究用于在人体中诱导针对HIV-1的持久性免疫应答的策略之一。本团队近期研发了一种具备复制能力的高度减毒Ad26载体，该载体可表达嵌合型HIV-1 Env蛋白（rcAd26.MOS1.HIV-Env，下称"rcAd26"）。本研究首次报道一项口服rcAd26的首个人体安慰剂对照临床试验结果，旨在评估该疫苗的安全性、免疫原性以及黏膜排毒情况。
方法：本试验于美国纽约州罗切斯特市罗切斯特大学医学中心开展，将健康成人按5:1的比例随机分配，接受单次口服疫苗或安慰剂，剂量递增范围为10^8至10^11 rcAd26病毒颗粒数（VP, viral particles，标称剂量）。受试者在接种后需隔离并监测反应原性，时长为10天；不良事件的记录持续至接种后第112天。采集受试者直肠和口咽分泌物以检测疫苗排毒情况，同时检测体液免疫与细胞免疫应答。此外，对受试者的家庭接触者进行监测以评估疫苗的二次传播风险。
结果：本研究于2015年2月7日至6月24日期间，共纳入22名受试者与11名家庭接触者。其中18名受试者接种单次HIV-1疫苗，4名受试者接种安慰剂。该疫苗仅引发轻至中度不良事件，未观察到与疫苗相关的严重不良事件（SAEs）。所有受试者的直肠及口咽分泌物中，均未检测到具有感染性的rcAd26病毒颗粒。Env特异性酶联免疫吸附试验（ELISA）与酶联免疫斑点试验（ELISPOT）均未检测到免疫应答。所有家庭接触者均未出现疫苗诱导的HIV-1血清阳转，亦未发生与疫苗相关的疾病。
结论：在健康的HIV-1未感染成人中，最高至10^11 VP剂量的高度减毒rcAd26.MOS1.HIV-Env疫苗具有良好的耐受性，但单次接种的免疫原性较差，提示该载体的复制能力被过度减毒。在隔离观察期内，未发现感染性病毒排毒或疫苗二次传播的证据。上述结果提示，在未来的口服活HIV-1疫苗研究中，可采用减毒程度更低的病毒载体。
临床试验注册：NCT02366013