Evidence to Recommendations (EtR) Framework: PCV15 use in children aged <2 years

Question: Should PCV15 be recommended as an option for pneumococcal conjugate vaccination according to currently recommended dosing and schedules, for U.S. children <2 years of age?

Population: U.S. children <2 years of age

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 years of age

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, PCV13 is recommended for routine use in all infants aged <2 years as a 4-dose series at ages 2, 4, 6, and 12–15 months. Catch-up vaccination is recommended through age 59 months for healthy children, and through age 71 months for children with 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 as an option for pneumococcal conjugate vaccination.

Problem

Public Health Problem
Criteria Work Group Judgement 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, the incidence of all-cause AOM was approximately 30,000 per 100,000 person-years in children aged 2–4 years, and 43,000 per 100,000 person-years in children aged <1 year (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, the incidence of all-cause pneumonia was the highest in children aged <5 years, ranging from 2,250 (aged <1 year) to 3,990 (aged 1 year) per 100,000 person-years (4).
  • According to National Inpatient Sample data, the incidence of hospitalized all-cause pneumonia in children aged <5 years ranged from 290 (children aged 2–4 years) to 680 (children aged <1 year) per 100,000 population.

Invasive pneumococcal disease

  • After PCV13 introduction in U.S. children in 2010, IPD rates in children aged <5 years decreased; in 2018–2019, the IPD rate was 7.2 per 100,000 population. This decrease was driven by PCV13+6C type IPD, which decreased by 89%, from 14.2 per 100,000 population in 2007-2008 to 1.6 per 100,000 population in 2018-.
  • IPD rates due to 2 additional serotypes included in PCV15 but not in PCV13 have been stable; in 2018–2019 these serotypes caused 17% of all IPD in children aged <5 years, while PCV13+6C types caused 21% of all IPD.
  • The estimated burden of pneumococcal pneumonia in children varies depending on the methods used for case ascertainment and the year of study.
  • The proportion of inpatient pneumonia due to pneumoniae in the EPIC study was estimated to be 3–4 % in children aged <18 years, though underdetection is a concern given that 20% of children did not have any pathogen detected (5).

Benefits and Harms

Benefits and Harms
Criteria Work Group Judgement Evidence Additional Considerations
How substantial are the desirable anticipated effects? Moderate
  • One Phase 2 (6) and three Phase 3 (7-9) randomized-controlled trials compared the immunogenicity of PCV15 to that of PCV13.

PCV15 vs PCV13 using a 3+1 schedule

  • In the Phase 2 proof of concept study (6) and the Phase 3 pivotal study (7) evaluating PCV15 use in children <2 years, PCV15 met noninferiority criteria compared to PCV13 for all 13 shared serotypes (post-dose 3 in both studies when assessing proportion of participants meeting IgG threshold value of >=0.35μg/mL [“% seroresponders”] and post-dose 4 when assessed by GMC ratio in the pivotal study). PCV15 met noninferiority criteria for 12 of 13 serotypes (all except 6A) when assessed by GMC ratio post-dose 3 in the Phase 3 pivotal study (7).
  • PCV15 had statistically significantly higher immune responses compared to PCV13 for serotype 3  and PCV15 unique serotypes (22F and 33F) when given as a 3+1 schedule (6, 9).

Mixed PCV15/PCV13 dosing vs. PCV13 only

  • Groups that received PCV15 (with or without PCV13) had higher IgG GMCs compared to the group that received PCV13 only for 2 to 7 shared serotypes

Sub-analysis

  • Sub-analyses were performed for two studies (V114-029, pivotal trial (7); V114-027, PCV13/PCV15 interchangeability study (8), both targeting healthy infants aged 42 to 90 days of age using 3+1 vaccination schedule). The sub-analyses excluded participants who received Pentavac, a pentavalent vaccine that is not licensed in the U.S., reducing the sample size by approximately 30%.

Sub-analyses findings did not differ substantially from the original findings, except for the analysis of concomitant use of mumps vaccine, in which the percentage point difference in mumps antigen for the PCV15 group versus the PCV13 group missed the non-inferiority criteria (observed lower bound of CI of -5.4, compared to the noninferiority margin of -5.0).PCV15 vs. PCV13 as Catch-up vaccination

  • PCV15 had higher IgG GMCs compared to PCV13 for 1 to 6 shared serotypes and PCV15 unique serotypes (22F and 33F)  (9).
  • Post licensure vaccine effectiveness data against pneumococcal disease exist for PCV13.
  • No PCV15 studies directly assessed clinical outcomes.
  • There are unknowns, such as the clinical implication of the improved immunogenicity against serotype 3. PCV15 provides protection against 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? Small
  • Safety data from phase 2 or 3 randomized-controlled trials (6-10)found that the percentage of subjects with serious adverse events was comparable among subjects who received PCV15 and PCV13 (2.3-13.3% in PCV15 group, 2.3-11.7% in PCV13 group). Four serious adverse events were associated with PCV15 use. One serious adverse event occurred after PCV13 use in a group that received a mixed PCV13 and PCV15 schedule.
  • Concerns for higher frequency of reactogenicity among the PCV15 recipients compared with PCV13 recipients, in particular, high fever (≥104◦F) post dose 4, were discussed during the February 2022 ACIP meeting.
  • 19/2772 (0.7%) of children who received a 4th dose of PCV15 and for whom temperature data were available developed fever of ≥104◦F post-dose 4, compared with 3/1312 (0.2%) children who received a 4th dose of PCV13; the difference was not statistically significant None of these children developed febrile seizures.
  • 4/19 children in the PCV15 group who developed ≥104◦F fever post-dose 4 had concurrent serious adverse events reported, but none were deemed to be associated with PCV15 use.
Do the desirable effects outweigh the undesirable effects? Favors both In comparing PCV15 with PCV13 for routine use in children aged <2 years, 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: Moderate
Safety of the intervention: Low
For critical outcomes, the certainty of evidence was moderate for effectiveness and low for safety of the intervention. Certainty of evidence for safety was downgraded twice due to imprecision based on fragility due to few events and a wide confidence interval crossing multiple decision thresholds.

Values

Values
Criteria Work Group Judgement 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 (11).
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 and safety of PCV15.
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 WG believed that there are 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 Work Group Judgement Evidence Additional Considerations
Is the intervention acceptable to key stakeholders? Probably yes
  • According to a survey of 600 HCP who prescribe/administer ≥10 pneumococcal vaccines per month (12),
    • 39% of respondents believed that the risk of pneumococcal disease is higher than that of other vaccine-preventable diseases (measles, mumps, rubella, rotavirus, chickenpox, diphtheria, tetanus, pertussis) in children aged <24 months
    • A larger proportion of respondents believed that unvaccinated children aged 0–12 months (vs. children aged 12 –24 months) were at high risk of developing invasive and non-invasive pneumococcal disease.
    • 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 Work Group Judgement Evidence Additional Considerations
Is the intervention a reasonable and efficient allocation of resources? Probably yes
  • Findings from two economic models (CDC, Merck), which used different methods, were reviewed.
  • In the base case, private cost was assumed to be less for PCV15 compared to PCV13, based on available cost for adults (13); PCV15 public cost was assigned a range from the current public price of PCV13 to 5% greater than public price of PCV13.
  • PCV15 and PCV13 were assumed to have the same vaccine effectiveness for disease caused by the 13 serotypes contained in PCV13.
  • The base case of both models showed that using PCV15 as an option for routine PCV vaccination for children was cost-saving.
  • Both models also included a one-way sensitivity analysis assuming a higher PCV15 public cost compared with PCV13, which showed that using PCV15 as an option for routine PCV vaccination for children was cost-saving.
  • Work Group members’ response were split between “Probably Yes” and “Yes”. Those who selected “Probably Yes” believed that there is uncertainty about the clinical efficacy of PCV15 (only immunogenicity data available), and the possibility of increased hospitalization among PCV15 recipients due to higher incidence of fever. Also, the actual price of PCV15 is unknown.

Equity

Equity
Criteria Work Group Judgement Evidence Additional Considerations
What would be the impact on health equity? Probably no impact Disease Burden
  • Compared with White children, Black children have higher invasive pneumococcal disease (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 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 Native American children in 2011–2018 have been >4 times higher compared with U.S. children of all races (14).
  • 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 (15).

Vaccine Coverage

  • In 2010–2012, foreign-born children aged 19–35 months had significantly lower pneumococcal vaccine coverage (46.4%) compared with U.S-born children (83.9%) (p<0.001) (16).
  • 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 (17).
  • 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) (18).
  • 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%) (19).
  • 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 on health equity compared with PCV13 use.

Feasibility

Feasibility
Criteria Work Group Judgement 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. Jain S, Williams DJ, Arnold SR, Ampofo K, Bramley AM, Reed C, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. The New England journal of medicine. 2015;372(9):835-45.
  6. Platt HL, Greenberg D, Tapiero B, Clifford RA, Klein NP, Hurley DC, et al. A Phase II Trial of Safety, Tolerability and Immunogenicity of V114, a 15-Valent Pneumococcal Conjugate Vaccine, Compared With 13-Valent Pneumococcal Conjugate Vaccine in Healthy Infants. The Pediatric infectious disease journal. 2020;39(8):763-70.
  7. Merck Sharp Dohme LLC. Safety, Tolerability, and Immunogenicity of V114 in Healthy Infants (V114-029). https://ClinicalTrials.gov/show/NCT03893448; 2019.
  8. Merck Sharp Dohme LLC. A Study to Evaluate the Interchangeability of V114 and Prevnar 13™ in Healthy Infants (V114-027/PNEU-DIRECTION). https://ClinicalTrials.gov/show/NCT03620162; 2018.
  9. Merck Sharp Dohme LLC. Safety and Immunogenicity of Catch-up Vaccination Regimens of V114 (V114-024). https://ClinicalTrials.gov/show/NCT03885934; 2019.
  10. Merck S, Dohme C. A Study to Evaluate the Safety and Tolerability of V114 and Prevnar 13™ in Healthy Infants (V114-031/PNEU-LINK) 2021 [updated March 26. Available from: https://ClinicalTrials.gov/show/NCT03692871.
  11. 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.
  12. Merck & Co. Inc. Healthcare Provider Preferences Related to Multi-Valent Pneumococcal Conjugate Vaccines. 2022.
  13. 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.
  14. 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.
  15. 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.
  16. Varan AK, Rodriguez-Lainz A, Hill HA, Elam-Evans LD, Yankey D, Li Q. Vaccination Coverage Disparities Between Foreign-Born and U.S.-Born Children Aged 19-35 Months, United States, 2010-2012. J Immigr Minor Health. 2017;19(4):779-89.
  17. Woinarowicz M, Howell M. Comparing vaccination coverage of American Indian children with White children in North Dakota. Public Health. 2020;186:78-82.
  18. 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.
  19. 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.