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 log₁₀-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 log₁₀ 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.

Funding

Office of the Director and the Division of Intramural Research at the National Institute of Allergy and Infectious Diseases, and National Institutes of Health.

中文翻译：

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蚊子唾液肽疫苗的安全性和免疫原性：一项随机、安慰剂对照、双盲、1 期试验。

 背景

在动物模型中，对蚊子唾液蛋白的免疫力可以保护动物免受蚊媒疾病的侵害。这些发现为针对蚊子唾液而不是病原体本身进行疫苗接种提供了理论依据。据我们所知，尚未对基于载体唾液蛋白的疫苗进行人体安全性和免疫原性测试。我们的目的是评估冈比亚按蚊唾液疫苗 (AGS-v) 的安全性和免疫原性，这是一种源自四种冈比亚按蚊唾液蛋白的肽疫苗。

 方法

在这项随机、安慰剂对照、双盲、1 期试验中，参与者在美国马里兰州贝塞斯达的国立卫生研究院临床中心入组。参与者如果是健康成年人，年龄在 18 至 50 岁之间，没有对蚊虫叮咬的严重过敏反应史，则符合资格。使用分组随机化和计算机生成的随机化序列，将参与者随机分配 (1:1:1)，分别接受 200 nmol AGS-v 疫苗单独治疗、200 nmol AGS-v 佐剂 (Montanide ISA 51) 治疗、或无菌水作为安慰剂。参与者和临床医生不知道治疗分配。参与者在第 0 天和第 21 天皮下注射分配的治疗药物，然后在第 42 天接受未感染的埃及伊蚊的喂养，以评估随后在受控环境中被蚊子叮咬的风险。主要终点是第一次免疫后第 42 天的安全性和免疫原性。对接受至少一剂指定治疗的参与者进行主要终点评估，并按意向治疗进行分析。该试验已在 ClinicalTrials.gov 注册（NCT03055000），并已结束累积。

 发现

2017 年 2 月 15 日至 9 月 10 日期间，我们招募了 49 名健康成年参与者，并将其随机分配至佐剂疫苗组 (n=17)、单独疫苗组 (n=16) 或安慰剂组 (n=16)。 5 名参与者在第 42 天时没有完成两次注射并喂蚊子的方案，但被纳入安全性分析。未发现系统性安全问题；然而，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。疼痛、肿胀、红斑和瘙痒是最常见的局部症状，与其他两个治疗组相比，佐剂疫苗组的症状显着增加（佐剂疫苗组 17 名参与者中的 9 名 [53%]，两名 [13%]仅疫苗组中有 16 人，安慰剂组中有 16 人 [6%]；p=0·004）。到第 42 天，与仅接种疫苗的参与者相比，接种佐剂疫苗的参与者的疫苗特异性总 IgG 抗体显着增加（log ₁₀倍变化的绝对差异为 0·64 [95% CI 0·39 至 0·89]；p=0·0002）和服用安慰剂的患者（0·62 [0·34 至 0·91]；p=0·0001）。我们发现，与安慰剂组相比，第 42 天时，佐剂疫苗组外周血单核细胞的 IFN-γ 产量显着增加（疫苗肽刺激与阴性对照的 log ₁₀比率的绝对差异 0·17 [95% CI 0·061 至 0·27]；p=0·009），但我们发现仅疫苗组与安慰剂组相比，IFN-γ 的产生没有差异（0·022 [–0·072 至 0·116） ]；p=0·63)。

 解释

AGS-v 具有良好的耐受性，并且在添加佐剂后具有免疫原性。这些发现表明，针对人类的载体疫苗接种是安全的，并且可能是解决日益增加的载体传播疾病负担的可行选择。

 资金

国家过敏和传染病研究所以及国立卫生研究院主任办公室和校内研究部。