A narrative review of immune-mediated adverse events in clinical trials of CpG oligonucleotide toll-like receptor 9 agonists

There is a concern that stimulating the innate immune system with vaccine adjuvants could, hypothetically, lead to autoimmunity; however, evidence is lacking to support these concerns. We review and evaluate immune-mediated adverse events from three sets of clinical studies using toll-like receptor 9 (TLR9) agonists (CpG-ODN) as vaccine adjuvants and therapeutic agents in patients with cancer: 1) a comparison of immune-mediated adverse events across phase 1-3 clinical trials of the hepatitis B vaccine HEPLISAV-B (HepB-CpG) with the alum-adjuvanted hepatitis B vaccine (HepB-alum); 2) an analysis of the rates of immune-mediated adverse events across clinical trials of COVID-19 vaccines using the CpG 1018 adjuvant; and 3) the rates of immune-mediated conditions in a study of the CpG-ODN nelitolimod (SD-101) combined with the immune checkpoint inhibitor pembrolizumab in patients with advanced melanoma or head and neck cancer, compared with rates in historical studies of pembrolizumab monotherapy. In the current analysis, the rate of potential immune-mediated adverse events was similar for HepB-CpG (0.32%) and HepB-alum (0.38%). Few adverse events of special interest (including immune-mediated events) were observed with any of the CpG 1018-adjuvanted COVID-19 vaccines (0-2.1% across studies), and rates were similar to placebo (0.6-3.3%). The rate of immune-mediated events for patients who received nelitolimod and pembrolizumab was 21.8% versus 19.8% for those who received pembrolizumab alone. No increased risk of potential immune-mediated adverse events was observed with HepB-CpG or CpG 1018-adjuvanted COVID-19 vaccines. In patients with cancer treated with programmed cell death protein 1 blockade, repeated treatment with nelitolimod did not increase the frequency of such events. Data evaluated in this review show no increased risk for potential autoimmune disorders with HepB-CpG or CpG 1018-adjuvanted COVID-19 vaccines. Combining CpG-ODN with a checkpoint inhibitor did not increase the rate of immune-mediated conditions.