Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Pneumococcal Vaccines for Adults aged ≥65 years

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Methods
Tables
References

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Methods

GRADE was used to evaluate 13-valent Pneumococcal Conjugate Vaccine (PCV13) for routine use among adults aged ≥65 years. Evidence of benefits, harms, values and preferences, and cost-effectiveness were reviewed in accordance with GRADE methods.[1] The primary policy question was “Should PCV13 be administered routinely to all adults aged ≥65 years?” The intervention evaluated was a single dose of PCV13 compared to a dose of 23-valent polysaccharide vaccine (PPSV23).

The benefits considered critical outcomes in GRADE included prevention of invasive pneumococcal disease (IPD), pneumococcal community-acquired pneumonia, and hospitalizations due to pneumococcal disease. Evidence used to evaluate efficacy of PCV13 against IPD and pneumococcal pneumonia was from the randomized placebo-controlled trial (RCT) conducted among approximately 85,000 adults aged ≥65 years in Netherlands (CAPiTA).[2] Evidence was not available for the critical outcome of hospitalizations due to pneumococcal disease. In addition, vaccine-induced immunogenicity was considered as an important outcome; immunogenicity evidence was assessed using two phase III RCTs of PCV13 compared to PPSV23, which measured antibody responses by opsonophagocytic assay (OPA) and four RCTs of PCV7 compared to PPSV23, which measured antibody responses by enzyme-linked immunosorbent assay (ELISA).[3-8]

The harms considered were overall serious adverse events (SAE), deaths and systemic adverse events including fatigue, rash, new generalized muscle pain, and use of medications to treat fever. Safety of PCV13 was evaluated based on 6 RCTs in immunocompetent adults, compared to PPSV23.[9]

Evidence type for each critical outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, and imprecision.

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Tables

Table 1a Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years:

Invasive Pneumococcal Disease and Community-Acquired Pneumonia

Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Outcome No. of subjects (# studies) Incidence in unvaccinated (cases/100,000) Vaccine efficacy (95% CI) Number Needed to Vaccinate ^a

PCV13-serotype Invasive Pneumococcal Disease Approximately 85,000 adults
(1 RCT)[2] 6.5[10] 74% (30-90%) ^b 20,400 (16,950 – 37,000)

Inpatient community-acquired pneumonia Approximately 85,000 adults
(1 RCT)[2] 137.5[11] ^c 45% (14-65%) 1,620 (1,110 – 5,130)

Outpatient community-acquired pneumonia Approximately 85,000 adults
(1 RCT)[12] 201[9] ^c 45% (14-65%) 1,110 (760-3,500)

Total community-acquired pneumonia Approximately 85,000 adults
(1 RCT)[2] — — 656 (454-2,110)

Table 1a Footnotes

^a Number needed to vaccinate or NNV=1 / (baseline rate — vaccinated rate)
^b Vaccine Efficacy versus placebo
^c Baseline estimates assume 10% of all CAP due to PCV13 types

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Table 1b Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years:

Immunogenicity ^a

Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Study No. of subjects Population Immunogenicity Results

Jackson et al 2013[3] 818 60 to 64 years
PPSV23 Naïve PCV13 > PPSV23 for 9/13 types (OPA)
PCV13=PPSV23 for 4/13 types (OPA)

Jackson et al 2013[4] 879 ≥70 years
PPSV23 >5 years previously PCV13>PPSV23 for 11/13 types (OPA)
PCV13=PPSV23 for 2/13 types (OPA)

Goldblatt et al 2009[5] 599 50 to 80 years
No PPSV23 within the past 5 years PCV7 = PPSV23 for 3/7 types (ELISA)
PCV7 > PPSV23 for 3/7 types (ELISA)
PCV7<PPSV23 for 1/7 types (ELISA)

De Roux et al 2008[6] 217 >70 years
PPSV Naïve PCV7 = PPSV23 for 1 type (ELISA)
PCV7>PPSV23 for 6/7 types (ELISA)

Ridda et al 2009[7] 241 >60 years, frail
PPSV Naïve PCV7 = PPSV23 for 4/4 types tested (ELISA)
Comparisons of other 3 types not done

Miernyk et al 2009[8] 203 55 to 70 years, Alaska Native
PPSV Naïve PCV7 = PPSV23 for 4/4 types tested (ELISA)
Comparisons of other 3 types not done

Table 1b Footnotes

^a Immunogenicity: Antibody response to vaccine serotypes, compared to PPSV23

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Table 2. Harms of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Harms of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Outcome No. of subjects Incidence in controls Incidence in vaccinated Risk Difference per 1000 (95% CI)

Serious adverse events (SAE)

Overall serious adverse events 6,000
(6 RCTs)[9] — 0.2-1.1% No difference ^a

Deaths 6,000
(6 RCTs)[9] — 16/6000 (0.3%) ^b No difference ^a

Systemic Adverse Events

Fatigue 3 RCTs &
PCV13 phase III[9] ^c 43.3% ^d 34.0% -9.3
(-16.4, -2.2)

Rash 3 RCTs &
PCV13 phase III[9] ^c 16.4% ^d 7.3% -9.1
(-14.3, -4.0)

New generalized muscle pain 3 RCTs &
PCV13 phase III[9] ^c 44.7% ^d 36.8% -7.9
(-15.2,-0.6)

Medications to treat fever 3 RCTs &
PCV13 phase III[9] ^c 17.5% ^d 8.6% -8.9
(-16.6,-1.9)

Table 2 Footnotes

^a No difference between the treatment groups
^b No deaths were considered vaccine related
^c Significant differences reported for 2 out of 3 RCTs (4 out of 13 outcomes); only significant findings presented in the table
^d Controls received PPSV23

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Table 3. Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Outcome Study design Risk of Bias Inconsistency Indirectness Imprecision Evidence Type ^a

Benefits ^b

Invasive Pneumococcal Disease 1 RCT No serious Not applicable Serious No serious 2

Community-acquired pneumonia 1 RCT No serious Not applicable No serious No serious 1

Immunogenicity 6 RCT No serious No serious Serious No serious 2

Harms

Systemic adverse events 3 RCTs No serious No serious No serious No serious 1

Table 3 Footnotes

^a Evidence type:

Randomized controlled trials (RCTs), or overwhelming evidence from observational studies.

RCTs with important limitations, or exceptionally strong evidence from observational studies.

Observational studies, or RCTs with notable limitations.

Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations.

^b Immunogenicity data which was considered an important outcome did not contribute to overall evidence type.
^c Indirectness due to different comparison group: 1) Placebo instead of PPSV and 2) PPSV efficacy against IPD among older adults = 50-80%
^d Indirectness due to different outcome (antibody response without correlates of protection)

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Table 4. Summary of Evidence for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Summary of Evidence for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Comparison Outcome Study design Findings Evidence type Overall evidence type ^a

PCV13 vs. no vaccination IPD 1 RCT Decreased risk among vaccinated 2 2

PCV13 vs.
no vaccination Pneumonia 1 RCT Decreased risk among vaccinated 1 2

PCV7 or PCV13 vs.
PPSV23 Immunogenicity 6 RCTs Response better for PCV than PPSV23 or no difference 2 2

PCV13 vs.
PPSV23 Serious and systemic adverse events 3 RCTs No difference or decreased risk with PCV13 1 2

Table 4 Footnotes

^a Overall evidence type is based on the weakest evidence type among the critical outcomes. This did not include immunogenicity data which was considered an important outcome.

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Table 5. Considerations for Formulating Recommendations for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥ 65 years

Considerations for Formulating Recommendations for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥ 65 years

Key factors Comments

Evidence type/quality for benefits and harms Data on efficacy against most critical outcomes available

Balance of benefits versus harms Benefits outweigh harms
Short-term: No uncertainty about the balance
Long-term: Indirect (herd) effects of infant vaccination expected to further reduce burden of pneumococcal disease in adults

Values General consensus reached on which outcomes are critical to prevent

Cost-effectiveness Short-term: The net benefits are worth the costs
Long-term: Uncertainty about whether the net benefits are worth the costs due to continued indirect effects

Summary The evidence supporting PCV13 vaccination of adults was determined to be type 2 (moderate level of evidence).
The recommendation was designated as Category A.

The ACIP Pneumococcal Work Group concluded that broader serotype protection can be achieved through use of both PCV13 and PPSV23 among adults >65 years of age; 20-25% of IPD among adults in this age group is caused by PCV13 serotypes, and an additional 38.5% by serotypes in PPSV23 not included in PCV13.[10] Conversely, PCV13 use among older adults will protect against inpatient community-acquired pneumonia.[2] Evidence from immunogenicity studies demonstrate that antibody response is non-inferior or superior when PCV is given before PPSV23 compared to PPSV23 administration before PCV.[3-8] Although the optimal interval for PCV13 followed by PPSV23 has not been directly studied, studies evaluating the immune response following a sequence of PCV7 or PCV13 followed by PPSV23 with intervals of 2, 6, 12 months, or 3-4 years demonstrated that following the PPSV23 dose, antibody levels were higher than the pre-PCV baseline, and a non-inferior response was observed when compared with post-PCV antibody levels.[5],[8],[13],[14] For adults previously immunized with PPSV23, waiting at least 1 year after PPSV23 before giving a dose of PCV13 may provide a better immune response according to expert opinion.

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References

Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ. Methods for developing evidence-based recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease Control and Prevention (CDC). Vaccine. 2011;29(49):9171-9176.

Bonten M, Bolkenbaas M, Huigts S, et al. Community Acquired Pneumonia Immunization Trial in Adults (CAPITA) Abstract # 0541 Cdc-pdf[3.91 MB, 289 pages]External. International Symposium on Pneumococci and Pneumococcal Diseases 2014.

Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naive adults. Vaccine. 8/2/ 2013;31(35):3577-3584.

Jackson LA, Gurtman A, Rice K, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Vaccine. 8/2/ 2013;31(35):3585-3593.

Goldblatt D, Southern J, Andrews N, et al. The Immunogenicity of 7-Valent Pneumococcal Conjugate Vaccine versus 23-Valent Polysaccharide Vaccine in Adults Aged 50–80 Years. Clinical Infectious Diseases. November 15, 2009 2009;49(9):1318-1325.

de Roux A, Schmidt N, Rose M, Zielen S, Pletz M, Lode H. Immunogenity of the pneumococcal polysaccharide vaccine in COPD patients. The effect of systemic steroids. Respir Med. Dec 2004;98(12):1187-1194.

Ridda I, MacIntyre CR, Lindley R, et al. Immunological responses to pneumococcal vaccine in frail older people. Vaccine. 2009;27(10):1628-1636.

Miernyk KM, Butler JC, Bulkow LR, et al. Immunogenicity and Reactogenicity of Pneumococcal Polysaccharide and Conjugate Vaccines in Alaska Native Adults 55-70 Years of Age. Clinical Infectious Diseases. July 15, 2009 2009;49(2):241-248.

US Food and Drug Administration. Vaccines and Related Biological Products Advisory Committee (VRBPAC) adult indication briefing document: Prevnar 13. Silver Spring, MD2011.

Active Bacterial Core Surveillance (ABCs): Emerging Infections Program Network. Unpublished 2013 ABCs Data on Streptococcus Pneumoniae. Vol 2014: CDC; 2013.

Simonsen L, Taylor RJ, Schuck-Paim C, Lustig R, Haber M, Klugman KP. Effect of 13-valent pneumococcal conjugate vaccine on admissions to hospital 2 years after its introduction in the USA: a time series analysis. The Lancet Respiratory Medicine. 2014;2(5):387-394.

Nelson JC, Jackson M, Yu O, et al. Impact of the introduction of pneumococcal conjugate vaccine on rates of community acquired pneumonia in children and adults. Vaccine. Sep 8 2008;26(38):4947-4954.

Greenberg RN, Gurtman A, Frenck RW, et al. Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine–naïve adults 60–64 years of age. Vaccine. 4/25/ 2014;32(20):2364-2374.

Jackson LA, Gurtman A, van Cleeff M, et al. Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. Vaccine. 8/2/ 2013;31(35):3594-3602.

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Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years
Outcome	No. of subjects (# studies)	Incidence in unvaccinated (cases/100,000)	Vaccine efficacy (95% CI)	Number Needed to Vaccinate ^a
PCV13-serotype Invasive Pneumococcal Disease	Approximately 85,000 adults (1 RCT)[2]	6.5[10]	74% (30-90%) ^b	20,400 (16,950 – 37,000)
Inpatient community-acquired pneumonia	Approximately 85,000 adults (1 RCT)[2]	137.5[11] ^c	45% (14-65%)	1,620 (1,110 – 5,130)
Outpatient community-acquired pneumonia	Approximately 85,000 adults (1 RCT)[12]	201[9] ^c	45% (14-65%)	1,110 (760-3,500)
Total community-acquired pneumonia	Approximately 85,000 adults (1 RCT)[2]	—	—	656 (454-2,110)

Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years
Study	No. of subjects	Population	Immunogenicity Results
Jackson et al 2013[3]	818	60 to 64 years PPSV23 Naïve	PCV13 > PPSV23 for 9/13 types (OPA) PCV13=PPSV23 for 4/13 types (OPA)
Jackson et al 2013[4]	879	≥70 years PPSV23 >5 years previously	PCV13>PPSV23 for 11/13 types (OPA) PCV13=PPSV23 for 2/13 types (OPA)
Goldblatt et al 2009[5]	599	50 to 80 years No PPSV23 within the past 5 years	PCV7 = PPSV23 for 3/7 types (ELISA) PCV7 > PPSV23 for 3/7 types (ELISA) PCV7<PPSV23 for 1/7 types (ELISA)
De Roux et al 2008[6]	217	>70 years PPSV Naïve	PCV7 = PPSV23 for 1 type (ELISA) PCV7>PPSV23 for 6/7 types (ELISA)
Ridda et al 2009[7]	241	>60 years, frail PPSV Naïve	PCV7 = PPSV23 for 4/4 types tested (ELISA) Comparisons of other 3 types not done
Miernyk et al 2009[8]	203	55 to 70 years, Alaska Native PPSV Naïve	PCV7 = PPSV23 for 4/4 types tested (ELISA) Comparisons of other 3 types not done

Harms of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years
Outcome	No. of subjects	Incidence in controls	Incidence in vaccinated	Risk Difference per 1000 (95% CI)
Serious adverse events (SAE)
Overall serious adverse events	6,000 (6 RCTs)[9]	—	0.2-1.1%	No difference ^a
Deaths	6,000 (6 RCTs)[9]	—	16/6000 (0.3%) ^b	No difference ^a
Systemic Adverse Events
Fatigue	3 RCTs & PCV13 phase III[9] ^c	43.3% ^d	34.0%	-9.3 (-16.4, -2.2)
Rash	3 RCTs & PCV13 phase III[9] ^c	16.4% ^d	7.3%	-9.1 (-14.3, -4.0)
New generalized muscle pain	3 RCTs & PCV13 phase III[9] ^c	44.7% ^d	36.8%	-7.9 (-15.2,-0.6)
Medications to treat fever	3 RCTs & PCV13 phase III[9] ^c	17.5% ^d	8.6%	-8.9 (-16.6,-1.9)

Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years
Outcome	Study design	Risk of Bias	Inconsistency	Indirectness	Imprecision	Evidence Type ^a
Benefits ^b
Invasive Pneumococcal Disease	1 RCT	No serious	Not applicable	Serious	No serious	2
Community-acquired pneumonia	1 RCT	No serious	Not applicable	No serious	No serious	1
Immunogenicity	6 RCT	No serious	No serious	Serious	No serious	2
Harms
Systemic adverse events	3 RCTs	No serious	No serious	No serious	No serious	1

Summary of Evidence for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years
Comparison	Outcome	Study design	Findings	Evidence type	Overall evidence type ^a
PCV13 vs. no vaccination	IPD	1 RCT	Decreased risk among vaccinated	2	2
PCV13 vs. no vaccination	Pneumonia	1 RCT	Decreased risk among vaccinated	1	2
PCV7 or PCV13 vs. PPSV23	Immunogenicity	6 RCTs	Response better for PCV than PPSV23 or no difference	2	2
PCV13 vs. PPSV23	Serious and systemic adverse events	3 RCTs	No difference or decreased risk with PCV13	1	2

Considerations for Formulating Recommendations for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥ 65 years
Key factors	Comments
Evidence type/quality for benefits and harms	Data on efficacy against most critical outcomes available
Balance of benefits versus harms	Benefits outweigh harms Short-term: No uncertainty about the balance Long-term: Indirect (herd) effects of infant vaccination expected to further reduce burden of pneumococcal disease in adults
Values	General consensus reached on which outcomes are critical to prevent
Cost-effectiveness	Short-term: The net benefits are worth the costs Long-term: Uncertainty about whether the net benefits are worth the costs due to continued indirect effects
Summary	The evidence supporting PCV13 vaccination of adults was determined to be type 2 (moderate level of evidence). The recommendation was designated as Category A.

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