近日，美国约翰斯·霍普金斯大学彭博公共卫生学院Anna P. Durbin团队报道了在对照人类感染模型中每日使用mosnodenvir预防登革热的效果。2025年11月27日出版的《新英格兰医学杂志》发表了这项成果。

全世界约有一半人口面临登革热风险。没有可用的抗病毒预防或治疗方案。

在一项2a期、双盲、随机试验中，研究组将健康成年人分配到每天一次口服mosnodenvir，作为低剂量（40毫克负荷剂量后10毫克维持剂量）、中剂量（200毫克后50毫克）、高剂量（600毫克后200毫克）或匹配的安慰剂。加载剂量为5天，维持剂量为21天。在受控的人类感染模型中，参与者在第一次维持剂量（第1天）当天皮下接种了欠减毒登革热病毒血清型3 （DENV-3）株（rDEN3Δ30）。主要疗效终点是DENV-3 RNA载量，从第1天（接种前）到第29天（AUCD1-29），以浓度-时间曲线下的log10面积来评估。在主要终点分析中比较高剂量组和安慰剂组。安全性、药代动力学特征、病毒学和血清学特征评估到第85天。

低剂量mosnodenvir组无DENV-3感染体征的受试者百分比为0%（6名受试者中0名），中剂量组为17%（6名受试者中1名），高剂量组为60%（10名受试者中6名），而安慰剂组为0%（7名受试者中0名）。与安慰剂相比，高剂量mosnodenvir导致DENV-3 RNA载量显著降低，评估为log10 AUCD1-29。在这个小型试验中，mosnodenvir没有导致任何严重的不良事件。mosnodenvir血药浓度从白天开始升高。第5 ~第1天，并维持至第21天。在具有NS4B测序数据的参与者中，14名mosnodenvir受体中有14名检测到rDEN3Δ30基因组NS4B区域出现的氨基酸变异，而7名安慰剂受体中没有检测到。

研究结果表明，在一个受控的人类感染模型中，高剂量的每日口服mosnodenvir导致DENV-3 RNA载量显著低于安慰剂。Mosnodenvir未导致任何严重的不良事件。

附：英文原文

Title: Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model

Author: Anna P. Durbin, Liesbeth Van Wesenbeeck, Kristen K. Pierce, Guillermo Herrera-Taracena, Laura Ebone, Annemie Buelens, Patricia Lutton, Beulah P. Sabundayo, Veerle Van Eygen, Kim De Clerck, Isabel Fetter, Natalia V. Voge, Xi Fang, Nele Goeyvaerts, Yannick Vandendijck, Jeffrey Mayfield, Oliver Lenz, Sandra De Meyer, Thomas N. Kakuda, Huili He, Emérito Amaro-Carambot, Ruxandra Draghia Akli, Marya Carmolli, Tine De Marez, Stephen S. Whitehead, Marnix Van Loock, Freya Rasschaert

Issue&Volume: 2025-11-27

Abstract:

BACKGROUND

Approximately half the worldwide population is at risk for dengue. No antiviral prophylaxis or treatment options are available.

METHODS

In a phase 2a, double-blind, randomized trial, we assigned healthy adults to receive oral mosnodenvir once daily as a low dose (40-mg loading dose followed by 10-mg maintenance dose), medium dose (200 mg followed by 50 mg), or high dose (600 mg followed by 200 mg) or matched placebo. Loading doses were given for 5 days and maintenance doses for 21 days. In a controlled human infection model, participants received subcutaneous inoculation of an underattenuated dengue virus serotype 3 (DENV-3) strain (rDEN3Δ30) on the day of the first maintenance dose (day 1). The primary efficacy end point was the DENV-3 RNA load, assessed as the log10 area under the concentration–time curve from day 1 (immediately before inoculation) through day 29 (AUCD1–29). The high-dose and placebo groups were compared in the primary end-point analysis. Safety, pharmacokinetic features, and virologic and serologic features were evaluated through day 85.

RESULTS

The percentage of participants without signs of DENV-3 infection was 0% (0 of 6 participants) with the low dose of mosnodenvir, 17% (1 of 6) with the medium dose, and 60% (6 of 10) with the high dose, as compared with 0% (0 of 7) with placebo. High-dose mosnodenvir led to a significantly lower DENV-3 RNA load, assessed as the log10 AUCD1–29, than placebo (two-sided P<0.001 by tobit analysis of variance). In this small trial, mosnodenvir did not result in any serious adverse events. Plasma concentrations of mosnodenvir increased from day 5 to day 1 and were maintained through day 21. Among participants with available NS4B sequencing data, emerging amino acid variations in the NS4B region of the rDEN3Δ30 genome were detected in 14 of 14 mosnodenvir recipients and none of 7 placebo recipients.

CONCLUSIONS

In a controlled human infection model, a high daily dose of oral mosnodenvir led to a significantly lower DENV-3 RNA load than placebo. Mosnodenvir did not result in any serious adverse events.

DOI: NJ202511273932109

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2500179