Au-Jensen M, et al.    Is the acute encephalopathy test in mice suited for control of pertussis vaccines? Dev Biol Stand. 1985;61:447-51. PMID: 3835081; UI: 86221312.

Animal models to control the serious neurological complications after vaccination against whooping cough are not available. In a recent paper pertussis vaccine induced acute encephalopathy in certain mouse strains (1). Healthy BALB/c mice died with shock-like symptoms after immunization with bovine serum albumin (BSA) and heat-killed pertussis. Mice not sensitized with BSA survived, and mice of strains with another H-2 type than H-2d were not susceptible. The authors concluded that the susceptibility to side effects to pertussis vaccine in mice and possibly in human is linked to the MHC. We tried to repeat the experiments reported by Steinman et al. in the hope that the murine encephalopathy model would be useful to evaluate possible neurological complications. In spite of having the same H-2d genotype, the BALB/c mice of two breeding stocks did not develop shock-like symptoms with fatal consequences after the last injection with BSA. This fact corresponds possibly with the author's observation that the pertussis vaccine encephalopathy is not under the control of H-2 genes alone. As shown in our tests the sudden deaths and encephalopathy in mice are not linked to BSA-sensitization because mice who received pertussis vaccine only showed the same symptoms as mice injected with BSA and vaccine. Histology did not indicate brain damage. It seems obvious that the deaths in our experiments were caused by the pertussis toxins present in the large numbers of bacteria given.

Cherkeziia SE (1979), Mikhailova GR, Gorshunova LP. [Disorders in the murine chromosome apparatus induced by immunization with a complex of antiviral vaccines]. Vopr Virusol 1979 Sep-Oct;(5):547-50 [Article in Russian]
Immunization of mice with a number of live virus vaccines (poliovaccine, smallpox vaccine, measles vaccine) given consecutively at 14-day intervals resulted in increased frequency of chromosomal aberrations in bone marrow cells of the animals after the completion of the entire vaccination course (14 and 30 days after the last vaccination). Measles vaccine and, particularly, smallpox vaccine exert a significant harmful effect on the karyotype of the bone marrow cells. The effect on the chromosomes of the vaccines given consecutively differs somewhat from the individual effect of each of them.

Iwasa, S (1985), Ishida, S; Akama, K; Swelling of the Brain in Mice Caused by Pertussis Vaccine – Its Quantitative Determination and the Responsible Factors in the Vaccine; Japanese Journal of Medicine; 38, 53-65, 1985

Summary: Intracerebral injection of vaccine into the mouse induced swelling of the brain. The swelling reached the maximum in the intensity by day 1 and persisted for several days. A method for quantitative determination of the brain-swelling activity of the vaccine was developed. A positive regression coefficient was found only between the brain-swelling and the lymphocytosis-promoting activities. Such activity was no longer shown with the vaccine heat-treated for 30 min. at 80C, but it was restored upon addition of the lymphocytosis-promoting factor (LPF) that caused no brain swelling itself. The activity, therefore was ascribed to cooperation of LPF and a certain heat-stable component other than endotoxin contained by pertussis vaccine.

Mikhašilova GR;   [Chromosome disorders in bone marrow cells of mice immunized with smallpox vaccine] ( Tsitologiia, 1974 Oct)

Munoz JJ, et al.   Adoptive transfer of experimental allergic encephalomyelitis in mice with the aid of pertussigen from Bordetella pertussis. Cell Immunol. 1984 Jul;86(2):541-5. PMID: 6329525; UI: 84234019.     

Adoptive transfer of experimental allergic encephalomyelitis (EAE) in (SJL X BALB/c)F1 mice was accomplished by an iv injection of 2.4 to 4.7 X 10(7) lymph node cells (LNC) from mice immunized with mouse spinal cord emulsified in complete Freund's adjuvant when both donors and recipients had been treated iv with 400 ng of pertussigen at the time of immunization for the donors and on transfer of cells for the recipients. Pertussigen was essential in both donors and recipients for development of frank EAE. Signs of EAE in recipients were delayed, appearing 21-23 days after cell transfer; the maximum response at about Day 27 is considerably delayed in comparison with other reported studies on passive transfer of EAE. Histologically, recipient mice with paralysis due to EAE had typical perivascular infiltrates of mononuclear cells in the brain and spinal cord. The mechanisms by which pertussigen promotes the development of EAE after adoptive transfer of sensitized LNC are uncertain.

Munoz JJ, et al.      Production of experimental allergic encephalomyelitis with the aid of pertussigen in mouse strains considered genetically resistant. J Neuroimmunol. 1984 Dec;7(2-3):91-6. PMID: 6542569; UI: 85080464.

Munoz JJ, et al.   Anaphylaxis or so-called encephalopathy in mice sensitized to an antigen with the aid of pertussigen (pertussis toxin). Infect Immun. 1987 Apr;55(4):1004-8. MID: 3557617; UI: 87164489.
Sensitization of mice with 1 mg of bovine serum albumin (BSA) or chicken egg albumin (EA) given intraperitoneally and 300 to 400 ng of pertussigen (pertussis toxin [Ptx]) given intravenously (i.v.) induced a high degree of anaphylactic sensitivity when the mice were challenged i.v. with 1 mg of antigen 14 days later. Regardless of H-2 haplotype, all of the strains tested (CFW, BALB/cJ, DBA/2J, and C3H.SW/SnJ) were susceptible to anaphylaxis. Sensitization of mice by a multiple-dose procedure that has been reported to induce fatal encephalopathy in mice (L. Steinman, A. Weiss, N. Adelman, M. Lim, R. Zuniga, J. Oehlert, E. Hewlett, and S. Falkow, Proc. Natl. Acad. Sci. USA 82, 8733-8736, 1982) (1 mg of BSA on day -1, 100 to 400 ng of Ptx on day zero 1 mg of BSA on day +1, 100 to 400 ng of Ptx on day +2, and 1 mg of BSA on day +6) induced shock in BALB/cJ, DBA/2J, and C3H.SW/SnJ mice, but not in CFW mice. When EA was used instead of BSA, CFW, BALB/cJ, and C3H.SW/SnJ mice did not develop fatal shock, whereas DBA/2J mice did. When dose 3 of antigen (BSA or EA) was postponed to day +21, all mouse strains sensitized by the multiple-dose procedure were found to be susceptible to shock. The fatal shock induced by this procedure, as well as that induced by giving a single sensitizing dose of antigen and Ptx, could be prevented by one to three 1-ml doses of saline given i.v. at the time signs of severe shock appeared. Although only one dose of saline was often sufficient to save the mice, two or three doses were usually needed. Microscopic changes were not found in midsagittal sections of the brains of mice sensitized by either procedure. This was true of mice that died from shock or were saved from shock by injections of saline. From these results, we concluded that the proposed model for encephalopathy induced in mice by Ptx and BSA demonstrates only the well-known anaphylactogenic effect of Ptx or pertussis vaccine. Since there are many other more sensitive methods to detect Ptx, induction of anaphylaxis is not of much value for detection or quantitation of Ptx in pertussis vaccine.
      

Peroutka SJ, et al.   Treatment of lethal pertussis vaccine reaction with histamine H1 antagonists. Neurology. 1987 Jun;37(6):1068-72. PMID: 2884595; UI: 87229533    

 We studied mortality after pertussis immunization in the mouse. Without treatment, 73 of 92 animals (80%) died after injection of bovine serum albumin (BSA) on day +7 of pertussis immunization. After pretreatment with 3 mg of cyproheptadine, 2 mg mianserin, or 2 mg chlorpheniramine, only 5 of 105 animals (5%) died after receiving BSA on day +7 (p less than 0.001). Blockade of histamine H1 receptors may reduce mortality in pertussis immunization-induced encephalopathy in mice.

Rao LV, et al.      Chromosomal aberrations in germ cells of male mice immunised with attenuated viral vaccines (human). J Med Microbiol. 1990 Feb;31(2):115-8. PMID: 2304066; UI: 90156355.

Romanov VA, Bereshkova RV.   Zh Mikrobiol Epidemiol Immunobiol 1975 Jun;(6):66-72 [Pathomorphological and immunofluorescent studies of smallpox vaccine neurotropism]. [Article in Russian] 
Experiments were conducted on guinea pigs sensitized with the AK C-vaccine components. In intracardiac injection with smallpox vaccine there was shown a possibility of development of marked hemodynamic disturbances, of the inflammatory-dystrophic processes of irreversibel character, with a subsequent neuronophagia and demyelinization. Injection of smallpox vaccine into the circulation of intact guinea pigs was accompanied by development in the nervous system of insignificant circulatory disturbances and of the inflammatory dystrophic phenomena of reversible character. A method of immunofluorescence was used and the antigen of the vaccine virus was revealed in the neurons of the brain and the spinal cord of the sensitized and intact animals. Marked hemodynamic and insignificant inflammatory-dystrophic processes were revealed in the nervous system of a child which died of the post-vaccinal encephalitis; an antigen of the smallpox virus was found by the immunofluorescent method in the nerve cells and the vessels in various portions of the nervous system. PMID: 239507, UI: 75221294

Sato Y, et al.  Comparison of toxicities of acellular pertussis vaccine with whole cell pertussis vaccine in experimental animals. Dev Biol Stand. 1991;73:251-62. PMID: 1778317; UI: 92137506.

There is no suitable animal model for pertussis encephalopathy in humans. In this study, we have compared the toxicity of acellular pertussis vaccine with whole cell pertussis vaccine in mice or guinea pigs. Two lots of acellular and two lots of whole cell vaccine produced in different countries were assayed in the test. 1. There was no statistical difference in mouse protective potency between these acellular or whole cell pertussis vaccines. 2. There were no differences in chemical ingredients between acellular and whole cell pertussis vaccines except for protein nitrogen content. The protein nitrogen content of whole cell vaccine was at least three times higher than that of the acellular product. 3. Anti-PT antibody productivity of the acellular vaccine was higher than that of the whole cell vaccine. 4. Anti-agglutinogen antibody productivity of the whole cell vaccine was higher than that of the acellular vaccine. 5. There was no pyrogenic activity with the acellular vaccine, but high pyrogenicity was seen with whole cell vaccine. 6. There was high body-weight decreasing toxicity in mice and guinea pigs by the whole cell vaccine. 7. The mice died when they received whole cell pertussis vaccine iv, but no deaths occurred in the mice which received acellular pertussis vaccine.

Steinman L, et al.     Pertussis toxin is required for pertussis vaccine encephalopathy. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8733-6. PMID: 2867545; UI: 86094299.
A mouse model for pertussis immunization encephalopathy has been described with features that closely resemble the severe adverse reactions occasionally seen after pertussis vaccine administration,m including seizures and a shock-like state leading to death. These reactions are produced with nearly one hundred percent efficiency provided that the mice immunized with Bordetella pertussis have 1) the appropriate major histocompatibility (H-2) genotype, 2) have been sensitized to bovine serum albumin (BSA), and 3) that the injected B. pertussis contained sufficient amounts of pertussis toxin. Antibody titres were measured in mice with haplotypes H-2d.s.k. that are highly susceptible to encephalopathy as well as in H-2b mice, that are totally resistant. Mice with H-2d.s.k. haplotypes were high responders to BSA, while H-2b (B10) mice were non-responders to BSA. Both H-2d and H-2b mice responded well to B. pertussis. Encephalopathy was induced in resistant H-2b mice with B. pertussis and passively administered anti-BSA antiserum, but not with B. pertussis and anti-(T,G)-A--L antibody. This indicated that B. pertussis and anti-BSA were absolutely required for development of encephalopathy. Encephalopathy could be induced in mice decomplemented with cobra venom factor and given BSA and B. pertussis. Several single-site mutants of B. pertussis affecting single virulence factors were induced with transposon Tn5. One of these mutants, BP357, deficient in pertussis toxin production, had a greatly reduced encephalopathic potential in the mouse model compared to the virulent strain BP 338, or to BP348, an adenylate cyclase and hemolysin double mutant, or to BP 349, a hemolysin mutant.      

Steinman L, et al.    Murine model for pertussis vaccine encephalopathy: role of the major histocompatibility complex; antibody to albumin and to Bordetella pertussis and pertussis toxin. Dev Biol Stand. 1985;61:439-46. PMID: 2872126; UI: 86221311.
   A mouse model for pertussis immunization encephalopathy has been described with features that closely resemble the severe adverse reactions occasionally seen after pertussis vaccine administration,m including seizures and a shock-like state leading to death. These reactions are produced with nearly one hundred percent efficiency provided that the mice immunized with Bordetella pertussis have 1) the appropriate major histocompatibility (H-2) genotype, 2) have been sensitized to bovine serum albumin (BSA), and 3) that the injected B. pertussis contained sufficient amounts of pertussis toxin. Antibody titres were measured in mice with haplotypes H-2d.s.k. that are highly susceptible to encephalopathy as well as in H-2b mice, that are totally resistant. Mice with H-2d.s.k. haplotypes were high responders to BSA, while H-2b (B10) mice were non-responders to BSA. Both H-2d and H-2b mice responded well to B. pertussis. Encephalopathy was induced in resistant H-2b mice with B. pertussis and passively administered anti-BSA antiserum, but not with B. pertussis and anti-(T,G)-A--L antibody. This indicated that B. pertussis and anti-BSA were absolutely required for development of encephalopathy. Encephalopathy could be induced in mice decomplemented with cobra venom factor and given BSA and B. pertussis. Several single-site mutants of B. pertussis affecting single virulence factors were induced with transposon Tn5. One of these mutants, BP357, deficient in pertussis toxin production, had a greatly reduced encephalopathic potential in the mouse model compared to the virulent strain BP 338, or to BP348, an adenylate cyclase and hemolysin double mutant, or to BP 349, a hemolysin mutant.(ABSTRACT TRUNCATED AT 250 WORDS)

 

 

 

Redhead K, et al.    The activity of purified Bordetella pertussis components in murine encephalopathy. J Biol Stand. 1987 Oct;15(4):341-51. PMID: 3680302; UI: 88059141.

A murine encephalopathic syndrome can be induced by the administration of BSA and whole-cell pertussis vaccine. The present paper reports studies of the capacity of purified individual pertussis components to induce this effect. Pertussis toxin and endotoxin together with a highly immunogenic sensitizer protein were required to induce the effect. The strength of the antibody response to the sensitizer appeared to be more important than the H-2 type of the recipient in determining the susceptibility of different mouse strains. The relevance of this syndrome to the study of possible vaccine-induced encephalopathy in man is uncertain and requires further investigation.

Redhead K, et al.     Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue. Pharmacol Toxicol. 1992 Apr;70(4):278-80. PMID: 1608913; UI: 92302160.

Aluminium is widely used as an adjuvant in human vaccines, and children can often receive up to 3.75 mg of parenteral aluminium during the first six months of life. We show that intraperitoneal injection of aluminium adsorbed vaccines into mice causes a transient rise in brain tissue aluminium levels peaking around the second and third day after injection. This rise is not seen in the saline control group of animals or with vaccine not containing aluminium. It is likely that aluminium is transported to the brain by the iron-binding protein transferrin and enters the brain via specific transferrin receptors.

Wiedmeier SE, et al.     Murine responses to immunization with pertussis toxin and bovine serum albumin: I. Mortality observed after bovine albumin challenge is due to an anaphylactic reaction. Pediatr Res. 1987 Sep;22(3):262-7. PMID: 3309858; UI: 88015343.
It has been suggested that pertussis toxin (Ptx) is involved in the pathogenesis of the adverse neurologic reactions that can occur in infants and children after pertussis immunization. One group of investigators has recently reported that a clinical syndrome with pathological features very similar to post-pertussis vaccination encephalopathy can be induced in specific strains of mice after their immunization with bovine serum albumin (BSA) and Ptx. The aim of this investigation was to further characterize the immunologic mechanisms operative in this murine model. Studies were undertaken to determine whether the role played by Ptx in this condition required the A-protomer of the toxin to enter a cell and ADP-ribosylate a nucleotide binding protein (a Class I activity) or was dependent upon the binding of the B-oligomer of the toxin to the surface of target cells (a Class II activity). The results of our experiments have established that the disease induced by coimmunizing mice with Ptx and BSA is due to an immediate type hypersensitivity reaction rather than an encephalopathy and that the mechanism of action of Ptx in this system seems to be dependent upon a Class II activity of the toxin and independent of its ADP-ribosyl transferase activity.

Munoz JJ, et al.    Anaphylaxis or so-called encephalopathy in mice sensitized to an antigen with the aid of pertussigen (pertussis toxin). Infect Immun. 1987 Apr;55(4):1004-8. PMID: 3557617; UI: 87164489.

Sensitization of mice with 1 mg of bovine serum albumin (BSA) or chicken egg albumin (EA) given intraperitoneally and 300 to 400 ng of pertussigen (pertussis toxin [Ptx]) given intravenously (i.v.) induced a high degree of anaphylactic sensitivity when the mice were challenged i.v. with 1 mg of antigen 14 days later. Regardless of H-2 haplotype, all of the strains tested (CFW, BALB/cJ, DBA/2J, and C3H.SW/SnJ) were susceptible to anaphylaxis. Sensitization of mice by a multiple-dose procedure that has been reported to induce fatal encephalopathy in mice (L. Steinman, A. Weiss, N. Adelman, M. Lim, R. Zuniga, J. Oehlert, E. Hewlett, and S. Falkow, Proc. Natl. Acad. Sci. USA 82, 8733-8736, 1982) (1 mg of BSA on day -1, 100 to 400 ng of Ptx on day zero 1 mg of BSA on day +1, 100 to 400 ng of Ptx on day +2, and 1 mg of BSA on day +6) induced shock in BALB/cJ, DBA/2J, and C3H.SW/SnJ mice, but not in CFW mice. When EA was used instead of BSA, CFW, BALB/cJ, and C3H.SW/SnJ mice did not develop fatal shock, whereas DBA/2J mice did. When dose 3 of antigen (BSA or EA) was postponed to day +21, all mouse strains sensitized by the multiple-dose procedure were found to be susceptible to shock. The fatal shock induced by this procedure, as well as that induced by giving a single sensitizing dose of antigen and Ptx, could be prevented by one to three 1-ml doses of saline given i.v. at the time signs of severe shock appeared. Although only one dose of saline was often sufficient to save the mice, two or three doses were usually needed. Microscopic changes were not found in midsagittal sections of the brains of mice sensitized by either procedure. This was true of mice that died from shock or were saved from shock by injections of saline. From these results, we concluded that the proposed model for encephalopathy induced in mice by Ptx and BSA demonstrates only the well-known anaphylactogenic effect of Ptx or pertussis vaccine. Since there are many other more sensitive methods to detect Ptx, induction of anaphylaxis is not of much value for detection or quantitation of Ptx in pertussis vaccine.