September 5, 2024

Evidence to Recommendations for PCV15 use among adults ≥65 years old

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
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].

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. In healthy adults aged ≥50 years [4], geometric mean titer (GMT) was higher in the group that received PCV15 in 13/13 shared PCV13 serotypes and GMT ratios were significantly higher in three (serotypes 1, 14, 23F); % seroresponders (% of subjects with ≥4-fold risk in OPA GMT post-vaccination) was higher in 11/13 shared serotypes (all non-significant). In Navajo adults or adults with chronic underlying medical conditions aged 18–49 years [2], PCV15 elicited higher GMTs in 9/13 serotypes, and higher % seroresponders in 5/13 serotypes (non-significant). In adults aged ≥18 years with HIV infection [3], PCV15 elicited higher GMTs in 11/13 serotypes and higher % seroresponders in 10/13 serotype. In all 3 studies, improved immunologic responses against serotype 3 were observed 30 days after administration of PCV15 compared with PCV13; however, the improved immunologic responses against serotype 3 were diminished when immunologic responses were assessed after administration of PPSV23 [2-4] 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 against serotypes 22F and 33F were diminished when immunologic responses were assessed after administration of PPSV23 [2-4]	No PCV15 studies directly assessed the impact on critical outcomes. Although subjects who received PCV15 in series with PPSV23 generally had higher geometric mean titers (GMTs) and % who had ≥4-fold rise in OPA GMT pre-/post-vaccination compared with subjects who received PCV13 in series with PPSV23, the clinical significance remains unknown. The 2014 recommendation to routinely use PCV13 in series with PPSV23 in adults aged ≥65 years did not significantly impact PCV13-type disease at the population level; as such, routine PCV13 use recommendation in adults without immunocompromising conditions, cochlear implant, or CSF leak was removed in 2019 [5], recognizing that historically low levels of PCV13-type disease in adults aged ≥65 years was primarily attained through indirect effects from pediatric PCV13 use in children. Anticipating pediatric licensure of PCV15, some WG members believed that the incremental benefit of routine PCV15 use in series with PPSV23 in adults aged ≥65 years may be small. Given that PCV15 provides coverage for 2 additional serotypes (approximately 15% of remaining IPD burden) compared with PCV13, the magnitude of the desirable anticipated effects was estimated to be small to moderate, or higher if the enhanced immune response to ST3 provided clinical protection. 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]: The recommendation of PCV13 use based on shared clinical decision-making is confusing Preference for a simplified pneumococcal vaccine recommendation Responses were mixed about use of PCV in series with PPSV23. In one survey [12], routine PCV use in series with PPSV23 was the most preferred among those provided options on vaccine recommendations, which included use of PCV routinely vs shared clinical decision-making, and with or without PPSV23. In another survey [11], concerns related to implementation (e.g., challenges in determining pneumococcal vaccination history, increased changes of dosing errors), communication, and series completion especially in hard-to-reach population were expressed.	Routine use of PCV13 in series with PPSV23 was implemented in 2014 [13]. Since some adults aged ≥65 years continue to receive PCV13 in series with PPSV23 after the shared clinical decision-making recommendation in 2019, the intervention may be acceptable to some providers. Work Group members agreed that recommending both PCV15 and PPSV23 to all adults aged ≥65 years will simplify the existing recommendations.

Resource Use

Criteria	Work Group Judgments	Research Evidence	Additional Information
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.	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

Criteria

Work Group Judgments

Research Evidence

Additional Information

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.

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

Equity

Criteria	Work Group Judgments	Research Evidence	Additional Information
What would be the impact on health equity?	Probably no impact	Disparities in pneumococcal disease burden 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. Disparities in pneumococcal vaccine coverage 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].	Some Work Group members believed that a recommendation that requires two vaccines is more likely to disadvantage the population who may have increased pneumococcal disease burden and have lower vaccine coverage or challenges with access to care. Some members thought that routine use of PCV15 in series with PPSV23 for all adults aged ≥65 years simplifies the recommendation and would lead to higher coverage and possibly improving equity. Overall, the Work Group believed that the new policy option will likely have little impact on equity for adults aged ≥65 years compared with the current recommendation.

Criteria

Work Group Judgments

Research Evidence

Additional Information

What would be the impact on health equity?

Probably no impact

Disparities in pneumococcal disease burden

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.

Disparities in pneumococcal vaccine coverage

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].

Some Work Group members believed that a recommendation that requires two vaccines is more likely to disadvantage the population who may have increased pneumococcal disease burden and have lower vaccine coverage or challenges with access to care.
Some members thought that routine use of PCV15 in series with PPSV23 for all adults aged ≥65 years simplifies the recommendation and would lead to higher coverage and possibly improving equity.
Overall, the Work Group believed that the new policy option will likely have little impact on equity for adults aged ≥65 years compared with the current recommendation.

Feasibility

Criteria	Work Group Judgments	Research Evidence	Additional Information
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.
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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.
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View the complete list of EtR Frameworks‎‎‎

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