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Pneumococcal DiseaseEpidemiology, Drug resistance
and prevention
By.A.Arputha Selvaraj APMP IIM Calcutta
Epidemiology
Estimated Annual Disease Burden Worldwide Pneumococcal infections are a major cause of morbidity and
mortality worldwide Streptococcus pneumoniae is the #1 cause of bacterial
pneumonia and a leading cause of otitis media Pneumococcal infections cause >1 million annual deaths
worldwide Most deaths occur in developing countries Even in developed countries, invasive pneumococcal disease carries
high mortality in certain population groups (ie, elderly people, especially those living in institutions, and patients with chronic organ failure, diabetes, nephrotic syndrome, and immunodeficiencies)
Adapted from World Health Organization. Weekly Epidemiological Record. 2003;78(14):97-120; Beers MH, et al. The Merck Manual of Diagnosis and Therapy. 18th edition. 2006.
The Primary Causes of Vaccine-Preventable Deaths in All Age Groups Worldwide
Hib = Haemophilus influenzae type b.WHO Official Mortality Rates, 2003, cited in and adapted from Global Alliance for Vaccines & Immunization. Speeding access to new, life-saving vaccines: GAVI’s pneumococcal and rotavirus ADIPs. Available at: http://www.who.int/vaccine_research/about/gvrf/Levine_Orin.pdf. Accessed October 23, 2006. Used with permission.
Vaccine-Preventable Deaths by Cause (WHO data), June 2003
0
200,000
400,000
600,000
800,000
1,000,000
1,200,000
1,400,000
1,600,000
<5 Years of Age ≥5 Years of Age Total
Nu
mb
er o
f D
eath
s
PneumococciMeaslesHepatitis B
RotavirusHibPertussis
TetanusYellow FeverMeningitis AC
DiphtheriaPolio
Estimated Annual Burden of Invasive Pneumococcal Disease in Defined Populations in the US According to Age, 1998–2005 (CDC Data)
CDC = Centers for Disease Control and Prevention.Adapted from Active Bacterial Core Surveillance Report, 1998. Available at: http://www.cdc.gov/ncidod/dbmd/abcs/survreports/spneu98.pdf. Accessed October 24, 2006; ABCs Report, 2001. Available at: http://www.cdc.gov/ncidod/dbmd/abcs/survreports/spneu01.pdf. Accessed October 24, 2006; ABCs Report, 2005. Available at: http://www.cdc.gov/ncidod/dbmd/abcs/survreports/spneu05prelim.pdf. Accessed October 24, 2006.
0
50
100
150
200
250
<1 1 2–4 5–17 18–34 35–49 50–64 65+ Total
Age (years)
1998 (N = 17,383,935)
2001 (N = 22,479,308)
2005 (N = 27,419,898)
Cas
es p
er 1
00,0
00
Epidemiology of Pneumococcal Pneumonia (US CDC Data) Total cases per year
500,000
Hospitalized cases per year 175,000
Case fatality rate 5%–7% (higher in elderly)
Responsible for: Up to 36% of adult community-acquired pneumonia Up to 50% of adult hospital-acquired pneumonia
CDC = Centers for Disease Control and Prevention.Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases: The Pink Book. 9th edition; CDC. MMWR. 2005;54(RR-05):1-9.
Epidemiology of Pneumococcal Bacteremia (US CDC Data)
Cases per year >50,000
Case fatality rate 20% (up to 60% in elderly)
Incidence in patients with pneumococcal pneumonia 25%–30%
CDC = Centers for Disease Control and Prevention.Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases: The Pink Book. 9th edition.
Epidemiology of Pneumococcal Meningitis (US CDC Data)
Cases per year 3,000–6,000
Case fatality rate ~30% (up to 80% in elderly)
Responsible for 13%–19% of all cases of bacterial meningitis
CDC = Centers for Disease Control and Prevention.Adapted from CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases: The Pink Book. 9th edition.
Temporal Incidence Patterns of Invasive Pneumococcal Disease
Pneumococcal infections occur year-round, with seasonal peaks in winter
Monthly Rates of Invasive Pneumococcal Disease in Adults and Children in Defined Populations in Australia, 2004 (N = 2,375) Based on a Surveillance
Study
Adapted from Roche P, et al. Commun Dis Intell. 2006;30(1):80-92. Used with permission.
Jan Feb Mar Apr May Jun Jul Aug Sept Oct Nov Dec
400
350
300
250
200
150
100
50
0
No
tifi
cati
on
s
Month
Total Cases<5 years≥5 years
Incidence of Invasive Pneumococcal Disease in Viral Season (US CDC Data)
Viral season
Mea
n W
eekl
y F
req
uen
cyo
f P
neu
mo
cocc
al D
isea
se
*P < 0.05; †P < 0.01.CDC ABCs = Centers for Disease Control and Prevention Active Bacterial Core Surveillance.Adapted from Talbot TR, et al. Am J Med. 2005;118(3):285-291. Figure used with permission; McCullers JA. Clin Microbiol Rev. 2006;19(3):571-582.
0
20
15
10
5
25
Early1995
1995-1996
1996-1997
1997-1998
1998-1999
1999-2000
2000-2001
2001-2002
Year (July 1–June 30)
††
††
† †
*
Nonviral season
Viral respiratory infections increase the risk of pneumococcal disease
Surveillance Study Conducted in Tennessee, US by CDC ABCs; Total Population of Surveillance Area N = 2,283,929
†
Population At Risk
Populations at Risk of Pneumococcal Disease
Certain age groups ie, persons ≥65 years of age and young children
Cigarette smokers People living in crowded environments People with chronic diseases Immunodeficient individuals Members of certain racial and ethnic groups
ie, African Americans, Alaskan Natives, and American Indians
Adapted from Whitney CG, et al. Clin Infect Dis. 2001;33:662–675; Ortqvist A, et al. Semin Respir Crit Care Med. 2005;26(6):563-574; Fletcher MA, et al. Int J Pract. 2006;60(4):450-456; CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases: The Pink Book. 9th edition.
Epidemiology of Pneumococcal Disease In India
Epidemiology of Pneumococcal Disease In India
CAP = community-acquired pneumonia.*Pseudomonas species, Enterobacter species, Citrobacter species, Acinetobacter species.Adapted from Bansal S, et al. Indian I Chest Dis Allied Sci. 2004;46:17-22. Used with permission.
S pneu
monia
e
K pneu
monia
e
S aure
us
M p
neum
oniae
E coli
Beta-
hemoly
tic
stre
ptoco
cci
Other
Gra
m-n
egat
ive
bacill
i*
0
5
10
15
20
25
30
35
40
% o
f Is
ola
tes
Microbiologic Diagnoses in Patients >15 Years of Age Presenting With CAP March 2000–February 2001 at an
Academic Hospital in Shimla, India (n = 70) Based on a Surveillance Study
Streptococcus pneumoniae: The Bacterium
Gram-positive Polysaccharide
capsule important virulence factor
>90 known capsular types
Type-specific antibody is protective
S pneumoniae and the associated pneumococcal capsular
polysaccharide
CDC. Epidemiology & Prevention of Vaccine-Preventable Diseases: The Pink Book. 9th edition; Ho CF, Lin TY. Chang Gung Med J. 2005;28(11):765-772.
Adapted from Jones C. An Acad Bras Cienc. 2005;77(2):293-324. Epub 2005. Used with permission.
DRUG RESISTANCE
Drug Resistance Complicates Management of Pneumococcal Disease
Multidrug-resistant pneumococci are common and increasing Up to 35% of pneumococcal isolates in some areas are
penicillin-resistant
There are multiple consequences of pneumococcal antibiotic resistance Treatment failures The need for expensive alternative antimicrobial agents Prolonged hospitalization Increased medical costs
Adapted from Whitney CG, et al. N Engl J Med. 2000;343:1917-1924; Whitney CG, et al. Clin Infect Dis. 2001;33:662–675; Schrag SJ, et al. Resistant Pneumococcal Infections. WHO, 2001; CDC. MMWR. 1997;46(RR-08):1-24.
Factors Associated With Pneumococcal Antibiotic Resistance
Young age Setting: day-care centers and hospitals HIV infection Certain infective serotypes (6, 9, 14, 19, and 23) Aspects of community/individual antibiotic use:
Ongoing, recent, repeated, frequent, and/or prophylactic use
Recent use of trimethoprim-sulfa
Adapted from Kristinsson KG. Microb Drug Resist. 1997;3(2):117-123; Schrag SJ, et al. Resistant Pneumococcal Infections. WHO, 2001.
Penicillin Resistance in Asia
ANSORP = Asian Network for Surveillance of Resistant Pathogens; MIC = minimum inhibitory concentrations.*According to the National Committee for Clinical Laboratory Standards (NCCLS) guidelines for breakpoints.Adapted from Song JH, et al. Antimicrob Agents Chemother. 2004;48(6):2101-2107.
0
20
40
60
80
100
China
(n =
111
)
Taiw
an (n
= 5
7)
Korea
(n =
31)
Sri Lan
ka (n
= 4
2)
Singap
ore (n
= 3
5)
Mal
aysi
a (n
= 4
4)
Vietn
am (n
= 6
4)
Philippin
es (n
= 2
2)
Hong Kong (n
= 1
12)
% o
f Is
ola
tes
Resistant (MIC >2 mg/L) Intermediately resistant (MIC 0.12-1 mg/L)
India
(n =
77)
Saudi A
rabia
(n =
39)
Resistance* to Penicillin of 111 S pneumoniae Isolates in ANSORP, 2000–2001
GUIDELINES FOR VACCINATION
Organizations That Have Issued Guidelines for Pneumococcal Vaccination
World Health Organization (International) Advisory Committee on Immunization Practices
(US) American Thoracic Society Canadian Medical Association United Kingdom Department of Health National Health and Medical Research Council
(Australia)Adapted from World Health Organization. Weekly Epidemiological Record. 2003;78(14):97-120; Centers for Disease Control and Prevention. MMWR. 1997;46(RR-08):1–24; National Advisory Committee on Immunization. Canadian Immunization Guide, 2002; United Kingdom Department of Health: The pneumococcal immunisation programme for older people and risk groups, 2005; National Health and Medical Research Council: The Australian Immunisation Handbook, 8th Edition, 2003.
Advisory Committee on Immunization Practices (US)
Recommendations
US ACIP* Recommendations for Pneumococcal Polysaccharide Vaccination: Overview of Candidates
High-risk patients who have not received prior immunization or whose prior vaccination status is unknown All persons ≥65 years of age Persons 2–64 years with underlying medical
conditions Immunocompromised persons >2 years of age
*US ACIP=United States Advisory Committee on Immunization Practices.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for Pneumococcal Polysaccharide Vaccination in Persons >2 Years With Underlying Medical Conditions
Chronic cardiovascular disease Chronic pulmonary disease Diabetes mellitus Alcoholism Chronic liver disease Cerebrospinal fluid leaks Functional or anatomic asplenia
*US ACIP=United States Advisory Committee on Immunization Practices.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for Pneumococcal Polysaccharide Vaccination in Immunocompromised Persons ≥2 Years of Age HIV† infection Leukemia Hodgkin’s disease Lymphoma Multiple myeloma Generalized malignancy Chronic renal failure Nephrotic syndrome Immunosuppressive chemotherapy/ Organ or bone marrow
transplant*US ACIP=United States Advisory Committee on Immunization Practices.†HIV=human immunodeficiency virus.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for Pneumococcal Polysaccharide Vaccination if Vaccination Status Is Unknown The ACIP recommends administration of the
pneumococcal vaccine for all immunocompromised persons if prior vaccination status is unknown
*US ACIP=United States Advisory Committee on Immunization Practices.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for Pneumococcal Polysaccharide Revaccination for Immunocompetent Persons
Group Special Considerations
Persons aged >65 years If patient received vaccine ≥5 years previously and was <65 years of age at time of initial vaccination, revaccinate
Persons 2–64 years with functional or anatomic asplenia†
If patient is >10 years of age, administer single revaccination ≥5 years after previous dose
If patient is <10 years of age, consider revaccination 3 years after previous dose
*US ACIP=United States Advisory Committee on Immunization Practices. †Including sickle cell disease and splenectomy.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for Pneumococcal Polysaccharide Revaccination for Immunocompromised Persons
Group Special Considerations
Persons ≥2 years of age with: HIV infection Leukemia, lymphoma, Hodgkin’s
disease, multiple myeloma, generalized malignancy
Chronic renal failure, nephrotic syndrome
Immunosuppressive chemotherapy (including long-term systemic corticosteroids)
Organ or bone marrow transplantation
Single revaccination ≥5 years after previous dose
In patients ≤10 years of age: single revaccination 3 years after previous dose
*US ACIP=United States Advisory Committee on Immunization Practices.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for
Revaccination of Immunocompetent Persons
Group Special Considerations
Persons aged >65 years If patient received vaccine ≥5 years previously and was <65 years of age at time of initial vaccination, revaccinate
Persons 2–64 years with functional or anatomic asplenia†
If patient is >10 years of age, administer single revaccination ≥5 years after previous dose
If patient is <10 years of age, consider revaccination 3 years after previous dose
*US ACIP=United States Advisory Committee on Immunization Practices. †Including sickle cell disease and splenectomy.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
US ACIP* Recommendations for Revaccination of
Immunocompromised Persons
Group Special Considerations
Persons ≥2 years of age with: HIV infection Leukemia, lymphoma, Hodgkin’s
disease, multiple myeloma, generalized malignancy
Chronic renal failure, nephrotic syndrome
Immunosuppressive chemotherapy (including long-term systemic corticosteroids)
Organ or bone marrow transplantation
If ≥5 years have elapsed since previous dose: single revaccination
In patients ≤10 years of age: consider single revaccination 3 years after previous dose
*US ACIP=United States Advisory Committee on Immunization Practices.Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
American Thoracic Society-Guidelines
23 Valent pneumococcal polysaccharide vaccine is recommended for persons >65 yr of age & for those with selected high-risk concurrent diseases (strong recommendations; level II evidence)
Smoking cessation should be a gial for persons hospitalized with CAP who smoke( Moderate recommendations, level III evidence)
American Thoracic Society-GuidelinesContd:
Smokers who will not quit should also be vaccinated for both pneumococcal & influenza ( weak recommendation; level III evidence)
Healthy people 2010 Goal
US Pneumococcal Vaccination Rates According to CDC* vs. Healthy People 2010 Goals
Adult vaccination rates in the US in 2002 and 2003 were far below Healthy People 2010 goals
* Data for persons >65 years of age from US Behavioral Risk Factor Surveillance System, 2003; data for high-risk persons 18-64 years of age from US National Health Interview Survey, 2002 **Persons with one or more risk factors for pneumococcal diseaseAdapted from Centers for Disease Control and Prevention. Healthy People 2010: Immunization and Infectious Diseases. Available at: http://www.healthypeople.gov/Document/pdf/Volume1/14Immunization.pdf. Accessed February 12, 2007; CDC MMWR. 2005;54(RR-5):1–13; CDC MMWR. 2004;53(43):1007–1012.
Healthy People 2010 Goal: 90%
Healthy People 2010 Goal: 60%
19.1
64.2
0102030405060708090
100
Individuals>65 Years of Age
(2003)
High-Risk Individuals**18-64 Years of Age
(2002)
% o
f ad
ult
s va
ccin
ated
Efficacy of polyvalent
polysaccharide
Pneumococcal vaccine
Protective Efficacy of 6- and 13-Valent Vaccines in Healthy Young Males*
*Combined results of 3 controlled clinical studies in 12,000 young adult males, mostly from Malawi and Mozambique, who were randomized to receive pneumococcal vaccine (containing serotypes 1,3,4,7,8, and 12 in Trial 1 and serotypes 1,2, 3, 4, 6, 7, 8, 9, 12,14, 18,19, and 25 in Trials 2 and 3), Group A meningococcal vaccine, or saline placebo. Adapted from Austrian R, et al. Trans Assoc Am Phys. 1976;89(7):184-194.
Protective Efficacy Against Pneumococcal Bacteremic Pneumonia
82.3%
78.5%
76
77
78
79
80
81
82
83
3 Trials of 6-Valent or 13-Valent Vaccine
(N=12,000)
2 Trials of 13-Valent Vaccine
(N=4,500)
% p
rote
ctiv
e ef
fica
cy
Combined Protective Efficacy of 6- and 12-Valent Vaccines in South African Gold Miners*
*Two separate controlled clinical studies in 4,694 South African gold miners conducted In the 1970s In which subjects were randomized to receive pneumococcal vaccine (6-valent in one study and 12-valent in the other), Group A meningococcal vaccine, or placebo**vs meningococcal vaccine and placeboAdapted from Smit P, et al. JAMA. 1977;238(24):2613-2616.
Protective Efficacy Against Pneumococcal Pneumonia in 2 Separate Trials:Pneumococcal Pneumonia Cases ≥14 Days After Vaccination
Protective Efficacy
76%p<0.001**
Protective Efficacy
92%p<0.004**
Trial of 6-Valent Pneumococcal Vaccine Trial of 12-Valent Pneumococcal Vaccine
9.2
1.8
38.1
15.4
38.6
29
0
5
10
15
20
25
30
35
40
45
Pneumococcus(n=983)
Meningococcus(n=1051)
Placebo (n=985)
Pneumococcus(n=540)
Meningococcus(n=585)
Placebo (n=550)
Rat
e/1,
000
pat
ien
ts
Protective Efficacy in Prospective Trials (Meta-Analysis)*
*Meta-analysis of 14 prospective, randomized trials in which the 6-, 12-, 13-, 14-, or 23-valent pneumococcal polysaccharide vaccine was administered to a total of 48,837 immunocompetent adults.
Note: There was no significance identified in the subgroup of patients >55 years of age, probably due to lack of statistical power.CI=confidence intervalAdapted from Cornu C, et al. Vaccine. 2001;19(32):4780-4790.
Protective Efficacy
40%(CI: 0.60–0.96)Protective
Efficacy71%
(CI: 0.2–0.42)
Definite Pneumococcal Pneumonia(6 Trials)
Presumptive Pneumococcal Pneumonia(8 Trials)
5.5
2219
34
0
5
10
15
20
25
30
35
40
Pneumococcal Vaccine(n=6689)
Control (n=6441)
Pneumococcal Vaccine(n=11945)
Control (n=13714)
rate
/1,0
00 p
atie
nts
Timing of Antibody Response (Seroconversion)
Antibody titers develop by the third week following vaccination
Duration of Protection
Following pneumococcal vaccination, serotype-specific antibody levels decline after 5–10 years A more rapid decline in antibody levels may occur in
some groups (eg, children, the elderly) The results of one epidemiologic study suggest that
vaccination may provide protection for at least 9 years after receipt of the initial dose
Indications
Indications
PNEUMOVAX ® 23 is indicated for vaccination against pneumococcal disease caused by those pneumococcal types included in the vaccine
Effectiveness of the vaccine in the prevention of pneumococcal pneumonia and pneumococcal bacteremia has been demonstrated in controlled trials in South Africa and France and in case-controlled studies
PNEUMOVAX® 23 is a registered trademark of Merck & Co., Inc. Whitehouse Station, NJ, USA
Indications for Immunocompetent Persons Vaccination with PNEUMOVAX ® 23 is recommended
for selected immunocompetent individuals as follows: Routine vaccination for persons aged ≥50 years Persons aged ≥2 years with chronic cardiovascular
disease, chronic pulmonary disease, diabetes mellitus, alcoholism, chronic liver disease, cerebrospinal fluid leaks, functional asplenia, or anatomic asplenia
Persons aged ≥2 years living in special environments or social settings
Indications for Immunocompromised Persons
Vaccination with PNEUMOVAX ® 23 is recommended for selected immunocompromised persons aged ≥2 years as follows: Persons with HIV infection, leukemia, lymphoma,
Hodgkin’s disease, multiple myeloma, generalized malignancy, chronic renal failure, nephrotic syndrome
Persons receiving immunosuppressive chemotherapy (including corticosteroids)
Persons who have received an organ or bone marrow transplant
Contraindications
PNEUMOVAX ® 23 is contraindicated in individuals who are hypersensitive to any component of the vaccine
Epinephrine injection (1:1000) must be available immediately should an acute anaphylactoid reaction occur due to any component of the vaccine
Precautions
Precautions—General If PNEUMOVAX ® 23 is used in persons receiving
immunosuppressive therapy, the expected serum antibody response may not be obtained and potential impairment of future immune responses to pneumococcal antigens may occur
Intradermal administration may cause severe local reactions Caution and appropriate care should be exercised in administering
PNEUMOVAX ® 23 to individuals with severely compromised cardiovascular and/or pulmonary function in whom a systemic reaction would pose a significant risk
Any febrile respiratory illness or other active infection is reason for delaying use of PNEUMOVAX ® 23, except when, in the opinion of the physician, withholding the agent entails even greater risk
In patients who require penicillin (or other antibiotic) prophylaxis against pneumococcal infection, such prophylaxis should not be discontinued after vaccination with PNEUMOVAX ® 23
Precautions—Special PopulationsPregnant Women Nursing Mothers
Children <2 years of age
• It is not known whether PNEUMOVAX ® 23 can cause fetal harm or can affect reproduction capacity when administered to a pregnant woman
• PNEUMOVAX ® 23 should be given to pregnant women only if clearly needed
• It is not known whether PNEUMOVAX ® 23 is excreted in human milk
• Caution should be exercised when PNEUMOVAX ® 23 is administered to a nursing mother
• PNEUMOVAX ® 23 is not recommended in this age group
Adverse Reactions
In clinical trials and/or postmarketing experience with PNEUMOVAX ® 23, the following adverse experiences were reported: Injection-site reactions (including soreness,
erythema, warmth, swelling, local induration, decreased limb mobility, and peripheral edema in the injected extremity), fever (≤38.8º C/102º F), and increases in lab values for C-reactive protein
Cellulitis-like reactions (very rare)
Dosage and Administration Inspect product visually for particulate matter and discoloration prior
to administration. PNEUMOVAX ® 23 is a clear, colorless solution Withdraw 0.5 mL from the vial using a sterile needle and syringe free
of preservatives, antiseptics, and detergents Administer a single 0.5 mL dose of PNEUMOVAX ® 23
subcutaneously or intramuscularly (preferably in the deltoid muscle or lateral mid-thigh), with appropriate precautions to avoid intravascular administration
Use a separate sterile syringe and needle for each individual patient to prevent transmission of infectious agents from one person to another
Store unopened and opened vials at 2°–8° C/35.6°–46.4° F. Use the vaccine directly as supplied, without dilution or reconstitution. Phenol 0.25% is added as a preservative. Discard all vaccine after the expiration date
Vaccine Schedule for Special Populations Pneumococcal vaccine should be given at least 2 weeks
before elective splenectomy, if possible For patients planning cancer chemotherapy or other
immunosuppressive therapy, the interval between vaccination and initiation of immunosuppressive therapy should be at least 2 weeks
Vaccination during chemotherapy or radiation therapy should be avoided
Pneumococcal vaccine may be given several months following completion of chemotherapy or radiation therapy for neoplastic disease
Vaccine Schedule for Special Populations, continued
In patients with Hodgkin’s disease, immune response to vaccination may be suboptimal for 2 years or longer after intensive chemotherapy (with or without radiation)
For some patients, during the 2 years following the completion of chemotherapy or other immunosuppressive therapy (with or without radiation), significant improvement in antibody response has been observed, particularly as the interval between the end of treatment and pneumococcal vaccination increased
Persons with asymptomatic or symptomatic HIV infection should be vaccinated as soon as possible after their diagnosis is confirmed
Use With Other Vaccines
The ACIP recommends that pneumococcal vaccine be administered at the same time as influenza vaccine
Concomitant administration of the pneumococcal and influenza vaccines does not increase side effects or decrease the antibody response to either vaccine
Influenza vaccine is recommended annually for appropriate populations
Pneumococcal vaccine is not given annually
ACIP=Advisory Committee on Immunization Practices
Adapted from CDC. MMWR. 1997;46(RR-08):1–24.
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