Part IV: H5N1 Human Outbreaks

Avian Influenza A(H5N1), 1997 Avian Influenza A(H5N1) caused 18 cases of influenza with 6 deaths in the Hong Kong area. Experts are concerned that the virus may acquire a mutation encouraging human-to-human transmission. Between May and December of 1997 a novel influenza A virus H5N1 emerged in Hong Kong and caused 6 deaths among 18 confirmed cases. Cases were spread throughout the province. Between March and May of 1997, the virus was detected in three chicken farms, resulting in killing 6,800 birds. The virus was eradicated by quarantine and extermination of more than 17 million birds costing US $60 million in direct and US $250 million in indirect cost (RC6). As most of the surveillance in Hong Kong was conducted in hospitals, there is a possibility that many milder cases may not have been recognized.

The H5N1 Influenza Pandemic Threat Avian infection in 9 countries 34 human cases and 23 deaths (68%) Culled >100 m chickens Avian infection in Hong Kong 18 human cases and 6 deaths (33%) Culled poultry Avian infection in 4 countries 7 human cases and 6 deaths (86%) Person-to-person? This slide shows the timeline from 1997 to 2004 of H5N1 among humans Ongoing avian H5N1 infections 1997 1998 1999 2000 2001 2002 2003 2004

Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2003 This map shows the affected countries and areas where confirmed human cases have been documented since 2003. The map is dated March 2, 2006. As of May 24, 2006. Source: WHO/WPRO

Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2006 This map shows the affected countries and areas where confirmed human cases have been documented since 2003. The map is dated March 2, 2006. As of May 24, 2006. Source: WHO/WPRO

Geographic Location of the North Sumatra Cluster and cases Confirmed on May 29, Indonesia, 2006 On May 23, the World Health Organization (WHO) acknowledged the likelihood that a large cluster of human cases of H5N1 infections in the northern portion of the Indonesian island of Sumatra is due to human to human transmission. The cluster comprises 8 individuals of one extended family. On April 27, a 38 year old woman became ill, and then died on May 4. While she was never tested for H5N1 infection, 7 members of her extended family, 3 adult siblings, 2 adolescent sons, a 10 year old nephew and an 18 month old niece subsequently became ill with WHO-confirmed H5N1 infections, and 6 of the 7 have died. The source of the woman’s infection is not known. Three of the infected family members shared a room with her on the night of April 29 while she was actively sick and coughing. The other family members lived nearby. While each of the 7 confirmed cases had prolonged and close contact with an actively sick individual, it appears that they may not have had close contact with the index case, raising the possibility of more than one generation of transmission. Full sequence analysis of 2 viral specimens from this cluster shows no evidence of reassortment or of known mutations thought to increase the likelihood of human to human transmission - the sequences appear to be similar to those of birds from the region last year. 6 new cases and 3 fatalities have been recently reported but none of these cases have been linked to the previous cluster.

Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 2006 Source: WHO As of May 24, 2006.

Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 2006 Mortality: 43% Mortality: 65% Mortality: 70% Mortality: 100% Each year since 2003 the number of human H5N1 cases have increased. 30 cases have already been confirmed in the first two months of 2006. If this trend continues there will be much more cases in 2006 then previously seen. Case-specific mortality in confirmed cases have fluctuated, perhaps due to: variation of medical support/assistance of availability and accessibility of the countries experience dealing with this illness. decrease in virulence Vietnam had 100% (3/3) deaths in 2003 and 69% (20/29) deaths in 2004. In 2005 the largest number of confirmed cases (61) were identified in Vietnam with only 19 deaths (31%). Source: WHO As of May 24, 2006.

Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 2006 In laboratory confirmed cases overall mortality since 2003 is over 50%. Critical to note is that a lot of cases might not have been identified due to non-reporting or due to a milder disease. Source: WHO As of May 24, 2006.

Avian & Human H5N1 Identified in No Avian & Human H5N1 Identified in No. of Countries (Since 26 December 2003 to 24 May 2006) Source: WHO As of April 24, 2006.

Nations With Confirmed Cases H5N1 Avian Influenza (May 19, 2006) Dept of Health and Human Services: www.pandemicflu.gov

Part V: Interventions

WHO Global Influenza Surveillance Network Makes recommendations on influenza vaccine formulation Serologic Studies National Licensing Agencies Antigenic & Genetic Analysis WHO CC Diagnostic Reagents Vaccine Strains Potency Testing Reagents What it take to make the vaccine? The WHO Global influenza surveillance network makes recommendations for the formation of influenza vaccine each year. This is a rather complex process requiring surveillance, isolation of representative strain, antigenic and genetic analysis, serological studies. Isolation of Representative Strain from Clinical Sample National Influenza Centers Disease & Epidemiology Data Source: WHO Global Influenza Program

Influenza Vaccine Development The recommendations for the formation of influenza vaccine by the WHO Global influenza surveillance network initiates the vaccine development process. This process requires many steps including various provisions, from early harvesting of eggs to clinical studies prior to the release of the vaccine for humans. Source: WHO Global Influenza Program

Influenza Pandemic Vaccine Lag between pandemic strain detection and full scale vaccine production Optimistic Projection Today Clinical batch production & Testing 1-2 months???? Thus it can take anywhere between 6 to 8 months for the annual vaccine to reach the population. Vaccine Prototype Development 1-2 months 2 4 6 Months Source: WHO Global Influenza Program

Clinical data allowing increase in vaccine Key “bottlenecks” “Purity” of strain Production requirements Production system “EGG” Biosecurity Clinical data allowing increase in vaccine availability … Reverse genetics Clinical data allowing increase in vaccine availability Other problems creating bottleneck affects are described in this slide. Clinical Trials Source: WHO Global Influenza Program

Vaccine Production Capacity It is interesting that most of the current vaccine production capacity (70%) lies in Europe which exports 50% of its production. Source: WHO Global Influenza Program

Vaccine Consumption - 2000 The previous slide showed the limited capacity of the US to produce vaccine. This slide shows the vaccine consumption for the year 2000. US and Canada are the largest consumers of the vaccine. Source: WHO Global Influenza Program

Vaccine Challenges: H5 HA is poorly immunogenic as compared to H3N2 or H1N1 viruses To date vaccines against H5 have required 2 doses or an adjuvant to induce necessary level of neutralizing antibodies Influenza virus has a high error rate making it evolve continuously There are already two clades of HPAI H5N1 virus circulating Manufacturing capacity is limited and licensing requirements are stringent

Vaccine September 16, 2005 – HHS News Headlines US DHHS buying $100 million of avian vaccine Vaccine has not been approved by FDA Proper dosage being determined Protection for 2 to 20 million Americans HHS Announces $100 Million to Accelerate State and Local Pandemic Influenza Preparedness Efforts States and municipalities will use these funds to accelerate and intensify current planning efforts for pandemic influenza and to exercise their plans. The focus is on practical, community-based procedures that could prevent or delay the spread of pandemic influenza, and help to reduce the burden of illness communities would contend with during an outbreak. President Bush has outlined a coordinated government strategy that includes the establishment of the new International Partnership on Avian and Pandemic Influenza, stockpiling of vaccines and antiviral medications, expansion of early-warning systems domestically and abroad, as well as new funding and initiatives for local and state level preparedness.

Vaccine Inactivated vaccine candidate: Sanofi Pasture has developed an unadjuvanted, inactivated H5N1 vaccine candidate Prospective, randomized, double-blind trials (~450 adults, 18-64 years) established the need for two doses (neutralizing titer 1:40) Now being tested in children and elderly Live, attenuated vaccine candidate: MedImmune will develop (under US contract) will develop at least one vaccine for each of the 16 HA Candidate vaccine has been developed for H5 & H9 (phase 1 clinical trials) Vaccines are produced each year for seasonal influenza but will not protect against pandemic influenza. According to the WHO although a vaccine against the H5N1 virus is under development in several countries, no vaccine is ready for commercial production and no vaccines are expected to be widely available until several months after the start of a pandemic. Some clinical trials are now under way to test whether experimental vaccines will be fully protective and to determine whether different formulations can economize on the amount of antigen required, thus boosting production capacity. Because the vaccine needs to closely match the pandemic virus, large-scale commercial production will not start until the new virus has emerged and a pandemic has been declared. Current global production capacity falls far short of the demand expected during a pandemic. Two candidate vaccines have been developed and are currently being tested.

Vaccine Sanofi Pasture has developed an unadjuvanted, inactivated H5N1 (virus isolated in Southeast Asia in 2004) vaccine candidate. Reported in NEJM The higher the dosage of vaccine, the greater the antibody response produced. Of the 99 people evaluated in the 90-mcg, high-dose group, 54 percent achieved a neutralizing antibody response to the vaccine at serum dilutions of 1:40 or greater Only 22 percent of the 100 people evaluated who received the 15-mcg dose developed a similar response to the vaccine. Generally, all dosages of the vaccine appeared to be well tolerated: Almost all reported side effects were mild The second dose of vaccine did not cause more local or systemic symptoms than the first Systemic complaints of fever, malaise, muscle aches, headaches and nausea occurred with the same frequency in all dosage groups as in the placebo group Lab tests did not reveal any clinically significant abnormalities

Vaccine A new genetically engineered vaccine created by scientists at the CDC, is egg-independent and adjuvant-independent. Hoelscher MA at al. Lancet. 2006 Feb 11;367(9509):475-81. A similar vaccine, adenovirus-based influenza A virus vaccine directed against the hemagglutinin (HA) protein of the A/Vietnam/1203/2004 (H5N1) (VN/1203/04) strain isolated during the lethal human outbreak in Vietnam from 2003 to 2005. Gao W et al. Protection of mice and poultry from lethal H5N1 avian influenza virus through adenovirus-based immunization. J Virol. 2006 Feb;80(4):1959-64. This CDC developed vaccine is a replication-incompetent, human adenoviral-vector-based, haemagglutinin subtype 5 influenza vaccine (HAd-H5HA), which induces both humoral and cell-mediated immune responses against avian H5N1 influenza viruses isolated from people. Their findings highlight the potential of an Ad-vector-based delivery system, which is both egg-independent and adjuvant-independent and offers stockpiling options for the development of a pandemic influenza vaccine. Gao et al showed in their study that mice vaccinated with full-length HA were fully protected from challenge with VN/1203/04. They next evaluated the efficacy of adenovirus-based vaccination in domestic chickens, given the critical role of fowl species in the spread of HPAI worldwide. A single subcutaneous immunization completely protected chickens from an intranasal challenge 21 days later with VN/1203/04, which proved lethal to all control-vaccinated chickens within 2 days. These data indicate that the rapid production and subsequent administration of recombinant adenovirus-based vaccines to both birds and high-risk individuals in the face of an outbreak may serve to control the pandemic spread of lethal avian influenza.

Chemotherapy Prevent membrane fusion (M2 Inhibitors) Amantidine (Symmetrel) Remantidine (Flumadine) Neuraminidase inhibitors Zanamivir (Relenza) US buying $2.8 million (could treat 84,300 people) Oseltamivir (Tamiflu) Peramivir (more potent in vitro)??? The M2 inhibitors: Amantadine and rimantadine, could potentially be used against pandemic influenza, but resistance to these drugs can develop rapidly and this could significantly limit their effectiveness against pandemic influenza. Some currently circulating H5N1 strains are fully resistant to these the M2 inhibitors. However, should a new virus emerge through reassortment, the M2 inhibitors might be effective. Neuraminidase (NA) inhibitors: Oseltamivir (commercially known as Tamiflu) and zanamivir (commercially known as Relenza) can reduce the severity and duration of illness caused by seasonal influenza. The efficacy of the NA inhibitors depends, among others, on their early administration (within 48 hours after symptom onset). For cases of human infection with H5N1, the drugs may improve prospects of survival, if administered early, but clinical data are limited. The H5N1 virus is expected to be susceptible to the NA inhibitors. Antiviral resistance to NA inhibitors has been clinically negligible so far but is likely to be detected during widespread use during a pandemic. A new NA inhibitor peramivir has shown potential in vitro studies.

Chemotherapy Relenza: Reduced the incidence of the disease in both young and older populations First Study: In participants 18 years of age or older, the proportion of people who developed symptoms confirmed to be flu was 6.1% for the placebo group and 2.0% for the Relenza group. The second community study: enrolled people 12 to 94 years of age (56% of whom were older than 65 years). In this trial, the percent of people who developed symptoms confirmed to be flu were reduced from 1.4% of the participants on placebo to 0.2% for those who used Relenza.

Types of protective masks Surgical masks Easily available and commonly used for routine surgical and examination procedures High-filtration respiratory mask Special microstructure filter disc to flush out particles bigger than 0.3 micron. These masks are further classified: • oil proof • oil resistant • not resistant to oil The more a mask is resistant to oil, the better it is The masks have numbers beside them that indicate their filtration efficiency. For example, a N95 mask has 95% efficiency in filtering out particles greater than 0.3 micron under normal rate of respiration. The next generation of masks are called Nanomasks. These boast of latest technologies like 2H filtration and nanotechnology, which are capable of blocking particles as small as 0.027 micron.

Food Safety Conventional cooking (temperatures at or above 70°C in all parts of a food item) will inactivate the H5N1 virus. Properly cooked poultry meat is therefore safe to consume. The H5N1 virus, if present in poultry meat, is not killed by refrigeration or freezing. Home slaughtering and preparation of sick or dead poultry for food is hazardous: this practice must be stopped. Eggs can contain H5N1 virus both on the outside (shell) and the inside (whites and yolk). Eggs from areas with H5N1 outbreaks in poultry should not be consumed raw or partially cooked (runny yolk); uncooked eggs should not be used in foods that will not be cooked, baked or heat-treated in other ways. There is no epidemiological evidence to indicate that people have been infected with the H5N1 virus following consumption of properly cooked poultry or eggs. The greatest risk of exposure to the virus is through the handling and slaughter of live infected poultry. Good hygiene practices are essential during slaughter and post- slaughter handling to prevent exposure via raw poultry meat or cross contamination from poultry to other foods, food preparation surfaces or equipment

Survival of Influenza Virus on Surfaces* (WHO) recommends that environmental surfaces be cleaned by : disinfectants such as Sodium hypochloride 1% in-use dilution, 5% solution to be diluted 1:5 in clean water for materials contaminated with blood and body fluids; bleaching powder 7 gram/liter with 70% available chlorine for toilets and bathrooms; and 70% alcohol for smooth surfaces, tabletops and other surfaces where bleach cannot be used. Environmental cleaning must be done on a daily basis. Source: World Health Organization. Highly pathogenic avian influenza (HPAI) Interim infection control guidelines for health care facilities.

New laboratory test The FDA has approved a new laboratory test developed by the CDC to diagnose H5 strains of influenza in patients suspected to be infected with the virus. The product – the Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set – provides preliminary results on suspected H5 influenza samples within four hours once a sample is tested. If the presence of the H5 strain is identified, then further testing is conducted to identify the subtype. If clinicians suspect a patient may be infected with an avian influenza virus, they should contact their state or local health department. For more information: CDC. New laboratory assay for diagnostic testing of avian influenza A/H5 (Asian lineage). MMWR. 2006;55(RR5):127.

Part VI: Where are we …..

CURRENT WHO PHASE of PANDEMIC ALERT Inter-Pandemic Phase New Virus in Animals, NO Human Cases Low Risk of Human Cases 1 High Risk of Human Cases 2 Pandemic ALERT New Virus Causes Human Cases No or Very Limited Human-to-Human Transmission 3 Evidence of Increased Human-to-Human Transmission 4 Evidence of Significant Human-to-Human Transmission 5 PANDEMIC Efficient & Sustained Human-to-Human Transmission 6 WHO: May 23 reported a cluster of 8 individuals (Sumatra is ) of one extended family – raising questions of potential Human-to-Human transmission Experts at WHO and elsewhere believe that the world is now closer to another influenza pandemic than at any time since 1968, when the last of the previous century's three pandemics occurred. WHO uses a series of six phases of pandemic alert as a system for informing the world of the seriousness of the threat and of the need to launch progressively more intense preparedness activities. The designation of phases, including decisions on when to move from one phase to another, is made by the Director-General of WHO. Each phase of alert coincides with a series of recommended activities to be undertaken by WHO, the international community, governments, and industry. Changes from one phase to another are triggered by several factors, which include the epidemiological behavior of the disease and the characteristics of circulating viruses. The world is presently in phase 3: a new influenza virus subtype is causing disease in humans, but is not yet spreading efficiently and sustainability among humans. Source: WHO Global Influenza Program

THE NEXT PANDEMIC? Potential impact of next pandemic (CDC) 2-7.4 million deaths globally In high income countries: 134-233 million outpatient visits 1.5-5.2 million hospitalizations ~25% increase demand for ICU beds, ventilators, etc.

Planning Assumptions: US Healthcare 50% or more of those who become sick will seek medical care Number of hospitalization and deaths will depend upon the virulence of the pandemic virus Moderate (1957-like) Severe (1918-like) Illness 90 million (30%) Outpatient medical care 45 million (50%) Hospitalization 865,000 9,900,000 ICU care 128,750 1,485,000 Mechanical ventilation 64,875 745,500 Deaths 209,000 1,903,000

What Needs to be Done? Surveillance Culling Domestic poultry vaccine issues Quarantine Ring?? Vaccination against circulating flu H5N1 vaccine development Stockpiling of antivirals Quicker laboratory testing Stringent infection control practices Handwashing Disinfection, Masks etc Masks Education Vaccination, antivirals, masks, food safety, handwashing, disinfection, etc Coordination Through planning & preparedness Can a pandemic occur and if it does can it be prevented? No one knows with certainty. The only guaranteed way would be to eliminate virus from the bird population globally – a task that is unachievable in the near future. Thus, being proactive is perhaps the best strategy. It is critical to develop: A complete and comprehensive understanding of the past pandemics A through preparedness plan An excellent surveillance and logistical capacity Strategies: To enforce movement restrictions in and out of the affected area For quarantine Culling Disinfection To increase the likelihood that early intervention using the WHO rapid-intervention stockpile of antiviral drugs will be successful (currently WHO has antiviral medications, sufficient for 3 million treatment courses) . These drugs could be used prophylactically near the start of a pandemic to reduce the risk that a fully transmissible virus will emerge or at least to delay its international spread, thus gaining time to augment vaccine supplies. Vaccine development Global coordination Mass education

Dept of Health and Human Services: www.pandemicflu.gov US Pandemic Influenza Plan Funding 2006 Appropriations: HHS Allocations ($3.3B) Dollars in Millions Dept of Health and Human Services: www.pandemicflu.gov

Take-home messages The threat to public health will remain so long as the virus continues to cause disease in domestic poultry The outbreaks in poultry are likely to take a very long time to control Should the final prerequisite for a pandemic be met, the consequences for human health around the world could be devastating Regardless of how the present situation evolves, the world needs to be better prepared to respond to the next influenza pandemic

Timing has a lot to do with the outcome of a rain dance “The only thing more difficult than planning for an emergency is having to explain why you didn’t.” Be Proactive NOT Reactive!!!! We have to prepare for the next pandemic!!!