Vaxart, South San Francisco, California, USA.
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, USA.
JCI Insight. 2018 Jul 12;3(13):121077. doi: 10.1172/jci.insight.121077.
Noroviruses are the leading cause of epidemic acute gastroenteritis and foodborne diarrheal disease in humans. However, there are no approved vaccines for noroviruses. Potential correlates of protection identified through human challenge studies include mucosal IgA, memory B cells, and serum-blocking antibody titers (BT50).
We conducted a single-site, randomized, double-blind, placebo-controlled clinical trial of an oral norovirus vaccine to determine safety and immunogenicity. This tablet vaccine is comprised of a nonreplicating adenovirus-based vector expressing the VP1 gene from the GI.1 norovirus strain and a double-stranded RNA adjuvant. Sixty-six adult subjects meeting inclusion/exclusion criteria were randomized 2:1 to receive a single vaccine dose or placebo, respectively. Immunogenicity was primarily assessed by serum BT50. Additional outcomes included serum ELISA titers, fecal and saliva antibody titers, memory and antibody-secreting cell (ASC) frequency, and B cell phenotyping.
The vaccine was well-tolerated, with no dose-limiting toxicities. Adverse events were mild or moderate. The primary immunological endpoint (increase in BT50 titers) was met in the high-dose group (P = 0.0003), with 78% showing a ≥2-fold rise in titers after a single immunization. Vaccine recipients also developed mucosally primed VP1-specific circulating ASCs, IgA+ memory B cells expressing gut-homing receptor (α4β7), and fecal IgA, indicating substantial and local responses potentially relevant to prevent norovirus infection.
This oral norovirus vaccine was well-tolerated and generated substantial immune responses, including systemic and mucosal antibodies as well as memory IgA/IgG. These results are a major step forward for the development of a safe and immunogenic oral norovirus vaccine.
ClinicalTrials.gov NCT02868073.
Vaxart.
诺如病毒是导致人类爆发性急性肠胃炎和食源性腹泻病的主要原因。然而，目前还没有针对诺如病毒的批准疫苗。通过人体挑战研究确定的保护相关因素包括黏膜 IgA、记忆 B 细胞和血清中和抗体滴度（BT50）。
我们进行了一项单站点、随机、双盲、安慰剂对照的口服诺如病毒疫苗临床试验，以确定其安全性和免疫原性。这种片剂疫苗由复制缺陷型腺病毒载体组成，该载体表达 GI.1 诺如病毒株的 VP1 基因和双链 RNA 佐剂。符合纳入/排除标准的 66 名成年受试者按 2:1 的比例随机分为疫苗组或安慰剂组，分别接受单次疫苗接种或安慰剂。免疫原性主要通过血清 BT50 评估。其他结果包括血清 ELISA 滴度、粪便和唾液抗体滴度、记忆和抗体分泌细胞（ASC）频率以及 B 细胞表型。
疫苗耐受性良好，无剂量限制毒性。不良事件为轻度或中度。高剂量组达到了主要免疫学终点（BT50 滴度增加）（P = 0.0003），单次免疫后 78%的患者滴度增加了 2 倍以上。疫苗接种者还产生了黏膜预刺激的 VP1 特异性循环 ASC、表达肠道归巢受体（α4β7）的 IgA+记忆 B 细胞和粪便 IgA，表明潜在的大量局部反应可能有助于预防诺如病毒感染。
这种口服诺如病毒疫苗耐受性良好，可产生大量免疫反应，包括系统和黏膜抗体以及记忆 IgA/IgG。这些结果是开发安全、免疫原性口服诺如病毒疫苗的重要一步。
ClinicalTrials.gov NCT02868073。
Vaxart。
