Influenza

• Highly infectious viral illness

• First pandemic in 1580

• At least 4 pandemics in 19th century

• Estimated 21 million deathsworldwide in pandemic of 1918-1919

• Estimated that $4.6B spent annuallyon direct medical costs in US/yr

• 20-40K adult deaths per yr in US

Abbreviated MOA

Virus grows best around 25 °C, doesn’t

grow well at 37 °C

Virus binds to cell surface receptor via

hemagglutinin (H)

!virus-mediated

fusion, via pH

triggered change

in conformation

Abbreviated MOA cont

Neuraminidase (N) acts late in life cycle

and aids in release of viral particles from

Infected surfaces

H and N used to type viral strains and as

antigens they provide protection against

infection

H is the major antigen, 5 major sites of

variability leading to new strains

Influenza Virus Strains

• Type A - moderate to severe illness- all age groups- humans and other animals

• Type B - milder disease- primarily affects children- humans only

• Type C - rarely reported in humans- no epidemics

Single-stranded RNA virus

Influenza Virus

A/Fujian/411/2002 (H3N2)

Neuraminidase

Hemagglutinin

Type of nuclearmaterial

Virustype

Geographicorigin

Strainnumber

Year ofisolation

Virussubtype

Influenza Antigenic Changes

• Hemagglutinin and neuraminidaseantigens change with time

• Changes occur as a result of pointmutations in the virus gene, or due toexchange of a gene segment withanother subtype of influenza virus

• Impact of antigenic changes dependon extent of change (more changeusually means larger impact)

Influenza Antigenic Changes

• Antigenic Drift–minor change, same subtype

–caused by point mutations in gene

–may result in epidemic

• Example of antigenic drift–in 2002-2003, A/Panama/2007/99

(H3N2) virus was dominant

–A/Fujian/411/2002 (H3N2) appearedin late 2003 and caused widespreadillness in 2003-2004

Influenza Antigenic Changes

• Antigenic Shift

–major change, new subtype

–caused by exchange of genesegments

–may result in pandemic

• Example of antigenic shift–H2N2 virus circulated in 1957-1967

–H3N2 virus appeared in 1968 andcompletely replaced H2N2 virus

Impact of Pandemic Influenza

• 200 million people could beaffected

• Up to 40 million require outpatientvisits

• Up to 700,000 hospitalized

• 89,000 - 200,000 deaths

Influenza Pathogenesis

• Respiratory transmission of virus

• Replication in respiratoryepithelium with subsequentdestruction of cells

• Viremia rarely documented

• Viral shedding in respiratorysecretions for 5-10 days

Influenza Clinical Features

• Incubation period 2 days(range 1-4 days)

• Severity of illness depends onprior experience with relatedvariants

• Abrupt onset of fever, myalgia,sore throat, nonproductive cough,headache

Influenza Complications

• Pneumonia–secondary bacterial

–primary influenza viral

• Reye syndrome

• Myocarditis

• Death 0.5-1 per 1,000 cases

Impact of Influenza

• ~36,000 excess deaths per year

• >90% of deaths among persons>65 years of age

• Average of >200,000 influenza-related excess hospitalizations

• 57% of hospitalizations amongpersons <65 years of age

Influenza Epidemiology

• Reservoir Human, animals(type A only)

• Transmission RespiratoryProbably airborne

• Temporal pattern Peak December – Marchin temperate climateMay occur earlier or later

• Communicability 1 day before to 5 daysafter onset (adults)

Month of Peak Influenza ActivityUnited States, 1976-2006

13%

20%

43%

13%

3% 3%

MMWR 2006;55(RR-10):22

Influenza Vaccines

• Inactivated subunit (TIV)–intramuscular

–Trivalent

– ! 6 months

• Live attenuated vaccine (LAIV)–intranasal

–Trivalent

– 5-49 yrs

Composition of the 2005-2006Influenza Vaccine*

• A/California/7/2004 (H3N2)

(A/New York/55/2004)

• A/New Caledonia/20/99 (H1N1)

• B/Shanghai/361/2002

(B/Jilin/20/2003 or B/Jiangsu/10/2003)

*strains in (parenthesis) are antigenically identical to the selected strains and may be used in the vaccines

Transmission of LAIV Virus

• LAIV replicates in the nasopharyngealmucosa

• Mean shedding of virus 7.6 days – longerin children

• One instance of transmission of vaccinevirus documented in a child care setting

• Transmitted virus retained attenuated,cold-adapted, temperature-sensitivecharacteristics

• No transmission of LAIV reported in theU.S.

Inactivated InfluenzaVaccine Efficacy

• 70%-90% effective among healthypersons <65 years of age

• 30%-40% effective among frailelderly persons

• 50%-60% effective in preventinghospitalization

• 80% effective in preventing death

LAIV Efficacy in HealthyChildren

• 87% effective against culture-confirmed influenza in children5-7 years old

• 27% reduction in febrile otitis media(OM)

• 28% reduction in OM withaccompanying antibiotic use

• Decreased fever and OM in vaccinerecipients who developed influenza

LAIV Phase 3, 10 sites, 1602 kids,1-6 yrs old

1 dose ! 89% efficacy2 doses ! 94% efficacy

1 year later 100% effective against 3 strainsadministered previously, plus 98% effectiveagainst the new circulating strain A/Sydney

PLUS

98% effective both years against ear infections

LAIV Phase 3, 92 adults, 18-45years

1 dose LAIV ! 85% efficacy1 dose TIV ! 71% efficacy

1 year later, A/SydneyLAIV ! 100% efficacy

TIV ! 0% efficacy

Timing of InactivatedInfluenza Vaccine Programs

• Actively target vaccine available inSeptember and October to personsat increase risk of influenzacomplications, children <9 years,and healthcare workers

• Vaccination of all other groupsshould begin in November

• Continue vaccinating throughDecember and later, as long asvaccine is available

Influenza VaccineRecommendations

• Healthcare providers, includinghome care*

• Employees of long-term carefacilities

• Household contacts of high-riskpersons

*LAIV should not be administered to healthcare workers who havecontact with severely immunosuppressed persons who requirehospitalization and care in a protective environment

Influenza Vaccination ofHealthcare Personnel

Only 42 percent of U.S. healthcarepersonnel were vaccinated in 2004

• Reduction in nosocomial influenza andinfluenza-related deaths

• Reduction in staff illness and illness-related absenteeism

• Reduction of direct medical costs andindirect costs from work absenteeism

Reasons HCP Do Not ReceiveInfluenza Vaccine

• Concern about vaccine adverseevents

• Perception of a low personal risk of

• influenza virus infection

• Insufficient time or inconvenience

• Reliance on homeopathicmedications

• Avoidance of all medications

• Fear of needles

MMWR 2006;55 (RR-2)

Inactivated Influenza VaccineAdverse Reactions

Local reactions 15%-20%

Fever, malaise not common

Allergic reactions rare

Neurological very rarereactions

Adverse Reactions in men

Live Attenuated Influenza VaccineContraindications and Precautions

• Children <5 years of age*

• Persons >50 years of age*

• Persons with chronic medicalconditions*

• Children and adolescentsreceiving long-term aspirintherapy*

*These persons should receive inactivated influenza vaccine

Live Attenuated Influenza VaccineContraindications and Precautions

• Immunosuppression from any cause

• Pregnant women*

• Severe (anaphylactic) allergy to eggor other vaccine components

• History of Guillian-Barré syndrome

• Moderate or severe acute illness

*These persons should receive inactivated influenza vaccine

LAIV Storage and Handling

• Must be stored at < 5°F (-15°C )*

• May be stored in a frost-free freezerwith a separate door

• May be thawed in a refrigerator andstored at 35°-46°F (2°-8°C) for up to 60hours before use

• Should not be refrozen after thawing

*a refrigerator-stable formulation of LAIV may beavailable beginning in the 2007-2008 influenza season

Influenza Antiviral Use, 2006-2007*

• Neither amantadine nor rimantadinebe used for the treatment orchemoprophylaxis of influenza Ainfections in the United States duringthe 2006- 2007 influenza season

• Oseltamivir (Tamiflu) or zanamivir(Relenza) should be prescribed if anantiviral drug is indicated for thetreatment or chemoprophylaxis ofinfluenza

*see influenza ACIP statement or CDC influenza website for details

Influenza Surveillance

• Monitor prevalence of circulatingstrains and detect new strains

• Estimate influenza-relatedmorbidity, mortality and economicloss

• Rapidly detect outbreaks

• Assist disease control throughrapid preventive action