1. Influenza, Hib and Rotavirus
Chapters 16,9 and 20

2. Influenza Highly infectious viral illness First pandemic in 1580
At least 4 pandemics in 19th century
Estimated 21 million deaths worldwide in pandemic of
Virus first isolated in 1933

3. Influenza Virus Single-stranded RNA virus Orthomyxoviridae family
3 types: A, B, C
Subtypes of type A determined by hemagglutinin and neuraminidase

4. 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

5. Influenza Virus A/Fujian/411/2002 (H3N2) Virus type Geographic origin
Neuraminidase
Hemagglutinin
Type of nuclear
material
Virus
type
Geographic
origin
Strain
number
Year of
isolation
subtype

6. Influenza Antigenic Changes
Hemagglutinin and neuraminidase antigens change with time
Changes occur as a result of point mutations in the virus gene, or due to exchange of a gene segment with another subtype of influenza virus
Impact of antigenic changes depend on extent of change (more change usually means larger impact)

7. Influenza Antigenic Changes
Antigenic Shift
major change, new subtype
caused by exchange of gene segments
may result in pandemic
Example of antigenic shift
H2N2 virus circulated in
H3N2 virus appeared in 1968 and completely replaced H2N2 virus

8. Influenza Antigenic Changes
Antigenic Drift
minor change, same subtype
caused by point mutations in gene
may result in epidemic
Example of antigenic drift
in , A/Panama/2007/99 (H3N2) virus was dominant
A/Fujian/411/2002 (H3N2) appeared in late 2003 and caused widespread illness in

9. Influenza Type A Antigenic Shifts
Severity of
Pandemic
Moderate
Severe
Mild
Year
1889
1918
1957
1968
1977
Subtype
H3N2
H1N1
H2N2

10. Impact of Pandemic Influenza Today
200 million people could be affected
Up to 40 million require outpatient visits
Up to 700,000 hospitalized
89, ,000 deaths

11. Influenza Pathogenesis
Respiratory transmission of virus
Replication in respiratory epithelium with subsequent destruction of cells
Viremia rarely documented
Viral shedding in respiratory secretions for 5-10 days

12. Influenza Clinical Features
Incubation period 2 days (range 1-4 days)
Abrupt onset of fever, myalgia, sore throat, nonproductive cough, headache
Severity of illness depends on prior experience with related variants

13. Influenza Complications
Pneumonia
secondary bacterial
primary influenza viral
Reye syndrome
Myocarditis
Death per 1,000 cases

14. Impact of Influenza-United States, 1990-1999
Highest rates of complications and hospitalization among young children and person 65 years and older
Average of more than 200,000 influenza-related excess hospitalizations
57% of hospitalizations among persons younger than 65 years of age
Greater number of hospitalizations during type A (H3N2) epidemics

15. Influenza Diagnosis Clinical and epidemiological characteristics
Isolation of influenza virus from clinical specimen (e.g., nasopharynx, throat, sputum)
Significant rise in influenza IgG by serologic assay
Direct antigen testing for type A virus

16. Influenza Epidemiology
Reservoir Human, animals (type A
only)
Transmission Respiratory Probably airborne
Temporal pattern Peak December – March in temperate climate May occur earlier or later
Communicability 1 day before to 5 days after onset (adults)

17. Month of Peak Influenza Activity United States, 1976-2006
45%
19%
13%
13% 3% 3%
MMWR 2007;55(RR-6):5

18. Influenza Vaccines Inactivated subunit (TIV) intramuscular trivalent
split virus and subunit types
duration of immunity 1 year or less
Live attenuated vaccine (LAIV)
intranasal
duration of immunity at least 1 year

19. Composition of the 2008-2009 Influenza 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

20. Inactivated Influenza Vaccines Available in 2007-2008
Package
Dose
Age
Fluzone
(sanofi pasteur)
Multi-dose vial*+
Age-dependent
>6 mos
Single dose syringe*
0.25 mL
6-35 mos
0.5 mL
>36 mos
Single dose vial*
*vaccines approved for children younger than 4 years
+all multi-dose vials contain thimerosal as a preservative

21. Inactivated Influenza Vaccines Available in 2007-2008
Package
Dose
Age
Fluvirin
(Novartis)
Multi-dose vial+
0.5 mL
>4 yrs
Fluarix
(GSK)
Single dose syringe
>18 yrs
FluLaval
Afluria
(CSL)
+all multi-dose vials contain thimerosal as a preservative

22. Transmission of LAIV Virus
LAIV replicates in the nasopharyngeal mucosa
Mean shedding of virus 7 days – longer in children
One instance of transmission of vaccine virus documented in a child care setting
Transmitted virus retained attenuated, cold-adapted, temperature-sensitive characteristics
No transmission of LAIV reported in the U.S.

23. Inactivated Influenza Vaccine Efficacy
70%-90% effective among healthy persons younger than 65 years of age
30%-40% effective among frail elderly persons
50%-60% effective in preventing hospitalization
80% effective in preventing death

24. LAIV Efficacy in Healthy Adults
20% fewer severe febrile illness episodes
24% fewer febrile upper respiratory illness episodes
27% fewer lost work days due to febrile upper respiratory illness
18%-37% fewer days of healthcare provider visits due to febrile illness
41%-45% fewer days of antibiotic use

25. Inactivated Influenza Vaccine Schedule
Dose
0.25 mL
0.50 mL
Age
Group
6-35 mos
3-8 yrs
>9 yrs
No.
Doses
1* or 2 1
*Only one dose is needed if the child received 2 doses of influenza vaccine during the previous influenza season

26. Influenza Vaccination of Children 6 Months Through 8 Years Of Age*
Previous vaccination
One dose last year
One dose in each of the last 2 years
One dose 3 years ago
One dose in each of the last 3 years
Vaccine THIS year
Two doses
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

27. Inactivated Influenza Vaccine Recommendations
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 years receiving chronic aspirin therapy
Persons 6 months of age or older with chronic illness

28. Inactivated Influenza Vaccine Recommendations
Persons with the following chronic illnesses should be considered for inactivated influenza vaccine:
pulmonary (e.g., asthma, COPD)
cardiovascular (e.g., CHF)
metabolic (e.g., diabetes)
renal dysfunction
hemoglobinopathy
immunosuppression, including HIV infection
any condition that can compromise respiratory function or the handling of respiratory secretions

29. Pregnancy and Inactivated Influenza Vaccine
Risk of hospitalization 4 times higher than nonpregnant women
Risk of complications comparable to nonpregnant women with high-risk medical conditions
Vaccination (with TIV) recommended if pregnant during influenza season
Vaccination can occur during any trimester

30. HIV Infection and Inactivated Influenza Vaccine
Persons with HIV at increased risk of complications of influenza
TIV induces protective antibody titers in many HIV infected persons
TIV will benefit many HIV-infected persons
Do not administer LAIV to persons with HIV infection

31. Live Attenuated Influenza Vaccine Schedule
Age Group
2 - 8 years, no previous influenza vaccine
2 - 8 years, previous influenza vaccine *
years
Number of Doses 2
(separated by 4 weeks) 1
* LAIV or inactivated vaccine

32. Live Attenuated Influenza Vaccine Adverse Reactions
Children
no significant increase in URI symptoms, fever, or other systemic symptoms
significantly increased risk of asthma or reactive airways disease in children months of age
Adults
significantly increased rate of cough, runny nose, nasal congestion, sore throat, and chills reported among vaccine recipients
no increase in the occurrence of fever
No serious adverse reactions identified
These symptoms were reported in 10 to 40 percent of both vaccine and placebo recipients. LAIV not licensed for children <60 months of age.

33. Inactivated Influenza Vaccine Contraindications and Precautions
Severe allergic reaction to a vaccine component (e.g., egg) or following a prior dose of vaccine
Moderate or severe acute illness
History of Guillian Barre’ syndrome within 6 weeks following a previous dose of TIV (precaution)

34. Live Attenuated Influenza Vaccine Contraindications and Precautions
Children younger than 2 years of age*
Persons 50 years of age or older*
Persons with chronic medical conditions*
Children and adolescents receiving long-term aspirin therapy*
*These persons should receive inactivated influenza vaccine

35. Live Attenuated Influenza Vaccine Contraindications and Precautions
Immunosuppression from any cause*
Pregnant women*
Severe (anaphylactic) allergy to egg or other vaccine components
History of Guillian-Barré syndrome
Children younger than 5 years with recurrent wheezing*
Moderate or severe acute illness
*These persons should receive inactivated influenza vaccine

36. Influenza Antiviral Agents*
Amantadine and rimantadine
Not recommended because of documented resistance in U.S. influenza isolates
Zanamivir and oseltamivir
neuraminidase inhibitors
effective against influenza A and B
should be used if an influenza antiviral drug is indicated for chemoprophylaxis or treatment
*see influenza ACIP statement or CDC influenza website for details

37. Haemophilus influenzae type B and Hib Vaccine
Chapter 9

38. Haemophilus influenzae type b
Severe bacterial infection, particularly among infants
During late 19th century believed to cause influenza
Immunology and microbiology clarified in 1930s

39. Haemophilus influenzae
Aerobic gram-negative bacteria
Polysaccharide capsule
Six different serotypes (a-f) of polysaccharide capsule
95% of invasive disease caused by type b

40. Haemophilus influenzae type b Pathogenesis
Organism colonizes nasopharynx
In some persons organism invades bloodstream and cause infection at distant site
Antecedent upper respiratory tract infection may be a contributing factor

41. Haemophilus influenzae type b
Clinical Features*
*prevaccination era

42. Haemophilus influenzae type b Medical Management
Hospitalization required
Treatment with an effective 3rd generation cephalosporin, or chloramphenicol plus ampicillin
Ampicillin-resistant strains now common throughout the United States

43. Haemophilus influenzae type b Epidemiology
Reservoir Human Asymptomatic carriers
Transmission Respiratory droplets
Temporal pattern Peaks in Sept-Dec and March-May
Communicability Generally limited but higher in some circumstances
Limited communicability implied from lack of secondary cases in household settings. Secondary cases may occur in some situations, such as day care settings.

44. Incidence*of Invasive Hib Disease, 1990-2005
Year
*Rate per 100,000 children <5 years of age

45. Haemophilus influenzae type b—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 or incompletely vaccinated children

46. Haemophilus influenzae type b Risk Factors for Invasive Disease
Exposure factors
household crowding
large household size
child care attendance
low socioeconomic status
low parental education
school-aged siblings
Host factors
race/ethnicity
chronic disease

47. Haemophilus influenzae type b Polysaccharide Vaccine
Available
Not effective in children younger than 18 months of age
Effectiveness in older children variable
Age-related immune response
Not consistently immunogenic in children 2 years of age and younger
No booster response
Antibody with less functional activity

48. Polysaccharide Conjugate Vaccines
Stimulates T-dependent immunity
Enhanced antibody production, especially in young children
Repeat doses elicit booster response

49. Haemophilus influenzae type b Conjugate Vaccines
Two conjugate vaccines licensed for use in infants as young as 6 weeks of age
Use different carrier proteins
3 doses of any combination confers protection

50. Conjugate Hib Vaccines*
PRP-T ActHIB, TriHIBit
PRP-OMP PedvaxHIB, Comvax
*HbOC (HibTiter) no longer available in the United States

51. Haemophilus influenzae type b Vaccine
Routine Schedule
Vaccine
2 mo
4 mo
6 mo
12-18 mo
PRP-T x x x x
PRP-OMP x x x

52. Haemophilus influenzae type b Vaccine Interchangeability
Both conjugate Hib vaccines (except TriHIBit) are interchangeable for primary series and booster dose
3 dose primary series if more than one brand of vaccine used

53. Haemophilus influenzae type b Vaccine Delayed Vaccination Schedule
Unvaccinated children 7 months of age or older may not need entire 3 or 4 dose series
Number of doses child requires depends on current age
All children months of age need at least 1 dose

54. Lapsed Immunization
Children who have fallen behind schedule with Hib vaccine may not need all the remaining doses of a 3 or 4 dose series
The number of doses needed to complete the series should be determined using the catch-up schedule*, published annually with the childhood schedule
*available at ww.cdc.gov/vaccines/recs/schedules/child-schedule.htm

55. Haemophilus influenzae type b Vaccine Vaccination Following Invasive Disease
Children younger than 24 months may not develop protective antibody after invasive disease
Vaccinate during convalescence
Complete series for age

56. Haemophilus influenzae type b Vaccine Use in Older Children and Adults
Generally not recommended for persons older than 59 months of age
Consider for high-risk persons: asplenia, immunodeficiency, HIV infection
One pediatric dose of any conjugate vaccine
3 doses recommended for all persons who have received a hematopoietic stem cell transplant

57. Combination Vaccines Containing Hib
DTaP—Hib
TriHIBit
Hepatitis B—Hib
Comvax

58. Hib Vaccination Recommendations During the Current Shortage
The booster dose of Hib vaccine usually administered at months of age should be deferred except for children at increased risk of Hib disease
asplenia
sickle cell disease
immunodeficiency (including HIV infection and cancer)
American Indian/Alaska Native children
MMWR 2007; 56(50);

59. Rotavirus and Rotavirus Vaccine
Chapter 20

60. Rotavirus First identified as cause of diarrhea in 1973
Most common cause of severe diarrhea in infants and children
Nearly universal infection by 5 years of age
Responsible for up to 500,000 diarrheal deaths each year worldwide

61. Rotavirus Reovirus (RNA) VP7 and VP4 antigens define virus serotype.
5 predominant strains in U.S. (G1-G4, G9) and account for 90% of isolates
G1 strain accounts for 73% of infections
Very stable and may remain viable for weeks or months if not disinfected

62. Rotavirus Pathogenesis
Entry through mouth
Replication in epithelium of small intestine
Replication outside intestine and viremia uncommon
Infection leads to isotonic diarrhea

63. Rotavirus Immunity
Antibody against VP7 and VP4 probably important for protection
First infection usually does not lead to permanent immunity
Reinfection can occur at any age
Subsequent infections generally less severe

64. Rotavirus Clinical Features
Incubation period 1-3 days
Clinical manifestations depend on whether it is the first infection or reinfection
First infection after age 3 months generally most severe
May be asymptomatic or result in severe dehydrating diarrhea with fever and vomiting
Gastrointestinal symptoms generally resolve in 3 to 7 days

65. Rotavirus Complications
Severe diarrhea
Dehydration
Electrolyte imbalance
Metabolic acidosis
Immunodeficient children may have more severe or persistent disease

66. Rotavirus Disease Burden in the United States
Estimated 2.7 million cases per year
95% of children infected by 5 years of age
The most severe disease occurs among children 3-24 months of age
Highest incidence among children 3 to 35 months of age
Responsible for 5%-10% of all gastroenteritis episodes among children younger than 5 years of age

67. Rotavirus Epidemiology
Reservoir Human-GI tract
Transmission Fecal-oral, fomites
Temporal Fall and winter pattern (temperate areas)
Communicability 2 days before to days after onset

68. Risk Groups for Rotavirus Diarrhea
Groups with increased exposure to virus
Children in child care centers
Children in hospital wards (nosocomial rotavirus)
Caretakers, parents of these children
Children, adults with immuno- deficiency related diseases (e.g. SCID, HIV, bone marrow transplant)

69. Rotavirus Vaccine (RotaTeq®)
Approved by FDA in February 2006
Contains five reassortant rotaviruses developed from human and bovine parent rotavirus strains
Vaccine viruses suspended in a solution of buffer (sodium citrate and phosphate) and stabilizer
Contains no preservatives or thimerosal

70. Rotarix® Rotavirus Vaccine
Approved by FDA in April 2008
Contains one strain of live attenuated human rotavirus (G1P[8])
Two oral doses at 2 and 4 months of age (minimum interval 4 weeks)
Minimum age 6 weeks
Maximum age 24 weeks
ACIP recommendations for use are pending

71. RotaTeq Vaccine Efficacy
Phase III trials included more than 70,000 infants 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 not known
N Eng J Med 2006;354:23-33

72. Rotavirus Vaccine Recommendations
Routine immunization of all infants without contraindications
Administered at 2, 4, and 6 months of age*
Minimum age of first doses is 6 weeks
First dose should be administered between 6 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.

73. Rotavirus Vaccine Recommendations
Minimum interval between doses is 4 weeks
Maximum age for ANY dose is 32 weeks*
Do not administer on or after age 32 weeks*, even if fewer than three doses have been administered
*24 weeks for Rotarix
MMWR 2006;55:(RR-12):1-13.

74. Rotavirus Vaccine Recommendations
Administer simultaneously with all other indicated vaccines
Breastfeeding infants should be vaccinated on usual schedule
Vaccinate infants who have recovered from documented rotavirus infection
Do not repeat dose if infant spits out or regurgitates vaccine- administer remaining doses on schedule
MMWR 2006;55:(RR-12):1-13.

75. Rotavirus Vaccine and Intussusception*
Recipients
6 cases
13 cases
Placebo
Recipients
5 cases
15 cases
Within 42 days
of vaccination
Within 1 year
*data shown are for RotaTeq; no increased risk of IS was observed in Rotarix clinical trials.
New Eng J Med 2006;354:23-33

76. Rotavirus Vaccine Adverse Reactions
Vomiting 15%
Diarrhea 24%
Nasopharyngitis 7%
Fever %
No serious adverse reactions reported
*data shown are for RotaTeq
MMWR 2006;55:(RR-12):1-13.

77. Rotavirus Vaccine Contraindications
Severe allergic reaction to a vaccine component or following a prior dose of vaccine

78. Rotavirus Vaccine Precautions*
Altered immunocompetence
Recent receipt of blood product
Acute, moderate to severe gastroenteritis or other acute illness
Pre-existing chronic GI disease
Infants with history of intussusception
*the decision to vaccinate if a precaution is present should be made on a case-by-case risk and benefit basis

79. Rotavirus Vaccine and Preterm Infants
Few data available
ACIP supports the vaccination of a preterm infant if:
the infant is at least 6 weeks of age; and
is being or has been discharged from the hospital; and
is clinically stable
MMWR 2006;55:(RR-12):1-13.

80. Immunosuppressed Household Contacts of Rotavirus Vaccine Recipients
Protection of the immunocompromised household member afforded by vaccination of young children in the household outweighs the small risk for transmitting vaccine virus to the immunocompromised household member
Household should employ measures such as good handwashing after contact with the feces of the vaccinated infant