Encephalopathy & vaccination
Nervous system disease & vaccination

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.

Cowan LD; Griffin MR; Howson CP; Katz M; Johnston RB Jr; Shaywitz BA; Fineberg HV  Acute encephalopathy and chronic neurological damage after pertussis vaccine. Institute of Medicine, National Academy of Sciences, Washington, DC. Vaccine, 11: 14, 1993 Nov, 1371-9
In August 1991, the Institute of Medicine released a report entitled Adverse Effects of Pertussis and Rubella Vaccines, which examined, among others, the relation between immunization with whole-cell diphtheria-tetanus-pertussis (DTP) vaccine and both acute encephalopathy and chronic neurological damage. The committee reviewed information from a wide range of both professional and lay sources and found that the evidence is consistent with a possible causal relation between DTP vaccine and acute encephalopathy, although it is insufficient to establish causality. The range of excess risk of acute encephalopathy following DTP immunization is consistent with that estimated from the National Childhood Encephalopathy Study: 0.0 to 10.5 cases per million immunizations. The committee concluded that the evidence is insufficient to indicate either the presence or absence of a causal relationship between DTP vaccine and permanent neurological damage. The evaluative methods used by the committee are briefly described and the evidence underlying its conclusions presented.

Greco D, et al, "Case-control study on encephalopathy associated with diphtheria-tetanus immunization in Campania, Italy," Bull World Health Organ 1985;63(5):919-925.

Lenard HG, Fest U, Scholz W.  [Complications of pertussis immunization (author transl)] Monatsschr Kinderheilkd. 1977 Jun;125(6):660-7. German. PMID: 18670 [PubMed - indexed for MEDLINE]

16 cases of neurological disease and/or death shortly after pertussis immunization are reported. Eight patients had convulsions, six with ensuing permanent defects. Severe polymyositis was observed in one case. Five infants died 12 h to 4 days after vaccination: two after acute encephalopathy and three in the form of a sudden unexpected death (SID). In two fatal cases the morphological changes in the brain corresponded to those of pertussis encephalopathy: neuronal degeneration in various parts of the cortex, especially in the region of the ammons horn, and in the cerebellum. There were no signs of inflammation. Three cases underwent forensic autopsy and death was attributed to bronchopulmonary infection. Complete neuropathological work-up was only done in one case, in which the brain was normal. The critique of episodical reports and the demand for prospective studies is appreciated. Knowledge of all possible forms of complications, however, is indispensable for future investigations. Polymyositis and SID have so far not been listed as abnormal reactions to immunization. The majority of our cases became known accidentally from hospital sheets or from discussions with collegues. For a detection of all possible cases a greater awareness of doctors for the problem of pertussis immunization appears necessary. Only another 23 cases have been reported to the health authorities of the state of Lower Saxony during the last 6 to 7 years. Of those, nine were either harmless reactions or diseases probably unrelated to vaccination. Two were cases of SID, 12 and 72 h after vaccination. It is concluded that only a minor proportion of possible complications is presently reported to the health authorities.

Menkes, J.H (1990). and Kinsbourne, M., Neuropediatrics 21 (1990) 171-176, Workshop on Neurologic Complications of Pertussis and Pertussis Vaccination,

In evaluating side-reactions to the vaccine, the following must be kept in mind: Vaccines are not standardized between manufacturers.

For a given manufacturer, vaccines are not standard from one batch to the next.

Unless the vaccine is properly prepared and refrigerated, its potency and reactivity varies with shelf life.

In fact, the whole question of vaccine detoxification has never been systematically investigated.

Listed in order of increasing severity, observed adverse reactions include irritability, persistent, unusually high-pitched crying, somnolence, seizures, a shock-like "hypotensive, hyporesponsive" state, and an encephalopathy. Since the neurologic picture is not specific for pertussis vaccination, its temporal relationship to the vaccination is the critical variable for determining causation.

Although the majority of seizures following pertussis vaccination are associated with fever, it was the consensus of the neurologists attending the workshop, that these do not represent febrile convulsions, but are non-benign convulsions.

The incidence of post-vaccine encephalopathy is difficult to ascertain. The most carefully conducted retrospective case-control study reported that the relative risk of a previously normal infant for the onset of an illness leading to encephalopathy with permanent subsequent disability was 4.2 time greater during the first 72 hours following DPT vaccination than in controls. From this study, the risk for permanent brain damage following DPT has been calculated as 1:310,000 doses. (my note – 1:310,000 doses translates to an actual risk of 1:62,000 – this figure is from the National Childhood Encephalopathy Study which excluded any child whose seizure lasted for less than 30 minutes and who was not hospitalised as a result of their seizure. )

It was the consensus of the workshop, and in particular of the participating neurologists, that although the vaccine may possibly accelerate neurologic signs or symptoms in some children, and a small proportion of apparent complications may be coincidental, there was no inherent difficulty in assigning cause and effect to the vaccine and subsequent permanent neurologic residua.

…In implicating pertussis vaccination in the evolution of subsequent neurologic residua, a careful consideration of the mechanism for vaccine-induced brain damage plays an important supporting role. Pertussis toxin has been shown to alter cellular signalling. It also affects the catecholaminergic and GABAergic systems in the brain. Although normally a protein the size of PT would not be able to cross the blood-brain barrier, factors known to disrupt the blood-brain barrier include brief hypertensive episodes such as might occur during a coughing paroxysm, hypoxia and prolonged seizures, whether or not they are accompanied by hypoxia. In addition, a direct endotoxin-mediated attack on the endothelial cells could create a local defect of the blood-brain barrier.

In summary, it was the consensus that there is sufficient experimental data to implicate both endotoxin and PT in adverse neurologic reactions to pertussis vaccine.

Miller D, et al(1985). Pertussis vaccine and whooping cough as risk factors in acute neurological illness and death in young children. Dev Biol Stand. 1985;61:389-94. PMID: 3879684; UI: 86221304.

The National Childhood Encephalopathy Study received reports on 1182 cases of serious acute neurological illnesses in children admitted to hospital in Britain. The frequency of risk factors in cases was compared with matched controls. A personal or family history of convulsions was found significantly more often in cases than in controls, but no such excess was found for a history of allergy. Case children were significantly more likely to have received diphtheria, tetanus and pertussis (DTP) vaccine within seven days before onset and to have a history of whooping cough during the month of onset. The risk of serious acute brain conditions after the disease was more than six times that of three doses of DTP. In addition, there is evidence that deaths attributed to whooping cough may seriously underestimate the number associated with pertussis infection. PMID: 3879684, UI: 86221304

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.
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)
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.