GRADE: 15-valent pneumococcal conjugate vaccine (PCV15) in series with 23-valent pneumococcal conjugate vaccine (PPSV23) for adults aged 19–64 years with underlying medical conditions or other risk factors

Grading of Recommendations, Assessment, Development, and Evaluation

Introduction

On October 21, 2021, the ACIP recommended use of 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.]) alone or 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme Corp.]) in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23) [Pneumovax23, Merck Sharp & Dohme Corp Inc.]) for all adults aged ≥65 years, and for adults aged 19–64 years with certain underlying medical conditions or other risk factors*, who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP’s deliberations regarding use of these vaccines.

Introduction Footnote

*Alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear implant, congenital or acquired asplenia, CSF leak, diabetes mellitus, generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppression, leukemia, lymphoma, multiple myeloma, nephrotic syndrome, solid organ transplants, or sickle cell disease or other hemoglobinopathies.

Methods

A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV15 and PCV20 among age groups for which the vaccines were approved.  Since only immunogenicity and safety data were available for PCV15 or PCV20, the search included PCV13 and PPSV23 efficacy or effectiveness studies to help interpret PCV15 and PCV20 immunogenicity study findings. Literature search for evidence on both PCV15 and PCV20 was done simultaneously given the similarities in the policy questions and given that use of both PCV15 and PCV20 were considered by the ACIP simultaneously. GRADE assessment was performed for PCV15 and PCV20 studies only. As a basis for the GRADE analysis, the policy question consisting of the population, intervention, comparison, and outcomes of interest was defined (Table 1).

Table 1. Policy Question and PICO

Table 1: Policy question and definition of the Population, Intervention, Comparison, and Outcome for GRADE analysis
Policy question: Should PCV15 in series with PPSV23 be recommended to US adults aged 19-64 years with immunocompromising or chronic medical conditions?
Population US adults aged 19-64 years with immunocompromising or chronic medical conditions
Intervention One dose of PCV15 followed by PPSV23
Comparison 1. PCV13 followed by PPSV23 (immunocompromised adults aged 19-64 years)*

2. PPSV23 (immunocompetent adults with chronic medical conditions aged 19-64 years)

Outcomes
  • Vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumococcal pneumonia, and vaccine-type pneumococcal mortality
  • Serious adverse events following immunization

Table 1. Footnote
*Immunocompromised adults include adults with immunocompromising condition (chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplants, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies), CSF leak, or cochlear implant; immunocompetent adults are those without these conditions.

Chronic medical conditions include chronic heart/lung/liver disease, diabetes mellitus, alcoholism, and cigarette smoking.

Table 2: Outcomes and Rankings

Table 2: Outcomes and Rankings
Outcome Importance* Included in evidence profile
Vaccine-type invasive pneumococcal disease Critical Yes
Vaccine-type non-bacteremic pneumococcal pneumonia Critical Yes
Vaccine-type pneumococcal mortality Critical Yes
Serious adverse events following immunization Critical Yes

Table 2. Footnote
*Three options: 1. Critical; 2.  Important but not critical; 3. Not important for decision making

We leveraged a systematic review presented to the World Health Organization Strategic Advisory Group of Experts (SAGE) meeting in October 2020, which included literature up to March 2019 (1). To identify literature published during April 2019 to February 2021, we searched Pubmed, Medline, Embase, CINAHL, Scopus, Epistemonikos and Cochrane library databases. The search terms are included in appendix I. Search results were supplemented by an updated Pubmed search using “V114*”, “PCV15”, “PCV20”. Unpublished data were provided by the vaccine manufacturers.

Studies were included if they presented primary data on PCV15 use in series with PPSV23 in adults with underlying medical conditions or other risk factors. Of the 2,499 titles screened for WHO SAGE and 923 titles screened for the updated review in 2021, 2 unpublished PCV15 studies were included in the GRADE analysis (2, 3). Characteristics of these studies are presented in appendix II. Beneficial and harmful outcomes for the GRADE assessment were selected by the ACIP Pneumococcal Vaccines Work Group calls and via an email survey in which the Work Group members were asked to rank the relative importance of each outcome. Vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumococcal pneumonia, vaccine-type pneumococcal mortality, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).

Methods Footnote
*V114 is the name used for Merck’s investigational 15-valent pneumococcal conjugate vaccine candidate

Alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear implant, congenital or acquired asplenia, CSF leak, diabetes mellitus, generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppression, leukemia, lymphoma, multiple myeloma, nephrotic syndrome, solid organ transplants, or sickle cell disease or other hemoglobinopathies

Table 3a. Summary of Studies Reporting Immunogenicity

Table 3a. Summary of Studies Reporting Immunogenicity
Study Age or other characteristic of importance N intervention N comparison Comparator vaccine GMR range* (Serotype) GMT/GMR Interpretation†, ‡ Absolute difference in % seroresponders§ (serotype) Seroresponders
Interpretation
Study limitations (Risk of Bias)
V114-017 Native Americans or adults with chronic medical conditions** aged 18-49 years of age 742-844 247-283 PCV13 + PPSV23
(6-month interval between vaccines; 1-month post PPSV23)
0.88(4) to 1.42 (18C)
  • PCV15+PPSV23>PCV13+PPSV23 in 9/13 serotypes
  • PCV15+PPSV23 significantly higher in 1/13 (serotype 18C)
  • PCV15+PPSV23<PCV13+PPSV23 for 22F and 33F (PCV15-unique serotypes) after PPSV23
-6.7 (6A) to 6.0 (14)
  • PCV15+PPSV23>PCV13+PPSV23 in 5/13 serotypes (all non- significant)
  • PCV15+PPSV23<PCV13+PPSV23 for 22F and 33F (PCV15-unique serotypes) after PPSV23
Not serious
V114-018 Adults ≥18 years of age with HIV 102-123 105-117 PCV13 + PPSV23
(8-week interval between vaccines; 1-month post PPSV23)
0.89 (6A) to 1.52 (5)
  • PCV15+PPSV23>PCV13+PPSV23 in 11/13 serotypes (all non-significant)
  • PCV15+PPSV23>PCV13+PPSV23 for serotype 22F and PCV15+PPSV23<PCV13+PPSV23 for serotype 33F (PCV15-unique serotypes) after PPSV23
-2.0 (3) to 15.0 (19F)
  • PCV15+PPSV23>PCV13+PPSV23 in 10/13 serotypes
  • Confidence interval not reported
  • PCV15+PPSV23<PCV13+PPSV23 for 33F and equivalent for 22F (PCV15-unique serotypes) after PPSV23
Not serious

Table 3a. Footnotes
GMR=geometric mean ratio, GMT=geometric mean titers, OPA=opsonophagocytic activity, PCV13=13-valent pneumococcal conjugate vaccine, PCV15=15-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine

*GMR (geometric mean ratio) is the ratio of pneumococcal OPA GMTs. Ratio calculated as [GMT (PCV15+PPSV23] / [GMT (comparator vaccine)]. Range is shown for the 13 serotypes shared between PCV13 and PCV15 only.

GMR noninferiority for a serotype was declared if the lower bound of the 2-sided 95% CI for the GMR for that serotype was greater than 0.5 (2-fold criterion).

If GMR non-inferiority was not assessed, “statistical significance” of GMTs (geometric mean titers) defined as: 95% CI of GMT point estimates did not overlap.

§Seroresponse: subjects with >=4-fold rise in OPA GMT titer 30 days post-vaccination compared to pre-vaccination. Range is shown for the 13 serotypes shared between PCV13 and PCV15

If seroresponse non-inferiority was not assessed, “statistical significance” defined as:  95% CI of % seroresponders did not overlap.

**Chronic heart/liver/lung disease, cigarette smoking, diabetes mellitus

Table 3b. Summary of Studies Reporting Safety

Table 3b. Summary of Studies Reporting Safety
Study Age or other characteristic of importance N intervention N comparison Comparator vaccine Absolute % difference (% SAE PCV15 – % SAE comparator) N related to vaccine Study limitations (Risk of Bias)
V114-017 Native Americans or adults with chronic medical conditions* aged 18-49 years of age 1036 345 PCV13 + PPSV23
(1-month observation period post-PPSV23)
-0.6 0 Not serious
V114-018 Adults ≥18 years of age with HIV 150 148 PCV13 + PPSV23
(4-month observation period post PPSV23)
-2.8 0 Not serious

Table 3b. Footnotes
PCV13=13-valent pneumococcal conjugate vaccine, PCV15=15-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine, SAE=serious adverse events

*Chronic heart/liver/lung disease, cigarette smoking, diabetes mellitus

Table 4. GRADE Summary of Findings Table

Table 4. GRADE Summary of Findings Table
Certainty assessment Number of patients Results Certainty Importance
№ of studies (reference) Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Intervention Comparison* Relative effect Absolute effect
Vaccine effectiveness (Vaccine-type invasive pneumococcal disease, Vaccine-type non-bacteremic pneumococcal pneumonia, Vaccine-type pneumococcal mortality)
2 (3, 4) Randomized studies Not serious Not serious Serious† Not serious Not serious 844 352 PCV15+PPSV23 had higher immune responses vs. PCV13+PPSV23 for 9–11 PCV13 serotypes (GMT) or 5–10 PCV13 serotypes (% seroresponders) across both studies. Of all comparisons across studies (PCV15+PPSV23 vs. PCV13+PPSV23), only one serotype in a single study was found to be significantly higher by GMTs (serotype 18C). 2, moderate Critical
Serious adverse events
2 (3, 4) Randomized studies Not serious Not serious Not serious Serious‡ Not serious 0/1186 0/493 non estimable 2, moderate Critical

Table 4. Footnote
GMT=geometric mean titers, PCV13=13-valent pneumococcal conjugate vaccine, PCV15=15-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine, SAE=serious adverse events

*Number of patients based on minimum number included in immunogenicity comparisons presented; some comparisons may have had more patients than this minimum.

These are all immunogenicity studies and there are no correlates of protection.

No vaccine-related serious adverse events reported.

Table 5: Summary of Evidence for Outcomes of Interest

Table 5. Summary of Evidence for Outcomes of Interest
Outcome Importance Included in evidence profile Certainty
Vaccine-type invasive pneumococcal disease Critical Yes 2, moderate
Vaccine-type non-bacteremic pneumococcal pneumonia Critical Yes 2, moderate
Vaccine-type pneumococcal mortality Critical Yes 2, moderate
Serious adverse events following immunization Critical Yes 2, moderate

Summary

The evidence type for use of PCV15 in series with PPSV23 for adults aged 19–64 years with certain underlying medical conditions or other risk factors* was determined to be 2 (moderate certainty of evidence). The ACIP reviewed the results of both GRADE analysis and the Evidence to Recommendations (EtR) framework in September 2021. In October 2021, the ACIP recommended use of PCV15 in series with PPSV23 for adults aged 19–64 years with certain underlying medical conditions or other risk factors who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown.

Summary Footnote
*Alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear implant, congenital or acquired asplenia, CSF leak, diabetes mellitus, generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppression, leukemia, lymphoma, multiple myeloma, nephrotic syndrome, solid organ transplants, or sickle cell disease or other hemoglobinopathies.

Appendix I. Search Strategy

Appendix I: Search Strategies
Database Strategy Run Date Records
Medline
(OVID)
1. streptococcus pneumoniae/
2. (pneumococcal or pneumococci or “streptococcus pneumonie” or “streptococcus pneumoniae” or “s pneumoniae”).tw,kf.
3. 1 or 2
4. vaccination/ or immunization/ or Vaccines, Conjugate/
5. (vaccine? or vaccination? or immunisation or immunization).tw,kf.
6. 4 or 5
7. Pneumococcal Vaccines/
8. (heptavalent or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or pcv10 or “pcv 10” or “13valent” or “13 valent” or pcv13 or “pcv 13” or ppv23 or “ppv 23” or “23 valent” or “23valent”).tw,kf.
9. 7 or 8
10. (3 and 6)
11. 10 or 9
12. comparative effectiveness research/ or treatment outcome/ or Vaccine Potency/
13. (efficacy or effectiveness or effects or “immune response” or impact or “treatment outcome”).tw,kf.
14. 12 or 13
15. adult/ or aged/ or “aged, 80 and over”/ or frail elderly/
16. (adult? or elderly or elderlies).tw,kf.
17. 15 or 16
18. 11 and 14 and 17
19. (201904* OR 201905* OR 201906* OR 201907* OR 201908* OR 201909* OR 201910* OR 201911* OR 201912* OR 2020* OR 2021*).ed,ep,yr,dp,dt.
20. 17 and 18
02/18/2021 351
Embase
(OVID)
1988-
1. Streptococcus pneumoniae/
2. (pneumococcal or pneumococci or “streptococcus pneumonie” or “streptococcus pneumoniae” or “s pneumoniae”).tw,kw.
3. 1 or 2
4. vaccination/ or immunization/ or vaccine/
5. (vaccine? or vaccination? or immunisation or immunization).tw,kw.
6. 4 or 5
7. Pneumococcus vaccine/
8. (heptavalent or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or pcv10 or “pcv 10” or “13valent” or “13 valent” or pcv13 or “pcv 13” or ppv23 or “ppv 23” or “23 valent” or “23valent”).tw,kw.
9. 7 or 8
10. 3 and 6
11. 9 OR 10
12. comparative effectiveness/ or treatment outcome/
13. (efficacy or effectiveness or effects or “immune response” or impact or “treatment outcome”).tw,kw.
14. 12 or 13
15. aged/ or adult/ or aged hospital patient/ or frail elderly/ or institutionalized elderly/ or very elderly/
16. (adult? or elderly or elderlies).tw,kw.
17. 15 or 16
18. 11 and 14 and 17
19. (201904* OR 201905* OR 201906* OR 201907* OR 201908* OR 201909* OR 201910* OR 201911* OR 201912* OR 2020* OR 2021*).dc
20. limit 19 to (conference abstracts or embase)
02/18/2021 521


duplicates

=
unique items

Cochrane Library (
(
(pneumococcal or pneumococci or “streptococcus pneumonie” or “streptococcus pneumoniae” or “s pneumoniae”):ti,ab
AND
([mh Vaccines] OR [mh Immunization] OR (vaccine# or vaccination# or immunisation or immunization):ti,ab)
)
OR
(MH “Pneumococcal Vaccine”) OR TI (heptavalent or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or pcv10 or “pcv 10” or “13valent” or “13 valent” or pcv13 or “pcv 13” or ppv23 or “ppv 23” or “23 valent” or “23valent”) OR AB (heptavalent or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or pcv10 or “pcv 10” or “13valent” or “13 valent” or pcv13 or “pcv 13” or ppv23 or “ppv 23” or “23 valent” or “23valent”)
)
AND[mh “Treatment Outcomes”] OR (efficacy or effectiveness or effects or “immune response” or impact or “treatment outcome”):ti,abAND[mh Adult] OR [mh Aged+] OR (adult# or elderly or elderlies):ti,ab
02/18/2021 56


duplicates

=
unique items

CINAHL
(EbscoHost)
(
(TI (pneumococcal or pneumococci or “streptococcus pneumonie” or “streptococcus pneumoniae” or “s pneumoniae”) OR AB (pneumococcal or pneumococci or “streptococcus pneumonie” or “streptococcus pneumoniae” or “s pneumoniae”)) AND ((MH “Vaccines”) OR (MH “Immunization”) OR TI (vaccine# or vaccination# or immunisation or immunization) OR AB (vaccine# or vaccination# or immunisation or immunization))
OR
(MH “Pneumococcal Vaccine”) OR TI (heptavalent or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or pcv10 or “pcv 10” or “13valent” or “13 valent” or pcv13 or “pcv 13” or ppv23 or “ppv 23” or “23 valent” or “23valent”) OR AB (heptavalent or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or pcv10 or “pcv 10” or “13valent” or “13 valent” or pcv13 or “pcv 13” or ppv23 or “ppv 23” or “23 valent” or “23valent”)
)
AND
(MH “Treatment Outcomes”) OR TI (efficacy or effectiveness or effects or “immune response” or impact or “treatment outcome”) OR AB (efficacy or effectiveness or effects or “immune response” or impact or “treatment outcome”)
AND
((MH “Adult”) OR (MH “Aged+”) OR TI (adult# or elderly or elderlies) OR AB (adult# or elderly or elderlies))Limiters – Published Date: 20190401-20210218; Exclude MEDLINE records
02/18/2021 43


duplicates

=
unique items

Scopus
(for WOS)
(TITLE-ABS-KEY(“heptavalent” or “7 valent” or “7valent” or “pcv 7” or pcv7* or “10 valent” or “10valent” or “pcv10” or “pcv 10” or “13valent” or “13 valent” or “pcv13” or “pcv 13” or “ppv23” or “ppv 23” or “23 valent” or “23valent”) OR (TITLE-ABS-KEY(“vaccine$” or “vaccination$” or “immunisation” or “immunization”) AND TITLE-ABS-KEY(“pneumococcal” or “pneumococci” or “streptococcus pneumonie” or “streptococcus pneumoniae” or “s pneumoniae”))) AND TITLE-ABS-KEY(“adult$” or “elderly” or “elderlies”) AND TITLE-ABS-KEY(“efficacy” or “effectiveness” or “effects” or “immune response” or “impact” or “treatment outcome”)

Limit April 2019 –

02/18/2021 458


duplicates

=
unique items

Epistemonikos Search 1:
(pneumococcal OR pneumococci OR “streptococcus pneumonie” OR “streptococcus pneumoniae” OR “s pneumoniae”) AND (vaccine* OR vaccination* OR immunisation OR immunization) AND (efficacy OR effectiveness OR effects OR “immune response” OR impact OR “treatment outcome”) AND (adult* OR elderly OR elderlies)
– limited to 2019-2021Search 2:
(heptavalent OR “7 valent” OR “7valent” OR “pcv 7” OR pcv7* OR “10 valent” OR “10valent” OR pcv10 OR “pcv 10” OR “13valent” OR “13 valent” OR pcv13 OR “pcv 13” OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”) AND (efficacy OR effectiveness OR effects OR “immune response” OR impact OR “treatment outcome”) AND (adult* OR elderly OR elderlies)
– limited to 2019-2021
02/18/2021 19 + 10


duplicates

=
unique items

Appendix II. Studies Included in the Review of Evidence

Appendix II. Studies Included in the Review of Evidence
Study Study design Country (or more detail, if needed) Age (measure central tendency – mean/SD) Total population N Intervention N comparison Outcomes Funding source
V114-017 Phase III randomized controlled trial US Native Americans or adults with chronic medical conditions* aged 18-49 years of age (mean 35.8, SD 8.9) 1381 1035 346 Immunogenicity,
Safety
Merck
V114-018 Phase III randomized controlled trial US Adults ≥18 years of age with HIV (mean 40.0) 298 150 148 Immunogenicity,
Safety
Merck

Appendix II Footnote
*Chronic heart/liver/lung disease, cigarette smoking, diabetes mellitus

References

  1. World Health Organization. Strategic Advisory Group of Experts on Immunization 5-7 October 2020. 2020 [cited 2021 July 28]; Available from: https://terrance.who.int/mediacentre/data/sage/SAGE_eYB_October_2020.pdf?ua=1pdf iconexternal icon.
  2. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults at Increased Risk for Pneumococcal Disease (V114-017/PNEU-DAY). . Available from: https://ClinicalTrials.gov/show/NCT03547167external icon.
  3. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults Infected With Human Immunodeficiency Virus (HIV) (V114-018). https://ClinicalTrials.gov/show/NCT03480802external icon.
  4. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults at Increased Risk for Pneumococcal Disease (V114-017/PNEU-DAY). https://ClinicalTrials.gov/show/NCT03547167external icon.
Page last reviewed: January 27, 2022