Role of specific hemagglutinin amino acids in the immunogenicity and protection of H5N1 influenza virus vaccines
Role of specific hemagglutinin amino acids in the immunogenicity and protection of H5N1 influenza virus vaccines
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DOI：
10.1073/pnas.0506416102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Webster, RG
中科院分区：
文献类型：
--
作者：
Hoffmann, E;Lipatov, AS;Webster, RG
如果H5N1流感病毒在人间传播，疫苗接种将是限制其传播的最有效选择。最近通过反向遗传学产生的两种人类候选疫苗基于从A/HK/213/03 （H5N1）和A/Vietnam/1203/04 （H5N1）病毒中提取的抗原性不同的血凝素（HA）糖蛋白。它们的HA1氨基酸序列在10个位置上不同，其中一个（N-154）在a /Vietnam/1203/04 （H5N1）中引入了一个潜在的糖基化位点。为了评估推定抗原位点上的5种氨基酸对免疫原性和免疫保护的影响，我们制作了一系列全病毒疫苗，这些全病毒疫苗仅在一种或两种HA氨基酸上存在差异。接种这些灭活制剂的雪貂血清具有高病毒中和滴度，但其血凝抑制（HI）滴度通常较低。有趣的是，将HA氨基酸S-223（2004年病毒的特征）转化为N-223（如a /HK/213/03）的重组病毒导致更高的HI滴度。这一观察结果表明，特定的HA残基，如N223，通过改变受体特异性和/或抗体抗原结合，增加了H1测定的敏感性。用突变病毒疫苗接种雪貂，可保护其免受野生型A/Vietnam/1203/04病毒的致命攻击。我们的研究结果表明，在诊断性参考病毒的HA糖蛋白中包含N223残基可能有助于评估疫苗在人类中的有效性。
If H5N1 influenza viruses become transmissible among humans, vaccination will offer the most effective option to limit their spread. Two human vaccine candidates recently generated by reverse genetics are based on antigenically different hemagglutinin (HA) glycoproteins derived from the A/HK/213/03 (H5N1) and A/Vietnam/1203/04 (H5N1) viruses. Their HA1 amino acid sequences differ at 10 positions, one of which (N-154) introduces a potential glycosylation site in A/Vietnam/1203/04 (H5N1). To assess the impact of five amino acids in the putative antigenic sites on immunogenicity and immune protection, we generated a series of whole-virus vaccines that differed only in one or two HA amino acids. Sera from ferrets vaccinated with these inactivated preparations had high virus neutralization titers, but their hemagglutination inhibition (HI) titers were usually low. Interestingly, a recombinant virus in which the HA amino acid S-223 (characteristic of 2004 viruses) was converted to N-223 (as in A/HK/213/03) resulted in higher HI titers. This observation indicates that specific HA residues, such as N223, increase the sensitivity of the H1 assay by altering receptor specificity and/or anti body-antigen binding. Ferrets vaccinated with mutant vaccine viruses were protected against lethal challenge with wild-type A/Vietnam/1203/04 virus. Our results suggest that inclusion of the N223 residue in the HA glycoproteins of diagnostic reference viruses may facilitate the evaluation of vaccine efficacy in humans.