Evidence to Recommendations for PCV20 use among adults ≥65 years old

About

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

Summary

Question: Should PCV20 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: PCV20

Comparison: Current pneumococcal vaccine recommendations:

  1. PCV13 followed by PPSV23 (immunocompromised adults* aged ≥65 years)
  2. 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

On June 8, 2021, a 20-valent pneumococcal conjugate vaccine (PCV20, Pfizer) was licensed for use in adults aged ≥18 years. Unlike previous conjugate vaccine formulations, PCV20 was licensed for adults before submission for licensure in children.

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 vary by age- and risk-groups. The ACIP Pneumococcal Vaccines Work Group reviewed available data to inform the use of PCV20 in adults and identified policy options that maximize pneumococcal disease prevention among adults, reduce disparity, and simplify recommendations to improve vaccine uptake.

Problem

References in this table: 1

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 U.S. adults aged ≥19 years, and approximately 40-55% of pneumococcal disease burden.
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, and serotype 3 has been the most common serotype. Among all IPD cases, in 2018–2019, 27% were serotypes included in PCV13 and 15% and 29% were additional serotypes included in PCV15 and PCV20 (but not in PCV13), respectively.
The estimated burden of pneumococcal pneumonia has varied. 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 2019–2020, 8% had pneumococcal pneumonia: 2.8% had PCV13-type pneumonia, 3.9% were due to PCV15-types, and 7% were due to PCV20-types[1].

Benefits and Harms

References in this table:23

Criteria Work Group Judgments Research Evidence Additional Information
How substantial are the desirable anticipated effects? Large One Phase 2[2] and one Phase 3[3] randomized-controlled trials compared the immunogenicity of PCV20 to that of PCV13 and PPSV23.
In both the phase 2 study targeting adults aged 60–64 years and phase 3 study targeting adults aged ≥60 years, geometric mean titer (GMT) was lower among those receiving PCV20 compared with those receiving PCV13 in 12-13/13 shared serotypes (range reflects differences reported across studies); GMT was significantly lower in 4/13 serotypes in the Phase 2 study[2], and non-interiority criteria was met for all 13 common serotypes in the Phase 3 study[3]. % seroresponders (% of subjects with ≥4-fold risk in OPA GMT post-vaccination) was lower in 12/13 serotypes in both Phase 2 and 3 studies. The difference was non-significant in the Phase 2 study, and was significant for serotype 3 in the phase 3 study[3].
Compared with PPSV23, GMT was higher in PCV20 for 6/7 common serotypes; GMT was significantly higher in 3/7 serotypes in the Phase 2 study, and significantly lower for serotype 8. In the Phase 3 study, noninferiority criteria was met for 6/7 serotypes, and not for serotype 8. In both studies, % seroresponders were higher in 6/7 serotypes and lower in serotype 8 (significant in the Phase 3 study, and not in the Phase 2 study).
  • No PCV20 studies directly assessed critical outcomes
  • No PCV20 studies specifically targeted adults with IC.
  • The Work Group believed that a recommendation consisting of one vaccine may improve vaccine uptake compared with the existing recommendations.
  • Some Work Group members expressed concerns that subjects who received PCV20 tended to have lower GMT and % seroresponders compared with PCV13; however, the clinical significance is unknown, and GMT ratio of PCV20 vs. PCV13 met noninferiority criteria for all 13 serotypes. Additionally, PCV20 showed improved immune response compared with PPSV23 for 6/7 serotypes not included in PCV13.
  • Uncertainties remain about duration of protection and indirect effects from future pediatric PCV20 vaccination if used. In most cost-effectiveness analysis scenarios (see “resource use”), the policy option was health improving across all age-based results.
Conclusion:
Despite uncertainties about the clinical significance of lower immunogenicity of PCV20 compared with PCV13, the impact of using PCV20 only against disease caused by PPSV23-nonPCV20 types, and the duration of PCV protection, the Work Group believed that the potential benefit from PCV20 use is large compared with the current recommendations.
How substantial are the undesirable anticipated effects? Minimal Safety data from phase 2 or 3 randomized-controlled trials [2, 3]  showed that the percentage of subjects who received PCV20 with serious adverse events were low and comparable to those who received PCV13 with or without PPSV23 (0-4.1% in PCV20 group, 0.5-5% in PCV13+/-PPSV23 group). No serious adverse events were associated with the vaccines.
Do the desirable effects outweigh the undesirable effects? Favors intervention The Work Group determined that desirable effects of PCV20 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)
 For critical outcomes, the certainty of evidence was moderate for both effectiveness and safety of the intervention.

Values

References in this table:4567

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 were available on how the target population values use of PCV20. All identified studies[4-7] 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 of the results to all adults aged ≥65 years in the U.S. The Work Group determined that most adults aged ≥65 years would value the individual level protection from PCV20 vaccination above the potential side effects.
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 all populations value the vaccine, for most populations, desirable effects probably outweigh undesirable effects.

Acceptability

References in this table: 8910

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 [8-10]:
  • PCV13 use based on shared clinical decision-making is confusing
  • There was a preference for a simplified pneumococcal vaccine recommendation
  • There were mixed responses on use of PCV in series with PPSV23. In one survey [10], 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 [9], 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.
 The Work Group believed that a recommendation consisting of a single dose will be more acceptable by stakeholders compared with the current pneumococcal vaccine recommendations.

Resource Use

Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes Three cost-effectiveness analysis models were reviewed. These models assessed the economic impact of use of PCV20 in adults aged 65 years. All models showed that PCV20 use was health-improving, and most estimates were cost saving, including all 5/5 scenarios explored in the CDC model.
3 scenarios in Merck model were not cost-saving, and in those scenarios, vaccination as estimated to cost <$39,000/QALY gained.
 Some key differences between the models included:
  • Serotype specific vaccine effectiveness assumptions
  • Transitions to higher levels of disease risk for individuals in the model who start at lower risk status

Given findings from these models, the Work Group determined that the new policy option is a reasonable and efficient allocation of resources.

Key uncertainties include effectiveness of PCV20 in adults with immunocompromising conditions, potential impact of indirect effects from future pediatric vaccinations, and duration of protection.

Equity

References in this table:111213

Criteria Work Group Judgments Research Evidence Additional Information
What would be the impact on health equity? Probably increased
  • Disparities in pneumococcal disease burden

Indirect effects from pediatric PCV13 vaccination reduced PCV13-type IPD incidence, including Black [11] and Navajo[12] adults. Among racial groups, most of the 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 U.S. 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%) [13]. 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 lower than PPSV23 those who received PPSV23 alone; the highest coverage was in White adults (31%) and the lowest was in Hispanic adults (14%) [13].

Some Work Group members expressed concerns that disparities may remain if differences in vaccine coverage persist and new vaccines provide improved protection against disease. Additionally, while PCV20 is expected to reduce pneumococcal disease burden, since the existing racial disparity in IPD burden is driven by non-PPSV23 type disease, some Work Group members were uncertain about the impact of PCV20 use in reducing racial disparity. However, the Work Group determined that a single dose vaccine recommendation is likely to improve access to vaccines for adults targeted for the new policy option and therefore increase equity.

Feasability

Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention feasible to implement? Yes The Work Group determined that a recommendation consisting of a single vaccine will be feasible compared with the existing recommendations.

Balance of Consequences

Desirable consequences clearly outweigh undesirable consequences in most settings.

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Content Source:
National Center for Immunization and Respiratory Diseases (NCIRD)
  1. Pfizer Inc. US, Prospective, Multicenter Surveillance Study of Hospitalized CAP Using SSUAD. 2021.
  2. Hurley D, Griffin C, Young M, Scott DA, Pride MW, Scully IL, et al. Safety, Tolerability, and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Adults 60 to 64 Years of Age. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
  3. Essink B, Sabharwal C, Cannon K, Frenck R, Lal H, Xu X, et al. Pivotal Phase 3 Randomized Clinical Trial of the Safety, Tolerability, and Immunogenicity of 20-Valent Pneumococcal Conjugate Vaccine in Adults 18 Years and Older.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. Association of Immunization Managers. 2021 AIM PCV ACIP Survey. 2021.
  10. 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.
  11. Active Bacterial Core Surveillance (ABCs) program. Centers for Disease Control and Prevention; unpublished data, September, 2013.
  12. Johns Hopkins Bloomberg School of Public Health. Center for American Indian Health Unpublished data. 2021.
  13. 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.