Understanding adult pneumococcal vaccine efficacy - CECity

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Understanding adult pneumococcal vaccine efficacy - CECity

Understanding

adult pneumococcal

vaccine efficacy

Bridget Bransteitter, DO

treptococcus pneumoniae,

otherwise known as

pneumococcus, is the

causative organism in a number of

different infections, including otitis

media, sinusitis, pneumonia, meningitis,

peritonitis, and bacteremia. It is a grampositive,

aerobic bacterium that has an external

capsule composed of polysaccharides. The external

capsule allows the bacteria to adhere to human cells

and facilitates invasion and infection. 1

4 AOA Health Watch Improving adult immunization coverage March 2013


Invasive disease, defined as bacteria

invading normally sterile areas, most

commonly presents as pneumonia with

bacteremia, bacteremia, and meningitis. 2

Pneumococcus is capable of producing a

variety of polysaccharides on the external

capsule, and this variety in polysaccharides

is responsible for the formation of 91

different serotypes of Streptococcus

pneumonia. 1 The polysaccharides also

provide the mechanisms for pneumococcal

vaccines. 3 The vaccines introduce the polysaccharides

to the immune system, which

produces an antibody response and

provides protection against disease.

Vaccination is an important tool to help

combat infections caused by Streptococcus

pneumoniae, which continues to cause significant

disease in the United States. Statistics

show that nearly all of the deaths attributed

to pneumococcal disease in 2009 were in

adults. 4 Despite widespread availability of

pneumococcal vaccines, however, the rate

of pneumococcal vaccination among adults

remains low. One study focusing on vaccine

efficacy in the population infected with

human immunodeficiency virus (HIV)

reports that about 80% of the enrolled

subjects had not been vaccinated prior to

their participation in the study. 5

The purpose of this article is to review

the differences between pneumococcal

vaccines available for the adult population,

and to review the current Advisory

Committee on Immunization Practices

(ACIP) guidelines for adult pneumococcal

immunization.

Vaccine benefits

Several benefits, both direct and indirect,

can be derived from pneumococcal

vaccination. One of the primary goals of

any vaccine program is to reduce the

incidence of disease. The number of cases

of invasive pneumococcal disease (IPD)

has declined with the introduction of

pneumococcal vaccines. IPD incidence

in 2010 was 3.8 cases per 100,000 adults

aged 18-34 years, and 6.4 per 100,000

adults aged 65 or older. 6 The rate

increased to 173 cases per 100,000 for

those persons infected with HIV, and 186

cases per 100,000 for those persons aged

18-64 years who were diagnosed with

hematologic cancer. 6 In 2010, there were

an estimated 39,750 cases of IPD and

4000 deaths. 2 This number has decreased

significantly from the estimated 64,400

cases and 7300 deaths in 1999. 2 The decline

in cases occurred after the 7-valent

pneumococcal conjugate vaccine for

children was introduced in 2000. 7 The IPD

rate in healthy adults, caused by serotypes

contained in the 7-valent conjugate vaccine,

dropped 6 cases per 100,000 in 2000 to 1

case per 100,000 in 2007. 6

However, in immunocompromised

individuals, the case rates remain elevated,

because 50% of IPD is caused by serotypes

contained in the 13-valent pneumococcal

conjugate vaccine and 23-valent pneumococcal

polysaccharide vaccine. 6 Another

benefit of vaccination is reduction in the

severity of pneumococcal disease.

Pneumococcal vaccination is associated

with a 40%-70% reduced risk of in-hospital

mortality, and has reduced hospital length

of stay from an average of 6.5 days in

patients without prior vaccination, to 4.5

days in patients who were vaccinated

prior to admission. 8

The vaccine program has provided

other indirect benefits, beyond its primary

goal of reducing the number of infections

and mortality from IPD. Pneumococcal

vaccination has reduced the number of

pneumococcal infections in unvaccinated

persons through a herd immunity effect. 4

In addition, by preventing pneumococcal

infections, the 7-valent pneumococcal

conjugate vaccine (PCV7) also has

prevented infections with resistant strains

of pneumococcus. 7 Rates of pneumococcal

resistance to penicillin and cephalosporin

resistance have decreased since PCV7 was

introduced for vaccination in children. In

1999, penicillin resistance was estimated

at 26.8% and cephalosporin resistance was

16.9% based on sampling from reference

laboratories. 2 By 2010, those numbers had

fallen to 10.6% and 8.6%, respectively

(see Figure 1, page 6).

History of pneumococcal vaccines

Recommendations and vaccine strategies

have evolved over the years as new vaccines

have become available. This holds true

for pneumococcal vaccines. The 23-valent

pneumococcal polysaccharide vaccine

(PPSV23), marketed as Pneumovax 23 by

Merck, was approved for use in adults in

1983. 3 In 2000, the PCV7 was introduced

for use in infants and young children. 6

The PCV7 was replaced by the 13-valent

pneumococcal conjugate vaccine (PCV13)

in 2010. 6 The PCV13 contains the same

7 serotypes as the PCV7, plus an additional

6 serotypes.

On December 11, 2011, the US Food

and Drug Administration (FDA) approved

the use of PCV13, marketed as Prevnar 13

by Wyeth Pharmaceuticals, Inc., for use in

adults 50 years and older based on studies

comparing the immune response of PCV13

to that of PSV23. 9 Studies on adults show

that among the 12 serotypes common to

both vaccines, PCV13 induced an antibody

level comparable to or higher than the

levels induced by PPSV23. 9 Additional

trials are being conducted. The approval

was granted under the FDA’s accelerated

approval pathway. On June 20, 2012,

ACIP recommended the use of PCV13

for adults 19 years and older with immunocompromising

conditions, asplenia,

cerebral spinal fluid (CSF) leaks, or

cochlear implants. 6

Comparison of PPSV23 and PCV13

The 2 vaccines now licensed for use among

adults differ in a few areas, including the

number of serotypes they protect against,

the way they stimulate the immune system,

and the magnitude of the immune

response. The PPSV23 vaccine contains

polysaccharides from 23 different serotypes

of Streptococcus pneumoniae (1, 2, 3, 4, 5,

6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B,

17F, 18C, 19F, 19A, 20, 22F, 23F, and 33F). 3

Table 1. Pneumococcal vaccines

Type of Vaccine Description Indicated for:

23-Valent polysaccharide

(PPSV23)

13-Valent pneumococcal

conjugate (PCV13)

Contains polysaccharides

from 23 serotypes of

Streptococcus pneumoniae

Contains 13 Streptococcus

pneumoniae serotypes

All adults >65 years of age

and for at-risk adults

19-64 of age

One dose for at-risk adults

(>19 years of age)

March 2013 Improving adult immunization coverage AOA Health Watch 5


Figure 1. Pneumococcal cases, death rates, and estimated

resistance to penicillin and cephalosporin

Sources: http://www.cdc.gov/abcs/reports-findings/surv-reports.html 1999-2010. (See Streptococcus pneumonia)

*resistance to penicillin and cephalosporins, includes strains with intermediate sensitivity.

**based on national estimates of invasive disease.

Of the 23 serotypes, 12 are the same as

those contained in the PCV13. 3,10

Epidemiologic data from 2008 show that

the serotypes contained in the PPSV23

were responsible for 78% of IPD in the

group aged 18-49 years, 76% in the group

aged 50-64 years, and 66% of people in

the group aged 65 or older. 4 The PCV13

vaccine contains 13 pneumococcal

serotypes: 1 3, 4, 5, 6a, 6b, 7f, 9v, 14, 18C,

19F, 19A, and 23F. 10 Those serotypes were

responsible for 53% of IPD in persons age

18-49 years, 49% in the group aged 50-64

years, and 44% of those 65 years and older

in 2008. 4 The serotype 19A is responsible

for most infections with drug-resistant

pneumococcus and is included in both

vaccines. 3,10

The 2 vaccines also differ in how

they stimulate the immune system. The

PPSV23 vaccine works by inducing typespecific

antibodies that enhance the

immune system’s ability to kill pneumococcus

through opsonization and phagocytosis.

The polysaccharides contained in the

PCV13 are conjugated to a carrier protein

that stimulates a T-cell-dependent

immune response in addition to the B-cell

antibody-mediated response. 10 Studies

show that the PCV13 does elicit an

increased antibody response among those

with compromised immune systems,

including HIV patients and transplant

recipients. 11 The degree to which the

immune system is stimulated, measured

by the geometric mean antibody titers and

the opsonophagocytic activity (OPA)

produced following vaccination, is used

to estimate a vaccine’s effectiveness. 5

Vaccine efficacy

Vaccine efficacy and immune response

varies among risk groups. The overall

efficacy of the PPSV23 is 74%, and ranges

from 50%-80% among immunocompetent

adults with underlying medical conditions. 4

OPA provides a measure of the ability

of serum antibodies to eliminate pneumococci.

10 Immunogenicity studies comparing

PPSV23 and PCV13 revealed the OPA, and

geometric mean antibody titers for PCV13

ACR Guidelines

The American College of

Rheumatology (ACR) recommends

pneumococcal vaccination for patients

who are starting therapy with certain

nonbiologic disease-modifying

antirheumatic drugs such as leflunomide,

methotrexate, and sulfasalazine and

all biologic agents.

Source: Saag KG, Teng GG, Patkar NM, et al. American

College of Rheumatology 2008 recommendations for the

use of nonbiologic and biologic disease-modifying

antirheumatic drugs in rheumatoid arthritis. Arthritis

Rheum. 2008;59:762-784.

were comparable or higher than those of

PPSV23. 6 It was these data that prompted

the approval of the PCV13 for use in

adults. 9 These studies were conducted in

healthy individuals.

Vaccine efficacy in the HIV population

has met with conflicting evidence. One

randomized, double-blinded, placebocontrolled

trial conducted on patients

infected with HIV in Uganda reports a

lack of efficacy in preventing IPD in this

population. However, the results of this

study are not considered applicable to the

HIV-infected population in developed

countries, where there is greater access

to antiretroviral therapy. 5

A case-controlled study conducted

in 4 hospitals in Spain demonstrated that

administering the PPSV23 to HIV-infected

adults did convey a protective effect. 5

In this study the protective effect was

stronger for those whose CD4 lymphocyte

count was below 200, compared with those

who had a CD4 count above 200. 5 In a

randomized trial comparing revaccination

of HIV-infected patients with PPSV23

versus HIV-infected patients with PCV7,

a greater number of HIV-infected patients

achieved a 2-fold rise in antibody levels in

the PCV7 group, when compared with the

number in the PPSV23 group. 11 The difference

in antibody titers waned after 180

days. 11 Another trial studied the efficacy

of PSV7 vaccine in HIV-infected adults

6 AOA Health Watch Improving adult immunization coverage March 2013


who survived an episode of IPD. 12 The

study participants were given 2 doses of

PCV7, at 4 weeks apart. The vaccine was

effective and prevented 74% of recurrent

IPD. 12 These studies help lay the foundation

for recommending PCV13 use in the

HIV-infected population, as well as in

other immunocompromised adults.

Adverse effects

Both vaccines produce similar adverse

effects. The most common adverse

reactions reported occur at the injection

site. Those reactions include pain, swelling

and redness, and limitation of movement in

the injected arm. 3,6,10 Other adverse effects

include chills, fever, fatigue, headache,

appetite loss, and generalized muscle and

joint pain. 3,6,9 In general, the vaccines are

well tolerated. The overall incidence of

side effects reported in the first 30 days

after vaccination is less than 2% for

both vaccines. 6

Indications for

pneumococcal vaccination

Recommendations on who should receive

the pneumococcal vaccine, and which

vaccine they should receive, are based on

IPD risk factors. IPD rates differ among

demographic variables, the strength of an

individual’s immune system, and with the

presence of those with certain underlying

medical conditions.

Demographic risk factors have

remained fairly constant over the years.

The case rates for IPD are highest among

the very young (children 1 year old or less)

and the elderly (adults 65 and older). 2 All

children, and all adults 65 years and older

are encouraged to receive pneumococcal

vaccination. 4,6 Other populations that

historically have been at risk are the

Alaskan Native and American Indian

populations, both children and adults. 4

The majority of adult IPD cases in this

demographic occur in individuals with

other risk factors, such as underlying

medical conditions. 4 Thus, when the

adult pneumococcal vaccination

guidelines were revised in 2010, the

Alaskan Native and the American Indian

populations were no longer given as a

separate indication category, as they were

included with those individuals with

underlying medical conditions. 4

Age Group

Table 2. Vaccination rates for pneumococcal vaccine

compared with Healthy People 2020 objectives

Another indication for adult

pneumococcal vaccination is persons

with underlying medical conditions. From

1999 to 2007, the rate of adult IPD cases

in individuals aged 18-64 years with underlying

medical conditions increased from

52% to 59%. 4 The rate increase suggests

that this group does not derive as much

benefit from herd immunity as the general

population does. The list of medical conditions

that put an individual at risk for IPD

continues to be evaluated and adjusted.

The most recent additions to this list

include individuals who smoke and those

who are diagnosed with asthma. 4 Cigarette

smokers have 4 times the risk for IPD

compared with persons who have never

smoked. 4 Smoking also further increases

the risk of IPD in other high-risk groups,

such as those adults who are immunocompromised.

One study indicatedthat in

addition to receiving a pneumococcal

vaccine, smokers can further reduce their

risk of IPD by smoking cessation. 4 For

adults with asthma, particularly severe

disease, the risk of IPD is nearly double

that of the general adult population. 4 The

full list of medical conditions that place

an adult at higher risk for IPD, and thus

should be vaccinated, is as follows:

chronic heart and lung disease

asthma

diabetes mellitus

chronic liver disease, including

cirrhosis

persons with alcoholism

persons with cochlear implants

persons with CSF leaks

persons who smoke

Healthy People 2020

Objective

Percent Vaccinated

During 2010

≥65 years, healthy 90% 59.7%

18-64 years, high-risk 60% 18.5%

>18 years, long-term care or nursing home 90% NA

Sources: Healthy People 2020: Immunization and infectious diseases. Washington, DC: Department of Health and Human

Services (US); 2000. http://www.healthypeople.gov/2020/topicsobjectives2020/objectiveslist.aspx?topicid=23. Centers for

Disease Control and Prevention. Final state-specific influenza vaccination coverage estimates for the 2010-11 season—

United States, National Immunization Survey and Behavioral Risk Factor Surveillance System, August 2010 through May 2011.

http://www.cdc.gov/flu/professionals/vaccination/coverage_1011estimates.htm.

The group considered at greatest risk for

IPD is adults with immunocompromising

conditions. A list of those conditions

includes:

congenital or acquired

immunodeficiency

abnormal innate immune response

HIV infection

functional or anatomic asplenia

chronic renal disease

nephrotic syndrome

hematologic malignancies

generalized malignancies

recipients of a solid organ

transplant

treatment with immunosuppressive

medications

In particular, the IPD risk for those

individuals infected with HIV has been well

documented. Streptococcus pneumoniae

is the most common cause of bacterial

pneumonia in adults infected with HIV. 5

IPD is more common in HIV-infected

patients whose CD4 count is below 200,

than in those whose CD4 count is above

200. 12 In addition to pneumococcal vaccination,

treatment with antiretroviral

therapy has reduced the incidence of

pneumococcal disease in the HIV-infected

population by 50%. 11

Pneumococcal vaccine

recommendations

ACIP updated its recommendations for

adult pneumococcal vaccine in October

2012 to reflect the approval of PCV13 in

this age group. These recommendations

can be stratified based on the at-risk groups.

All adults 65 years or older should receive a

March 2013 Improving adult immunization coverage AOA Health Watch 7


Table 3. ACIP recommendations for pneumococcal vaccination

Vaccine 19-49 years 50-64 years >65 years

23-Valent pneumococcal

polysaccharide (PPSV23)

13-Valent pneumococcal

conjugate (PCV13)

dose of the PPSV23 vaccine, even if they

have been previously vaccinated. 4,6 Adults

19 years or older, with 1 of the indicated

chronic medical conditions listed earlier,

should receive a dose of PPSV23 at the time

of diagnosis. 4 The PCV13 vaccine and the

PPSV23 vaccines both are recommended

for adults, aged 19 and older, who have an

immunocompromising condition, asplenia,

CSF leak, or cochlear implant. If a patient is

naive to pneumococcal vaccine, they should

be given the PCV13 vaccine at the time of

diagnosis, and then the PPSV23 vaccine at

least 8 weeks later. 6 Studies show a higher

concentration of antibodies develops if the

vaccines are given in sequence, pneumococcal

conjugate then pneumococcal polysaccharide,

over those vaccinated with the

pneumococcal polysaccharide vaccine

alone. 13 Adults in this category who have

previously received the PPSV23 should

receive a one-time dose of the PCV13

vaccine at least 1 year after the last PPSV23

dose. 6 Ideally, adults with HIV infection

should be vaccinated when their CD4 count

is above 200. 5 Geometric mean antibody

concentrations against pneumococcal polysaccharides

are lower when the CD4 count

is below 200 at the time adults with HIV

are vaccinated. 13

Recommendations for revaccination

depend on the risk group. If an adult is

receiving his or her first PPSV32 vaccine

dose at age 65, they will not need to be

revaccinated. 4,6 If a person has been vaccinated

prior to the age of 65 for any reason,

he or she should receive another dose of

PPSV23 at age 65, or later if 5 years have

not yet elapsed between vaccines. 4,6 Adults

who should receive a second dose of

PPSV23 vaccine include those who have

1 or 2 doses for at-risk adults a 1 dose b

1 dose for at-risk adults c in addition to vaccination with

pneumococcal polysaccharide vaccine d

a Chronic lung disease, chronic cardiovascular diseases, diabetes mellitus, chronic liver disease, alcoholism, cochlear implants,

cerebrospinal fluid leaks, immunocompromising conditions, and functional or anatomic asplenia. Nursing home or long-term

facility residents, smokers, and persons with HIV. One-time revaccination is recommended 5 years after first dose.

b Revaccination recommended for people who received 1 or 2 doses of PPSV23 before age 65 if at least 5 years have passed

since previous dose.

c Immunocompromising conditions (eg, chronic renal failure and nephrotic syndrome), functional or anatomic asplenia,

cerebrospinal fluid leaks, or cochlear implants.

d At-risk adults who have previously received ≥1 dose of PPSV23 should be vaccinated with PCV13 one or more years after

the last PPSV23 dose was received.

asplenia, CSF leaks, cochlear implants,

and those who are immunocompromised. 6

The second vaccine should be given 5

years after the first dose. ACIP does not

recommend multiple revaccination doses

because data are insufficient to indicate

additional clinical benefit or protection

from repeated vaccine doses. 4 Currently,

a second, or booster, dose of the PCV13

vaccine is not indicated in adults.

Final notes

Pneumococcal vaccination provides physicians

with an effective tool to help combat

IPD. The introduction of PCV13 for adult

use has expanded the options available for

protecting patients against infection.

Questions about the efficacy of pneumococcal

vaccines in the immunocompromised

population remain, particularly in HIVinfected

individuals. However, the potential

benefit from vaccination outweighs the

potential harm in this group. New trials

are attempting to clarify further the best

vaccination strategies to protect adults

against pneumococcal disease.

References

1. Musher D. Streptococcus pneumoniae. In: Mandell

G, Bennett J, Dolin R, editors. Mandell, Douglas,

and Bennett’s Principles and Practices of Infectious

Disease. 7th edition. Philadelphia, PA: Elsevier;

2010:2623-2638.

2. Centers for Disease Control and Prevention. Active

Bacterial Core Surveillance (ABCs) report, Emerging

Infections Program Network, Streptococcus

pneumoniae, 1999-2010. CDC Web site.

http://www.cdc.gov/abcs/reports-findings/

survreports/spneu10.pdf. Accessed January 5, 2013.

3. PNEUMOVAX 23 (Pneumococcal Vaccine Polyvalent)

full prescribing information. Merck & Co. Inc.

website. http://www.merck.com/product/usa/

pi_circulars/p/pneumovax_23/pneumovax_pi.pdf.

Accessed January 5, 2013.

4. Centers for Disease Control and Prevention;

Advisory Committee on Immunization Practices.

Updated recommendations for prevention of

invasive pneumococcal disease among adults

using the 23-valent pneumococcal polysaccharide

vaccine (PPSV23). MMWR Morb Mortal Wkly Rep.

2010;59:1102-1106.

5. Peñaranda M, Falco V, Payeras A, et al.

Effectiveness of polysaccharide pneumococcal

vaccine in HIV-infected patients: a case-control

study. Clin Infect Dis. 2007;45:e82-e87.

6. Centers for Disease Control and Prevention. Use

of 13-valent pneumococcal conjugate vaccine and

23-valent pneumococcal polysaccharide vaccine

for adults with immunocompromising conditions:

recommendations of the Advisory Committee on

Immunization Practices (ACIP). MMWR Morb

Mortal Wkly Rep. 2012;61:816-819.

7. Centers for Disease Control and Prevention.

Drug resistant Streptococcus pneumoniae disease.

CDC website. http://www.cdc.gov/ncidod/dbmd/

diseaseinfo/drugresisstreppneum_t.htm. Accessed

January 9, 2013.

8. Fisman DN, Abrutyn E, Spaude KA, Kim A, Kirchner

C, Daley J. Prior pneumococcal vaccination is

associated with reduced death, complications, and

length of stay among hospitalized adults with

community-acquired pneumonia. Clin Infect Dis.

2006;42:1093-1101.

9. US Food and Drug Administration. FDA expands use

of Prevnar 13 vaccine for people ages 50 and older.

FDA website. http://www.fda.gov/newsevents/

newsroom/pressannouncements/ucm285431.htm.

Accessed January 1, 2013.

10. PREVNAR 13 (Pneumococcal 13-valent Conjugate

Vaccine [Diphtheria CRM197 Protein]). FDA

website. http://www.fda.gov/downloads/

BiologicsBloodVaccines/Vaccines/ApprovedProduct

s/UCM201669.pdf. Accessed January 5, 2013.

11. Crum-Cianflone NF, Huppler Hullsiek K, Roediger M,

et al; Infectious Disease Clinical Research Program

HIV Working Group. A randomized clinical trial

comparing revaccination with pneumococcal

conjugate vaccine to polysaccharide vaccine among

HIV-infected adults. J Infect Dis. 2010;202:1114-1125.

12. French N, Gordon SB, Mwalukomo T, et al. A trial of

a 7-valent pneumococcal conjugate vaccine in HIVinfected

adults. N Engl J Med. 2010;362:812-822.

13. Kroon FP, van Dissel JT, Ravensbergen E, Nibbering

PH, van Furth R. Enhanced antibody response to

pneumococcal polysaccharide vaccine after prior

immunization with conjugate pneumococcal vaccine

in HIV-infected adults. Vaccine. 2000;19:886-894. HW

About the Author

Bridget Bransteitter, DO, has worked for

Midwest Infectious Disease Specialists since

August 2008; she also serves as the hospital

epidemiologist and as chair of the Infection

Control Committee at Centerpoint Medical

Center in Independence, Mo. Dr. Bransteitter

is board certified in internal medicine and

infectious disease. She can be reached at

branstb@gmail.com.

8 AOA Health Watch Improving adult immunization coverage March 2013

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