Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1.
Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1.
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DOI：
10.1371/journal.pone.0018577
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发表时间：
2011-04-07
期刊：
影响因子：
3.7
通讯作者：
Romanova J
中科院分区：
文献类型：
--
作者：
Krenn BM;Egorov A;Romanovskaya-Romanko E;Wolschek M;Nakowitsch S;Ruthsatz T;Kiefmann B;Morokutti A;Humer J;Geiler J;Cinatl J;Michaelis M;Wressnigg N;Sturlan S;Ferko B;Batishchev OV;Indenbom AV;Zhu R;Kastner M;Hinterdorfer P;Kiselev O;Muster T;Romanova J
与季节性类似物相比，H5 N1流感疫苗，包括活的鼻内疫苗，似乎免疫原性相对较低。高致病性禽流感病毒（HPAIV）的主要流感病毒表面糖蛋白血凝素（HA）比人或低致病性禽流感病毒更容易受到酸性pH处理。人鼻通道的酸化机制响应于不同的刺激因素开始释放质子酸化粘膜表面（pH降至5.2）。我们推测H5 HA对酸性环境的敏感性可能是鼻内H5 N1疫苗对哺乳动物的低感染性和免疫原性的原因。我们证明了原始的人流感病毒在酸性pH（低至5.4）下感染原代人鼻上皮细胞，而H5 N1 HPAIV在pH≤5.6时失去感染性。A/Vietnam/1203/04的HA通过引入单一取代HA 2 58 K →I进行修饰，降低了HA构象变化的pH值。与那些没有修饰的相比，含有所示突变的H5 N1抑制剂显示出对酸性pH和高温处理的增加的抗性。如小鼠呼吸道免疫组织化学所示，该突变确保了更高的病毒摄取，并使小鼠感染剂量降低25倍50。此外，保留58 K →I突变的重组子设计为缺乏NS 1基因的活减毒疫苗候选物，在小鼠鼻内免疫后诱导上级全身和局部抗体应答。我们的研究结果表明，一个有效的鼻内接种减毒活H5 N1病毒可能需要一定水平的pH值和温度稳定性的HA，以实现最佳的病毒吸收鼻上皮细胞和诱导足够的免疫应答。H5 HA蛋白活化的pH值可能在HPAIV对哺乳动物的感染性中起重要作用。
H5N1 influenza vaccines, including live intranasal, appear to be relatively less immunogenic compared to seasonal analogs. The main influenza virus surface glycoprotein hemagglutinin (HA) of highly pathogenic avian influenza viruses (HPAIV) was shown to be more susceptible to acidic pH treatment than that of human or low pathogenic avian influenza viruses. The acidification machinery of the human nasal passageway in response to different irritation factors starts to release protons acidifying the mucosal surface (down to pH of 5.2). We hypothesized that the sensitivity of H5 HA to the acidic environment might be the reason for the low infectivity and immunogenicity of intranasal H5N1 vaccines for mammals. We demonstrate that original human influenza viruses infect primary human nasal epithelial cells at acidic pH (down to 5.4), whereas H5N1 HPAIVs lose infectivity at pH≤5.6. The HA of A/Vietnam/1203/04 was modified by introducing the single substitution HA2 58K→I, decreasing the pH of the HA conformational change. The H5N1 reassortants containing the indicated mutation displayed an increased resistance to acidic pH and high temperature treatment compared to those lacking modification. The mutation ensured a higher viral uptake as shown by immunohistochemistry in the respiratory tract of mice and 25 times lower mouse infectious dose50. Moreover, the reassortants keeping 58K→I mutation designed as a live attenuated vaccine candidate lacking an NS1 gene induced superior systemic and local antibody response after the intranasal immunization of mice. Our finding suggests that an efficient intranasal vaccination with a live attenuated H5N1 virus may require a certain level of pH and temperature stability of HA in order to achieve an optimal virus uptake by the nasal epithelial cells and induce a sufficient immune response. The pH of the activation of the H5 HA protein may play a substantial role in the infectivity of HPAIVs for mammals.
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影响因子：
4.2
作者：
Limberis, M;Anson, DS;Parsons, DW
通讯作者：
Parsons, DW
影响因子：
5.4
作者：
Reed, Mark L.;Bridges, Olga A.;Russell, Charles J.
通讯作者：
Russell, Charles J.
影响因子：
5.1
作者：
Belshe, RB;Gruber, WC;Wolff, M
通讯作者：
Wolff, M
影响因子：
3.8
作者：
Ilyushina, Natalia A.;Govorkova, Elena A.;Webster, Robert G.
通讯作者：
Webster, Robert G.
DOI：
10.1073/pnas.94.26.14306
发表时间：
1997-12-23
影响因子：
11.1
作者：
Carr, CM;Chaudhry, C;Kim, PS
通讯作者：
Kim, PS