Evidence to Recommendations for PCV20 use among adults 19-64 years old

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invasive pneumococcal disease (IPD) incidence due to PCV13-types in both adults with CMC and IC aged 19–64 years (ABCs unpublished data). Nonetheless, 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 to 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 higher and among those with IC was 11–18 times higher than adults without these conditions [4].

• PCV20 vs PCV13 (13 shared serotypes)

One Phase 2[5] and two Phase 3[6, 7] randomized-controlled trials compared the immunogenicity of PCV20 vs. PCV13 against the 13 shared serotypes.

In the phase 2 study targeting adults aged 60–64 years and the phase 3 studies, geometric mean titer (GMT) was lower among adults receiving PCV20 vs. PCV13 in 12-13/13 shared serotypes. GMT was significantly lower in 4/13 serotypes (no overlap in GMT confidence intervals) in the Phase 2 study[5], and 3-5/13 serotypes in the Phase 3 studies (range reflects differences in results across studies), although non-interiority criteria was met for all 13 common serotypes in the Phase 3 studies[6, 7]. %  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 significant for serotype 3 in one phase 3 study and for serotypes 1, 5, and 19F in another phase 3 study[6, 7].

• PCV20 vs PPSV23 (7 shared serotypes)

One Phase 2[5] and one Phase 3[6] randomized-controlled trials provided comparison on the immunogenicity of PCV20 vs PPSV23 against the 7 shared serotypes.

Compared to PPSV23, GMT was higher in PCV20 for 6/7 common serotypes in both studies; GMT was significantly higher in 3/7 serotypes in the Phase 2 study, although significantly lower in serotype 8 (GMT confidence intervals did not overlap). In the Phase 3 study, noninferiority criteria was met for 6/7 serotypes, but not for serotype 8 (significantly lower). % seroresponders was higher in 6/7 serotypes in both studies (significant for all serotypes in the Phase 3 study and for 2/7 serotypes in the Phase 2 study) and lower in serotype 8 (significant in the Phase 3 study only).

• PCV20 in 18–49 years vs 60–64 years

A Phase 3 study [6] compared the immunogenicity of PCV20 in adults aged 18–49 years compared to adults aged 60–64 years; compared to adults aged 60–64 years, GMT was higher (significant for serotype 14), and met the noninferiority criteria for all 20 serotypes. % seroresponders was higher in 18/20 serotypes (significantly higher in 11/20 and lower in 1/20) in adults aged 18–49 years.

• PCV20 vs PCV13+PPSV23 (13 shared serotypes)

A Phase 2 study [5] provided data on GMTs one month after PCV20 administration vs. one month after PPSV23 administration (given as the second dose of the PCV13-PPSV23 series). GMT was lower in PCV20 in all serotypes (significant in 9/13 serotypes).

• Proportion of pneumococcal disease that are contained in PPSV23 but not in PCV20

The proportion of IPD due to PPSV23-non-PCV20 types in adults with CMC or IC aged 19–64 years was 12–13% of all IPD in 2017–2018 (ABCs unpublished data).

According to NHIS 2017–2018 data, the proportion of adults with CMC and IC among all adults aged 18–64 years was 39% and 4%, respectively. Given that adults with CMC were recommended to receive PPSV23 only, the largest impact of recommending PCV20 is estimated to come from adults with CMC, assuming that PCV20 has better vaccine effectiveness against disease (especially vaccine-type pneumococcal pneumonia) compared to PPSV23.

• No PCV20 studies directly assessed the critical outcomes.
• No PCV20 studies specifically targeted adults with IC or CMC.
• While immunogenicity of PCV20 tended to be lower compared to PCV13 for the 13 shared serotypes, both Phase 3 trials met the non-inferiority criteria. Additionally, indirect effects from pediatric PCV13 vaccinations reduced PCV13 disease burden in both adults with CMC (no PCV13 recommendation) and IC (with PCV13 recommendation). The direct benefit of PCV13 vaccination in adults with IC is unknown.
• On the other hand, PCV20 had higher immunogenicity compared to PPSV23 for 6/7 serotypes (except serotype 8) that are not included in PCV13.
• Some expressed concerns that four fewer serotypes covered by PCV20 compared to PPSV23.
• The Work Group believed that a simplified recommendation with a single vaccine would increase vaccine coverage and would have the potential to prevent more disease than existing recommendations.

Conclusion:

Despite uncertainties about the clinical significance of lower immunogenicity of PCV20 compared to PCV13, and the impact of using PCV20 only against disease caused by PPSV23-nonPCV20 types, the Work Group believed that the potential benefit from PCV20 use is large compared to existing recommendations.

Safety of the intervention is Level 2 (Moderate)

• Overall evidence type was 3 for vaccine effectiveness.
  • Assessment on indirectness was downgraded to “very serious”:
    • Only immunogenicity studies were available. Correlates of protection have not been established for PCV20 in adults.
    • No studies specifically targeted adults with CMC or IC

• Overall evidence type was 2 for serious adverse events.

Assessment on imprecision was downgraded to “serious” because there were no vaccine-related serious adverse events reported in studies with relatively low sample sizes.

One online cross-sectional survey conducted in March–April, 2019 was identified [8]. 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 respondents indicated that pneumococcal vaccines were offered to them, 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 ever reporting hesitancy or resistance, 77% were hesitant or reluctant to the influenza vaccine, and 27% for the pneumococcal vaccine. The common reasons for hesitancy (for any vaccines) were:

• Not knowing it was needed (36%)
• Fear of needles (29%)
• Concerns about safety (24%)

The odds of vaccine hesitancy or resistance was greater in:

• Minorities (OR: 1.6)
• Those believing others like them do not get vaccinated (OR: 1.8)
• Those recalling negative media about vaccines (OR: 2.6)

None of these studies assessed values on use of PCV20 or values on single vs. series administration, and the findings may not be generalizable to the US population.

• Preference for a simplified pneumococcal vaccine recommendation
• Mixed responses on use of PCV in series with PPSV23. In one survey [14], 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 [12], a single pneumococcal vaccination was preferred over a sequential regimen for all, primarily due to convenience for patients [13].
• With a sequential regimen, concerns related to implementation (e.g., challenges in determining pneumococcal vaccination history, increased changes of dosing errors), communication, and series completion especially in hard-to-reach population were expressed [13].
• Immunogenicity and additional coverage of residual invasive disease burden were given the highest scores in one survey when respondents were asked to score their preference between different hypothetical vaccines with different attributes [12].

• Serotype specific vaccine effectiveness assumptions
• Transitions to higher levels of disease risk for individuals in the model who start at lower risk status
• Specification of the comparator strategy (existing recommendations, or PCV20 use at age 65)

Given the findings from the CDC model on the combined impact of the risk- and age-based use of PCV20, the Work Group determined that the intervention is a reasonable and efficient allocation of resources.

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

• 25% were vaccinated within 1 year of CMC/IC diagnosis
• Odds of vaccination were lower in:
  • Areas of higher poverty (OR: 0.14)
  • Areas with limited internet access (OR:0.14)
  • Adults not receiving a seasonal influenza vaccine (OR: 0.05)
• Time to vaccination was longer in rural communities and communities with less internet access.