GRADE: PCV15 use in children aged 2–18 years with certain underlying medical conditions that increase the risk of pneumococcal disease

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Introduction

On June 22, 2022, ACIP recommended use of 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) as an option for pneumococcal conjugate vaccination for persons aged <19 years according to currently recommended PCV13 dosing and schedules. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP’s deliberations regarding use of this vaccine.

Methods

A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV15 among pediatric age groups for which the vaccine was approved. Since only immunogenicity and safety data were available for PCV15, the search included 13-valent pneumococcal conjugate vaccine ((PCV13 [Prevnar 13, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer, Inc.]) efficacy or effectiveness studies to help interpret PCV15 immunogenicity study findings. GRADE assessment was performed for PCV15 studies only. As a basis for the GRADE evidence assessment, 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 PICO
Policy question: Should PCV15 be recommended as an option for pneumococcal conjugate vaccination according to currently recommended dosing and schedules, for U.S. children aged 2 through 18 years of age with underlying medical conditions?
Population U.S. children with underlying medical conditions* 2–18 years of age
Intervention PCV15 according to dosing and schedules currently recommended for PCV13
Comparison PCV13 according to currently recommended dosing and schedules
Outcomes Vaccine-type invasive pneumococcal disease, vaccine-type pneumonia, vaccine-type acute otitis media, vaccine-type pneumococcal deaths, serious adverse events following immunization

* Underlying medical conditions defined as cerebrospinal fluid leak; chronic renal failure or nephrotic syndrome; cochlear implant; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; sickle cell disease and other hemoglobinopathies. For children aged 2–5 years, also includes chronic heart or lung disease, diabetes mellitus.

This systematic review leveraged strategies used in existing systematic reviews, which captured literature published between January 1994–December 2019 targeting PCV7, PCV10 and PCV13 using various dosing schedules in the general pediatric population. Specifically, we utilized:

  • Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules (Loo 2014); searched literature from January 1994 – September 2010
  • Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules and Products (Cohen 2017); searched literature from October 2010 – December 2016
  • Updated literature search to Cohen 2017, which was conducted to review evidence regarding dosing schedule changes; searched literature from January 2017 – December 2019

In addition, we conducted a search of literature published during January 2010 – October 2021 from the following databases: Medline (OVID), Embase (OVID), Cochrane Library, CINAHL (EbscoHost), Scopus (for WOS). The search terms are included in Appendix 1. The updated search sought to capture:

  • Pneumococcal vaccine studies specifically targeting children with underlying medical conditions, which were not captured in the previous literature searches
  • Additional literature on pneumococcal vaccines published since January 2020 to update the previous systematic reviews evaluating PCV13 use in the general pediatric population

Search results were supplemented by an updated Pubmed search using “V114*” or “PCV15” and a search of clinicaltrials.gov using “V114”. Unpublished data were provided by the vaccine manufacturer.

Studies with primary data on PCV15 use in children 2 – 18 years of age with underlying medical conditions were included. Seventy-one studies were initially identified; after screening, deduplication and exclusion, 2 were included for GRADE. Characteristics of these studied are included in Appendix 2.  No PCV15 studies directly assessed vaccine effectiveness against the critical outcomes.  Beneficial and harmful outcomes for the GRADE assessment were selected by the ACIP Pneumococcal Vaccines Work Group during 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 acute otitis media, vaccine-type pneumococcal deaths, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).

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

Table 2: Outcomes and Rankings

Table 2: Outcomes and Rankings
Outcome Importance* Included in evidence profile
Vaccine-type invasive pneumococcal disease Critical No**
Vaccine-type pneumonia Critical No**
Vaccine-type acute otitis media Critical No**
Vaccine-type pneumococcal deaths Critical No**
Serious adverse events following immunization Critical Yes
*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making
**No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes

Table 3a. Summary of Studies Reporting Immunogenicity

Table 3a. Summary of Studies Reporting Immunogenicity
Author, year Study design; population and age N intervention N comparison Comparator vaccine IgG GMC ratios [range (serotype)]* Absolute difference in % seroresponders (serotype) Interpretation** Study limitations (Risk of Bias)
V114-023
Merck, unpublished		 Phase 3 RCT (one dose of V114 vs. PCV13), children with sickle cell disease, 5 – 17 years 69 34 PCV13 0.54 (4) to 1.67 (6B) Not reported GMC ratio (post-dose 1):
  • PCV15 > PCV13 for 6/13 shared st
  • PCV15 > PCV13 for 22F and 33F
 Not serious
V114-030
Merck, unpublished		 Phase 3 RCT (V114+PPSV23 vs. PCV13 + PPSV23), children living with HIV, 6 – 17 years 203 204 PCV13 followed by PPSV23 8 weeks later Post-PCV:
0.61 (4) to 1.65 (6B)
Post-PPSV23:
0.65 (4) to 1.43 (6B)		 Not reported Post-PCV:
  • PCV15 > PCV13 for 8/13 shared st; significant for st3 and 6B
  • PCV15 = PCV13 for 18C
  • PCV15 > PCV13 for 22F and 33F

Post-PPSV23:

  • PCV15+PPSV23 > PCV13 + PPSV23 for 3/13 shared st; significant for 6B
  • PCV15+PPSV23 < PCV13 + PPSV23 for 22F and 33F
 Not serious
GMC = Geometric mean concentration; st = serotype; RCT = randomized controlled trial; V114 = 15-valent pneumococcal conjugate vaccine; PCV13 = 13-valent pneumococcal conjugate vaccine; PPSV23 = 23-valent pneumococcal polysaccharide vaccine
* IgG GMC ratio = [GMC (PCV15)] / [GMC (comparator vaccine)]
**Blood draws occurred 30 days post-dose

Table 3b. Summary of Studies Reporting Safety

Table 3b. Summary of Studies Reporting Safety
Author, year Study Design; population and age N intervention N comparison Comparator vaccine Absolute % difference
(% SAE PCV15 –
% SAE comparator)*		 N related to vaccine Study limitations (Risk of Bias)
V114-023
Merck, unpublished		 Phase 3 RCT, children with sickle cell disease, 5 – 17 years 69 34 PCV13 -4.7 0 Not serious
V114-030
Merck, unpublished		 Phase 3 RCT, children living with HIV, 6 – 17 years 203 204 PCV13 0 0 Not serious
203 202 PCV13 +
PPSV23		 0 0
RCT = randomized controlled trial
*Reported serious adverse events include those that occurred after dose 1 through completion of study participation.

Table 4. Grade Summary of Findings Table

Table 4. Grade Summary of Findings Table
Certainty assessment № of patients Results Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations PCV15
Intervention		 PCV13
comparison		 Relative
(95% CI)		 Absolute
(95% CI)
Vaccine effectiveness: Vaccine-type pneumococcal disease (assessed with immunogenicity data)
21,2 Randomized studies Not serious Not serious Seriousa Seriousb Not serious 272 238 Post-PCV dose: PCV15 had higher immune responses (IgG GMC) vs. PCV13 for 6 to 8 PCV13 serotypes and unique serotypes (22F and 33F) across studies.
Post-PPSV23 dose: PCV15 + PPSV23 had higher immune response (IgG GMC) vs. PCV13 + PPSV23 for 3 of 13 PCV13 serotypes, but not for PCV15 unique serotypes (22F and 33F).		 3 Critical
Serious adverse events following immunization
21,2 Randomized studies Not serious Not serious Not serious Very seriousc Not serious 0/272 0/238 not estimable — 3 Critical
  1. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered
  2. Small sample size
  3. No vaccine-related serious adverse events reported; sample size very small

References

  1. V114-023. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Children With Sickle Cell Disease (V114-023/PNEU-SICKLE)
  2. V114-030. Safety and Immunogenicity of V114 in Children Infected With Human Immunodeficiency Virus (HIV) (V114-030/PNEU-WAY PED)

Table 5. Summary of Evidence for Outcomes of Interest

Table 5. Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty
VT- invasive pneumococcal disease Critical No* 3
VT- pneumonia Critical No* 3
Vaccine-type acute otitis media Critical No* 3
Vaccine-type pneumococcal deaths Critical No* 3
Serious adverse events following immunization Critical Yes 3

*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes

Summary

The evidence type for use of PCV15 in children aged 2–18 years of age with underlying medical conditions was determined to be 3 (low certainty of evidence) for VT-invasive pneumococcal disease, VT-pneumonia, VT-acute otitis media, and VT- pneumococcal deaths and was downgraded once for indirectness due to lack of correlates of protection for the critical outcomes considered and once for imprecision due to small sample sizes of the studies. The evidence type for serious adverse events following immunization was 3 (low certainty of evidence); imprecision was downgraded two points to very serious for few vaccine-related serious adverse events reported and for very small samples sizes of the studies. ACIP reviewed the results of both the GRADE evidence assessment and the Evidence to Recommendations (EtR) framework in February 2022. An updated EtR table was shared with ACIP in June 2022. On June 22, 2022, ACIP recommended use of PCV15 as an option for pneumococcal conjugate vaccination for persons aged <19 years according to currently recommended PCV13 dosing and schedules.

References

Loo JD, Conklin L, Deloria Knoll M, Fleming-Dutra K, et al. Methods for a Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules. PIDJ. 2014; 33(1,S2); S182-S187.

Cohen OG. Pneumococcal Conjugate Vaccine (PCV) Product Assessment. Accessed August 2, 2021 at https://www.jhsph.edu/ivac/wp-content/uploads/2018/05/pcv-product-assessment-april-25-2017.pdf.

Platt HL, Greenberg D, Tapiero B, Clifford RA, Klein NP, Hurley DC. A Phase II Trial of Safety, Tolerability and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, Compared With 13-Valent Pneumococcal Conjugate Vaccine in Healthy Infants. Pediatric Infectious Diseases Journal 2020.

V114-023. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Children With Sickle Cell Disease (V114-023/PNEU-SICKLE)

V114-030. Safety and Immunogenicity of V114 in Children Infected With Human Immunodeficiency Virus (HIV) (V114-030/PNEU-WAY PED)

Appendices

Appendix 1: Studies Included in the Review of Evidence

Appendix 1. Search strategy
Database Strategy Run Date Records
Medline
(OVID)
1946–		 (((pneumococcal OR pneumococci OR streptococcus pneumoni* OR s? pneumoni*) ADJ5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR pnu immune vaccine* OR pnuimmune vaccine* OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”)
AND
Exp Child/ OR (Child* OR pediatric* OR paediatric*).ti,ab,kf,hw.
AND
Trial* OR study OR studies OR rct* OR review.ti,pt.
Limit English; 2010 –		 10/20/2021 2864
Embase
(OVID)
1988–		 (((pneumococcal OR pneumococci OR streptococcus pneumoni* OR s? pneumoni*) ADJ5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR pnu immune vaccine* OR pnuimmune vaccine* OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”)
AND
Exp Child/ OR (Child* OR pediatric* OR paediatric*).ti,ab,kw,hw.
AND
Trial* OR study OR studies OR rct* OR review.ti,pt.
NOT
exp animal/ NOT exp human/Limit English; 2010 – ; not pubmed/medline ; not conference abstracts		 10/20/2021 3236

-2304
duplicates

=932
unique items
Cochrane Library [mh “pneumococcal vaccines”] OR (((pneumococcal OR pneumococci OR streptococcus pneumoni* OR s? pneumoni*) ADJ5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR pnu immune vaccine* OR pnuimmune vaccine* OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”):ti,ab
AND
[mh Child] OR (Child* OR pediatric* OR paediatric*):ti,abLimit English; 2010 –		 10/20/2021 331

-192
duplicates

=139
unique items
CINAHL
(EbscoHost)		 (((pneumococcal OR pneumococci OR “streptococcus pneumoni*” OR “s? pneumoni*”) N5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR “pnu immune vaccine*” OR “pnuimmune vaccine*” OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”)
AND
(Child* OR pediatric* OR paediatric*)
Limit English; 2010 – ; exclude Medline records		 10/20/2021 345

-267
duplicates

=78
unique items
Scopus TITLE-ABS-KEY(((pneumococcal OR pneumococci OR “streptococcus pneumoni*” OR “s? pneumoni*”) W/5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR “pnu immune vaccine*” OR “pnuimmune vaccine*” OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”) AND TITLE-ABS-KEY(Child* OR pediatric* OR paediatric*) AND NOT INDEX(medline)
Limit English; 2010 – ;		 10/20/2021 682

-492
duplicates

=190
unique items

Appendix 2. Studies Included in the Review of Evidence

Appendix 2. Studies Included in the Review of Evidence
Author, year Study design Country Age Total population N Intervention N comparison Outcomes Funding source
V114-023
Merck, unpublished		 Phase 3 RCT (one dose of V114 vs. PCV13), children with sickle cell disease, 5 – 17 years Brazil, Colombia, Dominican Republic, Greece, Italy, Panama, US 5–17 years 103 69 34 Immunogenicity, safety Merck
V114-030
Merck, unpublished		 Phase 3 RCT (V114+PPSV23 vs. PCV13 + PPSV23), children living with HIV, 6 – 17 years South Africa, Thailand, Ukraine 6–17 years 407 203 204 Immunogenicity, safety Merck

RCT = randomized controlled trial; V114 = 15-valent pneumococcal conjugate vaccine

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