On the possible interaction between vaccines and drugs

Abstract

Dear Sirs, Reduction in the hepatic cytochrome P450 system activity has been described after a vaccination in previous studies [1, 2]. While the mechanism behind such reduction was explained as the consequence of the activity of inflammatory cytokines on the mRNA level of hepatic cytochromes [3], it is unclear what effect this interaction may have in the clinical practice. To date, only few reports describe significant changes in drug pharmacokinetics after the administration of a vaccine [4, 5], and small cohort studies reported contrasting results in patients treated with drugs that may be influenced by this interaction [6, 7, 10–12]. Moreover, it is unclear how the effects of vaccines on hepatic cytochrome P450 system activity affect patients who present risk factors such as age or genetic predisposition [1, 2]. To explore this issue further, we used the Vaccine Adverse Event Reporting System (VAERS) database, which collects information about adverse events following the administration of vaccines and is useful to detect rare vaccine-related adverse events [8]. We carried out a search of all reports consistent with a vaccine–drug interaction resulting in an adverse drug reaction, in a detectable increase of drug serum level, or in a change of drug-related biomarkers such as the International Normalized Ratio (INR). As the patients were treated with more than a single drug in many of the cases, we considered only those cases in which there was no mention of recent therapy variation, or there was an explicit statement about the absence of variations. As highlighted in Table 1, we retrieved and validated 28 reports. Among these, 12 were related to an increase of INR, and ten described an increase of serum level of phenytoin, carbamazepine and theophylline (Table 1). The remaining six cases described an adverse drug reaction attributed to an interaction between the vaccine and the drugs (Table 1). As expected, considering previous observations [1], we found that most of the cases occurred in elderly patients and within the first weeks after vaccine administration. Aitken et al. recently observed that human CYP2C8, 2C9, 2C18, 2C19, 2B6, and 3A4 mRNA expression is downregulated by inflammatory cytokines [3], which are also released as result of a vaccination [1, 2]. As one or more of these hepatic cytochromes metabolizes phenytoin, theophylline and carbamazepine, a reduction in their expression due to vaccination may explain the increased level of these drugs that we observed after vaccination. In agreement, other studies showed an increase in phenytoin serum level after vaccination with pertussis vaccine [10] and successive studies confirmed this finding in other drugs such as theophylline [11, 12]. The increased INR we observed with warfarin may also be explained by the vaccination. Warfarin is metabolized primarily by CYP2C9, and a reduction in the activity of this hepatic cytochrome may result in an increase of INR [9]. The reduced activity of this enzyme due to genetic polymorphisms [9], as well as the presence of other variants that may affect the cytokines response to vaccination, may create a subgroup of patients at higher risk for this interaction than the ones observed in our analysis. Paolo Pellegrino and Carla Carnovale contributed equally to this work.