Evidence to Recommendations (EtR) Framework: PCV15 use in children aged 2–18 years with certain underlying medical conditions that increase the risk of pneumococcal disease

Question: Should PCV15 be recommended for U.S. children with underlying medical conditions 2–18 years of age as an option for pneumococcal conjugate vaccination according to currently recommended dosing and schedules?

Population: U.S. children 2–18 years of age with underlying medical conditions*

*underlying medical conditions defined as cerebrospinal fluid leak; chronic renal failure or nephrotic syndrome; cochlear implant; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; sickle cell disease and other hemoglobinopathies. For children aged 2–5 years, also includes chronic heart or lung disease, and diabetes mellitus.

Intervention: PCV15 according to currently recommended pneumococcal conjugate vaccination dosing and schedules

Comparison: PCV13 according to currently recommended dosing and schedules

Main Outcomes: Vaccine-type invasive pneumococcal disease; Vaccine-type non-bacteremic pneumococcal pneumonia; Vaccine-type acute otitis media; Vaccine-type pneumococcal death; Serious adverse events following immunization

Setting: U.S. children 2–18 years of age with underlying medical conditions*

Perspective: Clinical perspective

Background: In June 2022, the Food and Drug Administration approved an expanded usage of 15-valent pneumococcal conjugate vaccine (PCV15 [Merck Sharp & Dohme LLC]) to include children. PCV15 was licensed for use in adults in 2021.

Currently, use of both PCV13 and the 23-valent pneumococcal polysaccharide vaccine (PPSV23) is recommended for children aged 2–18 years with certain underlying medical conditions*. The ACIP Pneumococcal Vaccines Work Group employed the Evidence to Recommendation (EtR) framework, using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, to guide its deliberations regarding use of PCV15 in U.S. children with certain underlying medical conditions as an option for pneumococcal conjugate vaccination.

Problem

Public Health Problem
Criteria  Judgement Research Evidence Additional Considerations
Is the problem of public health importance? Yes Acute Otitis Media (AOM)
  • Acute otitis media (AOM) is one of the most common causes of pediatric medical visits, and Streptococcus pneumoniae is one of the most common bacterial causes of AOM (1, 2). Based on U.S. insurance claims data in 2014, incidence of all-cause AOM was much higher in children aged <5 years (range 299,800 to 478,600 per 100,000 person-years) compared with older children; the rate in children aged 5–17 years was 9,050 per 100,000 person-years (1).
  • In a 2015–2019 cohort study of children aged 6 –36 months in Rochester, New York, 24% of children with clinically-diagnosed AOM had pneumoniae isolated from culture; 9.3% with pneumococcal AOM had PCV13+6C type and 8.2% had 2 additional serotypes included in PCV15 (3).

Pneumonia

  • Based on U.S. insurance claims data in 2014, incidence of all-cause pneumonia was the highest in children aged <5 years (range 22,500 to 39,900 per 100,000 person-years) compared with older children, and the rate was 1,280 per 100,000 person-years in children aged 5–17 years (4).
  • According to National Inpatient Sample data, incidence of hospitalized all-cause pneumonia in children aged 5–17 years was 87 per 100,000 population.

Invasive pneumococcal disease

  • After PCV13 introduction in U.S. children in 2010, invasive pneumococcal disease (IPD) rates in children aged 5–18 years decreased; in 2018–2019, the IPD rate was 1.5 per 100,000 population. This decrease was driven by PCV13+6C type IPD, which decreased from 1.9 per 100,000 population in 2007–2008 to 0.5 per 100,000 population in 2018–2019.
  • IPD rates due to 2 additional serotypes included in PCV15 but not in PCV13 have been stable; in 2018–2019 these serotypes caused 16% of all IPD in children aged 5–18 years, while PCV13+6C types caused 34% of all IPD. Approximately 25% of IPD in children of this age group occurred in children with immunocompromising conditions, cochlear implants, or cerebrospinal fluid leaks (CDC ABCs unpublished data)

Benefits and Harms

Benefits and Harms
Criteria  Judgement Research Evidence Additional Considerations
How substantial are the desirable anticipated effects? Moderate
  • Two Phase 3 randomized-controlled trials evaluated immunogenicity of PCV15 use in children with underlying medical conditions. One trial evaluated one dose of PCV15 in children with sickle cell disease (5) and the other trial evaluated one dose of PCV15 followed by a dose of PPSV23 in children living with HIV (6). Following the PCV dose, PCV15 had numerically higher immune responses (IgG GMC) vs. PCV13 for 6 to 8 PCV13 serotypes including serotype 3 and PCV15 unique serotypes (22F and 33F) across studies.
  • Following one PPSV23 dose, PCV15+PPSV23 had higher immune response (IgG GMC) vs.  PCV13+PPSV23 for 3 of 13 PCV13 serotypes, but not for PCV15 unique serotypes (22F and 33F) (6).
  • No PCV15 studies directly assessed clinical outcomes.
  • The Work Group was split between “moderate” and “large” with some uncertainty about the added benefit from PCV15 use.
  • There are unknowns, such as the clinical implication of improved immunogenicity against serotype 3. PCV15 provides coverage for 2 additional serotypes compared with PCV13, if the improved immune response against these two serotypes translates to clinical effectiveness.
How substantial are the undesirable anticipated effects? Minimal
  • Safety data from phase 3 randomized-controlled trials (5, 6) found that the percentage of subjects who received PCV15 with serious adverse events were low and comparable to those who received PCV13 (0.5-18.8% in PCV15 group, 0.5-23.5% in PCV13 group). There was no difference in the proportion who developed serious adverse events among children who received PCV15 + PPSV23 and PCV13 + PPSV23 (6). No serious adverse events were associated with the vaccines.
Do the desirable effects outweigh the undesirable effects? Favors both In comparing PCV15 with PCV13 for use in children aged 2–18 years with underlying conditions, the Work Group felt that both interventions are favorable.
What is the overall certainty of this evidence for the critical outcomes? Effectiveness of the intervention: Low
Safety of the intervention: Low
For critical outcomes, the certainty of evidence was low for effectiveness and low for safety of the intervention. Certainty of evidence for effectiveness was downgraded for indirectness (immunogenicity studies only, no clinical efficacy data), and imprecision (small sample size of the studies). Certainty of evidence for safety was downgraded twice for imprecision (very small sample size of the studies and no vaccine-related serious adverse events reported in either study arm).

Values

Values
Criteria  Judgement Research Evidence Additional Considerations
Does the target population feel the desirable effects are large relative to the undesirable effects? Probably yes
  • There were no data on values of the target population toward inclusion of PCV15 as an option for pneumococcal vaccination.
  • However, the high vaccination coverage of 92.4% for ≥3 doses of PCV13 in children born during 2017–2018 demonstrates that the target population feels that the desirable effects of PCV vaccination outweigh the undesirable effects (7).
The WG members’ interpretation was split between “Yes” and “Probably Yes”. The split in interpretation was due to the uncertainties about the added benefit from PCV15 use.
Is there important uncertainty about or variability in how much people value the main outcomes? Probably no important uncertainty or variability
  • Uncertainties remain about the added benefit of PCV15 use. However, given that PCV13 is currently used among children, the Work Group believed that there is probably no important uncertainty or variability in values related to using PCV15 as an option for pneumococcal conjugate vaccination based on the currently recommended dosing and schedules.

Acceptability

Acceptability
Criteria  Judgement Research Evidence Additional Considerations
Is the intervention acceptable to key stakeholders? Probably yes
  • We did not identify evidence that specifically addressed risk-based pneumococcal vaccine use in children aged 2–18 years with underlying medical conditions.
  • According to a survey of 600 healthcare providers who prescribe/administer ≥10 pneumococcal vaccines per month (8),
    • 48% of respondents preferred a vaccine eliciting higher immune response with fewer serotypes compared with a vaccine with broad serotype coverage for healthy children aged <24 months; approximately 60% of respondents preferred a vaccine eliciting higher immune response with fewer serotypes compared with a vaccine with broad serotype coverage for children aged <24 months who have sickle cell disease, HIV infection, hematopoietic stem cell transplant recipients, or premature.
    • Indication against IPD, safety and side-effects, greater immune response to certain disease-causing serotypes, and overall immune response across vaccine serotypes, were commonly selected clinical features in pneumococcal vaccine choice.

Resource Use

Resource Use
Criteria Judgement Research Evidence Additional Considerations
Is the intervention a reasonable and efficient allocation of resources? Probably yes
  • A cost-effectiveness analysis specifically targeting children aged 2–18 years with underlying medical conditions was not performed.
  • Based on available cost for adults (9), private cost is assumed to be lower for PCV15 compared to PCV13; however, the actual public and private price of PCV15 are currently unknown.
  • Uncertainties remain regarding the effectiveness of PCV15 against pneumococcal disease and the cost of PCV15.
  • Given that changes in the recommended PCV doses or schedule are not being considered, the Work Group believed that using PCV15 as an option for pneumococcal conjugate vaccination would probably be a reasonable and efficient allocation of resources.

Equity

Equity
Criteria Judgement Research Evidence Additional Considerations
What would be the impact on health equity? Probably no impact Disease Burden
  • Compared with White children, Black children have higher IPD incidence (CDC Active Bacterial Core surveillance unpublished data).
    • IPD incidence decreased in both Black and White children after PCV13 introduction in 2010, and the absolute rate difference between Black and White children decreased in children aged <5 years, especially for IPD due to PCV13 types.
    • Among children aged <5 years, IPD incidence remains higher in Black children compared to White children; most of the remaining difference is due to serotypes not included in PCV15.
    • IPD rates in children aged 5–18 years have been much lower compared to IPD rates in children aged <5 years in both White and Black children.
  • IPD rates in Native American children in 2011–2018 have been >4 times higher compared with U.S. children of all races (10).
  • A cross-sectional analysis using 2012 Kid’s Inpatient Database showed that Native American/Alaska Native children had 1.78 (95% CI = 1.23, 2.57) greater odds of hospitalization due to pneumococcal infection compared to White children (11).

Vaccination Coverage

  • In 2010–2012, foreign-born children aged 19–35 months had significantly lower pneumococcal vaccination coverage (46.4%) compared with U.S-born children (83.9%) (p<0.001) (12).
  • According to the North Dakota Immunization Information System (NDIIS) for years 2014 through 2018, compared with White children, a smaller proportion of Native American children were up to date with 4 doses of PCV up to date at each immunization milestone for PCV (11).
  • According to a 2018–2019 cross-sectional survey in Washington, DC, children aged 19–35 months experiencing homelessness in the DC homeless sample showed significantly lower PCV coverage rates when compared to the estimates for children aged 19–35 months in Washington, DC (NIS DC) and children in US overall (NIS US) (61% vs 84% and 83%, respectively) (13).
  • The demographic groups showing the lowest ≥4 dose PCV coverage at age 24 months among children born in 2014–2017 were: uninsured children (62.2%), Black, non-Hispanic children (76.5%), children living in a non-Metropolitan Statistical Area (78.6%), and children living at <133% of the federal poverty line (75.5%) (14).
  • Given that the racial disparity in the burden of IPD due to PCV15-unique serotypes was small, the Work Group believed that PCV15 will probably have no impact compared to PCV13 on health equity.

Feasibility

Feasibility
Criteria Judgement Research Evidence Additional Considerations
Is the intervention feasible to implement? Probably yes
  • Certain groups of children currently have lower PCV coverage compared with others (see evidence under “Equity”).
  • Given that the ACIP is currently not considering a PCV schedule change and rather, the ACIP is considering adding PCV15 as an option for pneumococcal conjugate vaccination, and since the price of PCV15 is expected to be comparable to PCV13, the Work Group believed that the intervention will probably be feasible to implement. However, the price of PCV15 could change.

Balance of Consequences

The balance between desirable and undesirable consequences is closely balanced or uncertain

References

  1. Tong S, Amand C, Kieffer A, Kyaw MH. Trends in healthcare utilization and costs associated with acute otitis media in the United States during 2008-2014. BMC health services research. 2018;18(1):318.
  2. Lewnard JA, King LM, Fleming-Dutra KE, Link-Gelles R, Van Beneden CA. Incidence of Pharyngitis, Sinusitis, Acute Otitis Media, and Outpatient Antibiotic Prescribing Preventable by Vaccination Against Group A Streptococcus in the United States. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021;73(1):e47-e58.
  3. Kaur R, Fuji N, Pichichero ME. Dynamic changes in otopathogens colonizing the nasopharynx and causing acute otitis media in children after 13-valent (PCV13) pneumococcal conjugate vaccination during 2015-2019. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2022;41(1):37-44.
  4. Tong S, Amand C, Kieffer A, Kyaw MH. Trends in healthcare utilization and costs associated with pneumonia in the United States during 2008-2014. BMC health services research. 2018;18(1):715.
  5. Merck Sharp, Dohme Corp. A Study to Evaluate the Safety, Tolerability, and Immunogenicity of V114 in Children With Sickle Cell Disease (V114-023/PNEU-SICKLE) 2020 [updated June 8. Available from: https://ClinicalTrials.gov/show/NCT03731182.
  6. Merck Sharp, Dohme Corp. Safety and Immunogenicity of V114 in Children Infected With Human Immunodeficiency Virus (HIV) (V114-030/PNEU-WAY PED) 2021 [updated May 3. Available from: https://ClinicalTrials.gov/show/NCT03921424.
  7. Hill HA, Yankey D, Elam-Evans LD, Singleton JA, Sterrett N. Vaccination Coverage by Age 24 Months Among Children Born in 2017 and 2018 – National Immunization Survey-Child, United States, 2018-2020. MMWR Morb Mortal Wkly Rep. 2021;70(41):1435-40.
  8. Merck & Co. Inc. Healthcare Provider Preferences Related to Multi-Valent Pneumococcal Conjugate Vaccines. 2022.
  9. Centers for Disease Control and Prevention. CDC Vaccine Price List 2022 [Available from: https://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/price-list/index.html.
  10. Littlepage SJ, Sutcliffe CG, Simons-Petrusa B, Harker-Jones M, Weatherholtz RC, Roessler K, et al. Impact of PCV13 on Invasive Pneumococcal Disease among Native Americans Less than 5 Years of Age Living on Navajo Nation. 9th International Meeting on Indigenous Child Health; September 10 and 11, 2021; Virtual2021.
  11. Woinarowicz M, Howell M. Comparing vaccination coverage of American Indian children with White children in North Dakota. Public Health. 2020;186:78-82.
  12. Nickel AJ, Puumala SE, Kharbanda AB. Vaccine-preventable, hospitalizations among American Indian/Alaska Native children using the 2012 Kid’s Inpatient Database. Vaccine. 2018;36(7):945-8.
  13. Fu LY, Torres R, Caleb S, Cheng YI, Gennaro E, Thoburn E, et al. Vaccination coverage among young homeless children compared to US national immunization survey data. Vaccine. 2021;39(45):6637-43.
  14. Centers for Disease Control and Prevention. ChildVaxView [updated September 28, 2020. Available from: https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/interactive-reports/index.html.