New-Age Vaccine Adjuvants: Friend or Foe? - A major unsolved challenge in adjuvant development is how to achieve a potent adjuvant effect while avoiding reactogenicity or toxicity - BioPharm

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New-Age Vaccine Adjuvants: Friend or Foe?
A major unsolved challenge in adjuvant development is how to achieve a potent adjuvant effect while avoiding reactogenicity or toxicity


BioPharm International


The mechanism for alum's tendency to stimulate eosinophilia and enhance IgE production is unknown, but its consequence is an increased risk of vaccine allergy and anaphylaxis.9,16,18,19 This potential has been demonstrated in animal models of ovalbumin-induced asthma or anaphlylaxis, which are dependent on alum in the initial priming. In humans, there have been reports of a chronic inflammation syndrome called macrophagic myofascitis (MMF) being induced by alum-based vaccines.20 The original description of the syndrome was based on a group of patients with presumptive diagnoses of myopathy mimicking polymyositis. Symptoms included myalgias, arthralgias, marked asthenia, muscle weakness, and fever. Abnormal laboratory findings included elevated CK levels, increased ESR, and myopathic EMG, with muscle biopsies showing infiltration by sheets of macrophages with granular periodic-acid-Schiff positive content. The syndrome is due to the persistence of vaccine-derived aluminum at vaccine injection sites in the muscle, causing a chronic inflammatory reaction.21 Since its original description in 1993,22 more than 200 cases of MMF have been described in multiple countries.23 Neurological manifestations resembling multiple sclerosis have been reported in some patients.24 Children with MMF present with hypotonia and motor or psychomotor delay. A conclusive diagnosis is made by showing an aluminum peak in the lesion by energy-dispersive X-ray microanalysis. When Cynomolgus monkeys were immunized in the quadriceps muscle with diphtheria–tetanus vaccine, histopathological lesions similar to MMF in humans were observed up to three and 12 months after aluminum phosphate and aluminum-hydroxide-adjuvanted vaccine administration, respectively.25 Aluminum is widely used as an adjuvant in human vaccines, and children can receive up to 3.75 mg of parenteral aluminum during the first six months of life. Intraperitoneal injection of aluminum-adsorbed vaccines in mice causes a transient rise in brain tissue aluminum levels peaking around day. 2–3 It is likely that aluminum is transported to the brain by the iron-binding protein transferrin and enters the brain via specific transferrin receptors.26 Of major concern is the finding in cats of feline fibrosarcomas at the site of aluminum-adjuvanted vaccination. The tumors are sometimes surrounded by lymphocytes and macrophages that have taken up aluminum (with lesions identical to MMF), leading to the hypothesis that persistent inflammatory and immunological reactions associated with aluminum derange fibrous connective tissue repair responses, leading to neoplasia.27

Oil-in-Water Emulsions

General mechanism of action. Oil-in-water emulsions include Montanide, Adjuvant 65, and Lipovant.28 (MF59, also an oil-in-water emulsion, is discussed separately below.) Oil-in-water particles are irritants and cause local inflammation, inducing a chemotactic signal that elicits local macrophage invasion. The oil particles, along with associated antigen, are rapidly ingested by macrophages, which traffic to the draining lymph node. Because of frequent adverse reactions, the major human use of oil-in-water emulsions has been in therapeutic cancer and HIV vaccines29 although Adjuvant 65 was previously used in a prophylactic influenza vaccine. Montanide adjuvants are variously formulated as water in oil, oil-in-water, or water in oil-in-water emulsions.30,31 The water-in-mineral-oil adjuvant Drakeol/ISA-51 has been used in HIV-infected individuals.32 Water-in-squalene emulsion (ISA-720) has been evaluated in a malaria vaccine trial.31 Although potent, such adjuvants induced severe local reactions in some recipients.33,34 Emulsions have also been used as delivery systems for immunostimulatory adjuvants, including MPL and QS21. An oil-in-water emulsion containing MPL and QS21 (SBAS-2) induced protection in a mouse model of malaria equivalent to that seen with CFA35 and was subsequently shown to confer short-lived protection in a malaria challenge in human volunteers, though with a high reactogenicity profile.36 In trials with a HIV vaccine, SBAS-2 induced high antibody titers and proliferative but not CTL responses.37


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