Evidence to Recommendations for PCV15 use among adults 19-64 years old

Question: Should PCV15 in series with PPSV23 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: PCV15 in series with PPSV23

Comparison: Existing 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 pneumococcal death; Serious adverse events following immunization

Background:

A 15-valent pneumococcal conjugate vaccine (PCV15, Merck) was licensed for adults in July 2021. Unlike the 13-valent pneumococcal conjugate vaccine (PCV13), PCV15 was licensed for adults before submission for licensure for children.

Until October 20, 2021, two pneumococcal vaccines (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 PCV15 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 Information
Is the problem of public health importance?	Yes	Adults with certain underlying conditions are at increased risk of pneumococcal disease[1, 2]. Use of pneumococcal vaccines are recommended for these groups, but the recommendations 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); and 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). However, 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 with 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, 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 Information
How substantial are the desirable anticipated effects?	Moderate	Two Phase 3 randomized-controlled trials compared the immunogenicity of PCV15+PPSV23 series with PCV13+PPSV23 series [5, 6] (please refer to GRADE tables for details) among younger adults at increased risk of pneumococcal disease. These studies did not assess statistical non-inferiority or superiority. Among Native Americans or adults with chronic underlying medical conditions aged 18–49 years [5], PCV15 elicited higher GMTs in 9/13 serotypes shared with PCV13 (significant for 1/13 serotype), and higher percentage of seroresponders for 5/13 serotypes (non-significant). Among adults aged ≥18 years with HIV infection [6], PCV15 elicited higher GMTs in 11/13 serotypes shared with PCV13 (non-significant) and higher % seroresponders in 10/13 serotypes shared with PCV13 (no confidence interval available). In both studies, improved immunologic responses against serotype 3 were observed 30 days after administration of PCV15 compared with PCV13; however, the improved immunologic responses were diminished after administration of PPSV23, and lower GMTs were observed in some PCV15 groups [5, 6]. In both studies, improved immunologic responses against PCV15-unique serotypes 22F and 33F were observed 30 days after administration of PCV15 compared with PCV13; however, the improved immunologic responses were diminished after administration of PPSV23 [5, 6]. According to NHIS 2017–2018 data, 39% and 4% of adults aged 18–64 had CMC and IC, respectively [7, 8]. Given that adults with CMC were recommended to receive PPSV23 only, the largest impact of recommending PCV15 in series with PPSV23 is estimated to come from adults with CMC, assuming that PCV15 has better vaccine effectiveness against disease (especially vaccine-type pneumococcal pneumonia) compared with PPSV23. The incremental benefit of the new recommendation in adults is expected to provide longer duration of protection compared with PPSV23 alone and would be greater if the enhanced immune response to ST3 provided clinical benefit.	No PCV15 studies directly assessed the impact on critical outcomes. The 2014–2019 recommendation to routinely use PCV13 in series with PPSV23 in adults aged ≥65 years did not have significant impact on PCV13-type disease at the population level, resulting in the 2019 recommendation to remove routine PCV13 use recommendation in adults without immunocompromising conditions, cochlear implant, or CSF leak [3]. Data suggested that historically low levels of PCV13-type disease in adults aged ≥65 years was primarily attained through indirect effects from PCV13 use in children. Therefore, some WG members believed that the incremental benefit of PCV15 use in adults with CMC may be limited given that PCV15, non-PCV13 type IPD is 11–13% of all IPD. In adults with IC, many WG members believed that the incremental benefit of PCV15 use in series with PPSV23 is small, given that this recommendation provides coverage for 2 additional serotypes than the existing recommendation. The benefit would be greater if the enhanced immune response to ST3 provided clinical protection. Conclusion: Despite uncertainties around the clinical significance of immunogenicity study results, the Work Group believed that the potential benefit from PCV15 in series with PPSV23 use is moderate compared with the existing recommendations.
How substantial are the undesirable anticipated effects?	Minimal	Safety data from phase 3 randomized-controlled trials [5, 6] showed that the percentage of subjects with serious adverse events were low; slightly lower in subjects who received PCV15 followed by PPSV23 compared with those who received PCV13 followed by PPSV23 (0.3–1.3% vs. 0.9–4.1%). None of the serious adverse events were associated with the vaccines.
Do the desirable effects outweigh the undesirable effects?	Favors intervention	The Work Group decided that desirable effects of the use of PCV15 in series with PPSV23 outweigh undesirable effects.
What is the overall certainty of this evidence for the critical outcomes?	Effectiveness of the intervention is Level 2 (Moderate) Safety of the intervention is Level 2 (Moderate)	GRADE analyses were completed to assess certainty of evidence. Overall evidence type was 2 for vaccine effectiveness. Assessment on indirectness was downgraded to “serious” because only immunogenicity studies were available. There are no correlates of protection established for PCV15 in adults. Overall evidence type was 2 for serious adverse events. Assessment on imprecision was downgraded to “serious” because no vaccine-related serious adverse events were reported in studies with relatively low sample sizes.	Refer to the GRADE summary table for details.

Values

Values
Criteria	Work Group Judgments	Research Evidence	Additional Information
Does 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 that assessed beliefs, attitudes, and intentions related to pneumococcal vaccines in adults eligible for the existing risk-based pneumococcal vaccine recommendations [2, 3]. One online cross-sectional survey was conducted in March–April, 2019 [9]. 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 survey respondents indicated that pneumococcal vaccines were offered, 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 reporting ever being indicating hesitant or resistant, 77% was for 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 coverage about vaccines (OR: 2.6) This study did not assess values on use of PCV15 or values on single vs. series administration; these findings may not be generalizable to the US population.	Pneumococcal vaccines have been recommended for U.S. adults for many years and are considered safe [10, 11]. The Work Group determined that most adults aged 19–64 years at increased risk or pneumococcal disease from underlying conditions that increase their risk of pneumococcal disease would value the individual level protection from PCV15 vaccination in series with PPSV23 above potential side effects. Work Group members in practice believed that the acceptance of pneumococcal vaccines is higher compared with other vaccines recommended for adults.
Is there important uncertainty about or variability in how much people value the main outcomes?	Possibly important uncertainty or variability	No evidence was identified.	The Work Group acknowledged that there may be some uncertainties in how adults with CMC would value changing the recommendation from PPSV23 only to both PCV15 and PPSV23.The increase in the number of vaccine doses was thought to 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 Information
Is the intervention acceptable to key stakeholders?	Varies	Key findings from provider and immunization manager surveys [12-15]: Preference for a simplified pneumococcal vaccine recommendation. Mixed responses on use of PCV in series with PPSV23. In one survey [15], 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 [13], a single pneumococcal vaccination was preferred over a sequential regimen for all, primarily due to convenience for patients [14]. With a sequential regimen, concerns related to implementation (e.g., challenges in determining pneumococcal vaccination history, increased chances of dosing errors), communication, and series completion especially in hard-to-reach population were expressed [14]. Immunogenicity and additional coverage of residual invasive disease burden yielded the highest probability of preference in a survey by Merck when respondents were asked to score preferences among different hypothetical vaccines with different attributes [13].	Work Group members agreed that recommending both PCV15 and PPSV23 will be a simplification of the existing risk-based recommendation. Some believed that adding PCV15 to the recommendation of PPSV23 only for adults with CMC will add more burden (e.g., understanding the correct vaccine history for recommended series completion, cost of storage of vaccines) on the providers given that the proportion of CMC in adults aged 19–64 years is larger than adults with IC. Series has theoretic benefit of longer duration of protection and increased level of immunity over PPSV23 use alone for CMC. Cost-effectiveness analysis models showed new policy option will prevent more disease.

Resource Use

Resource Use
Criteria	Work Group Judgments	Research Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	Probably yes	Two cost-effectiveness analysis models were reviewed. These models assessed the economic impact of use of PCV15 in series with PPSV23 in adults aged 19–64 years with CMC or IC. In the CDC model, the combined risk-based use of PCV15 in series with PPSV23 for adults aged 19–64 years and an age-based use of PCV15 in series with PPSV23 at age 65 years was estimated to cost $338,000 per QALY gained compared to the existing recommendation. Both the CDC and Merck models conducted analyses that focused only on the risk-based use of PCV15 in series with PPSV23. From the two models, the estimated cost per QALY gained ranged from $250,000 to $656,000. In both models, risk-based use of PCV15 in series with PPSV23 for adults 19–64 prevented more disease compared to the existing recommendation and was associated with an increased cost. Differences across models were likely due to differences in model structure and uncertainties about serotype-specific vaccine effectiveness and vaccine coverage following a change in recommendations.	Some key differences between the two models included: Vaccine coverage assumptions Serotype specific vaccine effectiveness assumptions Transitions to higher levels of disease risk for individuals in the model who started at a lower risk status Other important assumptions included: Waning immunity Incidence of pneumonia and IPD The Work Group was split in the interpretation of resource use. Overall, the Work Group determined that the additional health benefit from the new policy option was potentially sufficient to outweigh the additional cost.

Equity

Equity
Criteria	Work Group Judgments	Research Evidence	Additional Information
What would be the impact on health equity?	Probably no impact	Historically, risk-based recommendation has resulted in lower vaccine coverage compared with age-based recommendation. Also, disparities in coverage existed by race and ethnicity[16]. 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 [17]. 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 the new recommendation will likely have little impact for adults with IC who were recommended to receive both PCV13 and PPSV23. For adults with CMC, the Work Group believed that a vaccine recommendation that requires two vaccines is more likely to disadvantage the population that has challenges with access to care and who may also be at increased pneumococcal disease burden. Some members thought that adults with CMC may benefit from receipt of PCV15 if PCV15 provides better protection and longer lasting protection against pneumococcal disease compared to PPSV23 for the 15 serotypes. Some members thought that the alignment of PCV15 and PPSV23 for CMC and IC simplifies the recommendation and would lead to higher coverage and possibly improving equity.

Feasibility

Feasibility
Criteria	Work Group Judgments	Research Evidence	Additional Information
Is the intervention feasible to implement?	Probably yes	Use of PCV13 in series with PPSV23 had been recommended for use for adults with IC since 2012 [2]. Extending this recommendation from IC to IC and CMC simplifies the existing risk-based recommendation. On the other hand, the new policy option will increase the required number of vaccine doses, given that 91% of adults aged 18–64 years with either CMC or IC have CMC only (recommended to receive PPSV23 only) [7, 8].	Compared with a recommendation if PPSV23 only (recommended for adults with CMC), a two dose vaccine series with PCV15 followed by PPSV23 is more challenging to implement and will increase cost. Providers often have challenges in determining an accurate pneumococcal vaccination history and completing the recommended vaccine series in patients. Without widespread use of vaccine registries for adults, there will be increased administrative burden to ensure patients receive both vaccines within the recommended interval by expanding the PCV-PPSV23 series recommendation from IC only to IC and CMC.

Balance of Consequences

Desirable consequences probably outweigh undesirable consequences in most settings.

Additional Considerations

Most Work Group members believed that desirable consequences of recommending PCV15 in series with PPSV23 for adults aged 19–64 years with CMC and IC outweighed undesirable consequences. The perceived benefits for adults with CMC or IC were from simplification of the existing risk-based recommendations and potential to prevent more vaccine-type disease, especially in adults with CMC who were previously not recommended to receive a pneumococcal conjugate vaccine. Given that adults with CMC constitute a large proportion targeted for this policy option, there will be increased visits from expanding from PPSV23 only to PCV15 in series with PPSV23 in this group. Therefore, some Work Group members believed that the new recommendation may be less acceptable to providers and potentially eligible adults, and less feasible to implement. Additionally, given that routine use of PCV13 had minimal impact on PCV13-type disease at the population level in the context of indirect effects from pediatric PCV13 use, some Work Group members believed that the incremental benefit of recommending PCV15 for adults with CMC may not be substantial, given that PCV15 covers 2 additional serotypes compared to PCV13. Others highlighted that making the recommendations for IC and CMC simplifies the recommendation and should lead to higher coverage with longer duration of benefit for persons with CMC. In addition, if the increased immune response from PCV15 to ST3 translates into a clinical benefit, then the benefits would be greater.

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