EtR Framework for Adults Aged 19–49 Years Who Currently Do Not Have a Risk-Based Pneumococcal Vaccine Indication

About

The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.

Summary

Question: Should 21-valent pneumococcal conjugate vaccine (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 pneumococcal vaccine indication

Intervention: One dose of PCV21

Comparison: No vaccine

Main outcomes: Vaccine-type invasive pneumococcal disease; Vaccine-type non-bacteremic pneumococcal pneumonia; Vaccine-type pneumococcal death; Serious adverse events following immunization

Setting: Currently, adults aged 19–64 years with a risk condition* are recommended to receive a pneumococcal conjugate vaccine. Expanding the recommendation to adults aged 19–49 years without a risk-based vaccine indication will imply a new age-based recommendation for adults aged 19–49 years.

*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.

Perspective: Clinical perspective

Background

  • On June 17, 2024, 21-valent pneumococcal conjugate vaccine (PCV21, Merck) was licensed for use in adults aged ≥18 years.
  • Unlike previous PCVs that were developed to target disease in children, PCV21 was developed to target pneumococcal disease in adults. It does not contain certain serotypes that are included in currently recommended PCVs (e.g., serotypes 1, 4, 5, 6B, 9V 14, 18C, 19F, and 23F in both PCV15 and PCV20; serotype 15B in PCV20) and instead, contains 8 new serotypes that are not included in currently recommended vaccines (e.g., serotypes 15A, 15C, 16F, 23A, 23B, 23F, 31, 35B).
  • The ACIP Pneumococcal Vaccines Work Group reviewed available data to inform the use of PCV21 in adults and identified policy options that maximize pneumococcal disease prevention among adults, reduce disparity, and simplify recommendations to improve vaccine uptake.

Public Health Importance

References in this table: 123456

Problem
Criteria Work Group Judgements Evidence Additional Information
Is the problem of public health importance? No

Probably no

Don't know (minority opinion)

 Prior to the COVID-19 pandemic, it was estimated that ≥100,000 non-invasive pneumococcal pneumonia hospitalizations and ≥30,000 invasive pneumococcal disease (IPD) cases (IPD defined as disease with pneumococcal detection in a normally sterile site) occurred among U.S. adults each year. In 2019, IPD incidence in adults was 4.6, 15.7, and 23.7 per 100,000 population in those aged 19–49 years, 50–64 years, and ≥65 years, respectively1, with rates in adults aged 50–64 years exceeding those in children aged <5 years. In 2020, IPD rates decreased in all age groups, likely due to COVID-19 non-pharmaceutical interventions that resulted in cessation of transmission of non-SARS-CoV-2 respiratory pathogens2. However, relaxation of COVID-19-related interventions resulted in an increase in transmission of these pathogens in more recent years3,4. Data from 2022 show that IPD rates have been nearing pre-COVID-19 baseline. Based on serotype distribution of IDP cases reported in 2018–2022, PCV20 and PCV21 covered 54% and 84% of IPD cases, respectively, in adults aged ≥65 years. In adults aged 50–64 years, the proportions were 56% and 83%, respectively.
Ascertainment of the true burden of non-bacteremic pneumococcal pneumonia is more challenging since the cause of pneumonia is not routinely tested or identified. An analysis using claims data from 2016–2019 reported that the incidence rates of all-cause pneumonia in any setting increase by age at 953, 2679, and 6930 per 100,000 person-years in adults aged 18–49 years, 50–64 years, and ≥65 years, respectively5.
A study conducted among adults aged ≥18 years hospitalized with community-acquired pneumonia (CAP) in Georgia and Tennessee (PNEUMO study) estimated the proportion of vaccine-type pneumococcal pneumonia among CAP cases using their serotype-specific urinary antigen detection (SSUAD) assays for 30 serotypes contained in PCV15, PCV20, and PCV21 except for serotype 15B (included in PCV20). Results showed that among all adults, 12.1% had pneumococcal detection, 9.3% had a pneumococcal serotype contained in PCV21, and 4.1% with a serotype unique to PCV21 (not contained in PCV15 or PCV20)6. By age group, the proportion of PCV21, PCV20 (without serotype 15B), and PCV15 serotypes were: 8.0%, 4.7%, and 4.0% (18–49 years); 11.3%, 8.4%, and 7.3% (50–64 years old); and 8.7%, 6.9%, and 5.8% (≥65 years).
The Work Group interpretation was split between “No”, “Probably No” and “Don’t Know” since the disease incidence in adults aged 19–49 years is expected to be even lower compared with adults aged 50–64 years.

Benefits and Harms

References in this table:7891011

Benefits and Harms
Criteria Work Group Judgements Evidence Additional Information
How substantial are the desirable anticipated effects? Minimal

Small

 In the pivotal Phase III clinical trial conducted among non-immunocompromised, pneumococcal vaccine naive adults aged ≥18 years7, the immunogenicity measured one month after PCV21 administration was compared in those aged 18–49 years compared with those aged 50–64 years. Results showed that geometric mean titer (GMT) was numerically higher in adults aged 18–49 years compared with adults aged 50 –64 years for all 21 serotypes (95% confidence interval for GMT ratio did not cross 1 except for serotypes 3 and 19A. All 21 serotypes met criteria for immunobridging (defined as the lower bound of the 2-sided 95% CI of the OPA GMT ratio [18–49 years]/[50–64 years] being >0.5). There are no studies that have assessed the efficacy or effectiveness of PCV21 against clinical outcomes.
How substantial are the undesirable anticipated effects? Minimal PCV21 Clinical Trial Safety Data
In the integrated safety analysis, data from three Phase III clinical trials (pneumococcal vaccine-naive adults aged 18–49 years8, pneumococcal vaccine naive adults aged ≥50 years7, and pneumococcal vaccine-experienced adults aged ≥50 years9) were pooled. Safety of PCV21 among 4020 recipients was compared to that of the 2018 recipients of the comparator vaccine (PCV15, PCV20, or PPSV23). The proportion of participants who experienced ≥1 solicited adverse events was comparable (63.3% among PCV21 recipients vs 63.9% among control vaccine recipients), with injection site adverse events occurring among 57.1% vs 56.5% of PCV21 vs control recipients, and solicited systemic adverse events occurring among 36.8% vs. 32.0% of PCV21 vs control recipients, respectively. Among solicited injection site events, injection site pain was the most common (55.6% vs 54.5% of all PCV21 vs control recipients). Among solicited systemic adverse events, fatigue (27.1% vs 23.7%), headache (18.4% vs 15.5%), myalgia (11.3% vs. 7.5%) were the common symptoms among all PCV21 vs control recipients. The majority of the solicited adverse events were mild (Grade 1) or moderate (Grade 2). A total of 4 (0.1%) potentially life-threatening (Grade 4) solicited adverse events were reported (3 in PCV21 group, 1 in control group). All were pyrexia, which resolved. No events of Guillain-Barré syndrome (GBS) were observed.
In a phase 3 pivotal trial, adverse events post-PCV21 administration were compared to those post-PCV20 administration in adults aged 18–49 years7. Serious adverse events occurred in 0.5% (1/200) of PCV21 participants and 3% (3/100) of PCV20 participants; none were considered to be vaccine-related.
Post-licensure PCV20 Safety Data
Analysis of reports to the Vaccine Adverse Event Reporting System (VAERS) showed that among 1,976 reports received after PCV20 vaccine in adults aged ≥19 years between October 2021 and December 2023, most reports were classified as non-serious and describe reactions consistent with pre-licensure PCV20 trials in adults10. There was a data mining alert for GBS after PCV20 vaccination. An analysis of Centers for Medicare & Medicaid Services data through November 2023 showed that GBS incidence rate post-PCV20 administration has been rare and that the estimated incidence rate ratios and confidence intervals did not identify statistically significant risk elevation for any of the pre-specified outcomes11.
Do desirable effects outweigh undesirable effects? Favors Intervention

Favors comparison
  • Some Work Group members believed that for adults aged 19–49 years, the degree of benefits for adults who currently don’t have vaccine recommendations was uncertain
  • Others believed that epidemiology of pneumococcal disease did not support expanding the vaccine indications to younger adults without a risk-based indication
  • In addition, younger adults in their early 20s would have received a PCV as a child
  • Some expressed concerns that we could miss the opportunity to provide protection against disease later in life if we lowered the age-based recommendation given limited data on duration of protection or protection against disease from multiple PCV doses in adults
What is the overall certainty of the evidence of effects? Effectiveness of the intervention
Moderate
Safety of the intervention
Moderate
 GRADE analyses were completed to assess the certainty of evidence.
  • Overall evidence type was moderate for the effectiveness of the intervention.
    • Assessment on indirectness was downgraded to “serious” since only immunogenicity studies were available and there are no established correlates of protection for PCV21 against some critical outcomes (vaccine-type non-invasive non-bacteremic pneumococcal pneumonia, vaccine-type pneumococcal disease mortality)
  • Overall evidence type was moderate for the safety of the intervention.
    • Assessment on imprecision was downgraded to “serious” because few vaccine-related serious adverse events were reported in studies with small sample sizes.
 Refer to GRADE summary tables for details. This population is covered in GRADE tables for adults aged 19–49 years who currently do not have a risk-based pneumococcal vaccine indication.

Values

References in this table:12

Values
Criteria Work Group Judgements Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Varies Evidence to support this discussion for this EtR domain was limited (see summary of surveys conducted among targeted adult population by the Healthcare and Public Perceptions of Immunizations [HaPPI] Survey Collaborative in “Additional Considerations” column). The WG members found it difficult to understand how the target population would perceive the benefits vs. harms of PCV21.
  • An online survey targeting adults aged 19–64 years with underlying conditions with risk-based pneumococcal vaccine indications was conducted by the HaPPI Survey Collaborative in January 202412. Results showed that a higher proportion of participants who self-reported having received a pneumococcal vaccine vs. those who did not had heard of pneumococcal disease and believed they would get pneumococcal disease in the next year. Among those who reported not receiving the pneumococcal vaccine, the most common reasons selected were not knowing they needed to get a pneumococcal vaccine or not being recommended by a healthcare provider that they needed a vaccine. Regardless of self-reported vaccination status, >60% of participants stated that they would receive a pneumococcal vaccine if recommended by a healthcare provider (range: 64% among unvaccinated to 88% among vaccinated).
Is there important uncertainty about or variability in how much people value the main outcomes? Important uncertainty or variability

Possibly important uncertainty or variability

 There was no evidence identified to support the discussion of this question and the WG interpretation was split between “important uncertainty or variability” and “possibly important uncertainty or variability”.

Acceptability

References in this table:13

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakeholders? No

Probably no

 A Merck-supported cross-sectional online survey was conducted among healthcare providers (HCPs, internal medicine physicians, family medicine physicians, nurse practitioners, physician assistants, pharmacists) March to May 202413. Participants were predominantly of White race (85.3%) and practiced in an urban location (82.9%). The most important vaccine attributes driving HCP decisions were related to disease coverage. The majority (95.9%) of survey respondents either strongly agreed or agreed to have more approved pneumococcal vaccine options for adults.

Resource Use

References in this table:1415

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? No Two economic models (Tulane-CDC, and Merck models) assessed the cost-effectiveness of the use of PCV21 among adults who are aged 19–49 but are not currently recommended for PCV14. For each of the models, the primary health outcome used to assess cost-effectiveness was the quality-adjusted life-year (QALY). The Tulane-CDC model compared vaccination with PCV21 at age 19 vs vaccination with PCV21 at age 50, and found that the intervention (vaccination with PCV21 at age 19) was dominated in the base case and in the 95% confidence interval generated by probabilistic sensitivity analysis15. The Merck model compared vaccination at age 19 and 65 with PCV21 vs vaccination at age 65 with PCV20 and found that the intervention (i.e., vaccination with PCV21 at age 19 and 65) cost $650,000 per QALY gained. Several key assumptions varied across the two models that were reviewed, including indirect effects from PCV20 use among pediatric populations, the modeling of sequalae following acute pneumococcal disease states, the case-fatality-rates following inpatient non-bacteremic pneumonia, and productivity loss assumptions14. The cost per dose of PCV21 varied across models from $287 in the Merck model and to $319 in the Tulane-CDC model. These variations in inputs and assumptions contributed to variations observed across the main results estimated by the models. Several limitations applied to all models, including limited available data on vaccine efficacy and duration of protection, the magnitude of indirect effects from PCV use, and the future epidemiology of pneumococcal serotypes that are not included in PCV21 (e.g., serotype 4, 19F).

Equity

References in this table:4161718192021222324252627

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact on health equity? Probably increased Pneumococcal vaccine coverage
Adults aged 19–64 years with risk-based vaccine indication have had lower pneumococcal vaccine coverage compared with adults aged ≥65 years16. Among adults with risk-based indications, differences in vaccine coverage by underlying condition (highest among people living with HIV) and age (higher among older adults) have been reported17. Among those eligible to receive pneumococcal vaccines, racial disparities in pneumococcal vaccination coverage exist, with White adults having higher vaccine coverage compared with other race/ethnicity, especially among adults aged ≥65 years.
Vaccine coverage for vaccines with age-based recommendation
Coverage of ≥1 dose of updated 2023–2024 COVID-19 vaccine was 14.3%, 25.2%, and 40.6% for adults aged 18–49 years, 50–64 years, and ≥65 years, respectively18. 2022–2023 influenza season vaccine coverage was 35.8%, 50.3%, and 68.4% for adults aged 18–49 years, 50–64 years, and ≥65 years, respectively19.
Racial disparities in pneumococcal disease incidence
Racial disparities in pneumococcal disease incidence have existed, with disproportionately higher disease burden among Black adults compared with non-Black adults, resulting in high U.S. societal costs20–22. Introduction of PCV13 among U.S. children reduced disparities that existed in PCV13-type IPD incidence, likely due to indirect effects from PCV13 vaccination in children23.
Racial disparities in the proportion of vaccine serotype coverage
The remaining disparities are driven by non-PCV13 type disease23. Based on 2014–2019 ABCs data, PCV20-non-PCV13 serotypes caused 46% of non-PCV13 IPD cases in adults aged 19–49 years (range: 39% in Black adults to 59% in Asian adults), 43% in adults aged 50–64 years (range: 37% in Black adults to 55% in American Indian/Alaska native [AI/AN] adults), and 38% in adults aged ≥65 years (range: 32% in Black adults to 49% in AI/AN adults). PCV21-non-PCV13 serotypes caused 89% of non-PCV13 IPD cases in adults aged 19–49 years (range: 68% in Asian adults to 94% in AI/AN adults), 90% in adults aged 50–64 years (range: 85% in Asian adults to 91% in White adults), and 86% in adults aged ≥65 years (range: 78% in Asian adults to 90% in AI/AN adults).
Emergence of serotype 4 disease in certain U.S. subpopulations
Clusters for IPD cases due to serotype 4 have been reported in certain populations, such as people experiencing homelessness4,24,25. Increase in IPD caused by pneumococcal serotype 4 has been reported through routine surveillance in recent years, especially post-2020 in the Western United States, such as adults in Alaska26, Navajo Nation27, and Western sites in CDC’s Active Bacterial Core surveillance. Serotype 4 is included in PCV7 and other licensed pneumococcal vaccines but not in PCV21 and had nearly been eliminated after PCV7 introduction in children. Affected adults are typically adults aged <65 years with underlying conditions with risk-based vaccine indications or with history of substance abuse.

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? No

Probably no

 The Work Group interpretation of this domain reflected the interpretation of the EtR domain resource use, which showed that PCV21 use for all adults aged ≥19 years was not an economically favorable option. Given that the Work Group was not supportive of lowering the age-based recommendations for other PCVs (e.g., PCV15, PCV20) to age ≥19 years, there were concerns that lowering the age-based recommendation for PCV21 only is expected to result in implementation challenges.

Balance of Consequences:

Undesirable consequences probably outweigh desirable consequences in most settings

Policy options for ACIP Consideration

ACIP does not recommend the intervention*

*Intervention may be used within FDA licensed indications

ACIP Recommendation:

(The Work Group did not propose any policy option related to this policy question)

Print
Content Source:
National Center for Immunization and Respiratory Diseases (NCIRD)
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  27. Navajo Epidemiology Center,. Serotype 4 Invasive Pneumococcal Disease (IPD) Information for Providers. Published March 2024. Accessed May 28, 2024. https://nec.navajo-nsn.gov/Portals/0/Reports/ST4%20alert%20for%20NN%20providers_2024.0312.pdf