Infectious Disease · Medical Literature
Comparative Efficacy and Safety of 15-Valent and 13-Valent Pneumococcal Conjugate Vaccines Alone and in Combination with the 23-Valent Polysaccharide Vaccine: A Systematic Review and Meta-analysis.
Abstract
In addition to the 23-valent pneumococcal polysaccharide vaccine (PPSV23), the 13-valent and 15-valent pneumococcal conjugate vaccines (PCV13 and PCV15, respectively) are currently utilized as optional vaccines for adults. Although PCV15 provides broader serotype coverage than PCV13, comparative evidence regarding their immunogenicity, safety, and optimal clinical application remains limited. This systematic review and meta-analysis evaluated the immunogenicity and safety of PCV13 and PCV15, both as monotherapy and in combination with PPSV23. We conducted a comprehensive systematic search of PubMed, the Cochrane Library, Web of Science, and ClinicalTrials.gov for randomized controlled trials (RCTs) published through September 15, 2023. Eligible studies included those comparing PCV13 and PCV15, as well as their respective sequential schedules with PPSV23, in adults. Outcomes included opsonophagocytic activity geometric mean titer ratios (OPA GMTRs), immunoglobulin G geometric mean concentration ratios (IgG GMCRs), and adverse event incidence. Risk ratios and 95% confidence intervals were calculated using the inverse variance-weighted method and DerSimonian-Laird random-effects model. Six RCTs (n = 6460) comparing PCV13 and PCV15 monotherapy demonstrated significantly higher OPA GMTRs and IgG GMCRs for the six shared serotypes in the PCV15 group. Injection-site pain and myalgia were more common with PCV15, whereas other adverse events showed no differences. Three RCTs (n = 2279) comparing PPSV23/PCV13 with PPSV23/PCV15 demonstrated higher immune responses for several serotypes in the PPSV23/PCV15 group, with comparable safety profiles. Overall, PCV15 provides broader serotype coverage and elicits robust immunogenicity while maintaining a safety profile comparable to that of PCV13, whether administered as monotherapy or in sequential vaccination with PPSV23.
Clinical relevance
In adults, does PCV15 demonstrate superior immunogenicity and a comparable safety profile relative to PCV13, whether administered as monotherapy or in sequential combination with PPSV23? __SNAPSHOT__ {"studyDesign":"Systematic review and meta-analysis of randomized controlled trials (RCTs); DerSimonian-Laird random-effects model with inverse variance-weighted method","setting":"Multinational; databases searched: PubMed, Cochrane Library, Web of Science, ClinicalTrials.gov; literature search through September 15, 2023. Authors affiliated with Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan","sampleSize":"Monotherapy arm: 6 RCTs (n = 6,460); Sequential vaccination arm (PPSV23/PCV15 vs. PPSV23/PCV13): 3 RCTs (n = 2,279); Total participants across all included trials: not reported as a single aggregate figure in the abstract","population":"Adults eligible for pneumococcal vaccination; specific age thresholds, comorbidity profiles, and prior vaccination status varied across included RCTs and are not individually specified in the abstract","intervention":"PCV15 monotherapy; or sequential vaccination with PPSV23 followed by (or preceded by) PCV15","comparator":"PCV13 monotherapy (monotherapy arm); sequential PPSV23/PCV13 (combination arm)","primaryOutcome":"Immunogenicity assessed by opsonophagocytic activity geometric mean titer ratios (OPA GMTRs) and immunoglobulin G geometric mean concentration ratios (IgG GMCRs) across shared serotypes; safety assessed by adverse event incidence (risk ratios with 95% CIs)","followUp":"Not reported in the abstract","fundingSource":"Not reported in the abstract"}
Key findings
Monotherapy comparison (6 RCTs; n = 6,460): PCV15 demonstrated significantly higher OPA GMTRs and IgG GMCRs for six shared serotypes relative to PCV13. Specific GMTR or GMCR point estimates, confidence intervals, and p-values for individual serotypes were not reported in the abstract. Regarding safety in the monotherapy arm, injection-site pain and myalgia occurred more frequently with PCV15; all other adverse events showed no statistically significant differences between groups. Specific risk ratios and confidence intervals for these adverse events were not reported in the abstract. Sequential vaccination comparison (3 RCTs; n = 2,279): The PPSV23/PCV15 sequential schedule demonstrated higher immune responses for several serotypes compared with PPSV23/PCV13. Specific serotypes, GMTR magnitudes, and confidence intervals were not reported in the abstract. The safety profiles of the two sequential schedules were described as comparable, with no additional specification of adverse event frequencies. No NNT or NNH was calculable from the abstract. No clinical endpoints (invasive pneumococcal disease, pneumonia, hospitalization, or mortality) were reported.
Practice implications
This meta-analysis establishes that PCV15 elicits superior immunogenicity compared with PCV13 across shared serotypes in adults, both as monotherapy and as part of sequential vaccination with PPSV23, while maintaining a broadly comparable safety profile—with the exception of modestly higher rates of injection-site pain and myalgia with PCV15 monotherapy. The two additional serotypes unique to PCV15 (22F, 33F) provide broader coverage than PCV13, which may be clinically relevant in settings where these serotypes contribute meaningfully to invasive pneumococcal disease burden. However, several important limitations constrain interpretive scope: (1) all outcomes are immunological surrogates; no clinical efficacy endpoints (IPD incidence, pneumococcal pneumonia, hospitalization, or mortality) were evaluated or reported, and the OPA GMTR has not been definitively correlated with clinical protection in adults; (2) the abstract does not report serotype-specific GMTR values, confidence intervals, or p-values, precluding independent assessment of the magnitude and precision of effect; (3) only the abstract was reviewed—full-text analysis including subgroup data, heterogeneity statistics, risk-of-bias assessments, and sensitivity analyses is unavailable to this reviewer; (4) the applicability to immunocompromised adults, prior PPSV23 recipients, and specific high-risk subgroups (e.g., HIV, asplenia, organ transplant) is unclear; (5) the absence of a PCV20 comparator is a notable gap given current guidelines that position PCV20 as an alternative single-agent strategy. Practice should not change on the basis of this meta-analysis alone; however, these findings are consistent with and supportive of current guideline frameworks (e.g., ACIP) that include PCV15 + PPSV23 as an acceptable adult pneumococcal vaccination strategy. __LIMITATIONS__ All endpoints are immunological surrogates (OPA GMTRs, IgG GMCRs); no clinical efficacy or effectiveness data against IPD, pneumococcal pneumonia, hospitalization, or death were reported.,Abstract-only review: serotype-specific effect sizes, confidence intervals, heterogeneity (I²) statistics, and risk-of-bias assessments are not available to this reviewer.,No comparison against PCV20, limiting guidance for clinicians choosing among currently available adult conjugate vaccines.,Number of included RCTs is small (6 for monotherapy; 3 for sequential schedules), limiting statistical power for subgroup analyses.,Participant-level characteristics (age distribution, comorbidities, immune status, prior vaccination history) were not specified in the abstract, constraining generalizability.,Literature search cut-off of September 15, 2023, may exclude more recent trial data.,Funding source is not disclosed in the abstract; potential conflicts of interest cannot be evaluated.,Heterogeneity across included trials is expected given differing patient populations, geographic settings, and vaccination schedules, but I² values were not reported in the abstract.,No duration-of-protection or waning immunity data are available.,The clinical significance of OPA GMTR differences between PCV15 and PCV13 remains uncertain, as no established OPA threshold for protection against pneumococcal disease exists in adults. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ This systematic review and meta-analysis of RCTs demonstrates that PCV15 elicits significantly higher immunogenicity than PCV13 for shared serotypes in adults, both as monotherapy and in sequential combination with PPSV23, with a generally comparable safety profile except for modestly more injection-site pain and myalgia with PCV15 alone. These findings support the immunological rationale for PCV15-based adult pneumococcal vaccination strategies but do not establish clinical superiority, as no hard endpoints (IPD, pneumonia, or mortality) were assessed. Clinicians should interpret these results as immunogenicity-level evidence consistent with current guideline recommendations, while awaiting post-licensure effectiveness data to confirm clinical benefit relative to PCV13 and PCV20.