part iv: h5n1 human outbreaks. chotani, gidsas-jhu, 2006 gidsas avian influenza a(h5n1), 1997 avian...

Part IV: H5N1 Human Part IV: H5N1 Human OutbreaksOutbreaks

Chotani, GIDSAS-JHU, 2006Chotani, GIDSAS-JHU, 2006

GIDSAS Avian Avian Influenza A(H5N1), 1997 Influenza A(H5N1), 1997

Avian Influenza A(H5N1) caused Avian Influenza A(H5N1) caused 18 cases of influenza with 6 deaths 18 cases of influenza with 6 deaths in the Hong Kong area. Experts are in the Hong Kong area. Experts are concerned that the virus may concerned that the virus may acquire a mutation encouraging acquire a mutation encouraging human-to-human transmission. human-to-human transmission.

3/9/99 46


GIDSAS The H5N1 Influenza Pandemic ThreatThe 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 20041997 1998 1999 2000 2001 2002

• Avian infection in Hong Kong• 18 human cases and 6 deaths (33%)• Culled poultry

• Ongoing avian H5N1 infections


GIDSAS Affected Countries with Confirmed Human Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2003Cases of H5N1 Influenza since 2003

As of May 24, 2006. Source: WHO/WPRO


GIDSAS Affected Countries with Confirmed Human Affected Countries with Confirmed Human Cases of H5N1 Influenza since 2006Cases of H5N1 Influenza since 2006

As of May 24, 2006. Source: WHO/WPRO


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


GIDSASCumulative Number of Confirmed Human Cases Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 20062003 to 24 May 2006

8 618

1

14

42

2

2212

93

5 612

06

33

214

4

42

0

25

50

75

100

Azerb

aija

n

Cambod

ia

China

Djibout

i

Egypt

Indon

esia

Iraq

Thaila

nd

Turke

y

Viet N

am

Countries

No

. o

f R

epo

rted

Cas

es

218 Cases 124 Deaths

Source: WHO

As of May 24, 2006.


GIDSAS Cumulative Number of Confirmed Human Cases Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 20062003 to 24 May 2006

3

46

95

74

3

3241

48

010

2030

405060

7080

90100

2003 2004 2005 2006

Countries

No

. of

Rep

ort

ed C

ases

Cases Deaths Linear (Cases)

Source: WHO

Mortality: 100%

Mortality: 70%

Mortality: 43%

Mortality: 65%

As of May 24, 2006.


GIDSASCumulative Number of Confirmed Human Cases Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) since 26 December of Avian Influenza A/(H5N1) since 26 December 2003 to 24 May 20062003 to 24 May 2006

Source: WHO

Deaths, 124, 57%

Survived, 95, 43%

As of May 24, 2006.


GIDSAS

Avian & Human H5N1 Identified in No. of Countries Avian & Human H5N1 Identified in No. of Countries

(Since 26 December 2003 to 24 May 2006)(Since 26 December 2003 to 24 May 2006)

1

11

18

46

1 25

10

05

1015

202530

3540

4550

2003 2004 2005 2006

Countries

No

. o

f R

ep

ort

ed

Cases Cases in Birds Cases in Humans

Source: WHO

As of April 24, 2006.


GIDSASNations With Confirmed Cases Nations With Confirmed Cases H5N1 Avian Influenza (May 19, 2006) H5N1 Avian Influenza (May 19, 2006)

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

Part V: InterventionsPart V: Interventions


GIDSAS WHO Global Influenza WHO Global Influenza Surveillance NetworkSurveillance Network

Antigenic & Genetic AnalysisWHO CC

Diagnostic ReagentsVaccine Strains

Potency Testing Reagents

Serologic StudiesNational

Licensing Agencies

Isolation of Representative Strain from Clinical SampleNational Influenza Centers

Disease & Epidemiology Data

Makes recommendations on influenza vaccine formulation

Source: WHO Global Influenza Program


GIDSAS Influenza Vaccine DevelopmentInfluenza Vaccine Development



GIDSAS

Lag between pandemic strain detection and full scale vaccine production

Clinical batch production & Testing

1-2 months????

Vaccine Prototype Development1-2 months

Influenza Pandemic VaccineInfluenza Pandemic Vaccine

2 4 60Months

TodayOptimistic Projection



GIDSAS Key “bottlenecks”Key “bottlenecks”

1. “Purity” of strain2. Production requirements

Production system “EGG”Biosecurity

3. Clinical data allowing increase in vaccine availability

……


Reverse genetics

Clinical Trials

Clinical data allowing increase in vaccine availability


GIDSAS Vaccine Production CapacityVaccine Production Capacity



GIDSAS Vaccine Consumption - 2000Vaccine Consumption - 2000



GIDSAS VaccineVaccine

Challenges:Challenges:H5 HA is poorly immunogenic as compared H5 HA is poorly immunogenic as compared to H3N2 or H1N1 virusesto H3N2 or H1N1 viruses

• To date vaccines against H5 have To date vaccines against H5 have required 2 doses or an adjuvant to induce required 2 doses or an adjuvant to induce necessary level of neutralizing antibodiesnecessary level of neutralizing antibodies

Influenza virus has a high error rate making Influenza virus has a high error rate making it evolve continuouslyit evolve continuously

There are already two clades of HPAI H5N1 There are already two clades of HPAI H5N1 virus circulatingvirus circulating

Manufacturing capacity is limited and Manufacturing capacity is limited and licensing requirements are stringent licensing requirements are stringent



September 16, 2005 – HHS September 16, 2005 – HHS

News HeadlinesNews HeadlinesUS DHHS buying $100 million of US DHHS buying $100 million of avian vaccineavian vaccine

Vaccine has not been approved Vaccine has not been approved by FDAby FDA

Proper dosage being determinedProper dosage being determined• Protection for 2 to 20 million Protection for 2 to 20 million

AmericansAmericans



Inactivated vaccine candidate:Sanofi Pasture has developed an unadjuvanted, inactivated H5N1 vaccine candidateProspective, 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 HACandidate vaccine has been developed for H5 & H9 (phase 1 clinical trials)



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 greaterOnly 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



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.


GIDSAS ChemotherapyChemotherapy

Prevent membrane fusion (M2 Inhibitors)

Amantidine (Symmetrel)Remantidine (Flumadine)

Neuraminidase inhibitorsZanamivir (Relenza)

• US buying $2.8 million (could treat 84,300 people)

Oseltamivir (Tamiflu)Peramivir (more potent in vitro)???


GIDSAS ChemotherapyChemotherapy

Relenza:Reduced the incidence of the disease in both young and older populationsFirst 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.


GIDSAS Types of protective masksTypes 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 oilThe more a mask is resistant to oil, the better it isThe 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.


GIDSAS Food SafetyFood SafetyConventional 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


GIDSAS

Source: World Health Organization. Highly pathogenic avian influenza

(HPAI) Interim infection control guidelines for health care facilities.

Survival of Influenza Virus on Surfaces*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.


GIDSAS New laboratory test New laboratory test

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

CDC. New laboratory assay for diagnostic testing of avian CDC. New laboratory assay for diagnostic testing of avian influenza A/H5 (Asian lineage). influenza A/H5 (Asian lineage). MMWRMMWR. 2006;55(RR5):127.. 2006;55(RR5):127.

GIDSAS


Part VI: Where are we …..Part VI: Where are we …..


GIDSAS CURRENT WHO PHASE of PANDEMIC ALERTCURRENT 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


GIDSAS 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.


GIDSAS Planning Assumptions: Planning Assumptions: US HealthcareUS Healthcare

50% or more of those who become sick will 50% or more of those who become sick will seek medical careseek medical careNumber of hospitalization and deaths will Number of hospitalization and deaths will depend upon the virulence of the pandemic depend upon the virulence of the pandemic virusvirus

Moderate (1957-like) Severe (1918-like)

Illness 90 million (30%) 90 million (30%)

Outpatient medical care 45 million (50%) 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


GIDSAS What Needs to be Done?What Needs to be Done?SurveillanceSurveillanceCullingCulling

Domestic poultry vaccine issuesDomestic poultry vaccine issuesQuarantineQuarantine

Ring??Ring??Vaccination against circulating fluVaccination against circulating fluH5N1 vaccine developmentH5N1 vaccine developmentStockpiling of antiviralsStockpiling of antiviralsQuicker laboratory testingQuicker laboratory testingStringent infection control practicesStringent infection control practices

Handwashing Disinfection, Masks etcHandwashing Disinfection, Masks etcMasksMasksEducationEducation

Vaccination, antivirals, masks, food safety, Vaccination, antivirals, masks, food safety, handwashing, disinfection, etchandwashing, disinfection, etc

CoordinationCoordinationThrough planning & preparednessThrough planning & preparedness


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

Dollars in Millions

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


GIDSAS Take-home messagesTake-home messages

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


GIDSAS

“The only thing more difficult than planning for an emergency is having to explain why you didn’t.”

We have to preparefor the next pandemic!!!

Be Proactive NOT Reactive!!!!Be Proactive NOT Reactive!!!!

Timing has a lot to do with Timing has a lot to do with the outcome of a rain dancethe outcome of a rain dance

part iv: h5n1 human outbreaks. chotani, gidsas-jhu, 2006 gidsas avian influenza a(h5n1), 1997 avian...

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