DPT vaccine animal studies
Citations
- 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.
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.
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.
- 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)
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