EtR Framework for Adults Aged 19–64 Years With an Immunocompromising Condition, Cochlear Implant, or Cerebrospinal Fluid Leak Who Have Previously Received Both PCV13 and PPSV23

Questions:

Should a dose of PCV20 be recommended for U.S. adults aged 19–64 years with an immunocompromising condition, cochlear implant, or cerebrospinal fluid leak who have previously received both PCV13 and PPSV23?

Population: U.S. adults aged 19–64 years with an immunocompromising condition¹, cochlear implant, or cerebrospinal fluid leak who have previously received both PCV13 and PPSV23

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 19–64 years with an immunocompromising condition, cochlear implant, or cerebrospinal fluid leak who have previously received both PCV13 and PPSV23

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 factors², 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.

¹ Chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, HIV, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplant, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies

² 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	Adults with certain underlying conditions are at increased risk of pneumococcal disease, especially adults with immunocompromising conditions [1, 2]. Since 2012, adults with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant (hereafter, IC) have been recommended to receive a dose of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) [3]. However, pneumococcal vaccine coverage among adults aged 19–64 years has been low. According to a study of adults aged 19–64 years with newly diagnosed IC identified through insurance claims data, 5% received at least a dose of PCV13, and 2% received both PCV13 and PPSV23 after 6 years of diagnosis [4]. 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). 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, 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 [5]. The exact duration of protection of pneumococcal vaccines is unknown. However, a post hoc analysis from a randomized controlled trial on PCV13 showed that there was no evidence of waning of protection against vaccine-type non-bacteremic pneumococcal pneumonia, or vaccine-type IPD over four years [6]. Data on the duration of protection of PPSV23 is available from observational studies only that reported variable results, although waning protection as early as 2 years since vaccination has been reported [7].

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 [8]. As a result, PCVs have an immunologic advantage over PPSV in that T-cell dependent responses enhance B-cell responses, and that serotype-specific memory B cells are generated [8]. 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 [9, 10]. Two studies that assessed the immunogenicity of PCV20 among adults aged ≥65 years without IC who had previously received pneumococcal vaccines were identified [11, 12]. 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 [11]. 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 [12]. Neither study directly compared the immunogenicity of PCV20 with PPSV23 after receipt of both PCV13 and PPSV23. Opsonophagocytic activity geometric mean titers (OPA GMTs) of serotypes included in PCV20 assessed one month after PCV20 vaccination was numerically higher among those who previously received both PCV13 and PPSV23 compared with adults who previously received PPSV23 only in 19 of 20 PCV20 serotypes (statistically significantly higher for serotype 23F) in one study [11] and for 15 of 20 PCV20 serotypes (statistically significantly higher for serotypes 6B, 18C and 23F) in another study [12]. Percent seroresponders (defined as ≥4-fold rise in OPA titer from before to 1 month after PCV20) was numerically higher for 3 of 20 serotypes in one study [11], and 6 of 20 serotypes in another [12]. None were statistically significantly higher.
How substantial are the undesirable anticipated effects?	Minimal	One Phase 3 trial assessed the safety of PCV20 use among adults aged ≥65 years without IC who had previously received PCV13 followed by PPSV23 at least 1 year previously [11]. There was no direct comparator to this group. Percentage of participants reporting any adverse events 1 month after vaccination was 10.4%, and the percentage reporting serious adverse events through 6 months after vaccination was 1.6%. None of the serious adverse events were deemed to be vaccine related [11].
Do the desirable effects outweigh the undesirable effects?	Favors intervention	Regardless of the magnitude of the desirable anticipated effects of recommending PCV20 for this population, the Work Group felt that the undesirable anticipated effects were even smaller given the vaccine’s safety profile.	Given the high cost of the intervention, some Work Group members believed that it is important to consider the potential negative impact from the societal perspective of recommending PCV20 for adults aged 19 –64 years who have already received both PCV13 and PPSV23. This concern was discussed further in the domain of “Resource Use.”
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 relatively low sample sizes.	Refer to GRADE summary tables for details.

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 both PCV13 and PPSV23, 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. Some Work Group members felt that there was not enough information to make the decision. Others believed that the target population’s perception of desirable effects and undesirable effects varies.
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 both PCV13 and PPSV23, 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 [13]. In another HCP survey targeting physicians and pharmacists who provide pneumococcal vaccines for adults, HCPs 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, HCPs were more agreeable to recommending a dose of PCV20 for adults aged 19–64 years with IC compared with adults aged ≥65 years [14].

Resource Use

Resource Use
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	Variable responses among WG members	Three economic models were reviewed. These models were conducted by CDC, Merck, and Pfizer, and each model assessed PCV20 use among adults younger than age 65 years with IC who have previously received both PCV13 and PPSV23. Each model used different assumptions, which could have contributed to the differences in the results across models. All cost estimates have been adjusted to 2022 USD using the consumer price index. In the CDC model, PCV20 use 1 or 5 years after receipt of both PCV13 and PPSV23 compared with PPSV23 as previously recommended in a single-age cohort of adults aged 42 years (age selected to represent adults aged 19–64 years) with IC. This cohort was followed through age 64 years. In this assessment of PCV20 use among adults with IC, the cost per quality-adjusted life year (QALY) gained ranged from 209,000 to 403,000 USD. The range of results was due to different assumptions about time since last dose, indirect effects, and PCV vaccine effectiveness (VE) against pneumococcal disease due to serotype 3. In the Pfizer model that used a multi-age cohort of adults with IC aged 19–64 years followed through their lifetime, cost per QALY gained ranged from 40,000 USD (PCV20 given 7 years since PCV13 dose, assuming no indirect effects from pediatric PCV20 vaccination) to 107,000 USD per QALY gained (PCV20 given 7 years since PCV13 dose, assuming indirect effects from pediatric PCV20 vaccination). In the Merck model that followed a single-age cohort of adults with IC aged 42 years through their lifetime, the use of a dose of PCV20 5 years after receiving both PCV13 and PPSV23 resulted in higher cost and worse health outcome compared with a strategy representing the current recommendations, which included additional doses of PPSV23 at age 52 and at age 65 years (occurring 5 years and 23 years after the initial receipt of vaccines). This comparator was not considered in the other models.	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. PPSV23 had no effectiveness against pneumococcal pneumonia. Assumed higher QALY loss for 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. Probably Yes Some Work Group members believed that the benefit of recommending PCV20 still outweighed the cost. Probably No Some believed that the added benefit from recommending PCV20 for adults who have already received PCV13 and PPSV23 is likely too small to justify the use of resources. Varies Some believed that the interpretation would depend on the time since the last vaccination, age, and degree of immunosuppression. Don’t know Since adults aged 19–64 years who have received both PCV13 and PPSV23 are a small population, some believed that the added benefit was small at the population level.

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 across racial groups [15], 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 [16].	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 will decrease the disparities in pneumococcal disease burden that exist, and 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 since pneumococcal vaccine coverage among adults aged 19–64 years with IC is low, and access and utilization of the vaccine are likely to follow existing patterns. The added benefit of recommending PCV20 to adults who have already received PCV13 and PPSV23 will be small. 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 to support the health departments’ adult pneumococcal vaccine program and 17% (4/23) reported complicated recommendations [17]. 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 [18].	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

Some Work Group members believed that the public health benefit of recommending PCV20 for adults who have already received both PCV13 and PPSV23 is marginal and that the evidence is not as compelling as recommending PCV15 or PCV20 for adults who have not previously received any pneumococcal vaccines. In addition, PCV20 may be recommended for use among children in the near future, and new pneumococcal vaccines are currently under development. Therefore, the added benefit of PCV20 use among adults may be time limited. However, the Work Group members acknowledged that the magnitude of the desirable consequences depends on the time since vaccination, age, and the degree of immunosuppression of the patient, and that some patients are likely to benefit from receiving PCV20.

References

[1] 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.

[2] Ahmed SS, Pondo T, Xing W, McGee L, Farley M, Schaffner W, et al. Early Impact of 13-valent Pneumococcal Conjugate Vaccine Use on Invasive Pneumococcal Disease among Adults with and without Underlying Medical Conditions-United States. Clin Infect Dis. 2019.

[3] 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 Morb Mortal Wkly Rep. 2012;61:816-9.

[4] 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.

[5] 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.

[6] Patterson S, Webber C, Patton M, Drews W, Huijts SM, Bolkenbaas M, et al. A post hoc assessment of duration of protection in CAPiTA (Community Acquired Pneumonia immunization Trial in Adults). Trials in Vaccinology. 2016;5.:92-6.

[7] World Health Organization. Strategic Advisory Group of Experts on Immunization 5-7 October 2020. 2020.

[8] 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.

[9] 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.

[10] 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.

[11] 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.

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

[13] 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.

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

[15] 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.

[16] 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.

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

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

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