May 15, = 2005

May=20 20, 2005

H5N1 Cases rise to 97 with Changing Epidemiology = in 2005:=20 WHO Director-General calls avian influenza =93the most serious known = health threat=20 the world is facing today=94.

On=20 May 19 the WHO announced that the number of lab-confirmed H5N1 avian = influenza=20 cases had increased to 97 with 53 deaths (55% case fatality rate = overall). The=20 WHO divided the cases into three chronological waves of infection in each of = the three=20 nations reporting human cases: Vietnam, Thailand, and Cambodia. Notably, the largest = number of=20 cases (53) have occurred = in the=20 third wave over the past five months (16 December 2004-5 May 2005) with = the=20 majority (49) being in Vietnam.

The=20 Director-General of the WHO, LEE Jong-wook, MD, MPH addressed the=20 58^th World Health Assembly on May 16. He concluded his overview of world health by = =93drawing=20 attention to the most serious known health threat the world is facing = today,=20 which is avian influenza. The timing cannot be predicted, but rapid=20 international spread is certain once the pandemic virus appears. This is = a grave=20 danger for all people in all countries.=94

Earlier=20 this week the WHO posted on their website (http://www.who.int/) findings of an = expert panel=20 on H5N1 avian influenza in Asia that met May 6-7 in Manila. This six = page=20 document provided important new data to support the view that the = epidemiology=20 of H5N1 is changing, especially during the outbreaks in 2005 in northern = Vietnam. Preliminary laboratory data in this report included three key = findings:=20 (a) mutations in the H5N1 hemagglutinin (HA) gene near the = receptor-binding=20 region; (b) one 2005 strain from Vietnam that is antigenically distinct = from the=20 2004 vaccine reference strains; = and=20 (c) one report of an H5N1 isolate that is less susceptible to the = only remaining oral anti-influenza = drug=20 (oseltamivir, or tradename =93Tamiflu=94) available to treat or prevent = H5N1=20 infection. =

The=20 epidemiologic = observations since=20 January 2005 in northern Vietnam that support =93the possibility that = recently=20 emerging H5N1 viruses may be more infectious for humans=94 (page 1) = include: =93an=20 increase in the number of case clusters in the north compared with the = south, a=20 prolonged interval between the first and last cases in clusters, = detection of=20 sub-clinical infections, and expanded age range of cases and fewer fatal = cases=94. WHO also noted = that the=20 case fatality rate for H5N1 virus in northern Vietnam is now much lower = (16/47,=20 or 34%) than in southern Vietnam (20/24, or 83%), while in Thailand = it remains at 12/17 (71%), and in = Cambodia 4/4=20 (100%).

In=20 response, the WHO made several recommendations. These included improved=20 monitoring and risk assessment in all nations with H5N1 in animals or = humans in=20 part through mobilizing technical assistance and providing it to these = nations;=20 WHO coordinating with international organizations such as the FAO and = OIE to=20 optimize exchange of information about H5N1 viruses and control measures = involving agricultural as well as public health and private sector = partners;=20 convening a WHO Pandemic Task force to meet regularly to review all data = and=20 update pandemic risk assessments; including returning travelers from = risk=20 areas in surveillance for = H5N1=20 viruses and the characterization of any clusters of suspected or = confirmed H5N1=20 infections.

Additional=20 key recommendations from the WHO included: to develop an international = stockpile=20 of antiviral drugs that can be rapidly deployed to control sustained human outbreaks of = H5N1, make=20 human H5N1 vaccine available to affected nations BEFORE the start of a = pandemic;=20 consider further vaccination of poultry against H5N1; and rehearsal = exercises=20 (e.g., perhaps both tabletop and live-field exercises) in individual = nations=20 with assistance from WHO to test initial rapid responses to H5N1 = outbreaks=20 including deployment of antiviral stockpile drugs. (similar to the = =93Pacific=20 Storm=94 serial tabletop exercises proposed in this http://www.bepast.org/ Newsletter of = May 9,=20 2005).

In=20 this writers=92s view, one finding in this WHO report warrants = additional emphasis=20 in terms of implications for pandemic preparedness, and that is the = prospect of=20 needing new generation vaccines against H5N1 as this virus continues to = evolve=20 over the next few years. While the first H5N1 human vaccine tests in the = USA=20 have begun in the past month at the University of Maryland, UCLA, and = the=20 University of Rochester (New York), =20 the WHO report = this week of=20 an H5N1 strain from Vietnam in 2005 that is =93antigenically distinct = from the=20 2004 reference/vaccine strains=94 =20 could be a harbinger of the need to develop even newer H5N1 = vaccines in=20 the near future based on the antigenically-predominant H5N1 strains as = they=20 evolve. Precedent for = this scenario=20 exists: The current = vaccine=20 prototypes are based on = 2004=20 vaccine strains, having been chosen by scientists to replace those H5N1=20 candidate vaccine strains from earlier years (1997-2002). By 2004 = changes in the=20 H5N1 virus had occurred such that a vaccine based on earlier = (pre-2004) H5N1 viruses would not have = induced an=20 immune response in humans that was likely to protect them against the = 2004=20 strains of H5N1. =20

If=20 the virus continues to mutate and evolve in this manner in 2005-2006 = then=20 vaccine development against H5N1 will become more complicated and the = timeline=20 to produce sufficient amounts of vaccine more problematic. The urgent = need will=20 be heightened for adopting new technology, such as reverse genetics, and = for=20 creating the capacity for surge production of new influenza vaccine, = ideally=20 requiring only one, and not two, = immunizations for protection against H5N1 infection.=20

An=20 end-to-end analysis of all needs for a mass vaccination program against = pandemic=20 influenza, not only in = the USA but=20 internationally, should be undertaken now. =20 For example, as with smallpox vaccine requiring more bifurcated = needles=20 than were available in 2001, so most there be a sufficient supply of = syringes=20 and conventional vaccine needles for a mass vaccination program against=20 H5N1. As of today the = number of=20 syringes and needles must be calculated based on the assumption that two = doses of vaccine per = person will be=20 required to develop protective immunity, until proven otherwise, by = ongoing and=20 future vaccine trials with the antigenically-relevant strains of H5N1.=20 Similarly, resilient and robust information technology (IT) systems must = be=20 available, and field-tested in advance, to be able to provide = centralized=20 regional and national coordination both for tracking vaccinations and = for side=20 effects of the new vaccine(s).

Daniel=20 R. Lucey, MD, MPH

Adjunct=20 Professor of Microbiology and Immunology

Georgetown=20 University School of Medicine

Director,=20 Center for Biologic Counterterrorism and Emerging = Diseases

Department=20 of Emergency Medicine

Washington=20 Hospital Center

Washington,=20 DC, USA

e-mail:=20 Daniel.R.Lucey@Medstar.net