GRADE: 15-valent pneumococcal conjugate vaccine (PCV15) in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults aged ≥65 years

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 be routinely recommended to US adults ≥65 years and older in series with PPSV23?
Population	US adults aged ≥65 years
Intervention	One dose of PCV15 followed by PPSV23
Comparison	1. PCV13 followed by PPSV23 (immunocompromised adults aged ≥65 years) 2. PPSV23 (immunocompetent or healthy adults aged ≥65 years)
Outcomes	Vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumococcal pneumonia, and vaccine-type pneumococcal mortality Serious adverse events following immunization

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 the 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 aged ≥18 years. Of the 2,499 titles screened for WHO SAGE and 923 titles screened for the updated review in 2021, 3 unpublished PCV15 studies were included in the GRADE analysis (2-4). Characteristics of these studies are presented in Table 2. Beneficial and harmful outcomes for the GRADE assessment were selected by the ACIP Pneumococcal Vaccine Work Group calls and via an email survey in which 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

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	OPA GMT Ratios^* (serotype)	Absolute difference in % seroresponders^† (serotype)	Interpretation	Study limitations (Risk of Bias)
V114-017	Native Americans or adults with chronic medical conditions‡ aged 18-49 years th	GMT: 830-844 %seroresponders: 742-831 th	GMT: 276-283 %seroresponders: 247-279 th	PCV13 + PPSV23th (6-month interval between vaccines; 1-month post PPSV23)	0.88 (4) to 1.42 (18C)th	-6.7 (6A) to 6.0 (14) th	GMT ratios PCV15+PPSV23>PCV13+PPSV23 in 9/13 PCV13 serotypes after PPSV23 PCV15+PPSV23<PCV13+PPSV23 for 22F and 33F (PCV15-unique serotypes) after PPSV23 % seroresponders PCV15+PPSV23>PCV13+PPSV23 in 5/13 PCV13 serotypes after PPSV23 Non-significant for all 5/5 PCV15+PPSV23<PCV13+PPSV23 for 22F and 33F (PCV15-unique serotypes) after PPSV23	Not seriousth
V114-018	Adults ≥18 years of age with HIVth	GMT: 118-123 %seroresponders: 102-119 th	GMT: 113-117 %seroresponders: 105-113 th	PCV13 + PPSV23th (8-week interval between vaccines; 1-month post PPSV23)	0.89 (6A) to 1.52 (5)th	-2.0 (3) to 15.0 (19F) th	GMT ratios PCV15+PPSV23>PCV13+PPSV23 in 11/13 PCV13 serotypes after PPSV23 PCV15+PPSV23>PCV13+PPSV23 for 22F and PCV15+PPSV23<PCV13+PPSV23 for 33F after PPSV23 % seroresponders PCV15+PPSV23> PCV13+PPSV23 in 10/13 PCV13 serotypes after PPSV23 PCV15+PPSV23<PCV13+PPSV23 for 33F after PPSV23, equivalent for 22F	Not seriousth
V114-016	Adults ≥50 years of age th	GMT: 320-321 %seroresponders: 243-273th	GMT: 322-323 %seroresponders:245-272th	PCV13 + PPSV23th (12-month interval between vaccines; 1-month post PPSV23)	1.03 (19F) to 1.38 (1)th	-1 (5) to 9.1 (1)th	GMT ratios PCV15+PPSV23>PCV13+PPSV23 in 13/13 PCV13 serotypes Significantly higher for 3/13 PCV13 serotypes (serotypes 1, 14, 23F) PCV15+PPSV23>PCV13+PPSV23 for 22F and PCV15+PPSV23<PCV13+PPSV23 for 33F after PPSV23 % serorespondersth PCV15+PPSV23>PCV13+PPSV23 in 11/13 PCV13 serotypes Significant for 1/11 (serotype 3) PCV15+PPSV23>PCV13+PPSV23 for 22F and 33F (PCV15-unique serotypes) after PPSV23	Not seriousth

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

*Ratio calculated as [GMT (PCV15)] / [GMT (comparator vaccine)]. Range of GMT ratios for 13 serotypes common to PCV13 and PCV15 is shown
^†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.
^‡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)	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	Not serious
V114-018	Adults ≥18 years of age with HIV	150	148	PCV13 + PPSV23 (4-month observation period post-PPSV23)	-2.8	Not serious
V114-016	Adults ≥50 years of age	298	302	PCV13 + PPSV23 (1-month observation period post-PPSV23)	-0.4	Not serious

Table 3b. Footnotes
PCV13=13-valent pneumococcal conjugate vaccine, PCV20=20-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine, SAE=serious adverse events

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	Certainty	Importance
Vaccine effectiveness (Vaccine-type invasive pneumococcal disease, Vaccine-type non-bacteremic pneumococcal pneumonia, Vaccine-type pneumococcal mortality)
3 (2-4)	Randomized studies	Not serious	Not serious	Serious*^,†	Not serious	Not serious	1611	854	PCV15+PPSV23 had higher immune responses vs. PCV13+PPSV23 for 9–13 PCV13 serotypes (GMT) or 5–11 PCV13 serotypes (% seroresponders) across studies.		2	Critical
Serious adverse events
3 (2-4)	Randomized studies	Not serious	Not serious	Not serious^†	Serious‡	Not serious	0/1484	0/795	non estimable	—	2	Critical

Table 4. Footnotes
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

*These are all immunogenicity studies and there are no correlates of protection
^†V114-017: population was Immunocompetent adults 18-49 years of age at risk of pneumococcal disease; V114-018: population was adults ≥18 years of age with HIV; similar responses observed compared to general population
^‡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 in adults aged ≥65 years 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 June 2021. An updated EtR table was shared with the ACIP in September 2021. In October 2021, the ACIP recommended use of PCV15 in series with PPSV23 for all adults aged ≥65 years who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown.

Appendix I. Search Strategy

Appendix I: Search Strategy
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 (range)	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	1381	1035	346	Immunogenicity, Safety	Merck
V114-018	Phase III randomized controlled trial	US	Adults ≥18 years of age with HIV	298	150	148	Immunogenicity, Safety	Merck
V114-016	Phase III randomized controlled trial	US	Adults ≥50 years of age	627	325	302	Immunogenicity, Safety	Merck

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

References

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=1.
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/NCT03547167.
Safety and Immunogenicity of V114 in Healthy Adults (V114-019/PNEU-AGE). https://ClinicalTrials.gov/show/NCT03950622.
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/NCT03480802.

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