Influenza, Hib andRotavirus

Chapters 16,9 and 20

Influenza

• Highly infectious viral illness

• First pandemic in 1580

• At least 4 pandemics in 19th century

• Estimated 21 million deaths worldwidein pandemic of 1918-1919

• Virus first isolated in 1933

Influenza Virus

• Single-stranded RNA virus

• Orthomyxoviridae family

• 3 types: A, B, C

• Subtypes of type A determined byhemagglutinin and neuraminidase

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

Influenza Virus

A/Fujian/411/2002 (H3N2)

Neuraminidase

Hemagglutinin

Type of nuclear

material

Virus

type

Geographic

origin

Strain

number

Year of

isolation

Virus

subtype

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 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

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 Type A Antigenic Shifts

Year

1889

1918

1957

1968

1977

Subtype

H3N2

H1N1

H2N2

H3N2

H1N1

Severity ofPandemic

Moderate

Severe

Severe

Moderate

Mild

Impact of Pandemic Influenza Today

• 200 million people could be affected

• Up to 40 million require outpatientvisits

• Up to 700,000 hospitalized

• 89,000 - 200,000 deaths

Influenza Pathogenesis

• Respiratory transmission of virus

• Replication in respiratory epitheliumwith subsequent destruction of cells

• Viremia rarely documented

• Viral shedding in respiratorysecretions for 5-10 days

Influenza Clinical Features

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

• Abrupt onset of fever, myalgia, sorethroat, nonproductive cough,headache

• Severity of illness depends on priorexperience with related variants

Influenza Complications

• Pneumonia

–secondary bacterial

–primary influenza viral

• Reye syndrome

• Myocarditis

• Death 0.5-1 per 1,000 cases

• Highest rates of complications andhospitalization among young childrenand person 65 years and older

• Average of more than 200,000influenza-related excesshospitalizations

• 57% of hospitalizations amongpersons younger than 65 years of age

• Greater number of hospitalizationsduring type A (H3N2) epidemics

Impact of Influenza-United States,1990-1999

Influenza Diagnosis

• Clinical and epidemiologicalcharacteristics

• Isolation of influenza virus fromclinical specimen (e.g., nasopharynx,throat, sputum)

• Significant rise in influenza IgG byserologic assay

• Direct antigen testing for type A virus

Influenza Epidemiology

• Reservoir Human, animals (type Aonly)

• 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%

19%

45%

13%

3% 3%

MMWR 2007;55(RR-6):5

Influenza Vaccines

• Inactivated subunit (TIV)

–intramuscular

–trivalent

–split virus and subunit types

–duration of immunity 1 year or less

• Live attenuated vaccine (LAIV)

–intranasal

–trivalent

–duration of immunity at least 1 year

Composition of the 2008-2009Influenza Vaccine*

• A/Brisbane/59/2007 (H1N1)

• A/Brisbane/10/2007 (H3N2)

• B/Florida/4/2006

*manufacturers may use strains that are antigenically identical to

the selected strains

Inactivated Influenza VaccinesAvailable in 2007-2008

0.5 mL

0.5 mL

0.25 mL

Age-dependent

Dose

>36 mosSingle dosevial*

>36 mosSingle dosesyringe*

6-35 mosSingle dosesyringe*

>6 mosMulti-dosevial*+

Fluzone(sanofipasteur)

AgePackageVaccine

*vaccines approved for children younger than 4 years

+all multi-dose vials contain thimerosal as a preservative

Inactivated Influenza VaccinesAvailable in 2007-2008

>18 yrs0.5 mLSingle dosesyringe

Afluria

(CSL)

>18 yrs0.5 mLMulti-dosevial+

>18 yrs0.5 mLMulti-dosevial+

FluLaval

(GSK)

>18 yrs0.5 mLSingle dosesyringe

Fluarix

(GSK)

0.5 mL

Dose

>4 yrsMulti-dosevial+

Fluvirin

(Novartis)

AgePackageVaccine

+all multi-dose vials contain thimerosal as a preservative

Transmission of LAIV Virus

• LAIV replicates in the nasopharyngealmucosa

• Mean shedding of virus 7 days – longer inchildren

• 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 younger than 65 years of age

• 30%-40% effective among frail elderlypersons

• 50%-60% effective in preventinghospitalization

• 80% effective in preventing death

LAIV Efficacy in Healthy Adults

• 20% fewer severe febrile illnessepisodes

• 24% fewer febrile upper respiratoryillness episodes

• 27% fewer lost work days due tofebrile upper respiratory illness

• 18%-37% fewer days of healthcareprovider visits due to febrile illness

• 41%-45% fewer days of antibiotic use

Inactivated Influenza Vaccine Schedule

AgeGroup

6-35 mos

3-8 yrs

>9 yrs

Dose0.25 mL

0.50 mL

0.50 mL

No.Doses1* or 2

1* or 2

1

*Only one dose is needed if the child received 2 doses of

influenza vaccine during the previous influenza season

Influenza Vaccination of Children 6Months Through 8 Years Of Age*

Previous vaccination

One dose last year

One dose in each ofthe last 2 years

One dose 3 years ago

One dose in each ofthe last 3 years

Vaccine THIS year

Two doses

One dose

One dose

One dose

*children 9 years and older should receive only one

dose of influenza vaccine per year regardless of the

number of doses in previous years

Inactivated Influenza VaccineRecommendations

• All persons 50 years of age or older

• Children 6-59 months of age

• Residents of long-term care facilities

• Pregnant women

• Persons 6 months to 18 yearsreceiving chronic aspirin therapy

• Persons 6 months of age or older withchronic illness

Inactivated Influenza VaccineRecommendations

• Persons with the following chronic illnessesshould be considered for inactivated influenzavaccine:

–pulmonary (e.g., asthma, COPD)

–cardiovascular (e.g., CHF)

–metabolic (e.g., diabetes)

–renal dysfunction

–hemoglobinopathy

– immunosuppression, including HIV infection

–any condition that can compromiserespiratory function or the handling ofrespiratory secretions

Pregnancy and InactivatedInfluenza Vaccine

• Risk of hospitalization 4 times higherthan nonpregnant women

• Risk of complications comparable tononpregnant women with high-riskmedical conditions

• Vaccination (with TIV) recommendedif pregnant during influenza season

• Vaccination can occur during anytrimester

HIV Infection and InactivatedInfluenza Vaccine

• Persons with HIV at increased risk ofcomplications of influenza

• TIV induces protective antibody titersin many HIV infected persons

• TIV will benefit many HIV-infectedpersons

• Do not administer LAIV to personswith HIV infection

Age Group2 - 8 years, no

previous influenzavaccine

2 - 8 years, previousinfluenza vaccine *

9 - 49 years

Number of Doses2

(separated by 4 weeks)

1

1

* LAIV or inactivated vaccine

Live Attenuated Influenza VaccineSchedule

Live Attenuated Influenza VaccineAdverse Reactions

• Children

–no significant increase in URI symptoms,fever, or other systemic symptoms

–significantly increased risk of asthma orreactive airways disease in children 12-59months of age

• Adults

–significantly increased rate of cough, runnynose, nasal congestion, sore throat, and chillsreported among vaccine recipients

–no increase in the occurrence of fever

• No serious adverse reactions identified

Inactivated Influenza VaccineContraindications and Precautions

• Severe allergic reaction to a vaccinecomponent (e.g., egg) or following aprior dose of vaccine

• Moderate or severe acute illness

• History of Guillian Barre’ syndromewithin 6 weeks following a previousdose of TIV (precaution)

Live Attenuated Influenza VaccineContraindications and Precautions

• Children younger than 2 years of age*

• Persons 50 years of age or older*

• Persons with chronic medicalconditions*

• Children and adolescents receivinglong-term aspirin therapy*

*These persons should receive inactivated influenza vaccine

Live Attenuated Influenza VaccineContraindications and Precautions

• Immunosuppression from any cause*

• Pregnant women*

• Severe (anaphylactic) allergy to egg orother vaccine components

• History of Guillian-Barré syndrome

• Children younger than 5 years withrecurrent wheezing*

• Moderate or severe acute illness

*These persons should receive inactivated influenza vaccine

Influenza Antiviral Agents*

• Amantadine and rimantadine

–Not recommended because ofdocumented resistance in U.S.influenza isolates

• Zanamivir and oseltamivir

–neuraminidase inhibitors

–effective against influenza A and B

–should be used if an influenzaantiviral drug is indicated forchemoprophylaxis or treatment

*see influenza ACIP statement or CDC influenza website for details

Haemophilus influenzae type B andHib Vaccine

Chapter 9

Haemophilus influenzae type b

• Severe bacterial infection, particularlyamong infants

• During late 19th century believed tocause influenza

• Immunology and microbiologyclarified in 1930s

Haemophilus influenzae

• Aerobic gram-negative bacteria

• Polysaccharide capsule

• Six different serotypes (a-f) ofpolysaccharide capsule

• 95% of invasive disease causedby type b

Haemophilus influenzae type bPathogenesis

• Organism colonizes nasopharynx

• In some persons organism invadesbloodstream and cause infection atdistant site

• Antecedent upper respiratory tractinfection may be a contributing factor

Haemophilus influenzae type bClinical Features*

*prevaccination era

Haemophilus influenzae type bMedical Management

• Hospitalization required

• Treatment with an effective 3rdgeneration cephalosporin, orchloramphenicol plus ampicillin

• Ampicillin-resistant strains nowcommon throughout the United States

Haemophilus influenzae type bEpidemiology

• Reservoir Human Asymptomatic carriers

• Transmission Respiratory droplets

• Temporal pattern Peaks in Sept-Decand March-May

• Communicability Generally limited buthigher in somecircumstances

Incidence*of Invasive Hib Disease,1990-2005

*Rate per 100,000 children <5 years of age

Year

Haemophilus influenzae typeb—United States, 2002-2006

• Incidence has fallen more than 99%since prevaccine era

• 123 confirmed Hib cases reported(average of 25 cases per year)

• Most recent cases in unvaccinated orincompletely vaccinated children

Haemophilus influenzae type bRisk Factors for Invasive Disease

• Exposure factors

–household crowding

– large household size

–child care attendance

– low socioeconomicstatus

– low parental education

–school-aged siblings

• Host factors

–race/ethnicity

–chronic disease

Haemophilus influenzae type bPolysaccharide Vaccine

• Available 1985-1988

• Not effective in childrenyounger than 18 months of age

• Effectiveness in older children variable

• Age-related immune response

• Not consistently immunogenic inchildren 2 years of age and younger

• No booster response

• Antibody with less functional activity

Polysaccharide ConjugateVaccines

• Stimulates T-dependent immunity

• Enhanced antibody production,especially in young children

• Repeat doses elicit booster response

Haemophilus influenzae type bConjugate Vaccines

• Two conjugate vaccines licensed foruse in infants as young as 6 weeks ofage

• Use different carrier proteins

• 3 doses of any combination confersprotection

PRP-T ActHIB, TriHIBit

PRP-OMP PedvaxHIB, Comvax

Conjugate Hib Vaccines*

*HbOC (HibTiter) no longer available in the United States

Vaccine 2 mo 4 mo 6 mo 12-18 mo

PRP-T x x x x

PRP-OMP x x x

Haemophilus influenzae type b Vaccine

Routine Schedule

Haemophilus influenzae type bVaccine Interchangeability

• Both conjugate Hib vaccines (exceptTriHIBit) are interchangeable forprimary series and booster dose

• 3 dose primary series if more than onebrand of vaccine used

Haemophilus influenzae type b VaccineDelayed Vaccination Schedule

• Unvaccinated children 7 months of ageor older may not need entire 3 or 4dose series

• Number of doses child requiresdepends on current age

• All children 15-59 months of age needat least 1 dose

Lapsed Immunization

• Children who have fallen behindschedule with Hib vaccine may notneed all the remaining doses of a 3 or 4dose series

• The number of doses needed tocomplete the series should bedetermined using the catch-upschedule*, published annually with thechildhood schedule

*available at ww.cdc.gov/vaccines/recs/schedules/child-schedule.htm

Haemophilus influenzae type b VaccineVaccination Following Invasive Disease

• Children younger than 24 months maynot develop protective antibody afterinvasive disease

• Vaccinate during convalescence

• Complete series for age

Haemophilus influenzae type b VaccineUse in Older Children and Adults

• Generally not recommended forpersons older than 59 months of age

• Consider for high-risk persons:asplenia, immunodeficiency, HIVinfection

–One pediatric dose of any conjugatevaccine

• 3 doses recommended for all personswho have received a hematopoieticstem cell transplant

Combination Vaccines ContainingHib

• DTaP—Hib

–TriHIBit

• Hepatitis B—Hib

–Comvax

Hib Vaccination RecommendationsDuring the Current Shortage

• The booster dose of Hib vaccine usuallyadministered at 12-15 months of ageshould be deferred except for children atincreased risk of Hib disease

–asplenia

–sickle cell disease

–immunodeficiency (including HIVinfection and cancer)

–American Indian/Alaska Native children

MMWR 2007; 56(50);1318-1320

Rotavirus and RotavirusVaccine

Chapter 20

Rotavirus

• First identified as cause of diarrheain 1973

• Most common cause of severediarrhea in infants and children

• Nearly universal infection by 5years of age

• Responsible for up to 500,000diarrheal deaths each yearworldwide

• Reovirus (RNA)

• VP7 and VP4 antigens define virusserotype.

• 5 predominant strains in U.S. (G1-G4, G9) and account for 90% ofisolates

• G1 strain accounts for 73% ofinfections

• Very stable and may remain viablefor weeks or months if notdisinfected

Rotavirus

Rotavirus Pathogenesis

• Entry through mouth

• Replication in epithelium of smallintestine

• Replication outside intestine andviremia uncommon

• Infection leads to isotonic diarrhea

Rotavirus Immunity

• Antibody against VP7 and VP4probably important for protection

• First infection usually does not lead topermanent immunity

• Reinfection can occur at any age

• Subsequent infections generally lesssevere

Rotavirus Clinical Features

• Incubation period 1-3 days

• Clinical manifestations depend onwhether it is the first infection orreinfection

• First infection after age 3 monthsgenerally most severe

• May be asymptomatic or result in severedehydrating diarrhea with fever andvomiting

• Gastrointestinal symptoms generallyresolve in 3 to 7 days

Rotavirus Complications

• Severe diarrhea

• Dehydration

• Electrolyte imbalance

• Metabolic acidosis

• Immunodeficient children may havemore severe or persistent disease

Rotavirus Disease Burden in theUnited States

• Estimated 2.7 million cases per year

• 95% of children infected by 5 years of age

• The most severe disease occurs amongchildren 3-24 months of age

• Highest incidence among children 3 to 35months of age

• Responsible for 5%-10% of allgastroenteritis episodes among childrenyounger than 5 years of age

Rotavirus Epidemiology

• Reservoir Human-GI tract

• Transmission Fecal-oral, fomites

• Temporal Fall and winterpattern (temperate areas)

• Communicability 2 days before to 10days after onset

Risk Groups for Rotavirus Diarrhea

• Groups with increased exposure tovirus

–Children in child care centers

–Children in hospital wards(nosocomial rotavirus)

–Caretakers, parents of thesechildren

–Children, adults with immuno-deficiency related diseases (e.g.SCID, HIV, bone marrow transplant)

Rotavirus Vaccine (RotaTeq®)

• Approved by FDA in February 2006

• Contains five reassortantrotaviruses developed from humanand bovine parent rotavirus strains

• Vaccine viruses suspended in asolution of buffer (sodium citrateand phosphate) and stabilizer

• Contains no preservatives orthimerosal

Rotarix® Rotavirus Vaccine

• Approved by FDA in April 2008

• Contains one strain of liveattenuated human rotavirus (G1P[8])

• Two oral doses at 2 and 4 months ofage (minimum interval 4 weeks)

• Minimum age 6 weeks

• Maximum age 24 weeks

• ACIP recommendations for use arepending

RotaTeq Vaccine Efficacy

• Phase III trials included more than 70,000infants in 11 countries

• Efficacy

–All rotavirus disease - 74%

–Severe rotavirus disease - 98%

–Physician visits for diarrhea-86%reduction

–Rotavirus-related hospitalization-96%reduction

• Efficacy of fewer than 3 doses is notknown

N Eng J Med 2006;354:23-33

Rotavirus VaccineRecommendations

• Routine immunization of all infants withoutcontraindications

• Administered at 2, 4, and 6 months of age*

• Minimum age of first doses is 6 weeks

• First dose should be administered between6 and 12 weeks of age (until age 13 weeks)

• Do not initiate series after 12 weeks of age

*2 doses at 2 and 4 months for Rotarix

MMWR 2006;55:(RR-12):1-13.

• Minimum interval between doses is 4weeks

• Maximum age for ANY dose is 32weeks*

• Do not administer on or after age 32weeks*, even if fewer than three doseshave been administered

Rotavirus VaccineRecommendations

*24 weeks for Rotarix

MMWR 2006;55:(RR-12):1-13.

• Administer simultaneously with allother indicated vaccines

• Breastfeeding infants should bevaccinated on usual schedule

• Vaccinate infants who haverecovered from documentedrotavirus infection

• Do not repeat dose if infant spits outor regurgitates vaccine- administerremaining doses on schedule

Rotavirus VaccineRecommendations

MMWR 2006;55:(RR-12):1-13.

Rotavirus Vaccine andIntussusception*

Within 42 days

of vaccination

Within 1 year

of vaccination

Vaccine

Recipients

6 cases

13 cases

Placebo

Recipients

5 cases

15 cases

*data shown are for RotaTeq; no increased risk of

IS was observed in Rotarix clinical trials.

New Eng J Med 2006;354:23-33

Rotavirus VaccineAdverse Reactions

• Vomiting 15%

• Diarrhea 24%

• Nasopharyngitis 7%

• Fever 43%

• No serious adverse reactionsreported

*data shown are for RotaTeq

MMWR 2006;55:(RR-12):1-13.

Rotavirus VaccineContraindications

• Severe allergic reaction to a vaccinecomponent or following a prior doseof vaccine

Rotavirus VaccinePrecautions*

• Altered immunocompetence

• Recent receipt of blood product

• Acute, moderate to severegastroenteritis or other acute illness

• Pre-existing chronic GI disease

• Infants with history ofintussusception

*the decision to vaccinate if a precaution is present should

be made on a case-by-case risk and benefit basis

Rotavirus Vaccine andPreterm Infants

• Few data available

• ACIP supports the vaccination of apreterm infant if:

–the infant is at least 6 weeks of age;and

–is being or has been dischargedfrom the hospital; and

–is clinically stable

MMWR 2006;55:(RR-12):1-13.

Immunosuppressed Household Contactsof Rotavirus Vaccine Recipients

• Protection of the immunocompromisedhousehold member afforded byvaccination of young children in thehousehold outweighs the small risk fortransmitting vaccine virus to theimmunocompromised householdmember

• Household should employ measuressuch as good handwashing aftercontact with the feces of the vaccinatedinfant