The Lancet forum on preparing for pandemic influenza
Authors: John McConnell
Journal: The Lancet Infectious Diseases (2006)

In his opening address to the first Lancet Asia Medical Forum, Preparing for Pandemic Influenza: The Avian Dimension and Other Emerging Threats (Singapore, May 3–4), Kandiah Satkunanantham (Director of Medical Services, Singapore Ministry of Health; figure 1) called for cooperation among nations affected by H5N1 avian influenza, sharing of critical information, and not a "beggar thy neighbour approach". Thijs Kuiken (Erasmus University, Rotterdam, Netherlands) described how highly pathogenic avian influenza (HPAI) is predominantly a disease of poultry and rarely affects other species. Mutation from low pathogenic (LPAI) viruses, whose natural reservoir is wild waterbirds, to HPAI forms occurs in poultry, but only viruses of the H5 and H7 haemagglutinin types cause highly pathogenic disease. The increase in size of HPAI outbreaks in the past decade is due to the growth of the poultry industry, with over 16 billion chickens and 1 billion duck being reared worldwide in 2004. Kuiken identified the unusual aspects of the current H5N1 outbreak as: direct transmission from birds to human beings and other mammals resulting in severe disease, systemic disease in human beings and other mammals, and free-living birds as a mode of virus spread, but without an evident link to to poultry. Hiroshi Kida (Hokkaido University, Sapporo, Japan) noted that in ducks, the virus replicates in the intestine and is therefore not under antibody selective pressure. Thus migratory ducks maintain apathogenic influenza viruses that cannot infect chickens, but passage through geese, turkey, or quail leads to LPAI that can infect chickens and hence mutate to HPAI. Kida noted that the 1957 H2N2 and 1968 H3N2 pandemic viruses were reassortants between avian viruses and the preceding human strains. Thus, because avian viruses of any subtype can contribute genes for reassortants, none of the 15 haemagglutinin and nine neuraminidase subtypes—all of which occur in ducks—can be ruled out as potential candidates for future pandemics. Kennedy Shortridge (University of Hong Kong, Hong Kong SAR, China) wondered why we don't we have a pandemic every year, because southern China abounds in influenza virus? A better understanding of the genetics, molecular markers, and antigenic features of the influenza virus might answer this question, and, Shortridge believed, make prevention of pandemics an achievable objective. Shortridge also noted how the spread of H5N1 from Asia followed the trans-Siberia railway, rather than any know patterns of wild-bird migration, and is thus probably the result of human movement of poultry and poultry products. Vietnam has been one of the countries worst affected by H5N1. Nguyen Tran Hien (National Institute of Hygiene and Epidemiology, Hanoi, Vietnam) described how human H5N1 disease occurred in three waves between Dec 2003 and Nov 2005. During this time, there were 93 human cases and 42 deaths, a case fatality rate of 45·2%, and 50 million poultry were killed. The incubation period for human infection was in the range 1–15 days, with a median of 3–5 days. However, there have been no new human or poultry cases since Nov 2005. Hien recommended that avian influenza should be considered a combined agricultural, public health, economic, and social threat. The H5N1 outbreak in Thailand also occured in three waves between Nov 2003 and Dec 2005, resulting in 22 human cases and 14 deaths. According to Kumnuan Ungchusak (Ministry of Public Health, Nonthaburi, Thailand), complacency caused the repeated outbreaks and political committment during the second wave was the eventual key to tackling the outbreak. Malik Peiris (University of Hong Kong, Hong Kong SAR, China) noted that human H5N1 disease is a qualitatively different disease from that caused by H3N2 or H1N1 viruses, with patients dying primarily of acute respiratory distress syndrome and respiratory failure. He speculated that H5N1 infects the lower respiratory epithelium leading to "hyper-induction" of chemokines, attraction of macrophage infiltrates into the lungs, induction of proinflammatory cytokines, and hence the characteristic immunopathology. James Campbell (University of Maryland Center for Vaccine Development, Baltimore, MD, USA) described human trials in the USA with a Sanofi Pasteur inactivated A/Vietnam/1203/2004/H5N1 subunit vaccine. Vaccine virus is grown in eggs, formaldehyde killed, and given by intramuscular injection. The process for producing seasonal influenza vaccines was used because of extensive experience with these vaccines and the likelihood of more rapid licensure. Among healthy volunteers given two doses of vaccine, there was an order of magnitude lower H5 antibody titre compared with seasonal flu vaccine. Only those volunteers given the highest vaccine doses (45 μg and 90 μg—ie, three to six times seasonal vaccine doses) had substantial antibody titres.1Treanor JJ Campbell JD Zangwill KM Rowe T Wolff M Safety and immunogenicity of an inactivated subvirion influenza A (H5N1) vaccine.N Engl J Med. 2006; 354: 1343-1351Crossref PubMed Scopus (646) Google Scholar Also describing the results of safety and immunogenicity trials with the Sanofi Pasteur H5N1 vaccine was Melanie Saville (Sanofi Pasteur, Lyon, France). The vaccine was given at one of three different doses, and with or without alum adjuvant, to healthy adult volunteers in France. Vaccination produced no serious adverse event, but two doses of 30 μg plus alum adjuvant given 21 days apart were required to produce an antibody response in more than 60% of participants.2Bresson JL Perronne C Launay O et al.Safety and immunogenicity of an inactivated split-virion influenza A/Vietnam/1194/2004 (H5N1) vaccine: phase I randomised trial.Lancet. 2006; 367: 1657-1664Summary Full Text Full Text PDF PubMed Scopus (386) Google Scholar According to Martine Denis (GlaxoSmithKline [GSK] Biologicals, Rixensart, Belgium), the worldwide manufacturing capacity for influenza vaccine is only 300 million doses per year. However, reducing the amount of antigen in each dose would allow for more doses. GSK has been working on an adjuvant that boosts the immune response in combination with lower amounts of antigen. Clinical trials are ongoing with an inactivated subunit H5N1 vaccine that uses the GSK adjuvant. In animal studies, the adjuvant gives cross protection between vaccination with one viral strain and challenge with another, which implies that stockpiling of vaccine may be feasible even if we do not know in advance the pandemic strain of virus. While reviewing the pandemic antiviral drug options, Frederick Hayden (University of Virginia Health Sciences Center, Charlottesville, VA, USA; and WHO Global Influenza Programme, Geneva, Switzerland; figure 2) stated that long-term prophylaxis is an inefficient use of limited drug supply. However, targeted geographic prophylaxis with a neuraminidase inhibitor (eg, oseltamivir) might succeed in containing or delaying emergence of a pandemic. Hayden also concluded that concerns over development of resistance to neuraminidase inhibitors should not be a deterrent to stockpiling of these drugs. A multicentre randomised trial in southeast Asia will compare standard and higher dose oseltamivir in hospitalised patients with H5N1 disease or severe influenza. An injectable antiviral is needed to help control a future influenza outbreak, and Hayden noted that trials are in progress with injectable forms of zanamivir and the investigational neuraminidase inhibitor peramivir. David Reddy (F Hoffman-La Roche Ltd, Basel, Switzerland) explained that the building of oseltamivir stockpiles was necessary because it is not possible to respond to an emergency with surge production capacity due to the long lead times in manufacturing the drug. Production capacity for oseltamivir will increase from 190 million courses in 2006 to 400 million courses in 2007. Roche will donate more than 5 million courses of oseltamivir to WHO as a global or regional stockpile. The company has received orders or letters of intent for national stockpiles from more than 65 countries. A national stockpile sufficient to treat 20–25% of the population could prevent 67% of hospital admissions and reduce deaths by 53% in the event of a pandemic,3Gani R Hughes H Fleming D Griffin T Medlock J Leach S Potential impact of antiviral drug use during influenza pandemic.Emerg Infect Dis. 2005; 11: 1355-1362Crossref PubMed Scopus (185) Google Scholar but Reddy noted that in past pandemics attack rates have reached 30–35%. In describing WHO preparedness planning for an influenza pandemic, Jai Narain (WHO Regional Office for South-East Asia, New Delhi, India) emphasised the key role of national preparedness plans and of these plans being tested and refined through mock drills and table-top exercises. Narain stated that collaboration among animal and human health agencies is vital, and warned that ministries in some countries are not responding to the threat of a pandemic. According to Roy Anderson (Imperial College, London, UK), we "cannot intuitively decide the best options [for pandemic control], and must, must do calculations". Modelling has allowed the effectiveness of various pandemic control measures to be tested. For example, closing schools would slow the spread of disease, but must be done in the first week or two of a national epidemic. Vaccinating 30–50% of the population—assuming an effective vaccine were available—could stop the spread of a national epidemic. However, closing borders would have to be 99% effective to have an impact on controlling a country epidemic. David Bell (Centers for Disease Control and Prevention, Atlanta, GA, USA) noted that during the severe acute respiratory syndrome (SARS) outbreak of 2003, among 35 million international travellers who were thermally scanned no SARS cases were detected; however, during an influenza pandemic, non-essential domestic travel to affected areas should be discouraged. Bell stated that forced isolation and quarantine are likely to be ineffective, but ill patients should be encouraged to stay at home. Whereas there is not sufficient evidence for recommendations on the use of masks by the public, hand hygiene lowers the rate of upper-respiratory-tract infections. Martin Meltzer (Centers for Disease Control and Prevention, Atlanta, GA, USA) estimated that an influenza pandemic might cost the USA around $166 billion, or produce a 2·3% reduction in economic demand in Asia. However, he emphasised that these estimates were based on very little data. Meltzer stated that, in the event of a pandemic, "I do not believe that there's a country in the world that can readily absorb the need for hospital and office-based medical care". Influenza surveillance is an integral part of pandemic preparedness according to Lance Jennings (Canterbury Health Laboratories, Christchurch, New Zealand). However, with only 158 000 samples collected annually from 600 million to 1·2 billion influenza cases, Jennings described the current standard of surveillance as being "in the dark ages". In summarising the gaps in pandemic preparedness, Robert Webster (St Jude Children's Research Hospital, Memphis, TN, USA) described H5N1 as "the worst flu virus" he has ever seen, and suggested that a minimum of ten mutations were required for human-to-human transmission. Webster called for the development of whole-virus H5N1 vaccines and for their stockpiling. He identified the gap between planning and implementation of plans as a crucial issue that must be addressed.