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

• 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.

• 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 4^th 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.

• 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).

• 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.

• 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.

• 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.

• 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.

• 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.