ISRs (redness, swelling, and soreness at the injection site) are typical 1–2 days following immunization. A delayed start of ISRs was also reported after administration of toxoid vaccinations, particularly diphtheria toxoid. The start of ISRs over 14 days was investigated in 8 adult trials with 19 cohorts because the serotype capsular polysaccharides in the 13-valent pneumococcal conjugate vaccination (PCV13) are conjugated to cross-reactive material 197 (CRM197), a harmless variation of diphtheria toxin. PCV13 with aluminum phosphate (AlPO4, n=5667) or without AlPO4 (n=304) was administered to patients, and 1097 got a 23-valent pneumococcal polysaccharide vaccination (PPSV23). 

Late ISRs with onset between days 6–14 were observed in 8/8 cohorts aged greater than or equal to 65 after PCV13 with AlPO4 (incidence across cohorts for redness, 2.3% -19.6%; swelling, 0.9% -10.8%; pain, 1.6% -10.0%) and in 1 out of 1 cohort after PCV13 without AlPO4 (redness, 10.5%; swelling, 7.5%; pain 12.3%); and in 2 out of 4 cohorts aged 50 to 64 (redness 3.1% -4.8%; swelling 1.0% -3.2% ; pain 3.7%-5%). Late ISRs were not seen in 1 out of 1 cohort aged 18 to 49 after PCV13, 2 out of 2 cohorts equal and above 53 years after PCV13 revaccination, and 3 out of 3 cohorts greater than or equal to 60 years of age who got PPSV23, which did not include CRM197. Post-hoc analysis revealed that subgroups with late ISRs had larger pneumococcal immune responses quantitatively than those without.

In conclusion, the cause of late ISRs was likely multifaceted, with aging and the PCV13 carrier protein CRM197 perhaps playing a role. The adjuvant vaccination AlPO4 did not appear to be causally connected. The observations did not affect PCV13’s positive risk-benefit profile.