About
- CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
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
| 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
| 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
| 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):
|
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:
Post-PPSV23:
|
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
| 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
| 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 |
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered
b. Small sample size
c. 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
| 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.
Appendices
Appendix 1: Studies Included in the Review of Evidence
| 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 =932 |
| 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 =139 |
| 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 =78 |
| 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 =190 |
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
View the complete list of GRADE evidence tables
- 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)