The effect of adsorption with aluminium hydroxide on the reactogenicity of pertussis vaccines.
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Adsorption↗
Biomedical subjects
K Redhead
Publications and source records attributed to K Redhead.
Necrotic enteritis challenge models with broiler chickens raised on litter: evaluation of preconditions, Clostridium perfringens strains and outcome variables.
The effect of Clostridium perfringens challenge, number of challenge days, and pre-challenge antibiotic treatment on the induction of necrotic enteritis in broiler chickens raised on litter was studied, and the relationship between bacterial counts and frequency of gut lesions was evaluated. Specific intestinal lesions in randomly selected birds were present despite a lack of disease-specific mortality. Challenge, number of challenge days and frequency of lesions were associated with median counts of C. perfringens. The effect of pre-challenge C. perfringens counts and antibiotics cannot be evaluated unless procedures for the control of pre-challenge infection and methods for the differentiation between wild-type and challenge strains are established.
Animals↗
Assessing the psychosocial consequences of epilepsy: a community-based study.
BACKGROUND: Few studies have measured, using validated scales, the psychosocial handicap of epilepsy in a general practice setting. AIM: To assess the prevalence of psychosocial problems associated with epilepsy. METHOD: A survey was undertaken of 309 subjects, with one or more non-febrile epileptic seizures, drawn from two general practices in the United Kingdom (UK). The outcome measures were the Subjective Handicap of Epilepsy Scale (SHE), the SF-36, and the Hospital Anxiety and Depression scale (HAD). RESULTS: One-third of persons with active epilepsy were significantly handicapped by their condition. The severity of subjective handicap was related to seizure frequency and to the duration of remission of seizures. Between one-third and one-half of subjects scored as 'cases' on the HAD scale and on the mental health subscale of the SF-36. Only one-third of the psychiatric morbidity revealed by the questionnaires had been recognized by the general practitioner (GP). Scores on the SF-36 indicated that people with active seizures perceived themselves as significantly less healthy than those in remission, and that, for persons in remission, drug treatment had a detrimental effect on certain aspects of well-being. CONCLUSIONS: The occurrence of seizures, even at low frequencies, is associated with psychosocial handicap, and this may remain covert in general practice.
Adolescent↗
Veterinary vaccines: In-VITRO--International Veterinary Industry Test Replacement Organisation.
The International Veterinary Industry Test Replacement Organisation (In-VITRO) was established in 1995 with the aim of developing, validating and harmonising in vitro alternatives to replace in vivo methods for in-process and potency testing of veterinary clostridial vaccines. The emphasis has been on the reduction of animal usage in the Clostridium chauvoei potency assay and its eventual replacement by an in vitro assay. Replacement of the toxin neutralisation assay for Cl. tetani by an internationally validated indirect ELISA has already started. A validation programme involving a collaboration organised through EDQM which could ultimately lead to the standardisation of in vitro tests for all clostridial vaccines is in progress. In addition In-VITRO is now considering the setting up of a programme for Erysipelas vaccines. The collaboration between manufacturers of veterinary vaccines in the development and validation of in vitro tests is a major step towards the reduction and replacement of animal tests.
Animal Testing Alternatives↗
Cross protection against Erysipelothrix rhusiopathiae serotype 10 induced by a serotype 1 and 2 vaccine.
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Animals↗
Effect of schedule on reactogenicity and antibody persistence of acellular and whole-cell pertussis vaccines: value of laboratory tests as predictors of clinical performance.
The performance of four acellular pertussis vaccines containing between two and five pertussis antigens combined with diphtheria and tetanus toxoids was compared with that of British whole-cell diphtheria/tetanus/pertussis (DTP) vaccine both in laboratory assays for potency, toxicity and immunogenicity, and for reactogenicity and immunogenicity in infants. Clinical responses were evaluated in double blind randomized Phase II trials using 3/5/9 month and 2/3/4 month schedules. The acellular DTPs had much lower toxicity than whole-cell DTP in laboratory tests and were significantly less pyrogenic than whole-cell DTP under both schedules. Local reactions were not consistently lower in acellular than whole-cell vaccinees and varied with the source of the diphtheria and tetanus antigens used. Differences in endotoxin level and content of active pertussis toxin (PT) between acellular DTP vaccines were not clinically significant. The reactogenicity advantage of the acellular vaccines was substantially reduced under the 2/3/4 month schedule due to the reduced reactogenicity of the whole-cell DTP vaccine when given at a younger age. There was no relationship between antigen content measured in micrograms per dose and ELISA antibody responses to filamentous haemagglutinin (FHA) and PT in infants, nor was murine immunogenicity predictive of immunogenicity in humans. Antibody response to PT was attenuated in the whole-cell group under the 2/3/4 month schedule but was unaffected in the group receiving acellular vaccines with individually purified components; antibody response to pertactin (69 kDa antigen) was similar in recipients of the whole-cell and component acellular vaccines under the 2/3/4 month schedule. PT antibody persistence until 4-5 years of age was significantly better in recipients of the component acellular than either the whole-cell vaccine or the co-purified acellular vaccine under the 3/5/9 month schedule. However, diphtheria antitoxin levels were reduced in acellular vaccine recipients under both schedules. Despite significantly lower tetanus potencies of the acellular vaccines in laboratory tests, no differences were found in tetanus anti-toxin responses in children.
Antibodies, Bacterial↗
Th1/Th2 cell dichotomy in acquired immunity to Bordetella pertussis: variables in the in vivo priming and in vitro cytokine detection techniques affect the classification of T-cell subsets as Th1, Th2 or Th0.
In studies of the mechanism of immunity to Bordetella pertussis in a murine respiratory infection model, we have previously demonstrated that natural infection of immunization with a whole cell vaccine induces a potent protective immune response, which is mediated by T-helper type-1 (Th1) cells. In contrast an acellular vaccine generates Th2 cells and is associated with delayed bacterial clearance following respiratory challenge. In the present study we have investigated the apparent Th1/Th2 cell dichotomy in acquired immunity and have examined the factors that affect their induction or detection. The cytokine profiles of B. pertussis-specific T cells in immune animals were determined using antigen-stimulated ex vivo spleen cells or CD4+ T-cell lines and clones established in the presence of interleukin-2 (IL-2) or IL-4. Antigen-specific T cells derived from mice immunized with the acellular vaccine were almost exclusively of the Th2 cell type. In contrast, T-cell lines and clones established following respiratory infection or immunization with the whole cell vaccine were predominantly of the Th1 type. However, a proportion of T cells from convalescent mice, especially when cultured in the presence of IL-4, secreted IL-4 and IL-5 with or without detectable IL-2 and interferon-gamma (IFN-gamma), suggesting that Th0 or Th2 cells were also primed during natural infection in vivo. Furthermore, when mice were assessed 6 months after infection, spleen cells produced significant levels of IL-4 and IL-5, which were not evident at 6 weeks. The route of immunization and the genetic background of the mice were also found to influence the preferential priming of Th1 cells, and this was directly related to the level of protection against respiratory or intracerebral (i.c.) challenge. Our findings underline the critical role of CD4+ Th1 cells in immunity to B. pertussis, but also demonstrate that a number of factors in the in vivo priming and in vitro restimulation can skew the apparent dominance of one Th cell type over another.
Animals↗
Developments in pertussis vaccines leading to reduction and replacement of in vivo testing.
The control of bacterial vaccines, in common with other biological products, requires that they conform to specified standards of purity, safety and efficacy. The specifications and the methods of assessment can vary between the different types of vaccines. Highly defined vaccines can be largely evaluated by physico-chemical methods. However, the control of whole-cell bacterial vaccines can be a very different proposition owing to the complex nature of the materials. Safety and efficacy testing of such products can involve number of in vivo assays. Our growing understanding of the pathogenesis of, and protective immune responses to, bacterial disease makes it possible to devise more effective and better-defined vaccines. In addition, it allows the the development of sensitive and precise in vitro assays. As a result, the requirement for in vivo control tests can be reduced and in some cases eliminated. This phenomenon is well illustrated by the recent advances in the development and control of pertussis vaccines. Certain in vitro tests, such as the LAL and CHO-cell assays, are proving valuable in checking for specific toxicities which can be associated with pertussis vaccines. Although some problems still exist in the development of a suitable potency assay for the acellular vaccines, as we gain more information on the contributions of the different aspects of the immune system towards protection from pertussis, the prospects for further improvements in both the vaccine and its control evaluation are promising.
Animal Testing Alternatives↗
Audit of the care of patients with epilepsy in general practice.
BACKGROUND: Previous studies have shown that there is great potential for improving the management of patients with epilepsy. AIM: To identify all patients with epilepsy, to evaluate and audit their care in relation to an annual review, to document seizure frequency and appropriateness of daily therapy to aid compliance and to propose strategies to improve these and other aspects of epileptic care. METHOD: An audit of the care of patients with epilepsy was undertaken in two King's Lynn practices with a combined population of 22,500. Principles for the management of epilepsy were established. From these principles, the following standards were agreed: 75% of patients on treatment for epilepsy should be seen every year, 75% of patients should have their seizure frequency documented, and 75% of patients should take their anti-epileptic drugs no more than twice daily. As a result of the first audit cycle, changes were made in the documentation and advice regarding treatment relating to these standards. RESULTS: The first audit cycle showed that 83% of patients had been seen at least once in the previous year, that documentation of seizure frequency existed for 51% of patients in the past year, and that 63% of patients were taking their treatment no more than twice daily. The evaluation was repeated 22 months later and an overall improvement was demonstrated in the first two results: 95% of patients had been seen in the past year, 93% had had their seizure frequency documented; however, only 66% of patients were taking their treatment twice daily or less. CONCLUSION: Call and recall, and documentation of seizure frequency were improved by this clinical audit. However, alterations in daily therapy appeared difficult for a variety of reasons; for example, therapy might have been initiated by a hospital specialist, and patients in a stable condition might have been apprehensive about changes. In order to improve the care of patients with epilepsy, a primary care team approach is desirable within a structure of good specialist services.
Anticonvulsants↗
Immune responses and protection against Bordetella pertussis infection after intranasal immunization of mice with filamentous haemagglutinin in solution or incorporated in biodegradable microparticles.
The intranasal (i.n.) immunization of mice with Bordetella pertussis filamentous haemagglutinin (FHA) either as a solution or incorporated in biodegradable microparticles induced very similar immune responses. Both resulted in strong systemic IgG responses to FHA and good levels of anti-FHA IgG and IgA in the lungs of immunized mice. In comparison, the intraperitoneal (i.p.) immunization of mice with FHA, as a solution, engendered anti-FHA antibody responses which were stronger for serum IgG, similar for lung IgG and lower for lung IgA. The anti-FHA antibody levels, as measured by immunosorbent assay, were shown to correlate with their functional activity in the blocking of B. pertussis adhesion to HeLa tissue-culture cells. All three forms of immunization appeared to stimulate T-cell responses as assessed by in vitro antigen-specific spleen cell proliferation and IL-2 secretion indicative of a Th1 type response, however, cells from i.p. immunized mice only secreted low levels of IL-5. All three methods of FHA immunization provided mice with significant protection against subsequent aerosol challenge with virulent B. pertussis. Mice which had been immunized intra-nasally eliminated the bacteria from their lungs slightly more rapidly than i.p. immunized mice, demonstrating the efficacy of intranasal administration of FHA in solution and in the more practical biodegradable microparticle form.
Administration, Intranasal↗
Combination of DTP and Haemophilus influenzae type b conjugate vaccines can affect laboratory evaluation of potency and immunogenicity.
A commonly used Diphtheria-Tetanus-Pertussis (whole-cell) vaccine was combined with each of three different Haemophilus influenzae type b (Hib) capsular polysaccharide vaccines. Each Hib vaccine incorporated one of three different protein conjugates: tetanus toxoid, diphtheria CRM197 toxoid or group B Neisseria meningitidis outer membrane vesicles. The effects of these combinations on the subsequent laboratory control testing were examined. The addition of the Hib vaccines had no significant effect on the reactogenicity or the potency of the whole-cell pertussis component. The potency of, and antibody responses to, the diphtheria component were also unaffected in all three combinations. However, combination with the Hib vaccine comprising polysaccharide conjugated to tetanus toxoid had dramatic effects on tetanus potency and immunogenicity when assayed in mice. This combination resulted in a five-fold potentiation of the tetanus potency and a similarly large increase in the antibody responses to tetanus toxin and toxoid. The level of the antibody response to the Hib polysaccharide in this vaccine was also elevated, more than 20-fold, as a result of the combination. Such phenomena were not evident with combinations involving the other two Hib vaccines. These results have implications for the control testing of combined vaccines containing a whole-cell pertussis component and Hib polysaccharide-tetanus protein conjugate vaccine.
Animals↗
Interaction of Haemophilus influenzae type b conjugate vaccines with diphtheria-tetanus-pertussis vaccine in control tests.
The effects of combining three Haemophilus influenzae type b (Hib) capsular polysaccharide vaccines, conjugated to different proteins, with DTP vaccine on the subsequent control testing were examined. The addition of the Hib vaccines had little effect on the reactogenicity or the potency of the whole-cell pertussis component. The potency of, and antibody responses to, the diphtheria component were also unaffected in all three combinations. However, combination with the Hib vaccine comprising polysaccharide conjugated to tetanus toxoid resulted in a fivefold potentiation of the tetanus potency and large increases in the antibody responses to tetanus toxin and toxoid and Hib polysaccharide. These results have implications for the control testing of combined vaccines containing a whole-cell pertussis component and Hib polysaccharide-tetanus protein conjugate vaccine.
Animals↗
Antibody response to accelerated immunisation with diphtheria, tetanus, pertussis vaccine.
From May, 1990, a new schedule of immunisation against diphtheria, tetanus, and pertussis (at 2, 3, and 4 months) replaced the previous more widely spaced schedule. A report that children had lower concentrations of diphtheria and tetanus antibodies a month after an accelerated schedule led us to undertake a controlled study to assess antibody response and the persistence of antibodies a year after immunisation in children receiving vaccine according to widely spaced and accelerated schedules. Concentrations of antibodies to diphtheria and tetanus toxoids and to Bordetella pertussis filamentous haemagglutinin (FHA) were measured by solid-phase radioimmunoassay (SP-RIA). We studied 57 children who received accelerated immunisation at median ages of 11, 16, and 21 weeks and two control cohorts (total n = 82) who received vaccine at median ages of 15, 21, and 45 weeks. 6-8 weeks after the third dose the accelerated-schedule group had lower (p < 0.0001) geometric mean concentrations of antibody to tetanus (0.522 [95% CI 0.383-0.710] vs 3.43 [2.45-4.81] IU/mL), diphtheria (0.266 [0.179-0.396] vs 2.39 [0.616-3.53] IU/mL), and FHA (0.044 [0.030-0.063] vs 0.270 [0.196-0.374] units/mL) than the longer-schedule group. 12 months after the third dose the differences between the groups had narrowed (tetanus 0.197 vs 0.341 IU/mL, p = 0.29; diphtheria 0.100 vs 0.131 IU/mL, p = 0.64; FHA 0.014 vs 0.016 units/mL, p = 0.72). At that time all children had tetanus antibody concentrations above protective levels (0.01 IU/mL); only 2 of 31 in the accelerated-schedule group and 3 of 31 in the longer-schedule group had diphtheria antibody concentrations below the protective level. The use of an accelerated schedule of diphtheria, tetanus, and pertussis vaccination is unlikely to lead to an increase in the proportion of children unprotected against these diseases before the preschool booster.
Antibodies, Bacterial↗
Mice are protected against Bordetella pertussis infection by intra-nasal immunization with filamentous haemagglutinin.
Intra-nasal immunization of mice with purified Bordetella pertussis filamentous haemagglutinin (FHA) or a crude cell sonicate was shown to protect against subsequent B. pertussis aerosol challenge. Immunization with FHA was found to be the most effective and resulted in complete clearance of the bacterial infection from the lungs within 14 days. Serum IgG and lung IgA anti-FHA antibodies were detectable within 4 weeks of the first immunization and anamnestic responses were seen following secondary immunization and subsequent challenge with B. pertussis. Nasal administration of pertussis antigens is a route which induces good systemic serum, as well as local secretory, antibody responses.
Adhesins, Bacterial↗
Cellular immunity in pertussis.
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Animals↗
Cell-mediated immunity to Bordetella pertussis: role of Th1 cells in bacterial clearance in a murine respiratory infection model.
A murine respiratory infection model was used to study the mechanism of protective immunity to Bordetella pertussis. We found that nude mice, which are deficient in T cells, developed a persistent infection and failed to clear the bacteria after aerosol inoculation. In contrast, normal adult nonimmune mice cleared a respiratory infection approximately 35 days after challenge. Before bacterial clearance, antipertussis antibody levels in serum were low or undetectable, whereas consistent antigen-specific T-cell responses were demonstrated throughout the course of infection. The in vitro responses detected in immune spleen cells were mediated by a population of CD4+ major histocompatibility complex class II-restricted Th1-like cells that secreted interleukin-2 and gamma interferon but not interleukin-4. Adoptive transfer of immune spleen cells into nude or sublethally irradiated immunosuppressed mice before challenge resulted in bacterial clearance within 14 to 21 days. In contrast, injection of serum from convalescent mice before challenge only marginally reduced the bacterial load early in the course of infection. Furthermore, transfer of enriched T cells or purified CD4+ T cells but not CD8+ T cells from immune mice conferred a high level of protection. Recipients of CD4+ T cells cleared the bacteria from the lungs within 20 days of challenge, at which time B. pertussis-specific antibodies in the serum were undetectable. Although we do not rule out a contribution of mucosal immunoglobulin A, our findings suggest that cellular responses mediated by CD4+ Th1 cells play an important role in protective immunity to B. pertussis.
Animals↗
Effective immunization against Bordetella pertussis respiratory infection in mice is dependent on induction of cell-mediated immunity.
A murine respiratory challenge model was used to examine the induction of cellular and humoral immune responses and their role in protection against Bordetella pertussis following immunization or previous infection. Spleen cells from mice convalescing from a B. pertussis infection exhibited extensive in vitro T-cell proliferation and secreted high levels of interleukin-2 (IL-2) and gamma interferon but not IL-4 or IL-5, a cytokine profile typical of CD4+ Th1 cells. Serum from these mice had low or undetectable anti-B. pertussis antibody levels. In contrast, mice immunized with an acellular pertussis vaccine had high levels of B. pertussis antibodies and spleen cells secreting IL-5 but not gamma interferon, a profile characteristic of CD4+ Th2 cells. Immunization with an inactivated whole-cell vaccine induced both CD4+ Th1 and serum antibody responses. After exposure to a B. pertussis respiratory challenge, the convalescent mice and those immunized with the whole-cell vaccine eliminated the bacterial infection significantly faster than mice immunized with the acellular vaccine. These findings show that the selection of antigens and their form of presentation are important in determining whether the subsequent immune response is cellular, mediated by Th1 cells, or humoral, mediated by Th2 cells. In the murine model, the induction of a Th1-mediated cellular immune response appears to be a key element in acquired immunity to a B. pertussis infection.
Animals↗
Aluminium-adjuvanted vaccines transiently increase aluminium levels in murine brain tissue.
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.
Adjuvants, Immunologic↗