Antigenic Characterization of Human Monoclonal Antibodies for Therapeutic Use against H7N9 Avian Influenza Virus.
Antigenic Characterization of Human Monoclonal Antibodies for Therapeutic Use against H7N9 Avian Influenza Virus.
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DOI：
10.1128/jvi.01431-22
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发表时间：
2023-01-31
影响因子：
5.4
通讯作者：
中科院分区：
文献类型：
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自2013年以来，H7N9禽流感病毒（AIV）已导致1,500多人感染，数百万家禽被扑杀。尽管大规模的家禽疫苗接种，H7N9禽流感病毒继续在中国的家禽中传播，并对人类健康构成威胁。在此之前，我们分离并产生了四种来自自然感染H7N9 AIV的人的单克隆抗体（mAb）。在这里，我们使用免疫逃逸研究研究了这些mAb（L3 A-44、K9 B-122、L4 A-14和L4 B-18）靶向的H7N9 AIV的血凝素（HA）表位。我们的结果揭示了HA氨基酸位置125、133、149和217处的四个关键抗原表位。代表逃逸突变的突变体H7N9病毒包含残基125处丙氨酸至苏氨酸的取代（A125 T）、残基133处甘氨酸至谷氨酸的取代（G133 E）、残基149处天冬酰胺至天冬氨酸的取代（N149 D）、或在残基217（L217 Q）处的亮氨酸至谷氨酰胺的取代显示与mAb的交叉反应性降低或完全消除，如通过血凝抑制（HI）测定所测量的。我们通过测量这些HA突变对病毒适应性和逃避宿主适应性免疫的影响，进一步评估了这些突变体在mAb治疗后出现时对人类的潜在风险。在这里，我们发现L4 A-14 mAb具有广泛的中和能力，其逃逸突变体N149 D具有降低的病毒稳定性和人受体结合，并且可以被感染后和抗原诱导的血清中和。因此，L4 A-14 mAb可能是人类H7N9 AIV感染的治疗候选物，并需要进一步研究其治疗应用。重要性禽流感病毒（AIV）H7N9继续在鸟类中传播和演变，对人类构成可信的威胁。抗病毒药物已被证明可用于治疗人类严重流感感染;然而，随着抗病毒耐药突变体的出现，人们对此表示担忧。单克隆抗体（mAb）已被研究用于传染病控制中的预防和治疗应用，并且已显示出巨大的潜力。例如，单克隆抗体治疗显著降低了人们患严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染的严重疾病的风险。除了保护效率外，我们还应通过评估mAb治疗产生的逃逸突变体的病毒适应性和损害宿主适应性免疫的潜力来考虑其对公共卫生的潜在风险。考虑到这些参数，我们评估了来源于自然感染H7N9 AIV的人的四种人mAb，并显示mAb L4 A-14显示出作为治疗候选物的潜力。
Since 2013, H7N9 avian influenza viruses (AIVs) have caused more than 1,500 human infections and the culling of millions of poultry. Despite large-scale poultry vaccination, H7N9 AIVs continue to circulate among poultry in China and pose a threat to human health. Previously, we isolated and generated four monoclonal antibodies (mAbs) derived from humans naturally infected with H7N9 AIV. Here, we investigated the hemagglutinin (HA) epitopes of H7N9 AIV targeted by these mAbs (L3A-44, K9B-122, L4A-14, and L4B-18) using immune escape studies. Our results revealed four key antigenic epitopes at HA amino acid positions 125, 133, 149, and 217. The mutant H7N9 viruses representing escape mutations containing an alanine-to-threonine substitution at residue 125 (A125T), a glycine-to-glutamic acid substitution at residue 133 (G133E), an asparagine-to-aspartic acid substitution at residue 149 (N149D), or a leucine-to-glutamine substitution at residue 217 (L217Q) showed reduced or completely abolished cross-reactivity with the mAbs, as measured by a hemagglutination inhibition (HI) assay. We further assessed the potential risk of these mutants to humans should they emerge following mAb treatment by measuring the impact of these HA mutations on virus fitness and evasion of host adaptive immunity. Here, we showed that the L4A-14 mAb had broad neutralizing capabilities, and its escape mutant N149D had reduced viral stability and human receptor binding and could be neutralized by both postinfection and antigen-induced sera. Therefore, the L4A-14 mAb could be a therapeutic candidate for H7N9 AIV infection in humans and warrants further investigation for therapeutic applications. IMPORTANCE Avian influenza virus (AIV) H7N9 continues to circulate and evolve in birds, posing a credible threat to humans. Antiviral drugs have proven useful for the treatment of severe influenza infections in humans; however, concerns have been raised as antiviral-resistant mutants have emerged. Monoclonal antibodies (mAbs) have been studied for both prophylactic and therapeutic applications in infectious disease control and have demonstrated great potential. For example, mAb treatment has significantly reduced the risk of people developing severe disease with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition to the protection efficiency, we should also consider the potential risk of the escape mutants generated by mAb treatment to public health by assessing their viral fitness and potential to compromise host adaptive immunity. Considering these parameters, we assessed four human mAbs derived from humans naturally infected with H7N9 AIV and showed that the mAb L4A-14 displayed potential as a therapeutic candidate.
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影响因子：
5.4
作者：
Bhat S;James J;Sadeyen JR;Mahmood S;Everest HJ;Chang P;Walsh SK;Byrne AMP;Mollett B;Lean F;Sealy JE;Shelton H;Slomka MJ;Brookes SM;Iqbal M
通讯作者：
Iqbal M
影响因子：
28.3
作者：
Huang, Kuan-Ying A.;Rijal, Pramila;Townsend, Alain R.
通讯作者：
Townsend, Alain R.
影响因子：
64.8
作者：
Imai, Masaki;Watanabe, Tokiko;Hatta, Masato;Das, Subash C.;Ozawa, Makoto;Shinya, Kyoko;Zhong, Gongxun;Hanson, Anthony;Katsura, Hiroaki;Watanabe, Shinji;Li, Chengjun;Kawakami, Eiryo;Yamada, Shinya;Kiso, Maki;Suzuki, Yasuo;Maher, Eileen A.;Neumann, Gabriele;Kawaoka, Yoshihiro
通讯作者：
Kawaoka, Yoshihiro
影响因子：
3.8
作者：
James, Joe;Howard, Wendy;Shelton, Holly
通讯作者：
Shelton, Holly
DOI：
10.1126/science.1213362
发表时间：
2012-06-22
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Herfst S;Schrauwen EJ;Linster M;Chutinimitkul S;de Wit E;Munster VJ;Sorrell EM;Bestebroer TM;Burke DF;Smith DJ;Rimmelzwaan GF;Osterhaus AD;Fouchier RA
通讯作者：
Fouchier RA