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
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.
|Work Group Judgments
|Is the problem of public health importance?
|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 . Adults with immunocompromising conditions were recommended to receive a second dose of PPSV23 at least 5 years after the first dose . 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 .
Benefits and Harms
|Work Group Judgments
|How substantial are the desirable anticipated effects?
|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.
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.
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?
|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?
|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.
|Refer to the GRADE summary table for details.
|Work Group Judgments
|Does the target population feel that the desirable effects are large relative to undesirable effects?
|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 . 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:
The odds of vaccine hesitancy or resistance was greater in:
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.
|Work Group Judgments
|Is the intervention acceptable to key stakeholders?
|Key findings from provider and immunization manager surveys [12-15]:
|Work Group Judgments
|Is the intervention a reasonable and efficient allocation of resources?
|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:
Other important assumptions included:
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.
|Work Group Judgments
|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.
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 . 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:
|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.
|Work Group Judgments
|Is the intervention feasible to implement?
|Use of PCV13 in series with PPSV23 had been recommended for use for adults with IC since 2012 . 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.
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.
- Centers for Disease Control and Prevention. Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (PPSV23). MMWR. 2010;59:1102-6.
- Centers for Disease Control & Prevention. Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine for Adults with Immunocompromising Conditions: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbidity and mortality weekly report. 2012;61:816-9.
- 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.
- Pelton SI, Bornheimer R, Doroff R, Shea KM, Sato R, Weycker D. Decline in Pneumococcal Disease Attenuated in Older Adults and Those With Comorbidities Following Universal Childhood PCV13 Immunization. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2019;68:1831-8.
- 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.
- National Center for Health Statistics. National Health Interview Survey, 2018. Public-use data file and documention.
- National Center for Health Statistics. National Health Interview Survey, 2017. Public-use data file and documentation. 2017.
- Gatwood J, McKnight M, Frederick K, Hohmeier K, Kapan S, Chiu CY, et al. Extent of and Reasons for Vaccine Hesitancy in Adults at High-Risk for Pneumococcal Disease. Am J Health Promot. 2021;35:908-16.
- Miller ER, Moro PL, Cano M, Lewis P, Bryant-Genevier M, Shimabukuro TT. Post-licensure safety surveillance of 23-valent pneumococcal polysaccharide vaccine in the Vaccine Adverse Event Reporting System (VAERS), 1990-2013. Vaccine. 2016;34:2841-6.
- Haber P, Arana J, Pilishvili T, Lewis P, Moro PL, Cano M. Post-licensure surveillance of 13-valent pneumococcal conjugate vaccine (PCV13) in adults aged ⩾19years old in the United States, Vaccine Adverse Event Reporting System (VAERS), June 1, 2012-December 31, 2015. Vaccine. 2016;34:6330-4.
- 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.
- Merck & Co. Inc. HCP Preferences for Adult Pneumococcal Vaccine. 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.
- Lu PJ, Hung MC, Srivastav A, Grohskopf LA, Kobayashi M, Harris AM, et al. Surveillance of Vaccination Coverage Among Adult Populations -United States, 2018. Morbidity and mortality weekly report Surveillance summaries (Washington, DC : 2002). 2021;70:1-26.
- Gatwood J, Chiu CY, Shuvo S, Ramachandran S, Jadhav S, Hohmeier KC, et al. Role of social determinants of health in pneumococcal vaccination among high-risk adults. Vaccine. 2021;39:1951-62.