The next influenza pandemic: lessons from Hong Kong

Summary, 70S Preamble, 71S Perspective on the H5N1 incident of 1997, 71S Pre-1997, 71S 1997, 71S Post-1997, 72S The H5N1 incident of 2001, 72S The H5N1 incident of 2002, 73S Lessons, 73S Immediate factors, 73S How? 73S What? 74S Where? 75S When? 75S Steps, 76S Adjunct factors 76S Teamwork, 76S Media, 76S Conclusion, 77S Acknowledgements, 77S References, 78S Pandemic influenza is a zoonosis. Studies on influenza ecology conducted in Hong Kong since the 1970s in which Hong Kong essentially functioned as an influenza sentinel post indicated that it might be possible, for the first time, to have influenza preparedness at the baseline avian level. This appreciation of influenza ecology facilitated recognition of the H5N1 ‘bird flu’ incident in Hong Kong in 1997 in what was considered to be an incipient pandemic situation, the chicken being the source of virus for humans and, if so, was the first instance where a pandemic may have been averted. The 2001 and 2002 H5N1 incidents demonstrated that it was possible to have an even higher order of baseline preparedness with the recognition in chicken of a range of genotypes of H5N1-like viruses before they had the opportunity to infect humans. Investigations of these incidents revealed a complex ecology involving variously precursor avian H5N1 virus in geese and ducks, and H9N2 and H6N1 viruses in quail, the quail possibly functioning as an avian ‘mixing vessel’ for key genetic reassortment events for onward transmission of H5N1 viruses highly pathogenic for chicken and humans. These findings highlight the importance of systematic virus surveillance of domestic poultry in recognizing changes in virus occurrence, host range and pathogenicity as signals at the avian level that could presage a pandemic. For example, there is now an increasing prevalence of avian influenza viruses in terrestrial (in contrast to aquatic) poultry. Prior to 1997, no particular virus subtype other than H4N6 would have been considered a candidate for pandemicity and this was based, in the absence of any other data, on its high frequency of occurrence in ducks in southern China. Now, with the isolation of H5N1 and H9N2 viruses from humans supported by genetic, molecular and biological studies on these and other avian isolates, there is credible evidence for the candidacy, in order, of H5N1, H9N2 and H6N1 viruses. These viruses have been made available for the production of diagnostic reagents and exploratory vaccines. The 1997 incident upheld the hypothesis that southern China is an epicentre for the emergence of pandemic influenza viruses. However, the intensification of the poultry (chicken) industry worldwide coupled with the spread of viruses such as the Eurasian lineage of H9N2 suggest that the genesis of a pandemic could take place elsewhere in the world. This re-emphasizes the importance of systematic virus surveillance of poultry globally for international public health and for economic and food concerns. Faced with an incipient pandemic in 1997, Hong Kong brought in international experts to join the investigative effort. Good teamwork at all levels is essential in dealing with the many facets. The threat of a pandemic should not be minimized, nor should governments be lulled into a sense of false security. The media is a powerful channel and has the responsibility and the avenues to convey and influence public perception of events. Close liaison between the media and those on the operational side ensures effective, accurate and timely dissemination of information. This will enhance public confidence in the investigative process and in steps taken for its safety and health. ‘Next to a battle lost, the greatest misery is a battle gained’ Duke of Wellington (1769–1852), In Rogers, Recollections (1859). The most intriguing thing about influenza viruses is the ability of the type A viruses to give rise unexpectedly to pandemics, doing so at intervals measured in decades. The H5N1 ‘bird flu’ incident in Hong Kong in 1997 (Claas et al. 1998; Subbarao et al. 1998; Yuen et al. 1998) showed signs of what the nature of an incipient pandemic might be (Shortridge et al. 2000) giving insight into ‘how’, ‘what’, ‘where’ and perhaps ‘when’ the next pandemic might arise offering for the first time the opportunity for an element of influenza pandemic preparedness. This new twist on pandemic influenza is all the more striking as it may now be possible to engender preparedness at a baseline avian level through improved understanding of the ecology and epidemiology of avian influenza viruses. This understanding derives in no small measure from the observation that the surface haemagglutinin antigens of the 1968 H3N2 ‘Hong Kong’ pandemic virus and a chronologically earlier duck isolate were related (Webster and Laver 1975) paving the way for the hypotheses that (1) pandemic influenza is a zoonosis (Shortridge 1992; Webster et al. 1992) and (2) southern China, especially in the countryside where humans and domestic animals live in close association, is an epicentre for the origin of pandemics (Shortridge and Stuart-Harris 1982). The incident of 1997 was caused by a highly pathogenic H5N1 virus (H5N1/97) that affected chicken and humans (Claas et al. 1998). This gave rise to a precautionary principle, essentially a watching brief of preparedness, that led to swift action in dealing with two subsequent incidents in Hong Kong in 2001 and 2002 caused by different sets of genotypes of precursor H5N1-like viruses that affected chicken. This report takes stock of lessons that may be learnt from these incidents as a guide for influenza pandemic preparedness. The ultimate ideal would be to recognize unusual influenza virus activity or pathology in a non-human host, reacting in such a way as to prevent a pandemic before it starts and so the disease never eventuates, an epidemiological principle espoused in the ancient Chinese literature (Needham 1980). This line of thinking constituted what Needham has called the ‘Chinese Hippocratic Corpus’. Influenza virus surveillance studies indicated well before 1997 that the domestic duck is the principal reservoir of influenza viruses in the countryside in southern China, isolations being few from geese and rare from chicken. Isolations were made from asymptomatically infected birds and from the had been no isolation of virus from chicken. The of surveillance of influenza viruses in animals influenza pandemic preparedness was (Shortridge was in this that the incident in Hong Kong in 1997 to In 1997 there was an of avian influenza on chicken in the of Hong The virus was as an H5N1 This in was not a for pathogenic have at intervals in many of the to the poultry they not humans. In to a of avian virus to humans were not and Webster and the of a between the avian and was The for reassortment between avian and viruses in an host such as the had been to the emergence of a virus that would to and disease in the ‘mixing vessel’ hypothesis et al. However, an influenza virus from a with influenza by in 1997 was as H5N1 et al. and to be related in all to the virus with the on the poultry in Hong Kong (Claas et al. 1998). This was the first instance of a avian virus disease and in humans. were no other of avian H5N1 influenza on the in Hong However, were in and In were with of with et al. 1998). the virus was in the host, especially so in it was from it had not pandemic in the and poultry in Hong Kong in 1997 revealed that of chicken and a small of ducks and geese were infected with the virus (Shortridge The virus was on chicken be in that the for poultry had in the of live poultry Hong Kong live birds and quail, as well as poultry such as ducks and geese an influenza virus in close to humans. The that the H3N2 virus to the earlier than in to the of the a that the virus might with the H3N2 virus in the host than in the host to give rise to a virus to from to a pandemic. that the virus was so the poultry this that the of of the to it was to all poultry in the and of Hong The of H5N1 disease was the before the of the on the is to that this an incipient pandemic to an pandemic and a pandemic was averted. The virus was possibly or two events from However, as with all that prevent an there is no way of In the of the 1997 the poultry was The of live ducks and geese was in the these being as poultry to be live in the However, all poultry for in Hong Kong were for subtype as evidence of H5N1-like virus to for in the The of these was an was essential to the virus it was a and, if so, other avian were in its The more that an H5N1 pandemic had been than was the order (Shortridge et al. this virus surveillance was and the with other viruses from poultry in 1997, as a preparedness. The virus was a In the that the haemagglutinin was from a precursor H5N1 virus from et al. the the were from an H9N2 or H6N1 virus from quail and the was of quail H6N1 the quail possibly being an avian ‘mixing vessel’ for the events et al. et al. et al. the virus was a avian virus that had highly pathogenic for chicken and humans in the process of its In this surveillance of the live poultry revealed the highly pathogenic virus was no the precursor viruses H5N1 virus in geese and H9N2 and H6N1 viruses in quail et al. et al. However, the of of geese well as these H5N1 viruses in the live poultry with the other of the this time, of two with H9N2 viruses were in Hong Kong et al. and there were isolations of H9N2 viruses from humans in to Hong H9N2 viruses of a different were from into Hong Kong et al. the of this virus subtype for all the more in the of the ‘mixing vessel’ However, the of Hong Kong of H5N1 In to the H5N1 virus a threat to surveillance the of the H9N2 virus being a virus surveillance the watching of ducks and geese into Hong Kong for revealed that H5N1 viruses to be in geese in China (Webster et al. In these viruses to ducks and with other influenza viruses of origin et al. and 2001 the surveillance revealed the of H5N1-like viruses in the genotypes of H5N1-like viruses were from chicken as well as from other poultry through between the H5N1 viruses and a virus of avian origin et al. The recognition of these H5N1-like viruses in chicken indicated that the H5N1 virus was to poultry. gave time to pathogenicity and to through a should birds to chicken by no evidence of disease was all poultry in the were in 2001 this time as a This was to the H5N1-like genotypes from the to prevent with precursor H9N2 and H6N1 viruses to give rise to a highly pathogenic This was all the more as the of these precursor H9N2 and H6N1 viruses were increasing in asymptomatically infected quail et al. et al. had not been possible in The 2001 were a in influenza pandemic preparedness possibly being or events from an H5N1 perhaps the ultimate level of of a The possible or events the H9N2 and H6N1 viruses from the of the were a all poultry and for a and with poultry the next Studies on the of isolation of of H9N2 virus from chicken now in chicken and different from the H9N2 in showed that virus isolation were the that influenza in the poultry The H5N1-like virus in 2001 to have well to poultry. genotypes had in the of the surface that to an to birds et al. This was an and it was that this to terrestrial poultry that it may be more to H5N1 viruses of Hong live in the the the of these viruses may be the of viruses through the diagnostic This about the H5N1 virus was with the of a new of genotypes of H5N1-like viruses in the in These viruses were from chicken in where the of birds were than the This was an of H5N1-like viruses were from chicken on in the of the being This was a in disease its was on the of the in the of even in poultry The facilitated The nature and to the 2002 incident and may be in a of the for the 2002 Influenza of Hong Kong China the of the H5N1 incidents in Hong Kong in 1997, 2001 and 2002, the that may be learnt is that it is now possible to have a level of baseline preparedness for the next influenza pandemic. This is there is now a understanding of the factors of preparedness the ‘how’, ‘what’, ‘where’ and ‘when’ of a pandemic than there was to 1997 (Shortridge there is an appreciation of the importance of factors teamwork and the media in to the importance of and in the spread of avian influenza viruses not the of this The incidents have the hypothesis that pandemic influenza is a zoonosis to the of would be the reservoir of influenza the most source of the virus for humans is domestic poultry. The Hong Kong studies showed that the chicken was the principal source of the virus that was pathogenic for humans as well as for chicken. This that of considered to be a rare host for influenza virus (Shortridge could be an of the for pandemicity of a virus subtype for humans. The studies that two sets of may have been place in the (1) the H5N1 virus was in the process of from to poultry from the duck the to the chicken and (2) two other H9N2 and were through a that to the quail and other poultry such as the The from these possibly in the quail which as a or avian ‘mixing vessel’ to the The H5N1-like genotypes in 2001 and 2002 may well have been viruses the that were not in the of et al. This process is complex it not the of an that or domestic birds could a virus into poultry. The intensification of the poultry industry through in could The to or these to range will opportunity for of chicken to birds the principle that poultry should be from duck and the virus was highly pathogenic for it had is possible that had the virus with a virus such as the H3N2 viruses that in in the et al. it could have as a pandemic virus at the this not as an incipient pandemic it for dealing with it and a for the the H5N1 incidents to the chicken as the source of virus for it would be to on and signals in chicken in the for a pandemic may well be that the and genetic events on the and host on the other in pandemic For example, the genetic of the of the 1968 H3N2 and pandemic viruses suggest that these viruses were to have caused of disease in chicken. these two pandemic viruses could have been from asymptomatically infected domestic or ducks for in the of the H3N2 pandemic an avian virus is would most have with the in the The of the of the H3N2 viruses in into Hong Kong in the H3N2 pandemic (Shortridge et al. at signals the ability of the to the of avian viruses in the and of viruses in the In a range of H3N2 has since been from in the the (Shortridge et al. et al. and by in of virus surveillance of before and 1997, no H5N1 virus was the of the of the to by avian subtype be for this especially as a few have activity to the than in poultry perhaps caused by viruses from time to time in of the These viruses may they of high pathogenicity or they the and not to infect humans to to the host so as to as a of in (Shortridge et al. The of to all the avian haemagglutinin in in southern China that of humans in these to avian influenza viruses may not be (Shortridge The key for recognizing disease and in poultry is to be of what its might the that the of as many as of geese on a in to Hong Kong in et al. 1998) the that it could presage at the avian level an incipient was a that the haemagglutinin of this virus was to be to those of the viruses that this was et al. The of this the H5N1-like in geese in the and they not of geese of to chicken and quail (Webster et al. virus surveillance of birds and is the of dealing with the of pandemic influenza at the baseline level of pandemic preparedness. avian will be the of the be haemagglutinin and of influenza A viruses have been in from In the pandemics were caused by and H3N2 viruses. In 1997 the H5N1 incipient pandemic an of had since the H3N2 pandemic and the time was for a new pandemic. Prior to 1997, the subtype was as a candidate subtype for pandemicity being the most subtype of viruses from ducks from southern China on the of an opportunity for The for this was that the subtype that had rise to the 1968 H3N2 pandemic virus was the most subtype (Shortridge 1982). The for the subtype in the of the 1997, 2001 and 2002 the H5N1 virus be the candidate for The of the H5N1 virus is by virus and genetic studies which for the first time, a of molecular and genetic with a pandemic For example, the of the virus in that may be with transmission et al. et al. a in the the of the virus in infected et al. et al. it had been earlier that the the of the virus and the H9N2 virus highly et al. there were few molecular as to the H9N2 viruses from two in Hong Kong in et al. were to humans et al. The that they caused than may be studies on these viruses may humans be infected by H9N2 viruses et al. et al. it might be that the H6N1 virus as well as the highly with the virus et al. 2000) would more be to infect humans. no H6N1 virus has been from humans. may have in the other factors at this may is as to the H6N1 virus was a precursor virus the for the virus or it was a from the genesis of the virus et al. 2000) now in the process of to poultry through the quail et al. this is so, the of the H5N1 and H9N2 virus it may be a of time before it is from humans. at this the candidate virus for pandemicity in order H5N1, H9N2 and H6N1 perhaps other of The of other such as be The H5N1 incidents have upheld the hypothesis that southern China is an epicentre for the emergence of pandemic influenza viruses (Shortridge and Stuart-Harris 1982). should be that Hong Kong is an influenza sentinel post for the it is not the influenza events there a of events place or have elsewhere in the epicentre or in the The principal is the of poultry in Hong Kong in 1997 (Shortridge et al. and 2001 and viruses. H5N1 precursor viruses in geese in China (Webster et al. as H9N2 and H6N1 viruses in quail et al. et al. the of the of viruses. virus surveillance of poultry and humans well as in the is essential for The spread of the Eurasian lineage of the H9N2 viruses from to in the and southern not for it the that the H9N2 virus could give rise to a pandemic the epicentre of southern China. This has been by the isolation of H9N2 viruses from poultry in et al. 2000) to those from humans in Hong Kong et al. et al. and by the recognition that H9N2 viruses from poultry in have that would transmission to humans et al. influenza A viruses of the a The isolation of viruses from chicken in not into well and Eurasian the viruses from in the process of to et al. so, the epicentre of southern China the of new highlight the importance of virus surveillance as baseline influenza pandemic preparedness. to the next pandemic. the that an H5N1 pandemic had been in 1997, the recognition that the precursor viruses in the epicentre that viruses could be in the process of or as by the 2001 and 2002 may have in the to the pandemic (Shortridge considered to be the greatest public health an a pandemic caused by an virus could arise The first of the H5N1 incident in chicken and humans in 1997 and in chicken in 2001 and 2002 in the This in with the 1968 H3N2 pandemic which Hong Kong in of earlier influenza activity in to Hong the pandemic Hong Kong in (Shortridge the of international a pandemic virus could be the in a or its on influenza and other This is a for to at the for example, a could as be infected as a with a or other virus it the epicentre to a new the understanding of health worldwide on the of pandemic influenza could an of Studies on influenza ecology conducted in Hong Kong since the 1970s have indicated that it might be possible, for the first time, to have baseline at the avian level to preparedness for a pandemic. understanding to avian influenza viruses to be taken of in this H5N1, H9N2 and Hong Kong made viruses available as as possible to through the so that diagnostic reagents and candidate might be and studies such as well in of a possible pandemic. The Influenza reagents for to in the Influenza for virus in and to for for possible and The with is The highly pathogenic nature of the viruses for the of a had a pandemic in 1997, or in 2001 and 2002 as a would not have been available in of and being they could be on in time and in the of a pandemic to be being for the H9N2 and H6N1 is than that for the H5N1 the ideal would be to to of on that may never of the of with the subtype of the pandemic of or of of the in the in the in et al. element in dealing with a disease and the investigative process is to the public perception of events and confidence in the on this is The H5N1 incident in 1997 was in that it was the first time an incipient pandemic was all being a for those of the nature of the there were two the side and poultry with its of enhance between the two the Hong Kong through its of a on Influenza A that and with of the avian side considered should be that the might be considered Hong Kong had its to the pandemic virus in 1968 with the that it could be with the was in the of an economic and the incident was the first the had to with since Hong with China. In a the of its international responsibility and that it was being Hong Kong had been for an influenza it through and its Influenza experts to join the the avian side an in the source of the H5N1 virus for humans (Shortridge et al. of the was that it gave the public and the media confidence in the investigative In other Hong Kong not it The of teamwork in the 1997 incident was as a of a doing so for The from this teamwork was a to the of the 2001 and 2002 These incidents were a on the 1997 to the precautionary of Hong influenza and with These two incidents were in the absence of international H5N1-like viruses been and in chicken before they in humans. through those were and in the of the The media and the public had a to what was especially as the 1997 incident to have for Hong Kong and, should the H5N1 virus from Hong the of the world. was at the that the media and the public could not with the was new there was the to with the media as as possible in the and the nature of the not a food the incident of the of live poultry Hong Kong the for chicken in the This the of the media was for example, in the there to be an between the and H5N1 virus chicken was not with of the of the influenza virus and its and public health in and and through on a between and was the order, on the available at the was that the experts were the that the media it to that it was for to have to all the The of the H5N1-like virus in 2001 caused the the incident was with there was time to an understanding of what was place through and studies and of pathogenicity studies of This a for the chicken to in the through the of a to the of the of a essentially through a and for the to be to be action and to be the media they were of the understanding way in which the incident was In other the investigative process was before the virus in no was The incident of 2002 which affected as well as poultry was to on the in it was of to the public the of Hong The media were to the of pandemic influenza at the time public about of poultry. the 2001 the 2002 incident not as as 1997 there was no and the was this time through a of poultry and two in the the of influenza viruses in nature and the influenza H5N1 virus incidents in Hong Kong in 1997, 2001 and 2002 it is that pandemic influenza is not a zoonosis a zoonosis. The appreciation of this the opportunity for the first time for influenza pandemic preparedness at the baseline avian level. candidate pandemic viruses have been in H5N1, H9N2 and for the production of diagnostic reagents and exploratory vaccines. the hypothesis that southern China is an epicentre for the emergence of pandemic influenza viruses was upheld in the H5N1 it is possible that a pandemic could arise in other of the world. The intensification of the poultry industry worldwide may be a in The H5N1 incidents showed that it is possible for a virus to arise as a of genetic that could a pandemic in humans and disease in the of a pandemic in chicken perhaps other if at the time, could a influenza virus surveillance of domestic poultry as the most source of virus for humans is The on Influenza takes stock of this through to influenza surveillance and to it with influenza and of the Influenza is to this will will be to into influenza pandemic preparedness. to be the in the H5N1 incidents in the Hong Kong influenza sentinel post will in an pandemic. Wellington could not have had pandemic influenza in ‘Next to a battle lost, the greatest misery is a battle gained’ the genetic of the influenza A there will be many influenza to be to to in the to the many in of the Hong Kong The of Hong Kong and in the of the 2002 The derives from those of this were considered in the report for in the by at the