New WHO Phases: Issues New WHO Phases: Issues Related to the Pandemic of a Related to the Pandemic of a

Novel A(H1N1) VirusNovel A(H1N1) Virus

Arnold S. MontoArnold S. MontoUniversity of MichiganUniversity of MichiganSchool of Public HealthSchool of Public Health

Ann Arbor, Michigan USAAnn Arbor, Michigan USA

Proposed 2008 Phases Proposed 2008 Phases

1 - 3

Phases 5-6

SustainedH-2-H

transmission

Time

Predominantly animalinfections; Limited infections of people

Geographic spread

5 - 6

4

PostPeak

PostPandemic

First Detection of Community Level Outbreaks Will Require Several Urgent Decisions

First Detection of Community Level Outbreaks Will Require Several Urgent Decisions

Sustained H-2-H

transmission

Consider rapid

containment

Consider Phase Change to 4 Consider

switch to pandemic

vaccine

Other

WHO Pandemic Phase DescriptionsWHO Pandemic Phase DescriptionsPhase Estimated probability

of pandemicDescription Main actions

in affected countries

Main actions in not-yet-affected countries

Phase 4 Medium to high Human-to-human transmission of an animal or

human-animal influenza reassortant virus able to sustain community-level

outbreaks has been verified

Rapid containment

Readiness for pandemic response

Phase 5 High to certain The same identified virus has caused sustained

community level outbreaks in at least two countries in

one WHO region Pandemic response: Each

country to implement

actions as called for in their

national plans.

Readiness for imminent responsePhase 6 Pandemic in progress In addition to the criteria

defined in Phase 5, the same virus has caused sustained community level outbreaks in at least one other country

in another WHO region.

Community Strategies by Pandemic Flu Severity (1)

Pandemic Severity Index

Interventions by Setting 1 2 and 3 4 and 5

Home

Voluntary isolation of ill at home (adults and children); combine with use of antiviral treatment as available and indicated

Recommend Recommend Recommend

Voluntary quarantine of household members in homes with ill persons (adults and children); consider combining with antiviral prophylaxis if effective, feasible, and quantities sufficient

Generally not recommended

Consider Recommend

School

Child social distancing–dismissal of students from schools and school-based activities, and closure of child care programs

Generally not recommended

Consider:≤ 4 weeks

Recommend:≤ 12 weeks

–reduce out-of-school contacts and community mixing

Generally not recommended

Consider:≤ 4 weeks

Recommend:≤ 12 weeks

Community Strategies by Pandemic Flu Severity (2)

Pandemic Severity Index

Interventions by Setting 1 2 and 3 4 and 5

Workplace/CommunityAdult social distancing

–decrease number of social contacts (e.g., encourage teleconferences, alternatives to face-to-face meetings)

Generally not recommended

Consider Recommend

–increase distance between persons (e.g., reduce density in public transit, workplace)

Generally not recommended

Consider Recommend

–modify, postpone, or cancel selected public gatherings to promote social distance (e.g., stadium events, theater performances)

Generally not recommended

Consider Recommend

–modify workplace schedules and practices (e.g., telework, staggered shifts)

Generally not recommended

Consider Recommend

Progress of Asian Influenza Pandemic, Progress of Asian Influenza Pandemic, February, 1957-January, 1958February, 1957-January, 1958

Langmuir AD,Am Rev Resp Dis. 1961; 83:3.

Status of Asian Influenza in the United States and Status of Asian Influenza in the United States and Major Routes of Spread through July 22, 1957Major Routes of Spread through July 22, 1957

Military Civilian Confirmed Sporadic Cases Confirmed Outbreaks Suspect Outbreaks

Arrows indicate probable spread from Foci of infection.

Langmuir AD,Am Rev Resp Dis. 1961; 83:5.

Influenza Attack Rates by Age in Tangipahoa Influenza Attack Rates by Age in Tangipahoa Parish, Louisiana – August, 1957Parish, Louisiana – August, 1957

0

10

20

30

40

50

60

70

0 4.5 7.5 12 20 30 40 55 77

Age in Years

Cas

es P

er 1

00 P

erso

ns

Dillon School Families West Side School Families Independence School Families

Langmuir AD,Am Rev Resp Dis. 1961; 83:5.

Weekly Incidence of Respiratory Illnesses (all ages) Weekly Incidence of Respiratory Illnesses (all ages) Per 100,000, July, 1957-June 1958Per 100,000, July, 1957-June 1958

Langmuir AD,Am Rev Resp Dis. 1961; 83:8.

19571957 19581958

6,000

5,000

4,000

3,000

2,000

1,000

0Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun

Clinical Influenza Attack Rates (Kansas Clinical Influenza Attack Rates (Kansas City, 1957) and Annual Mortality Rate City, 1957) and Annual Mortality Rate Pneumonia and Influenza (U.S. 1957)Pneumonia and Influenza (U.S. 1957)

0

5

10

15

20

25

30

35

40

45

50

55

60

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80

Age (Years)

Clin

ical

In

flu

enza

Att

ack

Rat

e p

er 1

00 Attack Rate

Mortality Rate

- 300

- 250

- 200

- 150

- 100

- 50

0

Mor

tali

ty R

ate

per

100

,000

Modified from Monto AS. Am J Med. 1987; 82:20-5.

Comparison of Amantadine and Rimantadine Comparison of Amantadine and Rimantadine StructuresStructures

NH2

NH2

Amantadine Rimantadine

Protective Efficacy of M2 Inhibitors Protective Efficacy of M2 Inhibitors Against Laboratory-Confirmed Clinical Against Laboratory-Confirmed Clinical

InfluenzaInfluenza

Site and Subtype Efficacy Significance

Michigan Type A(H1N1) Amantadine

71%

P<0.001

Vermont Types A(H3N2) & A(H1N1) Amantadine Rimantadine

91% 85%

P<0.001

Monto AS, et al. JAMA. 1979; 241:1003-7.Dolin R, et al. N Engl J Med. 1982; 307:580-4.

Cases of Influenza-like Illnesses and Resistant Viruses Cases of Influenza-like Illnesses and Resistant Viruses Isolated From Case-Patients at Nursing Home B, by Isolated From Case-Patients at Nursing Home B, by

Living UnitLiving Unit

0

1

2

3

4

5

6

16 18 20 22 24 26 28 30 1 3 5 7 9

Onset Date

Cas

es

Unit 5

Unit 4

Unit 3

Unit 2

Unit 1

Mast et al. Am J Epidemiol. 1991; 134:988-97.

Val to Ala, position 27

Ala to Val, position 30

Ser to Asn, position 31

Demonstrated Amino Acid Changes

JanuaryJanuary FebruaryFebruary

Trend of Adamantane-Resistant H3N2 Viruses, 1994-Trend of Adamantane-Resistant H3N2 Viruses, 1994-20052005

ChinaJapanUS

Hong KongSouth KoreaOverall

90

80

70

60

50

40

30

20

10

01995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Season of Isolate Collection

Res

ista

nce

Fre

qu

ency

(%

)

Bright RA, et al. Lancet. 2005;366:1175-81.

ZanamivirZanamivir

Oseltamivir CarboxylateOseltamivir Carboxylate

Efficacy of Seasonal Prophylaxis of Influenza Efficacy of Seasonal Prophylaxis of Influenza with Zanamivir (4 weeks) and Oseltamivir (6 with Zanamivir (4 weeks) and Oseltamivir (6

weeks)weeks)

Zanamivir Oseltamivir

Prevention of SymptomaticLaboratory Confirmed 67% 74%Influenza

Prevention of Influenza 84% 82%with Fever

Monto AS, et al. JAMA. 1999; 282:31-5.Hayden FG, et al. NEJM. 1999; 341-1336-43.

Efficacy of Oseltamivir in Preventing Lower Efficacy of Oseltamivir in Preventing Lower Respiratory Tract Complications (LRTCs) Respiratory Tract Complications (LRTCs)

Leading to Antibiotic UseLeading to Antibiotic Use

Percent ReductionPercent Reduction

OverallOveralln=2413n=2413

55%*55%*52%61%

55%55%

54%54%

Otherwise HealthyOtherwise Healthyn=1644n=1644

67%67%60%77%

63%63%

71%71%

At RiskAt Riskn=769n=769

34%34%††34%30%

34%34%

25%25%

LRTCs LeadingLRTCs Leadingto Antibiotic Useto Antibiotic Use

All LRTCAll LRTCBronchitisPneumonia

Influenza AInfluenza A Influenza BInfluenza B

* Comparison of oseltamivir vs placebo, P<.001.† Comparison of oseltamivir vs placebo, P=.02. Kaiser L, et al. Arch Intern Med. 2003; 163:1667-72.

Influenza Prevention in Household Studies with NAI’sInfluenza Prevention in Household Studies with NAI’s

Antiviral(Study)

Season (Virus)

Reduction in Secondary Cases %

ResistanceTransmission

No Treatment of Index

Zanamivir(Monto et al, 2002)

Oseltamivir(Welliver et al, 2001)

2000-01(A/H3N2, B)

1998-99 (A/H3N2, B)

81%

89%

—

—

With Treatment of Index

Zanamivir*(Hayden et al, 2000)

†Oseltamivir(Hayden et al, 2004)

1998-99 (A/H3N2, A/H1N1)

2000-01(A/H3N2, B)

79%

85%

No

No

*Prophylaxis is given ≥ 5 years.†Excludes contacts positive for influenza prior to prophylaxis.

• Four donors and 12 recipients each for wt and mt

• Groups of four housed together in cage

Ferret Transmission ModelFerret Transmission Model

Comparisons of Infectivity and Transmissibility of WT and MUT Comparisons of Infectivity and Transmissibility of WT and MUT Pairs for NA Genotypes Isolated During Treatment StudiesPairs for NA Genotypes Isolated During Treatment Studies

Wild type [WT] and Mutant [MUT] Wild type [WT] and Mutant [MUT] pairs isolated from pre- and follow-pairs isolated from pre- and follow-up specimens from the same subjectup specimens from the same subject

Infectious doseInfectious dose Donor Donor infection infection

statusstatus

Recipient Recipient infection infection

statusstatus

Sequence Sequence confirmation of confirmation of WT or MUT NA WT or MUT NA

genotypegenotype

A/Sydney/5/97-like (H3N2)A/Sydney/5/97-like (H3N2) R292 - WT R292 - WT

2.3 2.3 TCID50/0.5 mlTCID50/0.5 ml 4 of 44 of 4 12 of 1212 of 12 WTWT

*R292K – MUT*R292K – MUT SameSame 2 of 42 of 4 3* of 63* of 6 *Reversion to WT*Reversion to WT

A/Wuhan/359/95-like (H3N2)A/Wuhan/359/95-like (H3N2) E119 - WTE119 - WT

1.0 x 101.0 x 10-6-6

Dilution of stockDilution of stock4 of 44 of 4 11 or 1111 or 11 WTWT

E119V - MUTE119V - MUT 1.0 x 101.0 x 10-6-6

Dilution of stockDilution of stock4 of 44 of 4 11 or 1111 or 11 MUTMUT

A/New Calendonia (H1N1)A/New Calendonia (H1N1) H274 – WTH274 – WT

1.5 x 101.5 x 10-6-6

Dilution of stockDilution of stock4 of 44 of 4 12 or 1212 or 12 WTWT

H274Y – MUT H274Y – MUT 1.5 x 101.5 x 10-5-5

Dilution of stockDilution of stock0 of 40 of 4

@ day 7@ day 70 of 120 of 12

@ day 7@ day 7

1.5 x 101.5 x 10-3-3

Dilution of stockDilution of stock4 of 44 of 4 12 of 1212 of 12 MUTMUT

Herlocher, et al. 2002. Antiviral Research, 54: 99-111.

Herlocher, et al. 2004. J Infect Dis, 190:1627-30.

Antiviral Resistance in USA Antiviral Resistance in USA (Week 14, 2008-2009)(Week 14, 2008-2009)

Isolates tested

(N)

Resistant Viruses, n (%) Isolates

tested (N)

Resistant Viruses, n (%)

Oseltamivir Zanamivir Adamantanes

Influenza A (H1N1)

748 743 (99.3%) 0 729 3 (0.4%)

Influenza A (H3N2)

112 0 0 108 108 (100%)

Influenza B 227 0 0 N/A* N/A*

CDC, Apr 11, 2009

Antivirals and Health Care Antivirals and Health Care Workers, USAWorkers, USA

A fluid situation. When antivirals were in A fluid situation. When antivirals were in limited supply, early treatment only.limited supply, early treatment only.

More recently, prophylaxis considered.More recently, prophylaxis considered. Where do drugs come from?Where do drugs come from? Are you dealing with imported cases, or Are you dealing with imported cases, or

local transmission?local transmission? If latter, greater likelihood of acquiring If latter, greater likelihood of acquiring

infection outside health care setting.infection outside health care setting.