About
The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.
Summary
Question: Should PCV15 in series with PPSV23 vs. Current pneumococcal vaccine recommendation be used in U.S. adults aged ≥65 years for vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumonia, vaccine-type pneumococcal death?
Population: U.S. Adults aged ≥65 years
Intervention: PCV15 in series with PPSV23
Comparison: Existing pneumococcal vaccine recommendations:
- PCV13 followed by PPSV23 (immunocompromised adults* aged ≥65 years)
- PPSV23 (immunocompetent adults aged ≥65 years)**
*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.
**PCV13 recommended based on shared clinical decision making for immunocompetent adults ≥65 years
Outcome: Vaccine-type invasive pneumococcal disease; Vaccine-type non-bacteremic pneumococcal pneumonia; Vaccine-type pneumococcal death; Serious adverse events following immunization
Background
Until October 20, 2021, 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 PCV15 in adults in order to identify policy options that maximize pneumococcal disease prevention among adults, reduce disparity, and simplify existing recommendations to improve vaccine uptake.
Problem
Criteria | Work Group Judgments | Evidence | Additional Information |
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Is the problem of public health importance? | Yes | In adults, the burden of pneumococcal disease increases with age. Adults aged ≥65 years comprise 22% of all U.S. adults aged ≥19 years and approximately 40-55% of pneumococcal disease burden is in adults aged ≥65 years.
In 2018, invasive pneumococcal disease (IPD) incidence was approximately 24 per 100,000 population with a case fatality ratio of 14% in adults aged ≥65 years. IPD incidence caused by serotypes contained in the 13-valent pneumococcal conjugate vaccine (PCV13) has been stable since 2014, with serotype 3 as the most common serotype. Among all IPD serotypes in 2018–2019, PCV13 serotypes comprised 27% of IPD and additional serotypes included in PCV15 and PCV20 (but not in PCV13) comprised 15% and 29% of the IPD burden, respectively.
The estimated burden of pneumococcal pneumonia has been variable. According to CDC’s Surveillance for Non-invasive Pneumococcal Pneumonia (SNiPP), incidence of hospitalized pneumococcal pneumonia was approximately 105 per 100,000 population in adults aged ≥65 years in 2017. Based on a prospective multicenter surveillance study of adults hospitalized with community-acquired pneumonia conducted in 2013–2016, 8% had pneumococcal pneumonia, 4% had PCV13-type pneumonia, 6% were due to PCV15-types, and 7% were due to PCV20-types [1].
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Benefits and Harms
Criteria | Work Group Judgments | Research Evidence | Additional Information |
---|---|---|---|
How substantial are the desirable anticipated effects? | Moderate | We identified three Phase 3 randomized-controlled trials comparing the immunogenicity of PCV15 in series with PPSV23 to PCV13 in series with PPSV23[2-4] (please refer to GRADE tables for details). These studies did not assess statistical non-inferiority or superiority.
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Conclusion: Despite uncertainties about 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 [2-4] showed that the percentage of subjects with serious adverse events were low; slightly lower in subjects who received PCV15 compared with those who received PCV13 (0.3–1.3% vs. 0.7–4.1%). 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 the desirable effects of the Merck PCV15 in series with PPSV23 outweigh the 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) |
For the critical outcomes, the certainty of evidence was moderate for both the effectiveness and safety of the intervention. |
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 | No data are available on values of the target population toward use of PCV15 in series with PPSV23. All identified studies in adults[6-9] were performed before 2019, and most targeted a specific population with high representation of Blacks or Hispanics. Therefore, the survey sample populations may not be representative, limiting the generalizability to all U.S. adults aged ≥65 years. | The Work Group determined that most adults aged ≥65 years would value the individual level protection from PCV15 vaccination in series with PPSV23 above the potential side effects. The existing pneumococcal vaccine recommendation is similar to the new intervention, and the proportion of adults who received both PCV13 and PPSV23 have increased over time. |
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 determined that whereas there might be variability and uncertainty in how populations value the vaccine, for most, the desirable effects probably outweigh the undesirable effects. |
Acceptability
Criteria | Work Group Judgments | Research Evidence | Additional Information |
---|---|---|---|
Is the intervention acceptable to key stakeholders? | Probably yes | Key findings from provider and immunization manager surveys [10-12]:
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Resource Use
Criteria | Work Group Judgments | Research Evidence | Additional Information |
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Is the intervention a reasonable and efficient allocation of resources? | Probably no | Two cost-effectiveness analysis models were reviewed. These models assessed the economic impact of use of PCV15 in series with PPSV23 in adults aged ≥65 years.
In the CDC model, use of PCV15 in series with PPSV23 for adults at age 65 years was estimated to be cost-saving (i.e., an intervention strategy that yields higher health outcomes and lower costs) compared to the existing recommendation. Cost-savings were found in 4/4 scenarios investigated with the CDC model. In the Merck model, the estimated cost per QALY gained ranged from $237,000 to $282,000 in the base case and found cost-savings in a scenario that utilized alternative vaccine coverage assumptions. In both models, use of PCV15 in series with PPSV23 for adults at age 65 years prevented more disease compared to the existing recommendation.
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.
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Some key differences between the two models included:
Other important assumptions included:
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Equity
Criteria | Work Group Judgments | Research Evidence | Additional Information |
---|---|---|---|
What would be the impact on health equity? | Probably no impact |
Indirect effects from pediatric PCV13 vaccination reduced PCV13-type IPD incidence among those with increased IPD burden including Black [14] and Navajo[15] adults. Among racial groups, most of the remaining disparity in IPD burden was in non-PPSV23-type disease. Despite indirect effects from pediatric PCV13 vaccination, burden of PCV13-type IPD remains higher in Navajo and Alaska Native adults compared with the general adult population. Therefore, use of new vaccines may reduce, but not eliminate, disparities in disease burden.
An analysis of PCV13 and PPSV23 claims data of Medicare beneficiaries aged ≥65 years showed that in 2013 when routine use of PPSV23 was recommended for all adults aged ≥65 years without immunocompromising conditions, the proportion of beneficiaries who received at least one dose of PPSV23 was highest in Whites (46%) and lowest in Hispanics (33%%) [16]. In 2018 when all adults aged ≥65 years were recommended to receive PCV13 in series with PPSV23, the proportion of adults who received both PCV13 and PPSV23 was the highest in Whites (31%) and the lowest was in Hispanics (14%) [16]. |
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Feasibility
Criteria | Work Group Judgments | Research Evidence | Additional Information |
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Is the intervention feasible to implement? | Probably yes | In 2014, PCV13 was recommended in series with PPSV23 for all adults aged ≥65 years [13]. The Work Group believed that routine use of PCV15 in series with PPSV23 will be a simplification of the PCV13 use recommendation based on shared clinical decision-making for adults without immunocompromising conditions, CSF leaks or cochlear implants[5]. | Compared with a single-dose vaccine recommendation, a recommendation that requires vaccination with 2 different pneumococcal vaccines is more challenging to implement and is more likely to disadvantage adults with challenges with healthcare access. Providers often have challenges in determining accurate pneumococcal vaccination history to complete the recommended vaccine series. |
Balance of Consequences
The balance between desirable and undesirable consequences is closely balanced or uncertain.
Additional Considerations
The Work Group interpretation on balance of consequences was initially split between “Undesirable consequences probably outweigh desirable consequences in most settings” and “The balance between desirable and undesirable consequences is closely balanced or uncertain”. While use of PCV15 in series with PPSV23 is likely to prevent pneumococcal disease caused by additional serotypes included in PCV15 but not in PCV13, and there is a potential for improved protection against ST3 disease (the most common remaining PCV13-type disease), some Work Group members believed that the additional benefit may be small based on the 2014–2019 experience from routine PCV13 use in series with PPSV23 for all adults aged ≥65 years[13]. Additionally, some Work Group members believed that there may be potential undesirable consequences in the domains of health equity (a routine recommendation that requires >1 vaccine dose is likely to disadvantage those with healthcare access issues), resource use (based on findings from the initial CDC model), and feasibility (challenges with implementation and access for patients with routine use of PCV15 and PPSV23 series).
Since June, we reviewed updated cost-effectiveness analysis (CEA) results, which included updated model structure (e.g., assessing the impact of age-based recommendation only, vs. assessing the combined impact or risk- and age-based recommendations) and model assumptions (e.g., more rapid waning of PCV, improved VE against vaccine-type IPD for PPSV23 in healthy/CMC adults), and results from other groups. The updated CEA findings showed that use of PCV15 in series with PPSV23 was cost-saving in the CDC model, and prevented more disease in others compared with the existing recommendations.
Based on these updated findings, the WG determined that the balance between desirable and undesirable consequences is closely balanced or uncertain when recommending PCV15 in series with PPSV23 for all adults aged ≥65 years.
References
- 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. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021.
- A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults at Increased Risk for Pneumococcal Disease (V114-017/PNEU-DAY). https://ClinicalTrials.gov/show/NCT03547167.
- A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Adults Infected With Human Immunodeficiency Virus (HIV) (V114-018). https://ClinicalTrials.gov/show/NCT03480802.
- A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 Followed by PNEUMOVAX™23 in Healthy Adults 50 Years of Age or Older (V114-016/PNEU-PATH). https://ClinicalTrials.gov/show/NCT03480763.
- 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.
- Albright K, Hurley LP, Lockhart S, Gurfinkel D, Beaty B, Dickinson LM, et al. Attitudes about adult vaccines and reminder/recall in a safety net population. Vaccine. 2017;35:7292-6.
- Lu PJ, O'Halloran A, Kennedy ED, Williams WW, Kim D, Fiebelkorn AP, et al. Awareness among adults of vaccine-preventable diseases and recommended vaccinations, United States, 2015. Vaccine. 2017;35:3104-15.
- Brown T, Goldman SN, Acosta F, Garrett AM, Lee JY, Persell SD, et al. Understanding Black Patients' Refusal of Pneumococcal Vaccination. J Racial Ethn Health Disparities. 2017;4:1-8.
- Kaljee LM, Kilgore P, Prentiss T, Lamerato L, Moreno D, Arshad S, et al. "You need to be an advocate for yourself": Factors associated with decision-making regarding influenza and pneumococcal vaccine use among US older adults from within a large metropolitan health system. Human vaccines & immunotherapeutics. 2017;13:206-12.
- 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.
- 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.
- Tomczyk S, Bennett NM, Stoecker C, Gierke R, Moore MR, Whitney CG, et al. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults Aged >/=65 Years: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbidity and mortality weekly report. 2014;63:822-5.
- Active Bacterial Core Surveillance (ABCs) program. Centers for Disease Control and Prevention; unpublished data, September, 2013.
- Johns Hopkins Bloomberg School of Public Health. Center for American Indian Health Unpublished data. 2021.
- 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, Unpublished data.