EtR Framework for Adults Aged ≥19 Years Who Have Previously Received PCV13 Only

Questions:

Should a dose of PCV20 be recommended for U.S. adults aged ≥19 years who have previously received PCV13 only?

Population: U.S. adults aged ≥19 years who have previously received PCV13 only

Intervention: PCV20

Comparison: Use of PPSV23 based on currently recommended dosing and schedule

Main Outcomes: Vaccine-type invasive pneumococcal disease; vaccine-type non-bacteremic pneumococcal pneumonia; vaccine-type pneumococcal death; serious adverse events following immunization

Setting: U.S. adults aged ≥19 years who have previously received PCV13 only

Background:

In 2021, the 15-valent and the 20-valent pneumococcal conjugate vaccines (PCV15 and PCV20) were licensed by the FDA, and ACIP recommended the use of either PCV20 alone or PCV15 in series with the 23-valent pneumococcal polysaccharide vaccine (PPSV23), for all adults aged ≥65 years, and for adults aged 19–64 years with certain underlying medical conditions or other risk factors^*, who have not previously received a pneumococcal conjugate vaccine (PCV) or whose previous vaccination history is unknown.
At that time, adults who have previously received the 13-valent pneumococcal conjugate vaccine (PCV13) were recommended to complete their recommended vaccine series with PPSV23 since the incremental public health benefits of providing PCV15 or PCV20 to these adults had not been evaluated.

^*Alcoholism; chronic heart, liver, or lung disease; chronic renal failure; cigarette smoking; cochlear implant; congenital or acquired asplenia; cerebrospinal fluid leak; diabetes mellitus; generalized malignancy; HIV; Hodgkin disease; immunodeficiency; iatrogenic immunosuppression; leukemia, lymphoma, or multiple myeloma; nephrotic syndrome; solid organ transplant; sickle cell disease; or other hemoglobinopathies.

Public Health Problem

Problem
Criteria	Work Group Judgements	Evidence	Additional Information
Is the problem of public health importance?	Yes	Prior to 2022, CDC recommended the use of PCV13 for adults with an immunocompromising condition, cochlear implant, or cerebrospinal fluid leak (hereafter, IC), and adults aged ≥65 years [1]. Adults who received PCV13 are recommended to also receive PPSV23; however, not all adults have received the vaccines as recommended. A study using insurance claims data that assessed compliance to the pneumococcal vaccine recommendations showed that in a cohort of adults aged ≥65 years, 42% of adults received the second pneumococcal vaccine within 4 years following receipt of the first vaccine. Of adults aged 19–64 years with IC, 36% received the second pneumococcal vaccine within 6 years following the first vaccine [2]. Pneumococcal disease burden among adults aged 19–64 years with IC The estimated burden of pneumococcal pneumonia has varied. According to U.S. healthcare claims data, the risk of hospitalized pneumococcal pneumonia among adults aged 18–64 years with IC was 11–18 times higher than adults without these conditions [4]. According to a prospective multicenter surveillance study during 2013–2016, the serotypes contained in PCV13 and the additional 7 serotypes included in PCV20 caused 5.2% and 4.0%, respectively, of all-cause community-acquired pneumonia hospitalizations in adults aged 18–64 years with IC [3]. According to CDC’s Active Bacterial Core surveillance (ABCs) data, the incidence of invasive pneumococcal disease (IPD), defined as the detection of pneumococcus in a normally sterile site such as blood or cerebrospinal fluid, among adults with IC aged 19–64 years decreased since Introduction of PCV13 in children in 2010 (ABCs unpublished data). Nonetheless, in 2017–2018, adults aged 19–64 years with IC had 9 times higher risk of all-IPD (29.9 vs. 3.2 per 100,000 population), and 7 times higher risk of PCV13-type IPD compared to healthy adults (5.8 vs. 0.8 per 100,000 population). Among adults aged 19–64 years with IC, PCV13 serotypes caused 19% of all IPD, and the additional 7 serotypes included in PCV20 caused 26% of all IPD in 2017–2018 (ABCs unpublished data). Pneumococcal disease burden among adults aged ≥65 years Pneumococcal pneumonia is the most common type of pneumococcal disease in adults, although the estimated incidence of the disease has varied. The reported incidence of all-cause pneumonia hospitalization among U.S. adults aged ≥65 years ranges from 847–3,365 per 100,000 population^*[4]. According to a prospective multicenter surveillance study during 2013–2016, the serotypes contained in PCV13 and the additional 7 serotypes included in PCV20 caused 4.2% and 2.9% respectively, of all-cause community-acquired pneumonia hospitalizations in adults aged ≥65 years [3]. Invasive pneumococcal disease (IPD), defined as the detection of pneumococcus in a normally sterile site such as blood or cerebrospinal fluid, is less frequent but is associated with high morbidity and mortality. According to CDC’s ABCs data in 2018–2019, IPD incidence was 24 per 100,000 population with a case-fatality ratio of 14% in adults aged ≥65 years. Among all IPD cases, 27% were serotypes included in PCV13 and 29% were additional serotypes included in PCV20 (but not in PCV13).

^* Limited to studies that collected data during or after 2010, when PCV13 was introduced for use among U.S. children

Benefits and Harms

Benefits and Harms
Criteria	Work Group Judgements	Evidence	Additional Information
How substantial are the desirable anticipated effects?	Moderate	PCV20 contains the 13 serotypes in PCV13 and 7 additional serotypes. PPSV23 contains 4 additional serotypes not included in PCV20 (PPSV23 does not contain serotype 6A, which is included in PCV20). PPSV23 induces a T-cell-independent immune response that stimulates immediate B-cell responses, whereas PCVs induce a T-cell-dependent immune response [5]. As a result, PCVs have immunologic advantages over PPSV23 in that T-cell dependent responses enhance B-cell responses, and that serotype-specific memory B cells are generated [5]. A systematic review of the literature showed that point estimates of the effectiveness of PCV13 against vaccine-type pneumococcal disease are generally higher compared with those of PPSV23 [6, 7]. Two studies that assessed the immunogenicity of PCV20 among adults aged ≥65 years without IC who had previously received pneumococcal vaccines were identified [8, 9]. In one study, participants either received: 1) PCV13 ≥6 months previously, 2) PPSV23 1–5 years previously, or 3) both PCV13 followed by PPSV23, with PPSV23 at least 1 year previously [8]. Another was a post-hoc analysis of a Phase 3 clinical trial that assessed a subset of participants who received pneumococcal vaccines ≥6 months previously [9]. Neither study directly compared the immunogenicity of PCV20 with PPSV23 after receipt of PCV13. In both studies, opsonophagocytic activity geometric mean titers (OPA GMTs) of serotypes included in PCV20 assessed one month after PCV20 vaccination were numerically higher among those who previously received PCV13 compared with adults who previously received PPSV23 (statistically significantly higher for 6–17 of 20 serotypes). Percent seroresponders (defined as ≥4-fold rise in OPA titer from before to 1 month after PCV20) was numerically higher for 13–18 of 20 serotypes among adults who previously received PCV13 compared with adults who previously received PPSV23 (statistically significantly higher for 1–8 of 20 serotypes).
How substantial are the undesirable anticipated effects?	Minimal	One Phase 3 randomized controlled trial (RCT) assessed the safety of PCV20 use compared with PPSV23 use among adults aged ≥65 years without IC who had previously received PCV13 ≥6 months prior [8]. Adults reporting local reactions within 10 days of PCV20 or PPSV23 vaccination were similar between the two groups. The percentage of participants reporting any adverse events 1 month after vaccination was 4.9% (PCV20) vs. 11.0% (PPSV23), and the percentage reporting serious adverse events through 6 months after vaccination was 0.8% (PCV20) vs. 1.6% (PPSV23). None of the serious adverse events were deemed to be vaccine related [8].
Do the desirable effects outweigh the undesirable effects?	Favors intervention	Given that PCV20 provides a broader pneumococcal serotype coverage than PCV13, given the immunologic benefit that PCVs have over PPSV23, and given the minimal anticipated harm of administering PCV20, the Work Group believed that the use of PCV20 among this population is favorable.
What is the overall certainty of the evidence of effects?	Effectiveness of the intervention: Low Safety of intervention: Low	GRADE analyses were completed to assess the certainty of evidence. Overall evidence type was 3 (low) 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 aged 19–64 years with IC Overall evidence type was 3 (low) for serious adverse events. Assessment on indirectness was downgraded to “serious” because no studies specifically targeted adults aged 19–64 years with IC Assessment on imprecision was downgraded to “serious” because there were no vaccine-related serious adverse events reported in studies with small sample sizes.	Refer to GRADE summary tables for details. This population is covered in GRADE tables for adults aged 19–64 years with IC and adults aged ≥65 years who previously received PCV13 with or without PPSV23.

Values

Values
Criteria	Work Group Judgements	Evidence	Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects?	Probably yes	No research evidence was identified. Since these are adults who have already received PCV13, the Work Group felt that there is probably some understanding of the importance of receiving pneumococcal vaccines and would feel that the added effects from receiving PCV20 are large relative to undesirable effects. However, some Work Group members felt that there is not enough information to make the decision, or that the interpretation will vary among the target population.
Is there important uncertainty about or variability in how much people value the main outcomes?	Probably no important uncertainty or variability	No research evidence was identified. Since these are adults who have already received PCV13, the Work Group felt that there is probably no important uncertainty or variability.

Acceptability

Acceptability
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention acceptable to key stakehold-ers?	Probably yes	Findings from two healthcare provider (HCP) surveys were reviewed. According to a survey conducted in early 2021 among HCPs (physicians, physician assistants, nurse practitioners, pharmacists) involved in adult pneumococcal vaccination, 68% (514/712) of survey respondents either somewhat approved or strongly approved of recommending a higher-valent PCV in those who have previously received PCV13 [10]. In another HCP survey targeting physicians and pharmacists who provide pneumococcal vaccinations for adults, HCP were generally more agreeable to recommending a dose of PCV20 for adults who have only received PCV13, compared with adults who have already received both PCV13 and PPSV23. Among adults who have already received both PCV13 and PPSV23, HCP were more agreeable to recommending a dose of PCV20 for adults aged 19–64 years with IC compared with adults aged ≥65 years [11].

Resource Use

Resource Use
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	Probably yes/Yes	Three economic models were reviewed. These models were conducted by CDC, Merck, and Pfizer, and each model assessed PCV20 use among adults who previously received PCV13 only. Models used different assumptions, which could have contributed to differences in results across models (all cost estimates have been adjusted to 2022 USD using the consumer price index): In the CDC model, the cost per quality-adjusted life year (QALY) gained of PCV20 use 1 or 5 years after receipt of PCV13 compared with no vaccine in a cohort of adults aged ≥65 years with and without IC ranged from 139,000 to 611,000 USD. In a cohort of adults aged 42 years (age selected to represent adults aged 19–64 years) with IC, the cost per QALY gained of PCV20 use 1 or 5 years after receipt of PCV13 compared with no vaccine use ranged from 295,000 to 380,000 USD. Given the small estimated population size of adults aged 19–64 years with IC who have previously received PCV13 only [2, 12], and given the variability in how these younger adults were assessed, a comparison across the three models focused on adults aged ≥65 years who have previously received PCV13 only (Pfizer model also includes IC adults aged 19–64 years in their cohort). Cost per QALY gained of PCV20 use ranged from 87,000 (Pfizer model, PCV20 given 7 years after PCV13 dose) to 611,000 (CDC model, PCV20 given to adults aged 66 years with an ICi condition 1 year after PCV13 dose).	Additional details on economic models The variations in results across the models appear likely to be due to differences in selected assumptions across the models. Relative to the CDC model, the Pfizer model base case included several assumptions that could have contributed to differences in results across models, including: A higher vaccine effectiveness of PCVs (PCV13, PCV20) against pneumococcal disease due to serotype 3. Serotype 3 is the most common cause of remaining PCV13-type disease. Assumed higher QALY loss for IPD invasive pneumococcal disease and hospitalized pneumococcal pneumonia. Longer time period between previous vaccination and PCV20 use. Relative to the CDC model, the Merck model included several assumptions that could have contributed to differences in results across models, including: Comparator included PPSV23 vaccinations at age 52 and 65 years Case fatality ratios from hospitalized pneumococcal pneumonia among adults aged ≥65 years were higher. Indirect effects were not included. Work group interpretations The Work Group’s interpretation of this domain was variable. Yes/Probably Yes Among WG members who interpreted this domain as yes/probably yes, more Work Group members believed that the benefit of recommending PCV20 still outweighed the cost, especially for adults who have received PCV13 only. Probably No Among WG members who interpreted this domain as probably no, some believed that the added benefit from recommending PCV20 instead of PPSV23 for adults who have already received PCV13 is likely not large enough to justify the use of resources. Varies Among WG members who interpreted this domain as varies, some believed that the interpretation would depend on the time since the last vaccination, age, and underlying conditions.

Equity

Equity
Criteria	Work Group Judgements	Evidence	Additional Information
What would be the impact of the intervention on health equity?	Probably increased/probably no impact	Disparities in pneumococcal disease burden The introduction of PCV13 among children reduced the disparities that existed in PCV13-type IPD incidence among all racial and thnic groups [13], likely due to the indirect effects of PCV13 use in children. However, Black persons continue to have higher IPD incidence compared with White persons, due to non-PCV13 type disease, in particular, serotypes not contained in PCV20. Disparities in pneumococcal vaccine coverage According to the National Health Interview Survey in 2020, the proportion of adults aged 19–64 years with risk-based pneumococcal vaccination recommendations (not limited to adults with IC) who received any pneumococcal vaccine was estimated to be 24% overall; compared with White adults who had the highest pneumococcal vaccine coverage (26%), Hispanic (17%) and Asian (14%) adults had significantly lower coverage. Compared with 2019, vaccine coverage increased significantly among White adults and decreased significantly among Asian adults in 2020 [14]. An analysis of PCV13 and PPSV23 claims data of Medicare beneficiaries aged ≥65 years showed that in 2019, the proportion of beneficiaries who received at least one dose of PCV13 was the highest in White adults (51%) and lowest in Hispanic adults (30%) [15]. The proportion who received both PCV13 and PPSV23 was also the highest in White adults (33.9%) and the lowest in Hispanic adults (16%) [15].	The Work Group’s interpretation of this domain was variable. Increased or probably increased health equity WG members who interpreted this domain as increased/probably increased health equity believed that recommending the use of PCV20 for adults who have already received PCV13 only will prevent more pneumococcal disease and decrease the disparities in pneumococcal disease burden that exist. In addition, some Work Group members believed that access to preventive measures like vaccines is likely better for minority populations compared with access to care for the disease. Probably no impact on health equity WG members who interpreted this domain as probably no impact on health equity believed that adults who have received PCV13 only is a small proportion of the population, and since access and utilization of the vaccine are likely to follow existing patterns, there will be no impact on health equity. Reduced/probably reduced health equity There was a minority opinion that new recommendation will likely be adopted more rapidly among those who already have good access to care and will make the existing disparities more pronounced.

Feasibility

Feasibility
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention feasible to implement?	Yes	According to a survey among members of the Association of Immunization Managers conducted in September 2022, 26% (6 of 23) responded that their jurisdiction’s health department currently offers PCV13 for adults, and 36% (9/23) responded that their jurisdiction’s health department currently offers PCV20 to adults. Regarding what members saw as the major challenge with the adult pneumococcal vaccine program, 61% (14/23) reported a lack of funding for public health immunization programs to support the adult pneumococcal vaccine program and 17% (4/23) reported complicated recommendations [16]. An HCP survey by Merck targeting physicians, pharmacists, and physician assistants showed that HCPs know when a pneumococcal vaccine was given to their patients 56% of the time and which vaccine was given 58% of the time [17].	Most Work Group members believed that recommending PCV20 for adults who previously received pneumococcal vaccines is simple enough to implement. Since pneumococcal vaccination history is often hard to obtain, some Work Group members believed that there will be less guesswork involved to ensure that patients are up to date with pneumococcal vaccines since adults with IC conditions who are younger than age 65 years are currently recommended to receive multiple PPSV23 doses. Others believed that feasibility would depend on electronic medical record decision support and improvement in adult vaccine registries so that all vaccines that patients received are reported in a single registry.

Balance of consequences

Desirable consequences probably outweigh undesirable consequences in most settings

References

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[2] Deb A, Mohanty S, Ou W, Rajagopalan S, Johnson KD. Pneumococcal vaccination coverage among adults aged 19 to 64 years with immuno-compromising conditions, cerebrospinal fluid (CSF) leaks, or cochlear implants in the US. Expert Rev Vaccines. 2021;20:331-45.

[3] Isturiz R, Grant L, Gray S, Alexander-Parrish R, Jiang Q, Jodar L, et al. Expanded Analysis of 20 Pneumococcal Serotypes Associated With Radiographically Confirmed Community-Acquired Pneumonia in Hospitalized US Adults. Clin Infect Dis. 2021.

[4] McLaughlin JM, Khan FL, Thoburn EA, Isturiz RE, Swerdlow DL. Rates of hospitalization for community-acquired pneumonia among US adults: A systematic review. Vaccine. 2020;38:741-51.

[5] Durando P, Faust SN, Fletcher M, Krizova P, Torres A, Welte T. Experience with pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) in children and adults. Clin Microbiol Infect. 2013;19 Suppl 1:1-9.

[6] Farrar JL, Kobayashi M, Childs L, Pilishvili T. Systematic Review and Meta-Analysis of Pneumococcal Vaccine Effectiveness against Invasive Pneumococcal Disease among Adults. IDweek. Virtual Conference2021.

[7] Childs L, Kobayashi M, Farrar JL, Pilishvili T. The Efficacy and Effectiveness of Pneumococcal Vaccines against Pneumococcal Pneumonia among Adults: A Systematic Review and Meta-Analysis. IDweek 2021. Virtual Conference2021.

[8] Cannon K, Elder C, Young M, Scott DA, Scully IL, Baugher G, et al. A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination. Vaccine. 2021;39:7494-502.

[9] Safety and Immunogenicity of 20vPnC Coadministered With SIIV in Adults ≥65 Years of Age. https://ClinicalTrials.gov/show/NCT04526574.

[10] Vietri J, Meyers K, Poulos C, Chilson E, Sweeney C, Davis K, et al. 06. United States Healthcare Provider Preferences for Adult Pneumococcal Vaccine Recommendations. Open Forum Infect Dis. 2021;8:S127.

[11] University of Iowa, RAND Corporation, Centers for Disease Control & Prevention. Pneumococcal Vaccination Behabior, Knowledge, and Attitudes Among U.S. Pediatricians, Family Physicians, General Internits, and Pharmacists. 2022.

[12] 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. Clin Infect Dis. 2019;68:1831-8.

[13] Accorsi EK, Gierke R, Farley MM, Talbot K, Thomas A, Reingold A, et al. Impact of Pneumococcal Conjugate Vaccines on Racial Differences in Invasive Pneumococcal Disease in Black and White Persons in the U.S. from 2008 to 2019. 12th International Symposium on Pneumococci & Pneumococcal Disease. Toronto, Canada2022.

[14] Jatlaoui TC, Hung M-C, Srivastav A, Lu P-J, Black CL, Lindley MC, et al. Vaccination Coverage among Adults in the United States, National Health Interview Survey, 2019-2020.

[15] 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.

[16] Association of Immunization Managers. September 2022 General Membership Webinar Poll. 2022.

[17] Merck & Co. Inc. Adult Pneumococcal Vaccine Preferences. 2022.

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