Vaccine safety is a topic of concern for the treated individual, the family, the health care personnel, and the others involved in vaccination programs as recipients or providers. Adjuvants are necessary components to warrant the efficacy of vaccines, however the overstimulation of the immune system is also associated with adverse effects. Local reactions are the most frequent manifestation of toxicity induced by adjuvanted vaccines and, with the exception of the acute phase response (APR), much less is known about the systemic reactions that follow vaccination. Their low frequency or subclinical expression meant that this matter has been neglected. In this review, various systemic reactions associated with immune stimulation will be addressed, including: APR, hypersensitivity, induction or worsening of autoimmune diseases, modification of hepatic metabolism and vascular leak syndrome (VLS), with an emphasis on the mechanism involved. Finally, the authors analyze the current focus of discussion about vaccine safety and opportunities to improve the design of new adjuvanted vaccines in the future. (C) 2014 Elsevier B.V. All rights reserved.UNESPCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Med Sci Univ, Toxicol & Biomed Ctr TOXIMED, Immunotoxicol Lab, Santiago De Cuba 90400, CubaUniv Estadual Paulista, UNESP, Fac Pharmaceut Sci, BR-14801902 Araraquara, SP, BrazilCAPES PVE Brasil Grant, Foreigner Visiting Prof Program, Araraquara, BrazilUniv Med Sci Havana, Inst Preclin & Basic Sci ICBP Victoria de Giron, Dept Immunol, Havana, CubaUniv Estadual Paulista, UNESP, Fac Pharmaceut Sci, BR-14801902 Araraquara, SP, Brazil