Vaccine–Drug Interactions: Cytokines, Cytochromes, and Molecular Mechanisms

Abstract

Vaccinations are recommended throughout life to reduce the risk of vaccine-preventable diseases and their sequelae. Vaccines are often administered in patients with chronic diseases who are likely to be treated with several drugs. A growing number of clinical observations have indicated the possibility of interactions between vaccines and drugs, leading to changes in drug metabolism after vaccination. These interactions represent a significant concern because of the increasing use of vaccines in older patients who are likely to be treated with several drugs. Because of the possible implications of adverse reactions in terms of public health, several studies were performed to verify the risk posed by these interactions and to clarify the biologic mechanisms that drive these events. Of the several mechanisms proposed to be at the basis of vaccine-drug interactions, the most convincing evidence suggests a role of inflammatory cytokines on the regulation of specific cytochrome P450 enzymes in the liver. Differences in the cytochrome P450 enzymes involved in the metabolism of these drugs could explain these contrasting results and provide important insights to fully understand the clinical importance of these events. Further studies are required to verify whether vaccine-drug interactions may occur in other clinical settings, especially the ones for which patients are required to be vaccinated against specific diseases.

Current trends in drug metabolism and pharmacokinetics

“…Another indirect pharmacokinetic DDI mechanism is cytokine–CYP modulation. Several biologics with immunomodulatory effects may alter CYP activities via modulating the cytokine levels leading to the altered PK of co-administered small molecules that are substrates of the affected CYPs 159 , 163 , 166 . For instance, tocilizumab, which can induce CYP3A4 activity by decreasing interleukin 6 levels, was found to reduce simvastatin systemic exposure 167 .…”

Drug metabolism in the elderly: A multifactorial problem?

“…Upsurges in inflammatory activity have been observed in the earliest phases of dementia including Alzheimer's disease, and also in type 2 diabetes and Metabolic Syndrome as well as with chronic obstructive pulmonary disease and during bouts of rheumatoid and osteoarthritis. Such situations may compromise the ADME enzymes and inflammation has been shown both in vivo and in vitro to regulate the CYP isoforms which carry out Phase I metabolism [29]. Phase II metabolism may also be affected; the sulfation pathway is known to be reduced in inflammation, probably by the release of cytokines [30] whilst in vitro studies suggest that formation of glucuronide and glutathione metabolites may be reduced [31].…”

No signal of interactions between influenza vaccines and drugs used for chronic diseases: a case-by-case analysis of the vaccine adverse event reporting system and vigibase

“…INF, along with proinflammatory cytokines such as IL-10, has been reported to reduce the activity of several CYPs relevant to drug metabolism both in vivo and in vitro [47][48][49][50][51][52]. This support the notion that vaccines against influenza may influence drug metabolism, in a small number of susceptible patients, leading to significant changes in serum concentrations of drugs [4][5][6][7][8]12,[16][17][18][19][20][21][22][23][24][25][26][27]. This is the first study investigating the potential interactions between influenza vaccines and drugs used for chronic diseases in clinical practice, by assessing spontaneous reports submitted to VAERS and Vigibase, the largest archives on post-marketing vaccines safety.…”

“…In these cases, the AEs occurred within the first week after vaccine administration, i.e. the estimated time interval within which the vaccine may induce dysregulation of inflammatory cytokines (including IFNc, IL-6, IL-10) on CYPP450 regulation [4][5][6][7]26]. In cases with no causal correlation there was no plausible temporal relationship and/or patients had taken other drugs or had comorbidities (e.g., diabetes, renal impairment) potentially involved in the events of interest; 4) although current seasonal influenza virus vaccines possess very low reactogenicity and systemic effects, the inactivated, split-virus vaccine was the type of influenza virus vaccines mostly reported in our analysis (68 reports; 58.6%; data not provided in (41.3%), in line with literature data [5,8,18,19,[23][24][25].…”