上海地区人群甲型流感的传播与病毒抗原变异的研究
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摘要
流感病毒长期以来一直是威胁人类健康的重要病原体之一，以流行病学监测为基础和重点，对易感人群进行免疫保护是目前降低流感发病率和死亡率的重要措施。本研究借助近几年对上海地区的流感监测及全球范围的流感监测网络信息，对近几年全球流感动态以及上海地区人群免疫状况和流感病毒抗原变异状况进行了系统研究，主要包括以下内容：
1．鉴于对人群免疫状况的了解结合流感病毒变异情况，可对流感的流行形势进行估计和预测，首先对上海市人群(包括接触禽、畜类动物的职业人群和非接触人群)甲型流感病毒HAI抗体水平进行了调查，结果显示：2004年上海市人群对A/闽/411/2002(H3N2)流感毒株HAI抗体阳性率为52.1％，人群中已有较好的免疫屏障；对A/沪/7/1999(H1N1)流感病毒HAI抗体阳性率仅为8.5％，大部分人群对其具有易感性；接触人群中存在H5亚型流感病毒HAI抗体；一般人群和接触人群中均存在H9亚型流感病毒HAI抗体，后者阳性率较高：接触人群H1、H3、H5、H9亚型流感病毒HAI抗体阳性率均较一般人群高。
2．及时掌握最新的流感动态有助于防治工作的顺利进行，因此借助世界卫生组织(WHO)流感监测网络，分析近几年全球流感流行概况，同时在上海地区开展人群流感病毒病原学监测，结果表明全球流感动态与以往相似，每年流行强度存在差别，在北半球通常在11月至翌年3月间暴发流行，上海地区流感发生相对较晚，流行暴发多集中在翌年的1月至4月间；人群中同时存在H1，H3N2和乙型流感病毒，多数国家或地区以H3N2为主，H1N1和乙型流感病毒多呈低水平流行。
3．为进一步了解近几年上海地区流感病毒抗原变异状况，推测可能的发展趋势，在流感病毒病原学监测的基础上对甲型流感病毒分离株HA片段进行分析，发现H3亚型病毒株似乎尝试多方向进化途径，但新旧变异株系间存在着明确的变异继承关系，基本呈现出在A/Fujian/411/2002、A/Wyoming/3/2003相同类别毒株基础上变异，逐渐接近A/Wellington/1/2004、A/Califomia/7/2004，再向A/Wisconsin/67/2005相同类别株发展，并已开始出现抗原性不同的病毒株；上海市H1N1亚型流感病毒在A/New Caledonia/20/99基础上继续变异，2006年分离株与之相比抗原性差别较大，而与2007-2008年WHO新推荐的疫苗株A/SolomonIslands/3/2006位于同一分枝。
4．近年来H5N1亚型流感病毒人间感染不断发生，了解动物中H5N1高致病性禽流感病毒的情况，有助于及时发现人间病例并掌握H5N1亚型流感病毒抗原变异状况及其对人类的威胁，故借助世界动物卫生组织(OIE)禽流感更新信息，分析近几年全球H5N1高致病性禽流感动态，同时与上海市畜牧兽医站等动物部门合作，对上海市H5亚型禽流感病毒分离株HA片段进行分析，结果表明H5N1亚型高致病性禽流感病毒在某些国家和地区的家禽中形成地方性流行，地域范围不断扩大，人间病例不断增加，但尚未发现有效的人-人传播；上海市H5亚型禽流感病毒株与中国其他省市禽类中感染的禽流感病毒株同源性比较高，而与H5N1亚型流感病毒人间病例分离株差别比较大，但存在跨越宿主屏障直接感染人类的可能性。
综合上述分析结果，我们认为上海地区人群虽然对原有的H3亚型参考病毒株有较高的免疫保护，但H3亚型病毒HA已出现新的抗原漂移，人群现在对新变异株的保护水平尚未知，有可能在未来引起局限性暴发甚至地方性流行；人群对H1亚型流感病毒免疫保护水平低，同时H1亚型流感病毒株部分与原推荐疫苗株抗原性差别较大，并在现推荐疫苗株基础上继续变异，需警惕发生流行的可能性；H5N1亚型高致病性禽流感地域范围扩大，人间病例不断发生，存在演变成大流行株的威胁，上海市H5亚型禽流感病毒株存在跨宿主屏障感染人类的可能性，而且已发现人群尤其禽、畜类动物接触人群中存在H5、H9亚型流感病毒的既往感染，应警惕禽流感病毒的变异和人间病例的发生。
通过本研究的开展，我们进一步完善了实验室流感病原学及HA变异监测流程，同时补充更新了甲型流感病毒基因数据库，有助于甲型流感病毒基因进化和抗原变异规律的系统研究。因此，还须继续不间断地开展流感监测，及时地掌握流感最新动态，并系统研究甲型流感病毒抗原变异规律。
Influenza viruses have threatened the human health for a long time as an important pathogen, and at the present time, epidemic surveillance and protection of high-risk population are the major measures to decrease the morbidity and mortality caused by influenza. With the help of WHO global influenza programme and the development of influenza surveillance in Shanghai, we explored the global influenza activity, especially the antigenic variation of influenza A viruses and the human condition of immune to influenza in Shanghai region. The details were as follows:
Whereas the human immune condition, combining the variation of influenza viruses, can help to estimate and even forecast the trend of influenza activity, we investigated HAI antibodies of influenza A viruses in the population of Shanghai including the common population and the professional population contacting with avian or domestic animal. The results showed that the population had have strong immune barrier to A/Fujian/411/2002(H3N2) with a 52.1% positive rate of HAI antibody, while most were susceptible to A/Shanghai/7/99(H1N1) for the positive rate of HAI antibody was only 8.5%, the H5 HAI antibody was exist in the contacting population, while the H9 HAI antibody was found in both populations with higher positive rate in the contacting population, and all the positive rates of HAI antibody to H1, H3, H5, H9 were higher in contacting population than in common population.
As it is helpful to master the updating influenza activity, we analyzed the general situation of global influenza in recent years with the help of WHO global influenza surveillance net, and carried out influenza virus surveillance in Shanghai region. Data showed that the epidemic of influenza was similar to the past while generally mild to moderate though reported in Africa, the Americas, Asia, Europe and Oceania, and outbreaks usually occurred from November to next March in the northern hemisphere while it came late in Shanghai from January to April; H1, H3N2 and B co-circulated, but H3N2 predominated in most countries and H1 and B viruses circulated at low levels in most time.
Based on the influenza virus surveillance in Shanghai region, the phylogenetic analysis of HA segment was applied to know the antigenic variation of influenza A virus and consequently to conjecture its direction. We found that H3 viruses evolved towards multiplex directions, but showed a tend from A/Fujian/411/2002-like and A/Wyoming/3/2003-like to A/Wellington/ 1/2004-like and A/California/7/2004-like strains and then closing to A/Wisconsin/67/2005 while an emergence of the isolates distinguishable from vaccine strains. The recent H1 isolates in Shanghai were found some variation occurred on the vaccine strains A/New Caledonia/20/99-like and isolates of 2006 was distinguishing from it while was on the same cluster of the new vaccine strain A/Solomon Islands/3/2006.
For human cases of H5N1 viruses are continuing to occur in recent years and to master the epidemiology of H5N1 HPAI in animals is helpful to find human cases in time and to know the updating antigenic variation of the virus, we analyzed the global H5N1 HPAI activities in recent years with the help of OIE global surveillance net and applied phylogenetic analysis to the HA segment of avian H5 isolates in Shanghai with collaborating with center for animal disease control, Shanghai. Data showed that the H5N1 virus is now endemic in the poultries in parts of some countries and has expanded its geographical range to include new countries as well as human cases continue to emerge though an efficient human-to-human transmission hasn't been established. We found the H5 isolates in Shanghai was similar to those isolated from avian in other province in China and distinguishable from the human isolates, but the isolated might break the host barrier and infect human.
As showed above, we could draw the conclusion that H3 viruses could cause outbreaks or local epidemics in Shanghai for the immune of population to the new emerging antigenic drift was still unknown though there was strong immune barrier to the previous vaccine strain, H1 viruses also may caused epidemics as the population had a weak immune protection to the previous reference strains A/New Caledonia/20/99-like and part of the recent isolates were distingwishing from them and continued to evolute on the new reference strain, and H5N1 HPAI activities has expanded its geographical range thus increasing the size of the population at risk as the continuing emergence of human cases which give the virus an opportunity to evolve towards a fully transmissible pandemic strain. We should keep eyes on the human cases of avian influenza virus an its variation for the H5 isolates in Shanghai also has the possibility to infect human directly and the infection of H5, H9 viruses had previously occurred in the population especially in those contacting with animals.
While carrying out the above work, the surveillance system of influenza virus and its variation of HA antigen is also consummated, and the database of HA segment is complemented, which could be used to explore the genetic evolution and antigenic variation rule of influenza A viruses. So we should continue to carry out the influenza surveillance and master the updating influenza activity so that we could study the law of antigenic variation of influenza A viruses systematically.
1．鉴于对人群免疫状况的了解结合流感病毒变异情况，可对流感的流行形势进行估计和预测，首先对上海市人群(包括接触禽、畜类动物的职业人群和非接触人群)甲型流感病毒HAI抗体水平进行了调查，结果显示：2004年上海市人群对A/闽/411/2002(H3N2)流感毒株HAI抗体阳性率为52.1％，人群中已有较好的免疫屏障；对A/沪/7/1999(H1N1)流感病毒HAI抗体阳性率仅为8.5％，大部分人群对其具有易感性；接触人群中存在H5亚型流感病毒HAI抗体；一般人群和接触人群中均存在H9亚型流感病毒HAI抗体，后者阳性率较高：接触人群H1、H3、H5、H9亚型流感病毒HAI抗体阳性率均较一般人群高。
2．及时掌握最新的流感动态有助于防治工作的顺利进行，因此借助世界卫生组织(WHO)流感监测网络，分析近几年全球流感流行概况，同时在上海地区开展人群流感病毒病原学监测，结果表明全球流感动态与以往相似，每年流行强度存在差别，在北半球通常在11月至翌年3月间暴发流行，上海地区流感发生相对较晚，流行暴发多集中在翌年的1月至4月间；人群中同时存在H1，H3N2和乙型流感病毒，多数国家或地区以H3N2为主，H1N1和乙型流感病毒多呈低水平流行。
3．为进一步了解近几年上海地区流感病毒抗原变异状况，推测可能的发展趋势，在流感病毒病原学监测的基础上对甲型流感病毒分离株HA片段进行分析，发现H3亚型病毒株似乎尝试多方向进化途径，但新旧变异株系间存在着明确的变异继承关系，基本呈现出在A/Fujian/411/2002、A/Wyoming/3/2003相同类别毒株基础上变异，逐渐接近A/Wellington/1/2004、A/Califomia/7/2004，再向A/Wisconsin/67/2005相同类别株发展，并已开始出现抗原性不同的病毒株；上海市H1N1亚型流感病毒在A/New Caledonia/20/99基础上继续变异，2006年分离株与之相比抗原性差别较大，而与2007-2008年WHO新推荐的疫苗株A/SolomonIslands/3/2006位于同一分枝。
4．近年来H5N1亚型流感病毒人间感染不断发生，了解动物中H5N1高致病性禽流感病毒的情况，有助于及时发现人间病例并掌握H5N1亚型流感病毒抗原变异状况及其对人类的威胁，故借助世界动物卫生组织(OIE)禽流感更新信息，分析近几年全球H5N1高致病性禽流感动态，同时与上海市畜牧兽医站等动物部门合作，对上海市H5亚型禽流感病毒分离株HA片段进行分析，结果表明H5N1亚型高致病性禽流感病毒在某些国家和地区的家禽中形成地方性流行，地域范围不断扩大，人间病例不断增加，但尚未发现有效的人-人传播；上海市H5亚型禽流感病毒株与中国其他省市禽类中感染的禽流感病毒株同源性比较高，而与H5N1亚型流感病毒人间病例分离株差别比较大，但存在跨越宿主屏障直接感染人类的可能性。
综合上述分析结果，我们认为上海地区人群虽然对原有的H3亚型参考病毒株有较高的免疫保护，但H3亚型病毒HA已出现新的抗原漂移，人群现在对新变异株的保护水平尚未知，有可能在未来引起局限性暴发甚至地方性流行；人群对H1亚型流感病毒免疫保护水平低，同时H1亚型流感病毒株部分与原推荐疫苗株抗原性差别较大，并在现推荐疫苗株基础上继续变异，需警惕发生流行的可能性；H5N1亚型高致病性禽流感地域范围扩大，人间病例不断发生，存在演变成大流行株的威胁，上海市H5亚型禽流感病毒株存在跨宿主屏障感染人类的可能性，而且已发现人群尤其禽、畜类动物接触人群中存在H5、H9亚型流感病毒的既往感染，应警惕禽流感病毒的变异和人间病例的发生。
通过本研究的开展，我们进一步完善了实验室流感病原学及HA变异监测流程，同时补充更新了甲型流感病毒基因数据库，有助于甲型流感病毒基因进化和抗原变异规律的系统研究。因此，还须继续不间断地开展流感监测，及时地掌握流感最新动态，并系统研究甲型流感病毒抗原变异规律。
Influenza viruses have threatened the human health for a long time as an important pathogen, and at the present time, epidemic surveillance and protection of high-risk population are the major measures to decrease the morbidity and mortality caused by influenza. With the help of WHO global influenza programme and the development of influenza surveillance in Shanghai, we explored the global influenza activity, especially the antigenic variation of influenza A viruses and the human condition of immune to influenza in Shanghai region. The details were as follows:
Whereas the human immune condition, combining the variation of influenza viruses, can help to estimate and even forecast the trend of influenza activity, we investigated HAI antibodies of influenza A viruses in the population of Shanghai including the common population and the professional population contacting with avian or domestic animal. The results showed that the population had have strong immune barrier to A/Fujian/411/2002(H3N2) with a 52.1% positive rate of HAI antibody, while most were susceptible to A/Shanghai/7/99(H1N1) for the positive rate of HAI antibody was only 8.5%, the H5 HAI antibody was exist in the contacting population, while the H9 HAI antibody was found in both populations with higher positive rate in the contacting population, and all the positive rates of HAI antibody to H1, H3, H5, H9 were higher in contacting population than in common population.
As it is helpful to master the updating influenza activity, we analyzed the general situation of global influenza in recent years with the help of WHO global influenza surveillance net, and carried out influenza virus surveillance in Shanghai region. Data showed that the epidemic of influenza was similar to the past while generally mild to moderate though reported in Africa, the Americas, Asia, Europe and Oceania, and outbreaks usually occurred from November to next March in the northern hemisphere while it came late in Shanghai from January to April; H1, H3N2 and B co-circulated, but H3N2 predominated in most countries and H1 and B viruses circulated at low levels in most time.
Based on the influenza virus surveillance in Shanghai region, the phylogenetic analysis of HA segment was applied to know the antigenic variation of influenza A virus and consequently to conjecture its direction. We found that H3 viruses evolved towards multiplex directions, but showed a tend from A/Fujian/411/2002-like and A/Wyoming/3/2003-like to A/Wellington/ 1/2004-like and A/California/7/2004-like strains and then closing to A/Wisconsin/67/2005 while an emergence of the isolates distinguishable from vaccine strains. The recent H1 isolates in Shanghai were found some variation occurred on the vaccine strains A/New Caledonia/20/99-like and isolates of 2006 was distinguishing from it while was on the same cluster of the new vaccine strain A/Solomon Islands/3/2006.
For human cases of H5N1 viruses are continuing to occur in recent years and to master the epidemiology of H5N1 HPAI in animals is helpful to find human cases in time and to know the updating antigenic variation of the virus, we analyzed the global H5N1 HPAI activities in recent years with the help of OIE global surveillance net and applied phylogenetic analysis to the HA segment of avian H5 isolates in Shanghai with collaborating with center for animal disease control, Shanghai. Data showed that the H5N1 virus is now endemic in the poultries in parts of some countries and has expanded its geographical range to include new countries as well as human cases continue to emerge though an efficient human-to-human transmission hasn't been established. We found the H5 isolates in Shanghai was similar to those isolated from avian in other province in China and distinguishable from the human isolates, but the isolated might break the host barrier and infect human.
As showed above, we could draw the conclusion that H3 viruses could cause outbreaks or local epidemics in Shanghai for the immune of population to the new emerging antigenic drift was still unknown though there was strong immune barrier to the previous vaccine strain, H1 viruses also may caused epidemics as the population had a weak immune protection to the previous reference strains A/New Caledonia/20/99-like and part of the recent isolates were distingwishing from them and continued to evolute on the new reference strain, and H5N1 HPAI activities has expanded its geographical range thus increasing the size of the population at risk as the continuing emergence of human cases which give the virus an opportunity to evolve towards a fully transmissible pandemic strain. We should keep eyes on the human cases of avian influenza virus an its variation for the H5 isolates in Shanghai also has the possibility to infect human directly and the infection of H5, H9 viruses had previously occurred in the population especially in those contacting with animals.
While carrying out the above work, the surveillance system of influenza virus and its variation of HA antigen is also consummated, and the database of HA segment is complemented, which could be used to explore the genetic evolution and antigenic variation rule of influenza A viruses. So we should continue to carry out the influenza surveillance and master the updating influenza activity so that we could study the law of antigenic variation of influenza A viruses systematically.
引文
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