近日，广州医科大学呼吸疾病国家重点实验室呼吸道病毒与感染学组陈凌/潘蔚绮教授课题组在H7N9疫苗研究中取得系列研究进展。相关研究成果发表在国际病毒学期刊Antiviral Research（IF:4.101）“Evaluation of the immune response of a H7N9 candidate vaccine virus derived from the fifth wave A/Guangdong/17SF003/ 2016”和Journal of Virology（IF:4.501 “L226Q mutation on influenza H7N9 virus hemagglutinin increases receptor-binding avidity and leads to biased antigenicity evaluation”。
H7N9流感病毒自2013年出现以来，一直在不断进化。截至目前，H7N9流感病毒已经历了7个流行季，引发了5次流行高峰，并在第5波流行中出现了高致病性H7N9毒株（HPAI H7N9），严重威胁人类健康和国民经济的持续发展。课题组以世界卫生组织于2017年更新的H7N9疫苗候选株A/Guangdong/ 17SF003/2016 (H7/GD16) 为研究对象，在小鼠和猕猴动物模型中系统地分析了该疫苗株的免疫原性、抗原性及影响HA抗原性变异评估的关键氨基酸位点。研究发现：GD/16疫苗株在动物模型中具有良好的免疫原性，但血凝抑制抗体（HI）检出水平偏低；既往疫苗株A/Anhui/1/2013 (AH/13) 能够提供对GD/16的完全保护，但HI交叉反应性差。
进一步研究通过对H7/AH13和H7/GD16血凝素HA的氨基酸突变分析表明，L226Q定点突变增加了HA与红细胞唾液酸受体的结合亲和力，导致对HA Q226病毒的HI滴度降低，从而导致H7N9流感病毒抗原性变异评估产生偏差。这些结果表明，位于受体结合位点的氨基酸可能通过影响受体与红细胞的结合亲和力而误导抗原变异的评估，而不会真正导致抗原漂移。研究强调，在评估和选择H7N9和其他流感病毒亚型候选疫苗病毒时，应考虑病毒受体结合亲和力和多种血清学检测的组合。
两篇论文的第一作者分别为广州医科大学呼吸疾病国家重点实验室王洋博士、研究生董记博士和吕云华硕士，通讯作者为重点实验室陈凌教授与潘蔚绮副研究员。本研究得到国家重点研发计划、国家自然科学基金面上项目、国家博士后科学基金、广东省自然科学基金、广州市科技计划重点项目等经费支持。Evaluation of the immune response of a H7N9 candidate vaccine virus derived from the fifth wave A/Guangdong/17SF003/2016
Abstract
Highly pathogenic influenza H7N9 viruses that emerged in the fifth wave of H7N9 outbreak pose a risk to human health. The World Health Organization has updated the candidate vaccine viruses for H7N9 viruses recently. In this study, we evaluated the immune response to an updated H7N9 candidate vaccine virus, which derived from the highly pathogenic A/Guangdong/17SF003/2016 (GD/16) in mice and rhesus macaques. GD/16 vaccination elicited robust neutralizing, virus-specific immunoglobulin G antibodies and effective protection, but poor hemagglutination inhibition antibody titers. Furthermore, mouse and rhesus macaque serum raised against the previous H7N9 CVV A/Anhui/1/2013 (AH/13) were tested for its cross-reactivity to GD/16 virus. We found that although AH/13-immune serum has poor hemagglutination inhibition reactivity against GD/16 virus, AH/13 elicit efficient cross-neutralizing antibodies and in vivo protection against GD/16. Further studies showed that the hemagglutinin of GD/16 has strong receptor binding avidity, which might be associated with the decreased hemagglutination inhibition assay sensitivity. This study underscores the point that receptor binding avidity should be taken into account when performing quantitative interpretation of hemagglutination inhibition data. A combination of multiple serological assays is required for accurate vaccine evaluation and antigenic analysis of influenza viruses.L226Q mutation on influenza H7N9 virus hemagglutinin increases receptor-binding avidity and leads to biased antigenicity evaluation
ABSTRACT
Since the first outbreak in 2013, the influenza A (H7N9) virus has continued emerging and caused over five epidemic waves. Suspected antigenic changes of the H7N9 virus based on hemagglutination inhibition (HI) assay during the fifth outbreak have prompted the update of H7N9 candidate vaccine viruses (CVVs). In this study, we comprehensively compared the serological cross-reactivity induced by the hemagglutinins (HAs) of the earlier CVV A/Anhui/1/2013 (H7/AH13) and the updated A/Guangdong/17SF003/2016 (H7/GD16). We found that although H7/GD16 showed poor HI cross-reactivity to immune sera from mice and rhesus macaques vaccinated with either H7/AH13 or H7/GD16, the cross-reactive neutralizing antibodies between H7/AH13 and H7/GD16 were comparably high. Passive transfer of H7/AH13 immune sera also provided complete protection against the lethal challenge of H7N9/GD16 virus in mice. Analysis of amino acid mutations in the HAs between H7/AH13 and H7/GD16 revealed that L226Q substitution increases the HA binding avidity to sialic acid receptors on red blood cells, leading to decreased HI titers against viruses containing HA Q226 and thus resulted in a biased antigenic evaluation based on HI assay. These results suggest that amino acids located in the receptor-binding site could mislead the evaluation of antigenic variation by solely impact on the receptor-binding avidity to red blood cells without genuine contribution to antigenic drift. Our study highlights that viral receptor-binding avidity and combination of multiple serological assays should be taken into consideration in evaluating and selecting a candidate vaccine virus of H7N9 and other subtypes of influenza viruses.
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