- 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.
-