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Evidence to Recommendations for PCV20 use among adults 19-64 years old										Related Pages
					**Question: Should PCV20 be recommended for U.S. adults aged 19–64 years with chronic medical conditions or immunocompromising conditions?**
**Population:**U.S. adults aged 19–64 years with chronic medical conditions (CMC)* or immunocompromising conditions (IC)**
**Intervention:** PCV20
**Comparison:**Current pneumococcal vaccine recommendations:
PPSV23 (adults with CMC*)
PCV13 followed by PPSV23 (adults with IC**)*alcoholism, chronic heart/liver/lung disease, cigarette smoking, diabetes mellitus
**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.
**Outcome:** Vaccine-type invasive pneumococcal disease; Vaccine-type non-bacteremic pneumococcal pneumonia; Vaccine-type pnemococcal death; Serious adverse events following immunization**Background:**
On June 8, 2021, a 20-valent pneumococcal conjugate vaccine (PCV20, Pfizer) was licensed for use in adults aged ≥18 years. Unlike previous conjugate vaccine formulations, PCV20 was licensed for adults before submission for licensure in children.
Two pneumococcal vaccines (13-valent pneumococcal conjugate vaccine [PCV13] and 23-valent pneumococcal polysaccharide vaccine [PPSV23]) were recommended for use in adults, and the recommendations varied by age- and risk-groups. The ACIP Pneumococcal Vaccines Work Group reviewed available data to inform the use of PCV20 in adults and identify policy options that maximize pneumococcal disease prevention among adults, reduce disparity, and simplify recommendations to improve vaccine uptake.Problem
Resource use model, base, range
Criteria
Work Group Judgments
Evidence
Additional InformationIs the problem of public health importance?
Yes
Adults with certain underlying conditions are at increased risk of pneumococcal disease[1, 2]. Recommendations for use of pneumococcal vaccines varied by conditions. Adults with chronic medical conditions (CMC), such as alcoholism, chronic heart/lung/liver disease, cigarette smoking, and diabetes mellitus, were recommended to receive a dose of 23-valent pneumococcal polysaccharide vaccine (PPSV23); adults with immunocompromising conditions, cochlear implant or CSF leak were recommended to receive a dose of 13-valent pneumococcal polysaccharide vaccine (PCV13) followed by PPSV23 at least 8 weeks later [3]. Adults with immunocompromising conditions were recommended to receive a second dose of PPSV23 at least 5 years after the first dose [3]. In this document, adults with cochlear implant or CSF leak are grouped together as immunocompromising conditions (IC).
Introduction of PCV13 in children in 2010 reduced the invasive pneumococcal disease (IPD) incidence due to PCV13-types in both adults with CMC and IC aged 19–64 years (ABCs unpublished data). Nonetheless, in 2017–2018, adults aged 19–64 years with CMC or IC had 4–9 times higher risk of all-IPD, and 4–7 times higher risk of PCV13-type IPD compared to adults without these conditions; PCV15-type, non-PCV13-type comprised 11–13% of all IPD and serotype 3 in PCV13 comprised 10–13% of all IPD; PCV20-type, non-PCV13 type comprised approximately 27% of all IPD.
The estimated burden of pneumococcal pneumonia has varied. According to US healthcare claims data, the risk of hospitalized pneumococcal pneumonia among adults aged 18–64 years with CMC was 4–5 times higher and among those with IC was 11–18 times higher than adults without these conditions [4].Benefits and Harms
Benefits and Harms
Criteria
Work Group Judgments
Research Evidence
Additional InformationHow substantial are the desirable anticipated effects?
Large
PCV20 vs PCV13 (13 shared serotypes)One Phase 2[5] and two Phase 3[6, 7] randomized-controlled trials compared the immunogenicity of PCV20 vs. PCV13 against the 13 shared serotypes.
In the phase 2 study targeting adults aged 60–64 years and the phase 3 studies, geometric mean titer (GMT) was lower among adults receiving PCV20 vs. PCV13 in 12-13/13 shared serotypes. GMT was significantly lower in 4/13 serotypes (no overlap in GMT confidence intervals) in the Phase 2 study[5], and 3-5/13 serotypes in the Phase 3 studies (range reflects differences in results across studies), although non-interiority criteria was met for all 13 common serotypes in the Phase 3 studies[6, 7]. %  seroresponders (% of subjects with ≥4-fold risk in OPA GMT post-vaccination) was lower in 12/13 serotypes in both Phase 2 and 3 studies. The difference was non-significant in the Phase 2 study, and significant for serotype 3 in one phase 3 study and for serotypes 1, 5, and 19F in another phase 3 study[6, 7].
PCV20 vs PPSV23 (7 shared serotypes)One Phase 2[5] and one Phase 3[6] randomized-controlled trials provided comparison on the immunogenicity of PCV20 vs PPSV23 against the 7 shared serotypes.
Compared to PPSV23, GMT was higher in PCV20 for 6/7 common serotypes in both studies; GMT was significantly higher in 3/7 serotypes in the Phase 2 study, although significantly lower in serotype 8 (GMT confidence intervals did not overlap). In the Phase 3 study, noninferiority criteria was met for 6/7 serotypes, but not for serotype 8 (significantly lower). % seroresponders was higher in 6/7 serotypes in both studies (significant for all serotypes in the Phase 3 study and for 2/7 serotypes in the Phase 2 study) and lower in serotype 8 (significant in the Phase 3 study only).
PCV20 in 18–49 years vs 60–64 yearsA Phase 3 study [6] compared the immunogenicity of PCV20 in adults aged 18–49 years compared to adults aged 60–64 years; compared to adults aged 60–64 years, GMT was higher (significant for serotype 14), and met the noninferiority criteria for all 20 serotypes. % seroresponders was higher in 18/20 serotypes (significantly higher in 11/20 and lower in 1/20) in adults aged 18–49 years.
PCV20 vs PCV13+PPSV23 (13 shared serotypes)A Phase 2 study [5] provided data on GMTs one month after PCV20 administration vs. one month after PPSV23 administration (given as the second dose of the PCV13-PPSV23 series). GMT was lower in PCV20 in all serotypes (significant in 9/13 serotypes).
Proportion of pneumococcal disease that are contained in PPSV23 but not in PCV20The proportion of IPD due to PPSV23-non-PCV20 types in adults with CMC or IC aged 19–64 years was 12–13% of all IPD in 2017–2018 (ABCs unpublished data).
According to NHIS 2017–2018 data, the proportion of adults with CMC and IC among all adults aged 18–64 years was 39% and 4%, respectively. Given that adults with CMC were recommended to receive PPSV23 only, the largest impact of recommending PCV20 is estimated to come from adults with CMC, assuming that PCV20 has better vaccine effectiveness against disease (especially vaccine-type pneumococcal pneumonia) compared to PPSV23.
No PCV20 studies directly assessed the critical outcomes.
No PCV20 studies specifically targeted adults with IC or CMC.
While immunogenicity of PCV20 tended to be lower compared to PCV13 for the 13 shared serotypes, both Phase 3 trials met the non-inferiority criteria. Additionally, indirect effects from pediatric PCV13 vaccinations reduced PCV13 disease burden in both adults with CMC (no PCV13 recommendation) and IC (with PCV13 recommendation). The direct benefit of PCV13 vaccination in adults with IC is unknown.
On the other hand, PCV20 had higher immunogenicity compared to PPSV23 for 6/7 serotypes (except serotype 8) that are not included in PCV13.
Some expressed concerns that four fewer serotypes covered by PCV20 compared to PPSV23.
The Work Group believed that a simplified recommendation with a single vaccine would increase vaccine coverage and would have the potential to prevent more disease than existing recommendations.**Conclusion:**
Despite uncertainties about the clinical significance of lower immunogenicity of PCV20 compared to PCV13, and the impact of using PCV20 only against disease caused by PPSV23-nonPCV20 types, the Work Group believed that the potential benefit from PCV20 use is large compared to existing recommendations.How substantial are the undesirable anticipated effects?
Minimal
Safety data from phase 2 or 3 randomized-controlled trials [5-7]  showed that the % of subjects who received PCV20 with serious adverse events were low and comparable to those who received PCV13 with or without PPSV23 (0-4.1% in PCV20 group, 0-5.0% in PCV13+/-PPSV23 group). No serious adverse events were associated with the vaccines.Do the desirable effects outweigh the undesirable effects?
Favors intervention
The Work Group determined that desirable effects of the Pfizer PCV20 outweigh undesirable effects.What is the overall certainty of this evidence for the critical outcomes?
Effectiveness of the intervention is Level 3 (Low)
Safety of the intervention is Level 2 (Moderate)
GRADE analyses were completed to assess certainty of evidence.
Overall evidence type was 3 for vaccine effectiveness.
Assessment on indirectness was downgraded to “very serious”:
Only immunogenicity studies were available. Correlates of protection have not been established for PCV20 in adults.
No studies specifically targeted adults with CMC or ICOverall evidence type was 2 for serious adverse events.Assessment on imprecision was downgraded to “serious” because there were no vaccine-related serious adverse events reported in studies with relatively low sample sizes.
Refer to GRADE summary tables for details.Values
Values
Criteria
Work Group Judgments
Research Evidence
Additional InformationDoes the target population feel that the desirable effects are large relative to undesirable effects?
Probably yes
We conducted a Pubmed search on U.S. studies published within the past 5 years which assessed the beliefs, attitudes, and intentions related to pneumococcal vaccines in adults who are eligible for risk-based pneumococcal vaccine recommendations [2, 3].
One online cross-sectional survey conducted in March–April, 2019 was identified [8]. The survey assessed vaccine-related beliefs, reasons for hesitancy, external influences on vaccination, and prior vaccination in 1,002 Tennessee residents aged 19–64 years with CMC/IC. Survey respondents were mostly female (75%), White (68%), non-Hispanic (95%), and had at least some college education (72%). The most common qualifying conditions were current smoker (28%), asthma (26%), and diabetes (19%).
In the past five years, 19% of the respondents indicated that pneumococcal vaccines were offered to them, and more than half of those accepted the provider-initiated vaccine recommendation. While 92% indicated that vaccines can prevent serious disease, 32% reported ever being reluctant, hesitant, or resistant to a recommended vaccine. Of those ever reporting hesitancy or resistance, 77% were hesitant or reluctant to the influenza vaccine, and 27% for the pneumococcal vaccine. The common reasons for hesitancy (for any vaccines) were:
Not knowing it was needed (36%)
Fear of needles (29%)
Concerns about safety (24%)The odds of vaccine hesitancy or resistance was greater in:
Minorities (OR: 1.6)
Those believing others like them do not get vaccinated (OR: 1.8)
Those recalling negative media about vaccines (OR: 2.6)None of these studies assessed values on use of PCV20 or values on single vs. series administration, and the findings may not be generalizable to the US population.
Pneumococcal vaccines have been recommended for U.S. adults for a long time and are considered safe [9, 10]. The Work Group determined that most adults aged 19–49 years at increased risk of pneumococcal disease due to underlying conditions would value individual level protection from PCV20 vaccination over potential side effects. The Work Group determined that the target population would probably value a vaccine that is likely to provide improved protection against vaccine serotypes compared to PPSV23 even with loss of coverage in 4 serotypes. Additionally, a single regimen simplifies the recommendation for adults with IC.Is there important uncertainty about or variability in how much people value the main outcomes?
Probably no important uncertainty or variability
No evidence was identified.
The Work Group acknowledged that there may be some uncertainties in how adults would value changing the recommendation for those with CMC from PPSV23 only to PCV20, or for those with IC from both PCV13 and PPSV23 to PCV20 only. With one vaccine dose, the WG thought it would probably not be an important source of uncertainty or variability. However, the Work Group determined that most adults would probably perceive that desirable effects outweigh undesirable effects.Acceptability
Acceptability
Criteria
Work Group Judgments
Research Evidence
Additional InformationIs the intervention acceptable to key stakeholders?
Probably yes
Key findings from provider and immunization manager surveys [11-14]:
Preference for a simplified pneumococcal vaccine recommendation
Mixed responses on use of PCV in series with PPSV23. In one survey [14], routine PCV use in series with PPSV23 was the most preferred among provided options on vaccine recommendations, which included use of PCV routinely vs shared clinical decision-making, and with or without PPSV23. In another survey [12], a single pneumococcal vaccination was preferred over a sequential regimen for all, primarily due to convenience for patients [13].
With a sequential regimen, concerns related to implementation (e.g., challenges in determining pneumococcal vaccination history, increased changes of dosing errors), communication, and series completion especially in hard-to-reach population were expressed [13].
Immunogenicity and additional coverage of residual invasive disease burden were given the highest scores in one survey when respondents were asked to score their preference between different hypothetical vaccines with different attributes [12].
The Work Group agreed that recommending PCV20 only for adults with CMC or IC will simplify the risk-based recommendation. Additionally, cost-effectiveness analysis models showed that the new policy option will prevent more disease compared to the existing recommendation.Resource Use
Resource Use
Criteria
Work Group Judgments
Research Evidence
Additional InformationIs the intervention a reasonable and efficient allocation of resources?
Yes
Three cost-effectiveness analysis models were reviewed. These models assessed the economic impact of use of PCV20 in adults aged 19–64 years with CMC or IC.
In the CDC model, the combined effect of a risk-based PCV20 recommendation for adults aged 19–64 years and an age-based PCV20 recommendation at age 65 years was cost-saving (better health outcomes and lower costs) compared to the existing recommendation. An analysis on age-based use only of PCV20 at age 65 was cost-saving and an analysis that assessed the incremental benefit of PCV20 use in adults with CMC/IC aged 19–64 years compared to PCV20 at age 65 alone estimated that adding a risk-based recommendation would improve health and cost $292,000/QALY saved. In the combined analysis (age- and risk-based analysis), the additional cost from adding a risk-based recommendation was offset by the cost saved from the age-based recommendation, which lead to overall cost-savings. In two other models, risk-based use of PCV20 improved health and increased costs when compared to existing recommendations. In these models, the cost per QALY gained was between $58,000 to $183,000/QALY saved.
Some key differences between the models included:
Serotype specific vaccine effectiveness assumptions
Transitions to higher levels of disease risk for individuals in the model who start at lower risk status
Specification of the comparator strategy (existing recommendations, or PCV20 use at age 65)Given the findings from the CDC model on the combined impact of the risk- and age-based use of PCV20, the Work Group determined that the intervention is a reasonable and efficient allocation of resources.
Key uncertainties include the effectiveness of PCV20 in adults with immunocompromising conditions, impact of indirect effects from pediatric vaccination in the future, and duration of protectionEquity
Equity
Criteria
Work Group Judgments
Research Evidence
Additional InformationWhat would be the impact on health equity?
Probably increased
Historically, risk-based recommendations had lower vaccine coverage than age-based recommendation, and disparities in coverage existed by race and ethnicity [15].
One study evaluated the influence of social determinants of health on vaccine uptake and time to pneumococcal vaccination in adults aged 18–64 years with CMC/IC diagnosis [16].  Nationwide convenience samples of commercial insurance claims data (MarketScan, 2013–2016) identified 173,712 adults aged 18–64 years with at least one inpatient or outpatient visit and with no prior pneumococcal vaccination before CMC/IC diagnosis. Key findings from this study were:
25% were vaccinated within 1 year of CMC/IC diagnosis
Odds of vaccination were lower in:
Areas of higher poverty (OR: 0.14)
Areas with limited internet access (OR:0.14)
Adults not receiving a seasonal influenza vaccine (OR: 0.05)
Time to vaccination was longer in rural communities and communities with less internet access.
The Work Group believed that a single vaccine recommendation for both CMC and IC may increase vaccine uptake, and thereby increase equity. Some Work Group members believed that the new policy option may decrease equity by disadvantaging those who have challenges with access or lack of awareness.Feasibility
Feasibility
Criteria
Work Group Judgments
Research Evidence
Additional InformationIs the intervention feasible to implement?
Yes
The Work Group determined that a recommendation consisting of a single vaccine for both CMC and IC will be feasible compared to the existing recommendations.
Without widespread use of state or universal adult vaccine registries, providers often have challenges in determining the accurate pneumococcal vaccination history to complete the recommended vaccine series in patients.Balance of Consequences
Desirable consequences clearly outweigh undesirable consequences in most settings.
References
Centers for Disease Control and Prevention. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR. 2010;59:1102-6.
Centers for Disease Control & Prevention. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbidity and mortality weekly report. 2012;61:816-9.
Matanock A, Lee G, Gierke R, Kobayashi M, Leidner A, Pilishvili T. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged >/=65 Years: Updated Recommendations of the Advisory Committee on Immunization Practices. MMWR Morbidity and mortality weekly report. 2019;68:1069-75.
Pelton SI, Bornheimer R, Doroff R, Shea KM, Sato R, Weycker D. Decline in Pneumococcal Disease Attenuated in Older Adults and Those With Comorbidities Following Universal Childhood PCV13 Immunization. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2019;68:1831-8.
Hurley D, Griffin C, Young M, Scott DA, Pride MW, Scully IL, et al. Safety, Tolerability, and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Adults 60 to 64 Years of Age. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
Essink B, Sabharwal C, Cannon K, Frenck R, Lal H, Xu X, et al. Pivotal Phase 3 Randomized Clinical Trial of the Safety, Tolerability, and Immunogenicity of 20-Valent Pneumococcal Conjugate Vaccine in Adults 18 Years and Older.
Klein NP, Peyrani P, Yacisin K, Caldwell N, Xu X, Scully IL, et al. A phase 3, randomized, double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age. Vaccine. 2021;39:5428-35.
Gatwood J, McKnight M, Frederick K, Hohmeier K, Kapan S, Chiu CY, et al. Extent of and Reasons for Vaccine Hesitancy in Adults at High-Risk for Pneumococcal Disease. Am J Health Promot. 2021;35:908-16.
Miller ER, Moro PL, Cano M, Lewis P, Bryant-Genevier M, Shimabukuro TT. Post-licensure safety surveillance of 23-valent pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System (VAERS), 1990-2013. Vaccine. 2016;34:2841-6.
Haber P, Arana J, Pilishvili T, Lewis P, Moro PL, Cano M. Post-licensure surveillance of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾19years old in the United States, Vaccine Adverse Event Reporting System (VAERS), June 1, 2012-December 31, 2015. Vaccine. 2016;34:6330-4.
Hurley LP, O’Leary ST, Kobayashi M, Crane LA, Cataldi J, Brtnikova M, et al. Physician survey regarding updated PCV13 vaccine recommendations for adults ≥65 years. J Am Geriatr Soc. 2021.
Merck & Co. Inc. HCP Preferences for Adult Pneumococcal Vaccine. 2021.
Association of Immunization Managers. 2021 AIM PCV ACIP Survey. 2021.
Myers K, Poulos C, Sweeney C, Vietry J, Snow V, Chilson E. US Health Care Providers’ Preferences for Adult Pneumococcal Vaccine Recommendations. Pfizer, Inc. ; 2021.
Lu PJ, Hung MC, Srivastav A, Grohskopf LA, Kobayashi M, Harris AM, et al. Surveillance of Vaccination Coverage Among Adult Populations -United States, 2018. Morbidity and mortality weekly report Surveillance summaries (Washington, DC : 2002). 2021;70:1-26.
Hoehner J, Razzaghi H, Williams WW, Kobayashi M, Jatlaoui TC, Wu X, et al. Pneumococcal Vaccination among U.S. Medicare Beneficiaries Aged ≥65 years, 2010-2019. 2021.
							
					
						Page last reviewed:  January 27, 2022					Content source: 	National Center for Immunization and Respiratory Diseases homeACIP Home
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