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Centers for Disease Control and Prevention
National Center for Immunization and Respiratory Diseases
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Preliminary Work Group Interpretations of EtR and
Next Steps
February 2024, ACIP Meeting
February 29, 2024
Miwako Kobayashi, MD, MPH, FACP , FIDSA
1.Should PCV21 be recommended for U.S. adults aged ≥19 years who
currently have a recommendation to receive a PCV*?
Comparison (current recommendations):
Adults aged ≥19 years who have not received a PCV
One dose of PCV15 followed by PPSV23
One dose of PCV20
Adults aged ≥19 years who have received a PCV but have not completed the recommended series
One dose of PCV20
≥1 dose of PPSV23Policy Questions Being Considered by the Work Group
*Includes,
• Adults aged ≥65 years who have never received a PCV
• U.S. adults aged 19-64 years with a risk condition, who have never received a PCV
• U.S. adults aged ≥19 year who have received a PCV (i.e., PCV7, PCV13, or PCV15), but have not completed the recommended series
2. Should PCV21 be recommended for U.S. adults aged 50- 64 years who
currently do not have a risk -based pneumococcal vaccine indication?
3. Should PCV21 be recommended for U.S. adults aged 19 -49 years who
currently do not have a risk -based pneumococcal vaccine indication?
Comparison (current recommendation):
No vaccine
Questions 2 and 3 imply a new age -based recommendation for these age groups.Policy Questions Being Considered by the Work Group
EtR Domain Question
Public Health Problem •Is the problem of public health importance?
Benefits and Harms •How substantial are the desirable anticipated effects?
•How substantial are the undesirable anticipated effects?
•Do the desirable effects outweigh the undesirable effects?
•What is the overall certainty of this evidence for the critical outcomes?
Values •Does the target population feel the desirable effects are large relative to
the undesirable effects?
•Is there important variability in how patients value the outcomes?
Acceptability •Is the intervention acceptable to key stakeholders?
Feasibility •Is the intervention feasible to implement?
Resource Use •Is the intervention a reasonable and efficient allocation of resources?
Equity •What would be the impact of the intervention on health equity?Evidence to Recommendations ( EtR ) framework
4
EtR Domain Question
Public Health Problem •Is the problem of public health importance?
Benefits and Harms •How substantial are the desirable anticipated effects?
•How substantial are the undesirable anticipated effects?
•Do the desirable effects outweigh the undesirable effects?
•What is the overall certainty of this evidence for the critical outcomes?
Values •Does the target population feel the desirable effects are large relative to
the undesirable effects?
•Is there important variability in how patients value the outcomes?
Acceptability •Is the intervention acceptable to key stakeholders?
Feasibility •Is the intervention feasible to implement?
Resource Use •Is the intervention a reasonable and efficient allocation of resources?
Equity•What would be the impact of the intervention on health equity?Evidence to Recommendations ( EtR ) framework
5
EtR Public Health Problem
Is pneumococcal disease of public health importance?
Prior to the COVID-19 pandemic, estimated to have caused
every year1:
–≥100,000 non- invasive pneumococcal pneumonia hospitalizations
–≥30,000 invasive pneumococcal disease (IPD) cases (e.g., bacteremic pneumonia,
pneumococcal bacteremia, meningitis)
•3,000 IPD deaths
Risk of disease and severe outcomes is higher among older adults and adults with certain risk conditions.
–Over one -third of adults aged ≥65 years hospitalized with community -acquired
pneumonia in Louisville, KY died within 1 year2
–>80% of IPD cases occurred among adults with risk -based indications3Pneumococcal Disease Burden among U.S. Adults
1. Kobayashi M. October 20, 2021 ACIP Meeting Presentation. Considerations for Age -Based and Risk -Based Use of PCV15 and PCV20 amon g U.S. Adults and Proposed Policy Options.
2. Older Adults Hospitalized for Pneumonia in the United States: Incidence, Epidemiology, and Outcomes - Arnold - 2020 - Journal of the American Geriatrics Society - Wiley Online Library
3. CDC Active Bacterial Core surveillance unpublished data
IPD incidence reached a historically low level early in the COVID -19
pandemic, but increasing toward pre- COVID levels
IPD=invasive pneumococcal disease; 2022 data in gray are preliminary
ABCs Bact Facts Interactive Data Dashboard | CDC
New pneumococcal conjugate vaccines, PCV15 and PCV20,
were recommended for adults and children in recent years
2021 2023 2022
PCV15 : ChildrenPCV20 : Expanded
indication for adults
who previously
received PCV13
PCV20 : ChildrenPCV15 and PCV20: Adults
who have not received
PCV or whose vaccination history is unknown
30–40% of adult IPD cases* are caused by serotypes not
contained in currently available vaccines; PCV21 contains
most of them.
*Based on ABCs 2018 –2022 data421615216
0102030405060708090100Percent IPD
PCV15+6C PCV20/non-PCV15
PPV23/non-PCV20 PCV21/non-PPV23
NVT42129298
0102030405060708090100Percent IPD
PCV15+6C PCV20/ non-PCV15
PPV23/ non-PCV20 PCV21/ non-PPV23
NVTAged 19 –64 years, with a risk- based
indication Aged ≥65 years
1. In adults currently recommended to receive a PCV ? (group 1)Is pneumococcal disease of public health importance?
□ No
□ Probably no
□ Probably yes
□ Yes
□ Varies
□ Don’t know Minority opinion (probably yes):
•Pneumococcal disease burden has decreased from
before
•Increase in disease incidence in recent years does not mean the incidence will continue to increase (i.e., may stabilize at pre -COVID -19 levels)
2. In adults aged 50– 64 years who currently do not have a risk -based
pneumococcal vaccine indication ? (group 2)Is pneumococcal disease of public health importance?
□ No
□ Probably no
□ Probably yes
□ Yes
□ Varies
□ Don’t know •Disease incidence in this age group overall is lower
compared with adults aged ≥65 years (IPD incidence ~23% lower)
3. In adults aged 19 –49 years who currently do not have a risk -based
pneumococcal vaccine indication ? (group 3)Is pneumococcal disease of public health importance?
□ No
□ Probably no
□ Probably yes
□ Yes
□ Varies
□ Don’t know •The most common WG member responses were
“No”(19%), “Probably No”(31%), and “Don’t know (25%)
•Adults aged 19 –49 years have even lower disease
incidence compared with adults aged 50 –64 years
EtR Benefits and Harms
1. How substantial are the desirable anticipated effects of PCV21 vaccination?
2. How substantial are the undesirable anticipated effects of PCV21
vaccination?
3. Do the desirable effects of PCV21 vaccination outweigh the undesirable
effects?
4. What is the overall certainty of this evidence for the critical outcomes?
Outcomes (Benefits)
*Rated on a 1 to 9 scale, where 7 –9 are critical, 4 –6 are important, 1 –3 are of limited importance
GMT= geometric mean titers; OPA=opsonophagocytic activity
See supplementary slides for details of methodsOutcome Importance* Description
VT- IPD Critical
VT- non- bacteremic
pneumococcal pneumoniaCritical
VT- pneumococcal deaths Critical
All IPD Important
Non -bacteremic
pneumococcal pneumoniaImportant
All-cause death ImportantStudies assessing PCV21 against these
clinical outcomes are currently not
available
PCV21 immunogenicity studies
•OPA GMT
•≥4-fold rise in serotype -specific
OPA responses
Outcomes (Harms)
*Rated on a 1 to 9 scale, where 7 –9 are critical, 4 –6 are important, 1 –3 are of limited importance
See supplementary slides for details of methodsOutcome Importance* Description
Serious adverse events
(SAE)Critical Safety data for PCV21 are available.
Last name first
author, Publication
yearStudy design Country Age Total population N Intervention N comparison OutcomesFunding
source
Platt, Lancet ID
2023RCT (Phase II) U.S. Adults ≥50 years 508 254 PPSV23: 254Immunogenicity and
SafetyMERCK
V116 -003RCT (Phase III);
pivotal studyU.S., Australia, Belgium,
Chile, Germany, Korea,
New Zealand, Puerto
Rico, Sweden, Taiwan,
TurkeyHealthy adults ≥50 years,
pneumococcal vaccine –
naïve2,6631179 PCV20: 1,177
Immunogenicity and
SafetyMERCKHealthy adults 18 - 49 years,
pneumococcal vaccine –
naïve200 PCV20: 100
V116 -005RCT (Phase III)U.S. Adults ≥50 years 1,080(V116 + QIV,
coadministered): 536(QIV followed by
V116) : 536Immunogenicity and
SafetyMERCK
V116 -006RCT (Phase III)U.S., Canada, Israel,
France, Italy, Japan,
Korea, Spain, TaiwanAdults ≥50 years, previous
PPSV23 ≥1 year prior to
enrollment348 229PCV15, n=119
Immunogenicity
and
SafetyMERCKAdults ≥50 years, previous
PCV13 ≥1 year prior to
enrollment259 174PPSV23
N=85
Adults ≥50 years,
PCV13+PPSV23,
PCV15+PPSV23, PCV15,
PCV20, or PPSV23+PCV13 ≥1
year prior to enrollment105 105 None
V116 -007 RCT (Phase III)Belgium, Chile, France,
South Africa,
Thailand,
United StatesAdults living with HIV,
≥18 years; 36% prior PCV13
or PPSV23*313 156PCV15+PPSV23,
n=157Immunogenicity and
SafetyMERCK
V116 -004RCT (Phase III)U.S., Austria, Canada,
Denmark, Finland, Israel,
Poland, SpainAdults 18 - 49 years with
underlying chronic
conditions2,162 1,617 PPSV23:540 SafetyMERCKPCV21 Clinical Trials Included in Evidence Review
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
VT-IPD, VT -nonbacteremic pneumococcal pneumonia, VT -pneumococcal mortality outcome (Assessed with: Immunogenicity)
51-5Randomized
studiesNot
seriousNot serious SeriousaNot serious Not serious 123 - 1161 58 - 1162• PCV21 met non -inferiority criteriab
for 9/9 shared and superiority
criteriac for 12/12 unique serotypes
vs. PPSV23
• PCV21 met non -inferiority criteriad
for 10/10 shared and superiority
criteriae 10/11 unique serotypes vs.
PCV20
• PCV21 had numerically higher
immune responses for 1 -4/6 shared
and all unique serotypes vs. PCV15Moderate CriticalGRADE Summary of Findings Table
1: Adults currently recommended to receive PCV
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
b. Noninferiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio ({PCV21:PPSV23} to be > 0.33.
c. Superiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio [PCV21:PPSV23] to be > 1.0.
d. Noninferiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [PCV21 / PCV20] to be >0.5.
e. Superiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [PCV21 / PCV20] to be >2. 0.
References
1. Platt H, Omole T, Cardona J, Fraser NJ, Mularski RA, Andrews C, Daboul N, Gallagher N, Sapre A, Li J, Polis A, Fernsler D, Tamms G, Xu W, Murphy R, Skinner J, Joyce J, Musey L. Safety, tolerability, and immunogenicity of a 21- valent pneumococcal c onjugate vaccine,
V116, in healthy adults: phase 1/2, randomised, double- blind, active comparator -controlled, multicentre, U.S.- based trial. Lancet Infect Dis. 2023 Feb;23(2):233- 246. doi: 10.1016/S1473- 3099(22)00526 -6. Epub 2022 Sep 15. PMID: 36116461.
2. V116- 003. A clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vaccine -naïve adults
3. V116- 006. A Phase 3 Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine- Experienced Adults 50 Years of Age or Older
4. V116- 007. A Phase 3, Multicenter, Randomized, Double- blind, Active Comparator - Controlled Study to Evaluate the Safety, Tolerabi lity, and Immunogenicity of V116 in Adults Living With HIV
5. V166- 005. A clinical study comparing the immunogenicity and safety of V116 when administered concomitantly with inactivated infl uenza vaccine
GRADE Summary of Findings Table
1: Adults currently recommended to receive PCV
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
b. Noninferiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio ({PCV21:PPSV23} to be > 0.33.
c. Superiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio [PCV21:PPSV23] to be > 1.0.
d. Noninferiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [PCV21 / PCV20] to be >0.5.
e. Superiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [PCV21 / PCV20] to be >2. 0.
See supplementary slides for details
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
Serious adverse events following immunization
61-6Randomized
studiesNot
seriousNot serious Not serious SeriousfNot serious 57/4445
(1.3%)63/2962
(2.1%)Absolute % difference for SAEs across
studies is -0.8%; two SAEs deemed
vaccine -relatedg in the V116 group
reportedModerate CriticalGRADE Summary of Findings Table
1: Adults currently recommended to receive PCV
f. few vaccine- related serious adverse events reported.
g. Bronchospasm (V116- 005): 50- year-old female in the sequential group with bronchospasm within 30 minutes after the 2ndvaccination (V116); duration 23 hours; resolved; Injection site cellulitis (V116- 006): 67- year-old female in Cohort 1 (prior PPSV23) with i njection site cellulitis
on Day 6; duration 1.57 weeks; resolved (Merck, unpublished).
References
1. Platt H, Omole T, Cardona J, Fraser NJ, Mularski RA, Andrews C, Daboul N, Gallagher N, Sapre A, Li J, Polis A, Fernsler D, Tamms G, Xu W, Murphy R, Skinner J, Joyce J, Musey L. Safety, tolerability, and immunogenicity of a 21- valent pneumococcal c onjugate vaccine,
V116, in healthy adults: phase 1/2, randomised, double- blind, active comparator -controlled, multicentre, U.S.- based trial. Lancet Infect Dis. 2023 Feb;23(2):233- 246. doi: 10.1016/S1473- 3099(22)00526 -6. Epub 2022 Sep 15. PMID: 36116461.
2. V116- 003. A clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vaccine -naïve adults
3. V116- 006. A Phase 3 Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine- Experienced Adults 50 Years of Age or Older
4. V116- 007. A Phase 3, Multicenter, Randomized, Double- blind, Active Comparator - Controlled Study to Evaluate the Safety, Tolerabi lity, and Immunogenicity of V116 in Adults Living With HIV
5. V166- 005. A clinical study comparing the immunogenicity and safety of V116 when administered concomitantly with inactivated infl uenza vaccine
6. V116- 004. A Phase 3 Randomized, Double- blind, Active Comparator -controlled, Lot to- Lot Consistency Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Adults 18 to 49 Years of Age.
GRADE Summary of Findings Table
1: Adults currently recommended to receive PCV
f. few vaccine- related serious adverse events reported.
g. Bronchospasm (V116- 005): 50- year-old female in the sequential group with bronchospasm within 30 minutes after the 2ndvaccination (V116); duration 23 hours; resolved; Injection site cellulitis (V116- 006): 67- year-old female in Cohort 1 (prior PPSV23) with i njection site cellulitis
on Day 6; duration 1.57 weeks; resolved (Merck, unpublished).
See supplementary slides for details
1. How substantial are the desirable anticipated effects of
PCV21 vaccination?
□ Minimal
□ Small
□ Moderate
□ Large
□ Varies
□ Don’t know □ Minimal
□ Small
□ Moderate
□ Large
□ Varies
□ Don’t know □ Minimal
□ Small
□ Moderate
□ Large
□ Varies
□ Don’t know 1. Adults currently
recommended to receive PCV2. Adults aged 50 –64 years with
no risk -based indication3. Adults aged 19 –49 years with
no risk -based indication
1. Adults currently recommended to receive PCV
2. Adults aged 50 –64 years with no risk- based indication
3. Adults aged 19 –49 years with no risk- based indication2. How substantial are the un desirable anticipated effects
of PCV21 vaccination?
□ Minimal
□ Small
□ Moderate
□ Large
□ Varies
□ Don’t know
□ Favors PCV21 use
□ Favors current
□ Favors both
□ Favors neither
□ Varies
□ Don’t know 3. Do the desirable effects of PCV21 vaccination outweigh
the undesirable anticipated effects?
1. Adults currently
recommended to receive PCV2. Adults aged 50 –64 years with
no risk -based indication3. Adults aged 19 –49 years with
no risk -based indication
□ Favors PCV21 use
□ Favors current (no
vaccine)
□ Favors both
□ Favors neither
□ Varies
□ Don’t know □ Favors PCV21 use
□ Favors current (no
vaccine) □ Favors both
□ Favors neither
□ Varies
□ Don’t know
•None selected by the majority
•“Favors current” and “favors PCV21
use” were the most common responses selected by similar number of members
Based on available data, no concerns about the risks outweighing the
benefits of PCV21 vaccination
For adults who currently have a PCV recommendation, PCV21 provides broader serotype coverage than currently recommended vaccinesSummary of Work Group Discussions:
Comments in favor of PCV21 use
We can expect a more robust immune response from administering
PCV21 at age 50 –64 years (vs. age ≥65 years) and before a portion of that
population develops an immunocompromising condition Summary of Work Group Discussions:
In favor of lowering the age -based recommendation (question 2)
The degree of benefits for adults who currently don’t have vaccine
recommendations is uncertain
Epidemiology does not support expanding the vaccine indications to younger adults without a risk -based indication
Younger adults (early 20s) would have received a PCV as a child
We could miss the opportunity to provide protection against disease later in life if we lowered the age- based recommendation
–Limited data on duration of protection or protection against disease from multiple
PCV doses in adults
Need to review cost- effectiveness analysis dataSummary of Work Group Discussions:
Concerns/uncertainties of lowering the age- based recommendation
(especially question 3)
EtR : Equity
What would be the impact of recommending PCV21 use for adults on
health equity?
Racial disparities in IPD incidence exist
White non- Hispanic adults tend to have
highest vaccine coverage1 compared with
other race/ethnicity groups
Remaining disparities in IPD incidence are
primarily due to non- PCV13 -type diseaseRacial disparities exist in IPD incidence and vaccine
coverage
Figure: ABCs unpublished data
1. Vaccination Coverage among Adults in the United States, National Health Interview Survey, 2021 | CDC
Adults experiencing homelessness (especially Western United States)
•100– 300 times higher serotype 4 IPD incidence reported in people experiencing
homelessness (PEH) vs. non -PEH in the Western United States1
Adults in Alaska (especially Alaska Native adults)
•88-fold increase in serotype 4 IPD incidence reported in adults in Alaska, 2011 –2018
vs. 2019– 20202 Increase in serotype 4 (included in currently available vaccines,
not in PCV21) IPD reported in certain subpopulations
1. Upsurge of Conjugate Vaccine Serotype 4 Invasive Pneumococcal Disease Clusters Among Adults Experiencing Homelessness in C alifornia, Colorado, and New Mexico | The
Journal of Infectious Diseases | Oxford Academic (oup.com)
2. Invasive Pneumococcal Disease and Potential Impact of Pneumococcal Conjugate Vaccines Among Adults, Including Persons Experie ncing Homelessness— Alaska, 2011 –2020 |
Clinical Infectious Diseases | Oxford Academic (oup.com)
1. In adults currently recommended to receive a PCV ?What would be the impact of recommending PCV21 use for
adults on health equity?
□ Reduced
□ Probably reduced
□ Probably no impact
□ Probably increased
□ Increased
□ Varies
□ Don’t know •Additional serotype coverage by PCV21 is expected
to reduce racial disparities in remaining
pneumococcal disease burden.
•For adults who have already received a PCV,
recommending a second PCV dose to complete
series might magnify the underlying disparities in
vaccine coverage.
2. In adults aged 50– 64 years who currently do not have a risk -based pneumococcal
vaccine indication ?
3. In adults aged 19 –49 years who currently do not have a risk -based pneumococcal
vaccine indication ?What would be the impact of recommending PCV21 use for
adults on health equity?
□ Reduced
□ Probably reduced
□ Probably no impact
□ Probably increased
□ Increased
□ Varies
□ Don’t know •Probably more equitable to lower the age threshold
for the age -based recommendation, which may
improve vaccine coverage in those who currently have risk -based indications
EtR Domains 1. Adults with current PCV
recommendations2. Adults aged 50– 64
years, no risk -based
indication3. Adults aged 19– 49
years, no risk -based
indication
Public Health Problem Yes Probably Yes No/Probably No
Benefits and Harms
a. Benefits Moderate/Large Small/Moderate Minimal/Small
b. Harms Minimal
c. Benefit>Harm? Favors PCV21 use Favors PCV21/Favors no
vaccine (split)
d. Overall certainty: effectiveness Moderate
e. Overall certainty: safety Moderate
Equity Probably increasedSummary of Work Group Interpretation of the EtR Domains
Work Group Next Steps
Review findings from cost -effectiveness analyses
Review evidence and discuss interpretations of remaining EtR
domains (Values, Acceptability, Resource Use, Feasibility)
Draft policy options on PCV21 use in U.S. adults for
consideration by the committee
–Including considerations for expanding the current risk -based vaccine
indications to include adults with chronic kidney disease (CKD) who are not on
maintenance dialysisWork Group Next Steps
Considerations for including earlier stages of
CKD for risk -based pneumococcal vaccine
indications
Indications for risk -based pneumococcal vaccine recommendations Children Adults
Alcoholism
Chronic heart disease†
Chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome)Chronic liver disease
Chronic lung disease
Cigarette smokingDiabetes mellitusCerebrospinal fluid leakCochlear implant
Maintenance dialysis or nephrotic syndrome
Congenital or acquired asplenia, or splenic dysfunctionCongenital or acquired immunodeficiency
¶
Diseases and conditions treated with immunosuppressive drugs or radiation therapy**HIV infectionSickle cell disease or other hemoglobinopathies
Solid organ transplantRisk -based pneumococcal vaccine indication was expanded to
include earlier -stage CKD (i.e., those not on dialysis) in children.
Does evidence support the change in adults as well?
In favor of expanding indications in
adults:
Pneumococcal disease risk is increased in earlier CKD stages
Allows adults to receive vaccine when immune response is more robust Concerned/cautious about expanding indications in adults
Unlike children, CKD is more common in adults
Inclusion of earlier stages, such as CKD stage 3a, could potentially result in expanding the risk- based indication to
a much larger proportion of adults (unless they already have other risk-based indications)
Would like to see a cost -benefit
analysis Summary of Work Group Discussion to Date
Considering:
Additional pneumococcal vaccines for adults are currently under investigation and
may be approved in the near future, and
Dynamic changes in pneumococcal disease incidence are anticipated post -COVID -19
and with increased uptake in PCV15/PCV20 in children and adults
1. Do you have any feedback on the policy questions being considered by the WG?2. What additional data would be helpful to inform the discussions on PCV21 use in
adults?
In addition,
3. What additional data would be needed to help inform the discussions on expanding
the risk- based indications to include adults with CKD?
Questions for the Committee
ACIP and the Pneumococcal Vaccines Work Group
CDC contributors and consultants: Ryan Gierke, Jennifer Farrar, Kristin Andrejko,
Lindsay Zielinski, Emma Accorsi, Wei Xing, Adam Cohen, Alison Albert, Angela Jiles, Noele Nelson, Kimberly Fox, Pedro Moro, Elizabeth Velazquez, Janelle King, Fangjun Zhou, Marc Fischer, Cheryl Ward, Rebecca Morgan, Doug Campos -Outcalt
Active Bacterial Core surveillance sites and programAcknowledgments
For more information, contact CDC
1-800- CDC- INFO (232 -4636)
TTY: 1 -888 -232-6348 www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the official
position of the Centers for Disease Control and Prevention.
Photographs and images included in this presentation are licensed solely for CDC/NCIRD online and presentation
use. No rights are implied or extended for use in printing or any use by other CDC CIOs or any external audiences.
Thank you!
GRADE Evidence Summary
Supplemental Slides
PICO 1: Adults currently recommended to receive PCV
Policy question: Should PCV21 be recommended for U.S. adults aged ≥19 years who currently have a
recommendation to receive a pneumococcal conjugate vaccine?
Population •U.S. adults aged ≥65 years who have never received a PCV
•U.S. adults aged 19 –64 years with a risk condition, who have never received a PCV
•U.S. adults aged ≥19 years who have received a PCV (i.e., PCV7, PCV13, or PCV15), but
have not completed the recommended series
Intervention One dose of PCV21 (V116)
Comparison Adults who have not received a PCV
•One dose of PCV15 followed by PPSV23
•One dose of PCV20
Adults who have received a PCV but have not completed the recommended series
•One dose of PCV20
•≥1 dose of PPSV23
Outcomes Vaccine type (VT)-IPD, VT -non -bacteremic pneumococcal , VT -pneumococcal mortality,
serious adverse events
PICO2: Adults aged 50–64 years, no risk- based indications
Policy question: Should PCV21 be recommended for U.S. adults aged 50 –64 years who currently
do not have a risk -based pneumococcal vaccine indication?
Population U.S. adults aged 50 –64 years who currently do not have a risk -based pneumococcal
vaccine indication
Intervention One dose of PCV21
Comparison No vaccination
Outcomes Vaccine type (VT) -IPD, VT -non- bacteremic pneumococcal , VT -pneumococcal
mortality, serious adverse events
PICO3: Adults aged 19–49 years, no risk- based indications
Policy question: Should PCV21 be recommended for U.S. adults aged 19 –49 years who currently
do not have a risk -based pneumococcal vaccine indication?
Population U.S. adults aged 19 –49 years who currently do not have a risk -based pneumococcal
vaccine indication
Intervention One dose of PCV21
Comparison No vaccination
Outcomes Vaccine type (VT) -IPD, VT -non- bacteremic pneumococcal , VT -pneumococcal
mortality, serious adverse events
Search strategy
Database StrategyNo.
identifiedIncluded in
GRADE
clinicaltrials
.govSearch terms (searched separately): "V116"; "21 -valent pneumococcal conjugate vaccine";"PCV21"
Inclusion: Relevant Phase 2 or 3 randomized controlled trials of PCV21
• Involved human subjects
• Reported primary data
• Included adults (age ≥19 years)
• Included data relevant to the efficacy or effectiveness or immunogenicity and safety outcomes
being measured
10 6
Pubmed "V116" or "21 -valent pneumococcal conjugate vaccine" or "PCV21"
Included studies using the criteria listed above25 1
Additional
resourcesUnpublished and other relevant data by consulting with vaccine manufacturers and subject matter experts
5
Evidence Retrieval
Clinicaltrials.gov
N=10
6 studies included for GRADEPubmed
N=25
PCV21 50 – 64y, no risk
based indication
Immunogenicity (n=2)
SAE (n=2)Unpublished data
N=5
PCV21 for currently
recommended adults
(n=6)
Immunogenicity (n=5)
SAE (n=6)PCV21 19 – 49y, no risk
based indication
Immunogenicity (n=1)
SAE (n=1)
Last name first
author, Publication
yearStudy design Country Age Total population N Intervention N comparison OutcomesFunding
source
Platt, Lancet ID
2023RCT (Phase II) U.S. Adults ≥50 years 508 254 PPSV23: 254Immunogenicity and
SafetyMERCK
V116 -003RCT (Phase III);
pivotal studyU.S., Australia, Belgium,
Chile, Germany, Korea,
New Zealand, Puerto
Rico, Sweden, Taiwan,
TurkeyHealthy adults ≥50 years,
pneumococcal vaccine –
naïve2,6631179 PCV20: 1,177
Immunogenicity and
SafetyMERCKHealthy adults 18 - 49 years,
pneumococcal vaccine –
naïve200 PCV20: 100
V116 -005RCT (Phase III)U.S. Adults ≥50 years 1,080(V116 + QIV,
coadministered): 536(QIV followed by
V116) : 536Immunogenicity and
SafetyMERCK
V116 -006RCT (Phase III)U.S., Canada, Israel,
France, Italy, Japan,
Korea, Spain, TaiwanAdults ≥50 years, previous
PPSV23 ≥1 year prior to
enrollment348 229PCV15, n=119
Immunogenicity
and
SafetyMERCKAdults ≥50 years, previous
PCV13 ≥1 year prior to
enrollment259 174PPSV23
N=85
Adults ≥50 years,
PCV13+PPSV23,
PCV15+PPSV23, PCV15,
PCV20, or PPSV23+PCV13 ≥1
year prior to enrollment105 105 None
V116 -007 RCT (Phase III)Belgium, Chile, France,
South Africa,
Thailand,
United StatesAdults living with HIV,
≥18 years; 36% prior PCV13
or PPSV23*313 156PCV15+PPSV23,
n=157Immunogenicity and
SafetyMERCK
V116 -004RCT (Phase III)U.S., Austria, Canada,
Denmark, Finland, Israel,
Poland, SpainAdults 18 - 49 years with
underlying chronic
conditions2,162 1,617 PPSV23:540 SafetyMERCKPCV21 Clinical Trials included in Evidence Review
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
VT-IPD, VT -nonbacteremic pneumococcal pneumonia, VT -pneumococcal mortality outcome (Assessed with: Immunogenicity)
51-5Randomized
studiesNot
seriousNot serious SeriousaNot serious Not serious 123 - 1161 58 - 1162• V116 met non -inferiority criteriab for
9/9 shared and superiority criteriac
for 12/12 unique serotypes vs.
PPSV23
• V116 met non -inferiority criteriad for
10/10 shared and superiority
criteriae 10/11 unique serotypes vs.
PCV20
• V116 had higher immune responses
for 1 -4/6 shared and all unique
serotypes vs. PCV15Moderate CriticalGRADE Summary of Findings Table
PICO 1: Adults currently recommended to receive PCV
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
b. Noninferiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio ({V116:PPSV23} to be > 0.33.
c. Superiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio [V116:PPSV23] to be > 1.0.
d. Noninferiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be > 0.5.
e. Superiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be >2.0.
References
1. Platt H, Omole T, Cardona J, Fraser NJ, Mularski RA, Andrews C, Daboul N, Gallagher N, Sapre A, Li J, Polis A, Fernsler D, Tamms G, Xu W, Murphy R, Skinner J, Joyce J, Musey L. Safety, tolerability, and immunogenicity of a 21- valent pneumococcal c onjugate vaccine,
V116, in healthy adults: phase 1/2, randomised, double- blind, active comparator -controlled, multicentre, U.S.- based trial. Lancet Infect Dis. 2023 Feb;23(2):233- 246. doi: 10.1016/S1473- 3099(22)00526 -6. Epub 2022 Sep 15. PMID: 36116461.
2. V116- 003. A clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vaccine -naïve adults
3. V116- 006. A Phase 3 Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine- Experienced Adults 50 Years of Age or Older
4. V116- 007. A Phase 3, Multicenter, Randomized, Double- blind, Active Comparator - Controlled Study to Evaluate the Safety, Tolerabi lity, and Immunogenicity of V116 in Adults Living With HIV
5. V166- 005. A clinical study comparing the immunogenicity and safety of V116 when administered concomitantly with inactivated infl uenza vaccine
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
Serious adverse events following immunization
61-6Randomized
studiesNot
seriousNot serious Not serious SeriousfNot serious 57/4445
(1.3%)63/2962
(2.1%)Absolute % difference for SAEs across
studies is -0.8%; two SAEs deemed
vaccine -relatedg in the V116 group
reportedModerate CriticalGRADE Summary of Findings Table
PICO 1: Adults currently recommended to receive PCV
f. few vaccine- related serious adverse events reported.
g. Bronchospasm (V116- 005): 50- year-old female in the sequential group with bronchospasm within 30 minutes after the 2ndvaccination (V116); duration 23 hours; resolved; Injection site cellulitis (V116- 006): 67- year-old female in Cohort 1 (prior PPSV23) with i njection site cellulitis
on Day 6; duration 1.57 weeks; resolved (Merck, unpublished).
References
1. Platt H, Omole T, Cardona J, Fraser NJ, Mularski RA, Andrews C, Daboul N, Gallagher N, Sapre A, Li J, Polis A, Fernsler D, Tamms G, Xu W, Murphy R, Skinner J, Joyce J, Musey L. Safety, tolerability, and immunogenicity of a 21- valent pneumococcal c onjugate vaccine,
V116, in healthy adults: phase 1/2, randomised, double- blind, active comparator -controlled, multicentre, U.S.- based trial. Lancet Infect Dis. 2023 Feb;23(2):233- 246. doi: 10.1016/S1473- 3099(22)00526 -6. Epub 2022 Sep 15. PMID: 36116461.
2. V116- 003. A clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vaccine -naïve adults
3. V116- 006. A Phase 3 Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine- Experienced Adults 50 Years of Age or Older
4. V116- 007. A Phase 3, Multicenter, Randomized, Double- blind, Active Comparator - Controlled Study to Evaluate the Safety, Tolerabi lity, and Immunogenicity of V116 in Adults Living With HIV
5. V166- 005. A clinical study comparing the immunogenicity and safety of V116 when administered concomitantly with inactivated infl uenza vaccine
6. V116- 004. A Phase 3 Randomized, Double- blind, Active Comparator -controlled, Lot to- Lot Consistency Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Adults 18 to 49 Years of Age.
Certainty assessment № of patients Effect
Certainty Importance № of
studiesStudy designRisk
of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
VT-IPD, VT -nonbacteremic pneumococcal pneumonia, VT -pneumococcal mortality outcome (Assessed with: Immunogenicity)
21-2Randomized
studiesNot
seriousNot serious SeriousaNot serious Not serious 252 - 1161 254 - 1162 • V116 met non -inferiority
criteriab for 9/9 shared and
superiority criteriac for 12/12
unique serotypes vs. PPSV23
• V116 met non -inferiority
criteriad for 10/10 shared and
superiority criteriae 10/11
unique serotypes vs. PCV20Moderate CriticalGRADE Summary of Findings Table
PICO2: Adults aged 50–64 years, no risk- based indications
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
b. Noninferiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio ({V116:PPSV23} to be > 0.33.
c. Superiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio [V116:PPSV23] to be > 1.0.
d. Noninferiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be > 0.5.
e. Superiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be >2.0.
References
1. Platt H, Omole T, Cardona J, Fraser NJ, Mularski RA, Andrews C, Daboul N, Gallagher N, Sapre A, Li J, Polis A, Fernsler D, Tamms G, Xu W, Murphy R, Skinner J, Joyce J, Musey L. Safety, tolerability, and immunogenicity of a 21-
valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double- blind, active comparator -controlled, multicentre, U.S.- based trial. Lancet Infect Dis. 2023 Feb;23(2):233 -246. doi: 10.1016/S1473-
3099(22)00526 -6. Epub 2022 Sep 15. PMID: 36116461.
2. V116- 003. A clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vaccine- naïve adults
Certainty assessment № of patients Effect
Certainty Importance № of
studiesStudy designRisk
of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
Serious adverse events following immunization
21-2Randomized
studiesNot
seriousNot serious Not serious SeriousfNot serious 23/1431
(1.6%)27/1429
(1.9%)Absolute % difference for SAEs across
studies is -0.3%; no vaccine -related
serious adverse events reportedModerate CriticalGRADE Summary of Findings Table
PICO2: Adults aged 50–64 years, no risk- based indications
f. No vaccine -related serious adverse events reported.
References
1. Platt H, Omole T, Cardona J, Fraser NJ, Mularski RA, Andrews C, Daboul N, Gallagher N, Sapre A, Li J, Polis A, Fernsler D, Tamms G, Xu W, Murphy R, Skinner J, Joyce J, Musey L. Safety, tolerability, and immunogenicity of a 21-
valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double- blind, active comparator -controlled, multicentre, U.S.- based trial. Lancet Infect Dis. 2023 Feb;23(2):233 -246. doi: 10.1016/S1473-
3099(22)00526 -6. Epub 2022 Sep 15. PMID: 36116461.
2. V116- 003. clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vacc ine-naïve adults
Certainty assessment № of patients Effect
Certainty Importance
№ of
studiesStudy designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
VT-IPD, VT -nonbacteremic pneumococcal pneumonia, VT -pneumococcal mortality outcome (Assessed with: Immunogenicity)
11Randomized
studiesNot
seriousNot serious SeriousaNot serious Not serious 184 - 198 550 - 575 V116 met criteria for
immunobridgingb to 50 -
64y for all serotypesModerate CriticalGRADE Summary of Findings Table
PICO3: Adults aged 19–49 years, no risk- based indications
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
b. Immunobridging for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 18 to 49 group/V116 50 to 64 gr oup] to be >0.5.
References
1. V116 -003. A clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vaccine -naïve adults
Certainty assessment № of patients Effect
Certainty Importance№ of
studiesStudy designRisk
of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV21 comparisonRelative
(95% CI)Absolute
(95% CI)
Serious adverse events following immunization
11Randomized
studiesNot
seriousNot serious Not serious SeriouscNot serious 1/200
(0.5%)3/100
(3.0%)Absolute % difference
for SAEs is -2.5%; no
vaccine -related
serious adverse events
reportedModerate CriticalGRADE Summary of Findings Table
PICO3: Adults aged 19–49 years, no risk- based indications
c. No vaccine -related serious adverse events reported
References
1. V116 -003. clinical study to evaluate the safety, tolerability, and immunogenicity of V116 compared to PCV20 in pneumococcal vacc ine-naïve adults
PICO1: Adults currently recommended to receive PCV
Type Outcome ImportanceIncluded in evidence
profile Certainty of evidence
BenefitsVT- IPD Critical No* Moderate
VT-pneumonia Critical No* Moderate
VT- pneumococcal
deathsCritical No* Moderate
HarmsSerious adverse events
following
immunizationCritical Yes Moderate
*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes
PICO2: Adults aged 50 –64 years, no risk -based
indications
Type Outcome ImportanceIncluded in evidence
profile Certainty of evidence
BenefitsVT- IPD Critical No* Moderate
VT-pneumonia Critical No* Moderate
VT- pneumococcal
deathsCritical No* Moderate
HarmsSerious adverse events
following
immunizationCritical Yes Moderate
*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes
PICO3: Adults aged 19– 49 years, no risk -based
indications
Type Outcome ImportanceIncluded in evidence
profile Certainty of evidence
BenefitsVT- IPD Critical No* Moderate
VT-pneumonia Critical No* Moderate
VT- pneumococcal
deathsCritical No* Moderate
HarmsSerious adverse events
following
immunizationCritical Yes Moderate
*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes