PPV23 Vaccination Found to Not Reduced Cardiovascular Risk

Vaccination with pneumococcal polysaccharide vaccine 23 (PPV23) was not clearly associated with a reduced risk of acute coronary syndrome (ACS) events, stroke, or all-cause mortality, according to a meta-analysis published in JACC: Advances.¹

The analysis pooled data from 2 randomized controlled trials and 4 propensity-adjusted observational cohort studies—6 studies in total—using both Bayesian and frequentist random-effects models. Investigators searched MEDLINE, Embase, and the Cochrane Library (CENTRAL) from inception to October 10, 2025, without restrictions on publication date, status, or language.¹

About the Review and Outcomes

The review, registered with the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251266356), screened 5184 records after removing 1677 duplicates, then reviewed 89 full-text articles before settling on 6 eligible studies drawn from 8 reports. Included studies enrolled adults 18 years and older without active cancer, HIV, or other immunocompromising conditions, compared PPV23 with the placebo or no vaccination, and reported adjusted hazard ratios for stroke, ACS events, or all-cause mortality with at least 12 months of follow-up.¹

The 6 studies were conducted in Australia, Japan, Spain, Canada, and the United States, with follow-up ranging from about 1 to 7 years. Two reviewers independently extracted data and assessed risk of bias, using the Cochrane Risk of Bias 2 tool for the randomized trials and the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool for the cohort studies. Disagreements were resolved through panel discussion.¹

Five study-level estimates contributed to the ACS analysis, producing a Bayesian pooled HR of 0.87 (95% CrI, 0.64-1.14), corresponding to an 85% posterior probability of any directionally favorable association and a 38% posterior probability of an investigator-defined moderate benefit (HR <0.85). The frequentist pooled estimate was similar, at 0.86 (95% CI, 0.66-1.11; P = .24; I2 = 74%).¹

For stroke, based on three study-level estimates, the Bayesian pooled HR was 1.10 (95% CrI, 0.83-1.48), with only a 19% posterior probability of benefit; the frequentist HR was 1.10 (95% CI, 0.96-1.26; P = .17; I2 = 16%).¹

For all-cause mortality, drawn from five studies, the Bayesian pooled HR was 1.02 (95% CrI, 0.83-1.29), with a 45% posterior probability of benefit; the frequentist HR was 1.01 (95% CI, 0.85-1.19; P = .94; I2 = 0%). Certainty of evidence, rated using GRADE, was low for all three outcomes, driven largely by the predominantly observational evidence base and substantial heterogeneity between studies.¹

Underpowered Trial and More Favorable Older Data

The most directly relevant randomized trial in the pooled analysis, the Australian Study for the Prevention Through Immunization of Cardiovascular Events (AUSPICE), independently illustrates the uncertainty. In that double-blind, placebo-controlled trial, 4725 community-dwelling adults aged 55 to 60 years with at least 2 of 3 cardiovascular risk factors (obesity, hypertension, or hypercholesterolemia) were randomized to PPV23 or saline and followed for a median of 7.0 years.²

The composite primary outcome of fatal or nonfatal myocardial infarction or ischemic stroke occurred in 58 of 2366 participants in the vaccine group compared with 64 of 2357 in the placebo group (HR, 0.90; 95% CI, 0.63-1.28; P = .57), and there were no significant differences in all-cause mortality or other exploratory outcomes. The trial's investigators noted the anticipated 5-year event rate of 14% was far higher than the 3.4% actually observed, leaving the trial underpowered to detect a true effect.²

That contrasts with earlier observational literature. A 2020 systematic review and meta-analysis of 18 studies and 716,108 participants found PPV23 vaccination was associated with a reduced risk of any cardiovascular event (RR, 0.91; 95% CI, 0.84-0.99) and myocardial infarction (RR, 0.88; 95% CI, 0.79-0.98) across all ages, with the effect reaching significance only in adults 65 years and older, along with reduced all-cause mortality (RR, 0.78; 95% CI, 0.68-0.88). That review did not find a significant reduction in cerebrovascular events.³

The JACC: Advances authors noted this kind of favorable observational signal may reflect residual confounding and healthy-adherer bias, since people who seek out vaccination often differ systematically from those who do not in health-seeking behavior, access to care, and comorbidity burden.¹

What It Means for Pharmacists

The authors were careful to note that their findings are specific to PPV23 and should not be extrapolated to pneumococcal conjugate vaccines, including the 20-valent and 21-valent formulations that are increasingly replacing PPV23 in adult immunization schedules and do not require a follow-up PPV23 dose. They also emphasized that pneumococcal vaccination's established role in preventing invasive pneumococcal disease and its associated morbidity and mortality is unaffected by these results.¹

For pharmacists counseling patients on cardiovascular risk reduction, the message is one of unresolved uncertainty rather than confirmed benefit or harm. The authors concluded that current evidence remains insufficient to establish a cardiovascular benefit of PPV23 and that adequately powered trials are still needed before PPV23 can be considered part of a cardiovascular prevention strategy rather than solely an infectious-disease prevention tool.¹

REFERENCES

1. Pinilla J, Coy Z, Baral B, et al. PPV23 Vaccination and Risk of Cardiovascular Events: A Meta-Analysis. JACC Adv. Published online August 17, 2026. doi:10.1016/j.jacadv.2026.103134

2. Hure A, Peel R, D'Este C, et al. Prevention of Adverse Cardiovascular Events Using the 23-Valent Pneumococcal Polysaccharide Vaccine: A Randomized Clinical Trial. JAMA Cardiol. 2025;10(11):1112-1120. doi:10.1001/jamacardio.2025.3043

3. Marra F, Zhang A, Gillman E, Bessai K, Parhar K, Vadlamudi NK. The protective effect of pneumococcal vaccination on cardiovascular disease in adults: A systematic review and meta-analysis. Int J Infect Dis. 2020;99:204-213. doi:10.1016/j.ijid.2020.07.038