The pneumococcal polysaccharide vaccine (PPV) does not reduce the rates of fatal and nonfatal acute coronary syndrome and
A historical animal trial from 2003 suggested mice immunized with Streptococcus pneumoniae homogenate triggered an increase in immunoglobulin M (IgM) levels, which cross-reacted with oxidized low-density lipoprotein (LDL), reducing atherosclerotic plaque. The development of these antibodies was, at the time, attributed to molecular mimicry between the phosphocholine moiety in the pneumococcal cell wall and an epitope on the oxidized LDL molecule.1
Because the PPV vaccine is purified from the same homogenate used in the animal trial, investigators questioned whether similar atheroprotective effects would be seen in humans via the vaccine. To this end, the Australian Study for the Prevention Through Immunization of Cardiovascular Events (AUSPICE) study was established to test this hypothesis.1
“The AUSPICE study was established as the first and only, to our knowledge, randomized clinical trial to date to specifically test the hypothesis that the 23-valent PPV (PPV23) decreases the incidence of major CVD events related to atherosclerosis, including fatal and nonfatal acute coronary syndromes and ischemic strokes,” Alexis Hure, PhD, a professor at the School of Medicine and Public Health at the University of Newcastle, and colleagues wrote.1
AUSPICE was a national, double-blind, placebo-controlled, parallel-arm trial recruiting at 6 centers across Australia. Participants were randomly selected from the Medicare database, which includes all Australians eligible for health care funding. Patients were included if they were aged 55-60 years and displayed 2 of the following 3 risk factors for cardiovascular disease: self-reported hypertension, self-reported hypercholesterolemia, and/or overweight/obesity.1,2
A total of 155,000 people were contacted, and 21,526 responded to the screening questionnaire. Of these, 16,801 were excluded, leaving 4725 participants to be randomized. Patients had a mean (standard deviation [SD]) age of 58 (1.7) years, and 52% (n = 2433) of patients were male.2
After confirming eligibility, investigators randomly assigned participants in a 1:1 ratio to either the active vaccine or placebo, both of which were given by intramuscular injection in the deltoid region. The active group received PPV23 at 0.5mL (25 µg). The control group received saline 0.9% in an identical syringe. Immediate (7-day) and medium term (28-day) adverse events of immunization were tracked using an online program.1
The total number of emergency presentations for the AUSPICE cohort from 2016 to 2023 was 5628, of which 116 were related to CVD. A total of 50 deaths were recorded for the cohort, only 6 of which were for a CVD event related to the trial. There was no difference noted in all-cause mortality (hazard ratio [HR], 1.08; 95% CI, 0.62-1.88; P = .79).1
Additionally, investigators found no difference in the primary endpoint of composite fatal and nonfatal cardiac and cerebral events, nor in the individual components of the composite. This was also seen in the survival curves (58 of 2366 events in the active PPV23 group vs 64 of 2357 in control; HR, 0.9; 95% CI, 0.63-1.28; P = .57). Secondary outcomes, including capturing surrogate measures of CVD, also showed no significant difference between active and control groups in oxidized LDL, anti-bodies, pulse wave velocity, or carotid intima-media thickness.1
Despite multiple prior similarly constructed observational studies highlighting a cardioprotective effect, this was not borne out in AUSPICE. Investigators attribute this in part to the trial being underpowered, with the actual CVD event rate being substantially lower than predicted by the Australian Cardiovascular Risk Calculator (14% predicted, 3.4% actual).1
“In this randomized clinical trial, PPV23 did not reduce the rates of fatal and nonfatal acute coronary syndrome and ischemic stroke,” Hure and colleagues wrote. “The study was underpowered to definitively test this hypothesis and should be confirmed in larger prospective trials.”1
References
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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. Published online September 17, 2025.
doi:10.1001/jamacardio.2025.3043 -
Peel R, Ren S, Hure A, et al. Evaluating recruitment strategies for AUSPICE, a large Australian community-based randomised controlled trial. Med J Aust. 2019;210(9):409-415.
doi:10.5694/mja2.50117