the who reports that 345 of the confirmed 584 cases of human h5n1 infection have died ; the cumulative case - fatality rate is 59% and ranges from 30 to 80% depending on the country ( 16 ) . one group of investigators recently concluded that  the case - fatality rate that is offered by the who , and that is driving this controversy , is likely orders of magnitude too high  ( 14 ) . their conclusion was based on 10 published studies of h5n1 seroepidemiology in potentially exposed persons . the who has established criteria for the serologic identification of h5n1 in humans ( 17 ) . using literature search strategies similar to those of a previous review of h5n1 seroepidemiology ( 18 ) , we identified 24 studies published to date that evaluate the seroepidemiology of h5n1infection in humans ( 1942 ) . this analysis includes three follow - up studies related to the 1997 outbreak of h5n1 influenza in hong kong ; therefore , we excluded those three studies from further analysis since current h5n1 viruses are not similar to the strain that caused that outbreak ( 43 ) . this is consistent with the findings and actions of the who : the 1997 cases are not currently included in the case count for h5n1 infections , and the 1997 isolate is not recommended for inclusion in current h5n1 vaccines ( 16 , 44 ) . the remaining 21 studies were conducted and published after 2004 ; 13 meet the who criteria for serologic confirmation ( titer of 1:80 ) ( 19 , 24 , 26 , 27 , 3341 ) . three of the 13 studies reported serologic evidence of h5n1 infection ( 24 , 39 , 41 ) . in total , 26 ( 0.47% ) of 5,487 participants in these studies were seropositive for h5n1 . all 13 studies that used the who serologic screening criteria were conducted within 4  months of the occurrence of human h5n1 cases or within 6  months of h5n1 poultry outbreaks in the area from which participants were enrolled . the timing of the participant surveys maximized the possibility that these studies would detect recent h5n1 infections had they occurred ( 45 ) . most of the individuals tested were exposed to sick poultry and/or a symptomatic human case of h5n1 infection . ( 29 ) has been cited as documentation of an increased rate of h5n1 subclinical infections(12 , 14 ) . in that study , approximately 6% and 3.5% of participants were reported to have elevated antibody levels to one of two h5n1 viruses , respectively . serologic samples were obtained from villagers more than 2  years after sporadic h5n1 outbreaks were reported in poultry and one confirmed and two possible human h5n1 cases occurred in the area . this study was not included in the 13 studies detailed above because serologic results did not meet the who criteria for serologic confirmation ; the investigators used a low threshold antibody titer ( 1:10 ) as evidence of previous infection . this study has been criticized , since using such a low threshold could lead to overestimation of the true seroprevalence because of the increased likelihood of false - positive results ( 46 , 47 ) . in addition , the study was not initiated until 2  years after h5n1 infections in humans or poultry had been reported in the area . of the 13 studies that used the who criteria , five reported the range of serologic titers detected ( 26 , 27 , 33 , 34 , 37 ) . these studies were conducted within 4  months of the occurrence of human cases and within 6  months of poultry outbreaks . the five studies , which included 2,629 participants , found that no participants had evidence of previous infection based on the who criteria for serologic confirmation and only 13 ( 0.49% ) had neutralization titers between 1:10 and 1:40 . one study documented that most participants had detectable h5n1 titers below 1:80 ; however , a reevaluation of the dilutions used in the study led the authors to conclude that these serologic titers did not represent detectable antibody ( 33 ; j. katz , personal communication ) . the results of these five studies , which involved sampling of participants more contemporary to evidence of circulating h5n1 viruses than the study by khuntirat et al . , demonstrated at least a 10-fold - lower prevalence of intermediate serologic results ( i.e. , neutralization titers between 1:10 and 1:40 ) than to those found in the latter study . we believe that these data support the concern regarding false - positive results in the khuntirat et al . some researchers have stated that , because of the specificity of the who case definition , milder or asymptomatic h5n1 cases have been missed by traditional case - based surveillance and therefore a small fraction of the total number of infected cases has been accounted for under the who surveillance system ( 12 , 14 ) . when population - based seroepidemiology studies are used to supplement clinical - based surveillance , a more complete picture of the epidemiology of that infection is generated than that by use of clinical case - based surveillance alone . mild or asymptomatic cases can be detected by serologic evidence of prior infection even if such cases are missed by traditional surveillance at the time of their infection . another case detection strategy is to follow exposed persons over time to identify any influenza - like illnesses in such groups . exposed persons can include persons with known exposure to confirmed or suspected human h5n1 cases , persons with occupational or household exposure to sick birds , or persons living in the same locations as human and/or avian cases . periods of observation of exposed persons by health authorities have lasted for up to 6  months . to date , this type of targeted surveillance has not uncovered additional cases of mild influenza - like illness caused by h5n1 infection ( 48 ) . as with any surveillance system , case ascertainment for h5n1 infections certainly has not captured 100% of the cases . however , all of the data presented above suggest that the number of mild infections that have been missed is likely relatively small . up to this point , we have discussed the likelihood of missing mild cases of h5n1 infection ; however , it is also important to consider the potential to miss fatal cases of h5n1 infection . investigators have shown that current case - based surveillance for h5n1 infection in countries with ongoing avian h5n1 transmission does not always document fatal cases , with such cases being missed either because the diagnosis was not considered or virologic confirmation was lacking ( 46 , 47 , 49 ) . a more complete ascertainment of fatal cases of h5n1 infection would increase the current h5n1 case - fatality rate . while this is also likely an infrequent occurrence , the phenomenon of missing cases of fatal infectious illnesses has been documented in other situations . for example , one would expect that fatal cases of human rabies would rarely escape detection ; however , instances of previously fatal human rabies cases have been uncovered only after recipients of their donated organs subsequently developed rabies and died ( 50 , 51 ) . the available seroepidemiologic data for human h5n1 infection support the current who - reported case - fatality rates of 30% to 80% ( 16 ) . while some have suggested that concern about such high case - fatality estimates was a major factor in the nsabb decision , such estimates were only one of a number of factors considered by the nsabb ( 12 ) . in fact , if h5n1 virus does become a pandemic virus , the virulence ( as measured by the case - fatality rate ) could decrease 10- to 20-fold from what is currently documented and the virus would still generate a more severe pandemic than the 1918 pandemic , where the overall case - fatality rate was probably about 2% . given the global population and the current dynamics of population movement around the world , an h5n1 pandemic , even with a relatively low case - fatality rate , would be a truly catastrophic event . if an h5n1 strain , regardless of its origin , becomes readily transmissible between humans and begins to spread in the population , it likely will result in an influenza pandemic . the proposal that viable vaccines and available antivirals will make a substantial difference in the global morbidity and mortality associated with the pandemic is not supported by data from the previous three pandemics . the time required to manufacture both egg - based and cell culture - based influenza vaccines has resulted in vaccine responses for the 1957 , 1968 , and 2009 pandemics on a worldwide scale . for example , by 28 october 2009 , only 16.8 million doses of pandemic 2009  a(h1n1)pmd09 vaccine had been shipped by the u.s . an ample supply of the vaccine was not available until after the second wave had subsided in early october ; by that time , demand for the vaccine had dropped dramatically . the centers for disease control and prevention ( cdc ) estimated that the 2009  a(h1n1)pdm09 pandemic vaccine prevented only 200 to 520 deaths in the united states because of delay in availability ( 53 ) . mammalian cell - based pandemic vaccines were licensed for use in the european union in 2009 and were used there during the pandemic response . as in the united states , both the egg - produced and the cell culture - produced influenza vaccines arrived too late and in too little quantity to have a significant impact on the pandemic in the european union . according to the date of marketing authorization in europe , a mammalian cell - based vaccine was available only after three adjuvanted egg - based influenza vaccines were already in distribution ( 54 ) . the european experience with the availability of a pandemic cell - based vaccine did not demonstrate a measurable improvement in vaccine production speed nor was it sufficient to alter the overall public health impact of the pandemic in europe . given the need to distribute pandemic vaccines globally and the fact that not all countries have the financial assets to purchase sufficient quantities of vaccine for their populations during a pandemic , the who coordinates a program for donation and distribution of pandemic influenza vaccines . as of 10 november 2010 , the last who update for pandemic vaccine distribution , only 78 million doses of a(h1n1)pdm09 vaccine had been distributed to 77 countries ( 55 ) . all of these vaccine doses were distributed well after the second wave of the pandemic , months after developed countries had started their vaccine campaigns . from a historical perspective , influenza vaccine also arrived in quantities too small and too late to have a significant public health impact in the united states for both the 1957 and 1968 pandemics . given the experience of the three previous pandemics , unless newer and more effective influenza vaccine technologies are developed that facilitate substantially faster production and generate far greater numbers of doses in much shorter time frames , it is unlikely that influenza vaccine will have a significant public health impact during the next pandemic . the technology behind our current influenza vaccines is simply not sufficient to address the complex challenges associated with an influenza pandemic in the 21st century . currently there are limited h5n1 influenza vaccine stockpiles around the globe , including one in the united states . these vaccines are not designed to protect the general population but are to be targeted to a small subset of critical - asset individuals , until a pandemic - specific vaccine can be produced . furthermore , it is unclear as to how effective the currently stockpiled h5n1 vaccines would be against an emergent pandemic strain , given the diversity of existing h5n1 clades . antivirals are the only other pharmaceutical intervention available for influenza . as with influenza vaccines during a pandemic , the global capacity for antiviral manufacturing falls far short of global needs . while there are global and national stockpiles of antivirals devoted to pandemic response , during the 20092010 pandemic , there were significant disparities regarding use and availability of antivirals around the world ( 56 ) . current antiviral stockpiles and antiviral manufacturing capacity support the conclusion that should another influenza pandemic occur in the foreseeable future , the impact of antiviral use on human morbidity and mortality will be no better than was documented in the 2009 pandemic . in summary , we believe that the debate about the case - fatality rate of h5n1 influenza in humans and the suggested important role of currently available antivirals and vaccines in mitigating an h5n1 pandemic are without merit . furthermore , we do not believe that continued focus on these issues helps to address how best to manage research involving influenza viruses , such as h5n1 , that are transmissible between mammals and have the potential to be highly virulent in humans . future discussions specific to the current controversy need to resolve critical questions such as how we safely conduct h5n1 virus transmission studies in mammals , how we share critical methods and results with those who have a need to know , and how we ensure that laboratory - generated h5n1 viruses do not escape controlled environments . resolution of these issues with regard to h5n1 influenza viruses has the potential to serve as a template for similar situations involved existing or emergent pathogens . it is our belief that the current controversy provides a valuable opportunity for scientists and public policy experts to work together in creating this road map for the future .
abstracttwo recently submitted ( but as yet unpublished ) studies describe success in creating mutant isolates of h5n1 influenza a virus that can be transmitted via the respiratory route between ferrets ; concern has been raised regarding human - to - human transmissibility of these or similar laboratory - generated influenza viruses . 
 furthermore , the potential release of methods used in these studies has engendered a great deal of controversy around publishing potential dual - use data and also has served as a catalyst for debates around the true case - fatality rate of h5n1 influenza and the capability of influenza vaccines and antivirals to impact any future unintentional or intentional release of h5n1 virus . in this report , we review available seroepidemiology data for h5n1 infection and discuss how case - finding strategies may influence the overall case - fatality rate reported by the who . 
 we also provide information supporting the position that if an h5n1 influenza pandemic occurred , available medical countermeasures would have limited impact on the associated morbidity and mortality .