A Sequence-Based Update on Amino Acid Substitutions in Influenza Polymerase Acidic Protein in Europe That Alter Baloxavir Susceptibility From 2009 to 2025

IF 3.9 4区医学 Q1 INFECTIOUS DISEASES

Influenza and Other Respiratory Viruses Pub Date : 2026-06-26 DOI:10.1111/irv.70288

Alejandro Martín-Toribio, Inés Inchausti-Moya, Marina Toquero-Asensio, Sonia García-Díaz, Javier Sanchez-Martinez, Carla Rodriguez-Crespo, Silvia Galindo-Carretero, Raquel Iglesia-Aparicio, Celia Lopez-Gonzalo, Ana Antón-Contreras, Silvia Rojo-Rello, Marta Dominguez-Gil, Marta Hernández, Jose M. Eiros, Estanislao Nistal-Villan, Iván Sanz-Muñoz

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引用次数: 0

Abstract

Background

Influenza causes 650,000 deaths, 3–5 million hospitalizations, and 1 billion cases worldwide each year. There is a limited repertoire of antivirals available to tackle this burden, highlighting the risk of developing resistance to current drugs. An effort to develop new influenza antivirals has been made, leading to the approval of baloxavir. Some mutations leading to reduced susceptibility to baloxavir have been reported, but information about their epidemiology is scarce. Thus, we aim to evaluate the prevalence of substitutions in the polymerase acidic (PA) subunit associated with baloxavir susceptibility over 16 epidemiological seasons in Europe.

Methods

We evaluated 87,266 sequences collected from 2009 to 2025 in Europe, annotated the mutations, and identified all known amino acid substitutions related to changes in baloxavir susceptibility to assess their prevalence.

Results

A total of 149 (0.2%) sequences with at least one substitution were identified, 81 (0.09%) exhibiting reduced susceptibility. Overall, 17 different substitutions were detected, located both inside and outside baloxavir binding site. The number of substitutions detected ranged from 0 to 15 per season, with E23K, E23R, K34R, A36V, I38F, I38L, and E120D emerging after baloxavir approval in Europe. Double and triple concurrent substitutions were also identified.

Conclusion

While the prevalence of sequences with substitutions that alter baloxavir susceptibility remains stable, the number of circulating substitutions increases over time. This implies the emergence of amino acid substitutions that did not circulate before and the concurrence of double and triple substitutions that might synergize their individual effects. These results highlight the need for virological surveillance and novel antiviral treatments.

Abstract Image

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2009年至2025年欧洲流感聚合酶酸性蛋白氨基酸替换改变巴洛昔韦易感性的序列更新

背景：流感每年在全世界造成65万人死亡，300万至500万人住院，并造成10亿病例。可用于应对这一负担的抗病毒药物有限，这突出了对现有药物产生耐药性的风险。人们努力开发新的流感抗病毒药物，从而批准了巴洛昔韦。一些导致对巴洛昔韦易感性降低的突变已被报道，但有关其流行病学的信息很少。因此，我们的目的是评估欧洲16个流行病学季节中与巴洛昔韦易感性相关的聚合酶酸性（PA）亚基取代的流行程度。方法对2009年至2025年在欧洲收集的87,266个序列进行评估，对突变进行注释，并鉴定所有已知的与巴洛昔韦易感性变化相关的氨基酸取代，以评估其流行程度。结果共鉴定出149条（0.2%）至少有1次取代的序列，其中81条（0.09%）的易感性降低。总共检测到17个不同的取代，位于巴洛昔韦结合位点内外。baloxavir在欧洲获批后，每个季度检测到的替代数量为0 - 15个，其中E23K、E23R、K34R、A36V、I38F、I38L和E120D出现。同时还发现了双重和三重并行替换。结论虽然改变巴洛昔韦易感性的替换序列的流行率保持稳定，但循环替换的数量随着时间的推移而增加。这意味着以前不循环的氨基酸取代的出现，以及可能协同它们各自作用的双取代和三取代的同时发生。这些结果突出了病毒学监测和新型抗病毒治疗的必要性。

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来源期刊

Influenza and Other Respiratory Viruses 医学-病毒学

CiteScore

7.20

自引率

4.50%

发文量

120

审稿时长

6-12 weeks

期刊介绍： Influenza and Other Respiratory Viruses is the official journal of the International Society of Influenza and Other Respiratory Virus Diseases - an independent scientific professional society - dedicated to promoting the prevention, detection, treatment, and control of influenza and other respiratory virus diseases. Influenza and Other Respiratory Viruses is an Open Access journal. Copyright on any research article published by Influenza and Other Respiratory Viruses is retained by the author(s). Authors grant Wiley a license to publish the article and identify itself as the original publisher. Authors also grant any third party the right to use the article freely as long as its integrity is maintained and its original authors, citation details and publisher are identified.