美国国立卫生研究院Jessica E Manning团队分析了一种基于蚊子唾液肽的疫苗的安全性和免疫原性。相关论文在线发表在2020年6月11日的《柳叶刀》杂志上。
在动物模型中，对蚊子唾液蛋白的免疫力可保护动物免受蚊媒疾病的侵害。该发现为蚊子唾液而非病原体本身接种疫苗提供了理论依据。但基于载体唾液蛋白的疫苗在人类中的安全性和免疫原性尚未明确。
为了评估冈比亚按蚊唾液疫苗（AGS-v）的安全性和免疫原性，研究组在美国马里兰州贝塞斯达的国立卫生研究院临床中心进行了一项随机、安慰剂对照、双盲、1期临床试验。2017年2月15日至9月10日，研究组招募了49名年龄18-50岁，没有蚊虫叮咬严重过敏反应史的健康成年人，将其按1:1:1随机分组，其中16例单独接种200 nmol AGS-v疫苗，17例接种200 nmol AGS-v佐剂（Montanide ISA 51），16例接种无菌水作为安慰剂。参与者分别在第0天和第21天接种，在第42天接受未感染的埃及伊蚊叮咬，以评估在受控环境下蚊虫叮咬的后续风险。
有5名参与者未在第42天接受蚊子叮咬，但被纳入安全性分析。未发现系统性安全隐患，但佐剂疫苗组的一名参与者在注射部位出现了3级红斑皮疹。最常报告的局部症状是疼痛、肿胀、红斑和瘙痒，佐剂疫苗组中的发生率为53%，显著高于单独疫苗组（13%）和安慰剂组（6%）。佐剂疫苗组与单独疫苗组和安慰剂组相比，第42天时的疫苗特异性总IgG抗体较基线显著增加。佐剂疫苗组与安慰剂组相比，第42天时外周血单个核细胞产生的IFN-γ明显增加，但与单独疫苗组之间没有显著差异。
总之，AGS-v具有良好的耐受性，佐剂后具有免疫原性。该结果表明，人体接种以载体为靶标的疫苗是安全的。
附：英文原文
Title: Safety and immunogenicity of a mosquito saliva peptide-based vaccine: a randomised, placebo-controlled, double-blind, phase 1 trial
Author: Jessica E Manning, Fabiano Oliveira, Iliano V Coutinho-Abreu, Samantha Herbert, Claudio Meneses, Shaden Kamhawi, Holly Ann Baus, Alison Han, Lindsay Czajkowski, Luz Angela Rosas, Adriana Cervantes-Medina, Rani Athota, Susan Reed, Allyson Mateja, Sally Hunsberger, Emma James, Olga Pleguezuelos, Gregory Stoloff, Jesus G Valenzuela, Matthew J Memoli
Issue&Volume: 2020-06-11
Abstract: Background
In animal models, immunity to mosquito salivary proteins protects animals against mosquito-borne disease. These findings provide a rationale to vaccinate against mosquito saliva instead of the pathogen itself. To our knowledge, no vector salivary protein-based vaccine has been tested for safety and immunogenicity in humans. We aimed to assess the safety and immunogenicity of Anopheles gambiae saliva vaccine (AGS-v), a peptide-based vaccine derived from four A gambiae salivary proteins, in humans.
Methods
In this randomised, placebo-controlled, double-blind, phase 1 trial, participants were enrolled at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Participants were eligible if they were healthy adults, aged 18–50 years with no history of severe allergic reactions to mosquito bites. Participants were randomly assigned (1:1:1), using block randomisation and a computer-generated randomisation sequence, to treatment with either 200 nmol of AGS-v vaccine alone, 200 nmol of AGS-v with adjuvant (Montanide ISA 51), or sterile water as placebo. Participants and clinicians were masked to treatment assignment. Participants were given a subcutaneous injection of their allocated treatment at day 0 and day 21, followed by exposure to feeding by an uninfected Aedes aegypti mosquito at day 42 to assess subsequent risk to mosquito bites in a controlled setting. The primary endpoints were safety and immunogenicity at day 42 after the first immunisation. Participants who were given at least one dose of assigned treatment were assessed for the primary endpoints and analysis was by intention to treat. The trial was registered with ClinicalTrials.gov, NCT03055000, and is closed for accrual.
Findings
Between Feb 15 and Sept 10, 2017, we enrolled and randomly assigned 49 healthy adult participants to the adjuvanted vaccine (n=17), vaccine alone (n=16), or placebo group (n=16). Five participants did not complete the two-injection regimen with mosquito feeding at day 42, but were included in the safety analyses. No systemic safety concerns were identified; however, one participant in the adjuvanted vaccine group developed a grade 3 erythematous rash at the injection site. Pain, swelling, erythema, and itching were the most commonly reported local symptoms and were significantly increased in the adjuvanted vaccine group compared with both other treatment groups (nine [53%] of 17 participants in the adjuvanted vaccine group, two [13%] of 16 in the vaccine only group, and one [6%] of 16 in the placebo group; p=0·004). By day 42, participants who were given the adjuvanted vaccine had a significant increase in vaccine-specific total IgG antibodies compared with at baseline than did participants who were give vaccine only (absolute difference of log 10-fold change of 0·64 [95% CI 0·39 to 0·89]; p=0·0002) and who were given placebo (0·62 [0·34 to 0·91]; p=0·0001). We saw a significant increase in IFN-γ production by peripheral blood mononuclear cells at day 42 in the adjuvanted vaccine group compared with in the placebo group (absolute difference of log 10 ratio of vaccine peptide-stimulated vs negative control 0·17 [95% CI 0·061 to 0·27]; p=0·009) but we saw no difference between the IFN-γ production in the vaccine only group compared with the placebo group (0·022 [–0·072 to 0·116]; p=0·63).
Interpretation
AGS-v was well tolerated, and, when adjuvanted, immunogenic. These findings suggest that vector-targeted vaccine administration in humans is safe and could be a viable option for the increasing burden of vector-borne disease.
DOI: 10.1016/S0140-6736(20)31048-5
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31048-5/fulltext
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本期文章：《柳叶刀》：Online/在线发表
