mink and ferrets (Shen et al., 1981) examined combined vaccination with live distemper virus, inactivated mink virus enteritis, and type C botulinum toxoid vaccine. Good protection was afforded to all antigens, and the authors did not mention any adverse effects. In guinea pigs, a comparative study was done to assess the efficacy of a protective antigen anthrax vaccine, either alone or in combination with a pertussis vaccine (Turnbull, 1990). The authors did not mention adverse effects from administration of either vaccine. Studies by Ramyar and Baharsefat (1969) in sheep indicated that the administration of the anthrax live spore vaccine in combination with sheep pox virus with saponin resulted in local skin reactions. Adverse effects occurred at the same rate for animals vaccinated with both anthrax and pox virus compared to each vaccination alone.

Adverse immunological reactions. Repeated exposure to the same antigen (Hyperimmunization). Studies in experimental animals have shown that repeated or large-dose injection with a single antigen may result in adverse health effects in animals. These hyperimmunization studies have been conducted only in animals, and it is not known whether the much smaller doses of antigen normally administered to humans as vaccines would result in similar adverse health effects.

Many studies, including those of Germuth (1953), have demonstrated that intravenous injection of a single high-dose antigen (0.5 g of bovine serum albumin) will stimulate the immune system, antibody production, and the development of a hypersensitivity serum sickness-like response in rabbits, characterized by glomerulonephritis and arteritis. Repeated injection of rabbits with egg albumin (20–40 mg intravenously divided into approximately 20 vaccinations over 2 months) led to the development of antibodies to antibodies (Aho and Wager, 1961). In addition, extensive injections of rabbits with casein (0.5 g injected subcutaneously twice a week for up to 15 months or more) led to the development of amyloidosis (Giles and Calkins, 1958). However, amyloidosis can also occur in the absence of extensive vaccination (Anderson, 1971). Other studies have demonstrated that injection of Balb/c mice with mineral oil can lead to the development of myeloma (Azar, 1968; Potter, 1971). For unknown reasons, the development of myeloma in response to mineral oil is unique to the Balb/c mouse strain, strongly suggesting a role for the genetic composition of this mouse strain in this unusual response.

Exposure to multiple antigens. A multiple vaccination study by Classen (1996) examined adverse immunological reactions. Classen found that vaccination, whether with one antigen or many, may predispose certain laboratory animals to the development of autoimmune conditions. Classen used strains of rats and mice that spontaneously develop diabetes. These animals are models of human insulin-dependent diabetes mellitus, an autoimmune disease. NOD/ MrkTacfBR mice were used as well as diabetic-prone and diabetic-resistant BB/Wor rats. Classen also used a group of MRL/lpr mice that develop an auto-



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