JIT: The Impact of Pandemic Influenza on Public Health: JIT: The Impact of Pandemic Influenza on Public Health Rashid A. Chotani, MD, MPH Director, Global Infectious Disease Surveillance & Alert System Johns Hopkins Bloomberg School of Public Health 410-502-3116/410-322-7469 rchotani@jhsph.edu


Part I : Basics: Part I : Basics


Influenza Virus: Influenza Virus RNA, enveloped Viral family: Orthomyxoviridae Size: 80-200nm or .08 – 0.12 μm (micron) in diameter Three types A, B, C Surface antigens H (haemaglutinin) N (neuraminidase) Credit: L. Stammard, 1995


Influenza Virion: Influenza Virion


Slide6: The Burden of Influenza Seasonal Influenza Globally: 250,000 to 500,000 deaths per year In the US (per year) ~35,000 deaths >200,000 Hospitalizations $37.5 billion in economic cost (influenza & pneumonia) Pandemic Influenza An ever present threat


Contagiousness: Influenza is a highly contagious disease Typical incubation 2 days (range 1-4 days) Individuals are contagious for 1 to 4 days before the onset of symptoms and about 5 days after the first symptoms Peak viral shedding - first 3 days of illness Subsides usually by 5-7th day in adults can be 10+ days in children Approximately 50% of infected people do not present any symptoms but are still contagious Contagiousness


Spread of Influenza: Spread of Influenza Most human influenza infections are spread by virus-laden respiratory droplets that are expelled during coughing and sneezing. Influenza viruses range in size from 0.08 to 0.12 μm. They are carried in respiratory secretions as small-particle aerosols (particle sized <10μm). Sneezing generates particles of varying sizes 10-100 μm


Modes of Transmission: Modes of Transmission The 3 modes of transmission include: Droplet transmission Airborne transmission, and Contact transmission


Droplet Transmission: Droplet Transmission Droplet transmission occurs when contagious droplets produced by the infected host through coughing or sneezing are propelled a short distance and come into contact with another person’s conjunctiva, mouth, or nasal mucosa.


Airborne Transmission: Airborne Transmission Airborne transmission occurs when viruses travel on dust particles or on small respiratory droplets that may become aerosolized when people sneeze, cough, laugh, or exhale. They can be suspended in the air much like invisible smoke. They can travel on air currents over considerable distances. With airborne transmission, direct contact with someone who is infected is not necessary to become ill.


Contact Transmission: Contact Transmission Two Types Direct: involves body-to-body surface contact Indirect: occurs via contact with contaminated intermediate objects, such as contaminated hands, or inanimate objects (fomites), such as countertops, door knobs, telephones, towels, money, clothing, dishes, books, needles etc.


Survival of Influenza Virus on Surfaces*: Source: Bean B, et al. JID 1982;146:47-51 Survival of Influenza Virus on Surfaces* Hard non-porous surfaces 24-48 hours Plastic, stainless steel Recoverable for > 24 hours Transferable to hands up to 24 hours Cloth, paper & tissue Recoverable for 8-12 hours Transferable to hands 15 minutes Viable on hands <5 minutes only at high viral titers Potential for indirect contact transmission *Humidity 35-40%, temperature 28C (82F)


Affects of humidity on infectivity influenza, Loosli et al, 1943: Affects of humidity on infectivity influenza, Loosli et al, 1943


Definitions: Definitions Epidemic – a located cluster of cases Pandemic – worldwide epidemic Antigenic drift Changes in proteins by genetic point mutation & selection Ongoing and basis for change in vaccine each year Antigenic shift Changes in proteins through genetic reassortment Produces different viruses not covered by annual vaccine


Reassortment (in humans): Reassortment (in humans) Migratory water birds Source: WHO/WPRO


Reassortment (in pigs): Migratory water birds Reassortment (in pigs) Source: WHO/WPRO


Mutation (in humans): Mutation (in humans) Source: WHO/WPRO


From birds to humans: Migratory water birds Hong Kong, SAR China 1997, H5N1 Hong Kong, SAR China 1999, H9N2 The Netherlands 2003, H7N7 Hong Kong, SAR China 2003, H5N1 From birds to humans Source: WHO/WPRO


Part II : History: Part II : History


Slide22: “Spanish Flu” A(H1N1): 1918-19 Approximately 20-40 million people died worldwide, and over 500,000 in US.


The big pandemic of 1918: The big pandemic of 1918


Slide24: Images from the 1918 Influenza Epidemic National Museum of Heath and Medicine


The big pandemic of 1918: The big pandemic of 1918


Slide26: Images from the 1918 Influenza Epidemic National Museum of Heath and Medicine


Slide28: “Asian Flu” A(H2N2) 1957-58 During the 1957-58 Asian flu epidemic, a school child in Islington, London, gargles to keep the virus at bay. More than a million people died worldwide and about 70,000 in US.


Spread of H2N2 Influenza in 1957 “Asian Influenza”: Spread of H2N2 Influenza in 1957 “Asian Influenza”


Slide30: “Hong Kong Flu” A(H3N2) 1968-69 Members of the Red Guard in China covered their mouths against flu germs in 1968 on the orders of Chairman Mao. The Hong Kong flu of 1968-69 killed more than 1 million people worldwide, and 34,000 in US.


Slide31: Timeline of Emergence of Influenza A Viruses in Humans 1918 1957 1968 1977 1997 1998/9 2003 H1 H1 H3 H2 H7 H5 H5 H9 Spanish Influenza H1N1 Asian Influenza H2N2 Russian Influenza Avian Influenza Hong Kong Influenza H3N2


Recorded Influenza Pandemics: Recorded Influenza Pandemics


Part III: H5N1 Avian Outbreaksfrom July 2004 : Part III: H5N1 Avian Outbreaks from July 2004


Current Pandemic Concerns: Current Pandemic Concerns


Slide35: Countries Reporting Confirmed Occurrence of H5N1 Influenza in Poultry and Wild Birds Since 2003 As of May 30, 2006. Source: WHO/WPRO


Slide36: Countries Reporting Confirmed Occurrence of H5N1 Influenza in Poultry and Wild Birds Since 2006 As of May 30, 2006. Source: WHO/WPRO


In Cats???: 7 March 2006, Rome ­ Following the finding of the H5N1 avian influenza virus in a dead cat on the island of Rügen in Germany, the European Commission has advised its member states to take specific measures regarding cats and dogs in the infected areas. The general public and cat owners especially have increasingly shown concern and are consulting veterinarians for advise. In Cats???


Slide43: Dept of Health and Human Services: www.pandemicflu.gov


Slide45: Current Pandemic Concerns


Slide46: Current Pandemic Concerns


Part IV: H5N1 Human Outbreaks: Part IV: H5N1 Human Outbreaks


Slide49: 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.


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


Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2003: Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2003 As of May 24, 2006. Source: WHO/WPRO


Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2006: Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2006 As of May 24, 2006. Source: WHO/WPRO


Geographic Location of the North Sumatra Cluster and cases Confirmed on May 29, Indonesia, 2006: Geographic Location of the North Sumatra Cluster and cases Confirmed on May 29, Indonesia, 2006


Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 2006: 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: Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 2006 Source: WHO Mortality: 100% Mortality: 70% Mortality: 43% Mortality: 65% As of May 24, 2006.


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


Avian & Human H5N1 Identified in No. of Countries (Since 26 December 2003 to 24 May 2006): 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) : Nations With Confirmed Cases H5N1 Avian Influenza (May 19, 2006) Dept of Health and Human Services: www.pandemicflu.gov


Part V: Interventions: Part V: Interventions


WHO Global Influenza Surveillance Network: WHO Global Influenza Surveillance Network Antigenic & Genetic Analysis WHO CC Diagnostic Reagents Vaccine Strains Potency Testing Reagents Serologic Studies National Licensing Agencies Isolation of Representative Strain from Clinical Sample National Influenza Centers Disease & Epidemiology Data Makes recommendations on influenza vaccine formulation Source: WHO Global Influenza Program


Influenza Vaccine Development: Influenza Vaccine Development Source: WHO Global Influenza Program


Influenza Pandemic Vaccine: Lag between pandemic strain detection and full scale vaccine production Clinical batch production & Testing 1-2 months???? Vaccine Prototype Development 1-2 months Influenza Pandemic Vaccine 2 4 6 0 Months Today Optimistic Projection Source: WHO Global Influenza Program


Key “bottlenecks”: Key “bottlenecks” “Purity” of strain Production requirements Production system “EGG” Biosecurity Clinical data allowing increase in vaccine availability … … Source: WHO Global Influenza Program Reverse genetics Clinical Trials Clinical data allowing increase in vaccine availability


Vaccine Production Capacity: Vaccine Production Capacity Source: WHO Global Influenza Program


Vaccine Consumption - 2000: Vaccine Consumption - 2000 Source: WHO Global Influenza Program


Vaccine: 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: 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


Vaccine: 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)


Vaccine: 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: 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.


Chemotherapy: 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)???


Chemotherapy: 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: 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: 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*: Source: World Health Organization. Highly pathogenic avian influenza (HPAI) Interim infection control guidelines for health care facilities. 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.


New laboratory test : 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 …..: Part VI: Where are we …..


CURRENT WHO PHASE of PANDEMIC ALERT: CURRENT WHO PHASE of PANDEMIC ALERT Source: WHO Global Influenza Program WHO: May 23 reported a cluster of 8 individuals (Sumatra is ) of one extended family – raising questions of potential Human-to-Human transmission


THE NEXT PANDEMIC?: 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: 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


What Needs to be Done?: 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


US Pandemic Influenza Plan Funding 2006 Appropriations: HHS Allocations ($3.3B) : 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: 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


Slide84: “The only thing more difficult than planning for an emergency is having to explain why you didn’t.” We have to prepare for the next pandemic!!! Be Proactive NOT Reactive!!!! Timing has a lot to do with the outcome of a rain dance