M J Corbel

National Institute for Biological Standards and Control, Potters Bar, England, United Kingdom

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Publications (106)326.02 Total impact

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    ABSTRACT: We investigated the adjuvant effect of CpG ODN alone or in combination with aluminum hydroxide on the immune response to the three main antigens presented in current acellular pertussis vaccines: pertussis toxoid, filamentous haemagglutinin and pertactin. The development of protection in mice was investigated for the intra-peritoneal and intra-nasal immunisation routes. The results showed that CpG ODN alone, or in combination with aluminum hydroxide, gave enhancement in anti-pertussis toxin, anti- filamentous haemagglutinin and especially anti-pertactin titers after mucosal immunisation. Higher macrophage NO levels indicating activation were found when the antigens were co-formulated with CpG ODN. Vaccines containing CpG ODN gave enhanced humoral and CMI responses with a shift toward Th-1 and increased protection against challenge infection with B.pertussis in mice.
    Human vaccines & immunotherapeutics. 01/2013; 9(2).
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    ABSTRACT: Speculation that the Japanese modified intra-cerebral challenge assay, which is used in several countries for control of acellular pertussis vaccines, depends on the presence of small amounts of active pertussis toxin led to an assumption that it may not be appropriate for highly toxoided or genetically detoxified vaccines. Consequently, at the recommendation of a World Health Organisation AD Hoc Working Group on mouse protection models for testing and control of acellular pertussis vaccine, the effect of pertussis toxin on the modified intra-cerebral challenge assay (modified Kendrick, MICA) was evaluated in an international collaborative study. Results of this study showed that for genetically detoxified vaccines both with and without active pertussis toxin the MICA clearly distinguished mice vaccinated with acellular vaccines from unvaccinated mice and gave a significant dose–response relationship. However, vaccine samples containing active pertussis toxin (5 or 50 ng/single human dose) appeared to be more potent than the equivalent sample without active pertussis toxin. Similar results were also given by two respiratory infection models (intranasal and aerosol) included in the study. The results also indicated that the effect of pertussis toxin may vary depending on mouse strain.
    Biologicals 01/2013; · 1.62 Impact Factor
  • X. Lemercinier, C. Jones, M. J. Corbel, S. Yost
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    ABSTRACT: Bacterial glycoconjugate vaccines consist of capsular polysaccharide chemically conjugated to a carrier protein. Vaccines against Haemophilus influenzae type b (Hib) have proven effective in preventing invasive infection by Hib in young children. Because the stability of the conjugate is essential for vaccine efficacy, physicochemical analyses are necessary to ensure the integrity of these vaccines. Analytical methods used in conjugate vaccine development and production vary among manufacturers due to different components and conjugation chemistries. In the recent past, control authorities have focused on chemical analyses and conventional immunodiffusion and enzyme-linked immunosorbent assays to evaluate the protein and polysaccharide components of glycoconjugate vaccines.We have developed one-dimensional 500 MHz proton nuclear magnetic resonance (NMR) spectroscopy to determine the identity and purity of the polysaccharide component. The NMR spectrum of polyribosyl ribitol phosphate (PRP) was consistent with the structure of the repeating unit, and any trace contaminants were readily detected. We have also developed gel-permeation chromatography to assess the structure and stability of two conjugate vaccines. The characteristic peak height relationship for each manufacturer's product was consistent, with no detectable changes when stored according to manufacturer's specifications. Vaccine stability was determined by examining samples subjected to high temperatures for prolonged periods of time, and aggregation and degradation of vaccines was detected using this method. These physicochemical analyses are essential because there is no suitable animal model that correlates with immunogenicity in man. Therefore, there is an urgent need to develop new analytical procedures and biological correlates of activity in order to control Hib vaccines and develop new glycoconjugate vaccines against other pathogenic bacteria.In this study, NMR and fast-protein liquid chromatography (FPLC) analyses were used to determine the identity, purity, and stability of two Hib conjugate vaccines licensed for use in the UK. Our results demonstrate that physicochemical methods can be used to evaluate the manufacturing consistency and stability of protein-polysaccharide conjugate vaccines.
    Pharmacy and Pharmacology Communications. 03/2011; 3(1):19 - 23.
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    ABSTRACT: The WHO First International Reference Preparation for BCG vaccine is over forty years old and is no longer available for distribution due to stock depletion and its significant loss of viability. International consultations identified a demand for replacement with sub-strain specific BCG preparations. An International collaborative study was carried out to evaluate three candidates for WHO Reference Reagent for BCG vaccine of Danish 1331, Russian BCG-I and Tokyo 172-1 sub-strains. These candidates were quantified for viability using both cultural viable count and modified ATP assays. The proposal for the establishment of these First WHO Reference Reagents for BCG vaccines was discussed in the WHO Expert Committee on Biological Standardization meeting, October 2009.
    Vaccine 11/2010; 29(3):512-8. · 3.77 Impact Factor
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    ABSTRACT: Whole cell pertussis vaccine is still widely used in many countries. An International Standard is needed for its potency control. The Third International Standard for Pertussis Vaccine was prepared about 40 years ago and its replacement was recommended by the Expert Committee for Biological Standardisation (ECBS) of the WHO. Material in ampoules coded 94/532 was prepared as a candidate replacement and has been evaluated in international collaborative studies which consisted of two parts. The first part, to assess the suitability of the candidate standard by comparing it with the Second International Standard for Pertussis Vaccine (IS2) involved 14 laboratories in 11 countries. The second part to compare the candidate standard with the Third International Standard for Pertussis Vaccine (IS3) involved 16 laboratories in 14 countries. Since 1995 various other studies have included the international standards and the results of these are also considered in assessing likely continuity of the IU for potency of whole cell pertussis vaccine. The preparation in ampoules coded 94/532 was adopted by the WHO ECBS in October 2006 as the 4th International Standard for whole cell pertussis vaccine and assigned an activity of 40 IU per ampoule on the basis of the studies reported here.
    Biologicals 11/2010; 38(6):644-51. · 1.62 Impact Factor
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    ABSTRACT: Current methods for the identification of BCG vaccine in quality control settings involve acid-fast staining with microscopic examination. However, this method is unable to distinguish the many different sub-strains of BCG, or to differentiate BCG strains from virulent members of the Mycobacterium tuberculosis complex. A multiplex PCR (mPCR) which uses six target regions in mycobacteria has been developed to identify specific sub-strains of BCG. This study reports the findings from an international collaborative study to assess the accuracy, robustness and reproducibility of this mPCR method to differentiate BCG sub-strains. The method was found to fulfil these criteria successfully and was able to distinguish BCG sub-strains in vaccine preparations. The majority of the participants in the study generated the expected PCR product profiles indicating the method is also robust.
    Vaccine 10/2010; 28(43):6964-9. · 3.77 Impact Factor
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    ABSTRACT: The histamine sensitisation test (HIST) for pertussis toxin is currently an official batch release test for acellular pertussis containing combination vaccines in Europe and North America. However, HIST, being a lethal endpoint assay, often leads to repeated tests due to large variations in test performance. Although a more precise HIST test based on measurement of temperature reduction after the histamine challenge is used in Asian countries, this test still uses animals. An in vitro test system based on a combination of enzyme coupled-HPLC and carbohydrate-binding assays with results analysed by a mathematical formula showed a good agreement with the in vivo HIST results based on measurement of temperature reduction after histamine challenge. The new in vitro test system was shown to be a potential alternative to the current in vivo HIST.
    Vaccine 03/2010; 28(21):3714-21. · 3.77 Impact Factor
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    ABSTRACT: Biosimilarity is a significant issue for vaccines and a reasonable approach to this could facilitate licensing of follow-on products of similar design. However, the definitions and guideline criteria developed for similar versions of biotherapeutics may be too restrictive for vaccines, as the molecular composition of their active substances can rarely be defined precisely, and immunogenicity is an essential rather than an undesirable characteristic. Similarity in antigenic composition may be more relevant. The criteria that determine biosimilarity need more careful definition; superficial similarity may conceal significant differences in performance that can only be disclosed by careful clinical evaluation. These issues have been reviewed in detail for current types of bacterial and viral vaccines. For truly biosimilar products, limited clinical studies could be acceptable provided that they permit side-by-side comparison with the original product or another suitable reference. The prospect of the development of biosimilar products also emphasizes the need for improved regulatory tests capable of detecting subtle but biologically significant differences in vaccines. The need for an acceptable definition of biosimilarity and guidelines relevant to vaccines is emphasized.
    Expert Review of Vaccines 10/2009; 8(10):1439-49. · 4.22 Impact Factor
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    ABSTRACT: The modified intra-cerebral challenge assay for acellular pertussis vaccines is used in Japan, Korea, China and possibly other Asian countries as the potency assay for routine release of acellular pertussis (aP) and combination vaccines. National reference standards, typically of whole cell pertussis (Pw) vaccine, are in use in these countries, but there is no agreed international reference standard for acellular pertussis vaccines. We report here the results of a collaborative study initiated in September 2006 in which fourteen laboratories performing the modified intra-cerebral challenge assay took part. These laboratories compared their various national references of Pw vaccine, the third International Standard for whole cell pertussis vaccine, a previously studied two-component freeze-dried aP vaccine preparation coded JNIH-3, and four different aP vaccines in combination with diphtheria and tetanus toxoids. The results of this study show that the modified intra-cerebral challenge assay works reliably although there are inter-laboratory variations in potency estimates. Pw and aP vaccines show apparent differences in dose-response lines in some assay systems. This indicates dissimilarity in performance in at least some of these assay systems. Estimates of relative potency for aP vaccines in terms of the Pw vaccine national or in-house reference preparations differ significantly from one another. Different mouse strains were used in each country and the different strains may also differ in their responsiveness to Pw and aP vaccines. Estimates for different types of aP vaccine formulations show less inter-laboratory variation in terms of JNIH-3 than in terms of the third IS for Pw vaccine and the remaining variation is not apparently related to the different mouse strains. This study thus suggests that an aP vaccine standard would improve inter-laboratory agreement. These data do not show significant dissimilarity in dose-response lines between JNIH-3 and the various vaccine products included, irrespective of the differences in aP components. Available data indicate that JNIH-3 is sufficiently stable to serve as an International Standard. On the basis of these results and with the agreement of the participants, it was proposed that JNIH-3 should be established as an International Standard for acellular pertussis vaccine for use in the modified intra-cerebral challenge assay and other protective bioassays, with an assigned activity of 34 International Units (IU) per ampoule. A WHO Working Group on Standardization of Acellular Pertussis Vaccines: potency assay met in Beijing, China, 7-9 November 2007. This group considered the report of this study, the comments of the participants and implications of the use of JNIH-3 as a reference standard and recommended establishment of JNIH-3 as an International Standard. The results of this study and the report of the Working Group were submitted to the Expert Committee on Biological Standardization (ECBS) of WHO which established JNIH-3 as the first International Standard for acellular pertussis vaccine in the modified intra-cerebral challenge assay and other protective bioassays with an assignment of 34IU per ampoule in October 2008.
    Vaccine 09/2009; 27(49):6824-32. · 3.77 Impact Factor
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    ABSTRACT: All current acellular pertussis vaccines (ACVs) contain detoxified pertussis toxin (PT) as a major component. An essential part of the safety evaluation of these vaccines, required by regulatory authorities, is to monitor their active PT content and to check for reversion to toxicity of the detoxified PT. Although various in vitro tests are under investigation, the only practicable means for detecting active PT at present is the histamine sensitization test. The methods given in the European Pharmacopoeia and in the US Pharmacopoeia are based on recording a binary response to histamine challenge (using a lethal end point). A more sensitive method based on measurement of rectal temperature is given in the Japanese Minimum Requirements for Biological Products. More recently, a refinement of this method based on dermal temperature measurement has been developed for ACVs in combination with diphtheria and tetanus vaccines (DTaP). We show that this method also can be used for more complex combination vaccines and is readily transferable. Furthermore use of dermal temperature provides a more precise quantitative estimate of toxin activity than the binary response, leading to an increase in information from a specified number of animals, or allowing a reduction in the number of animals required. We suggest that, pending the development of an alternative in vitro replacement method, the temperature based method may serve as an intermediate solution to the estimation of PT activity giving a precise estimate with reduction in animal numbers.
    Human vaccines 04/2009; 5(3):166-71. · 3.14 Impact Factor
  • Fatme Mawas, Mei Mei Ho, Michael J Corbel
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    ABSTRACT: The success of the immunization programs against Haemophilus influenzae type b and, more recently, Streptococcus pneumoniae in developed and some developing countries has demonstrated that invasive disease caused by these bacteria can be very effectively controlled by vaccination. There is also evidence that pneumococcal vaccines can reduce the incidence of acute otitis media in children. More complete control of this disease would be achieved if infections caused by Moraxella catarrhalis and nontypeable H. influenzae, the other common agents of otitis media in children and of a number of respiratory-associated infections in both children and adults, could also be controlled. Since these bacteria do not possess capsules and are not known to secrete exotoxins, the search for vaccine candidates has focused on the conserved epitopes exposed on the bacterial outer membrane. In this article, we review the contribution of M. catarrhalis to disease and recent advances in the development and testing of various vaccine candidates against this bacterium, including those still in the development stage and those approaching clinical trials. Recommendations are proposed for approaches needed for the standardization of assays and use of appropriate animal models for quality-control testing of these vaccine candidates. Regulatory issues surrounding vaccines of this type are also discussed.
    Expert Review of Vaccines 02/2009; 8(1):77-90. · 4.22 Impact Factor
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    ABSTRACT: Enzyme-linked immunosorbent assay (ELISA) has been widely used to evaluate antibody responses to pertussis vaccination and infection. A common reference serum is essential for the standardization of these assays. However, no internationally recognized reference serum is available. At the request of the Expert Committee on Biological Standardization (ECBS) of the World Health Organization (WHO), a set of four candidate international standards has been prepared. These candidate materials have been assessed for suitability and compared to the widely used U.S. reference pertussis antiserum (human) lot 3, lot 4, and lot 5 by 22 laboratories from 15 countries in an international collaborative study. Laboratories measured immunoglobulin G (IgG) and IgA antibodies to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin (PRN), and fimbriae (Fim2&3) using their established immunoassays. The results of this study showed each of the four candidates to be suitable as an international standard. With the agreement of the participants, a recommendation has been made to the ECBS that the candidate material coded 06/140 be established as the First International Standard for pertussis antiserum (human), with the following assigned international units (IU): IgG anti-PT, 335 IU/ampoule; IgA anti-PT, 65 IU/ampoule; IgG anti-FHA, 130 IU/ampoule; IgA anti-FHA, 65 IU/ampoule; IgG anti-PRN, 65 IU/ampoule; and IgA anti-PRN, 42 IU/ampoule. No formal units have been proposed for anti-Fim2&3 because most assays used a mixture of fimbrial antigens. In addition, the candidate material coded 06/142 has been proposed as a WHO working preparation for characterization of assay systems.
    Clinical and vaccine Immunology: CVI 12/2008; 16(3):303-11. · 2.60 Impact Factor
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    ABSTRACT: As part of the World Health Organisation (WHO) initiative to update the current requirements for BCG vaccine a collaborative study was carried out to establish the robustness, reproducibility and the suitability of the modified ATP assay. This assay was developed by Statens Serum Institut, Denmark, as a potential replacement of the method for detection of viable counts of BCG vaccine which is routinely used as a quality control test for lot release. Two BCG preparations, of same strain but different production methods, were tested. For each preparation, two different storage conditions of -20 or 37 degrees C were used in order to establish the suitability of this assay for testing heat-treated BCG vaccine as in the temperature stability test. The lyophilised BCG samples were tested using the ATP reagents from the same source and same principle of testing but some procedural modifications were allowed to accommodate different equipment and resource availability in different laboratories. Data from four laboratories showed that the heat-treated BCG samples contained significantly lower ATP content per sample than the untreated control stored at -20 degrees C. Three laboratories gave consistent mean ATP contents, especially for control samples, even with variations in testing protocol. The present study showed that this modified ATP assay is very robust and can be reproducible. Once the correlation of cultural viable count and ATP content of a BCG vaccine product has been established, this rapid alternative assay may be used to monitor BCG viable count. Due to the fact that this study was small, further investigation is planned. A collaborative study will be carried out using this modified ATP assay in parallel with the cultural viable count method in the establishment of the replacement of the WHO International Reference Preparation of BCG vaccine.
    Vaccine 07/2008; 26(36):4754-7. · 3.49 Impact Factor
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    ABSTRACT: This report reflects the discussion and conclusions of a WHO group of experts from National Regulatory Authorities (NRAs), National Control Laboratories (NCLs), vaccine industries and other relevant institutions involved in standardization and control of diphtheria, tetanus and pertussis vaccines (DTP), held on 20-21 July 2006 and 28-30 March 2007, in Geneva Switzerland for the revision of WHO Manual for quality control of DTP vaccines. Taking into account recent developments and standardization in quality control methods and the revision of WHO recommendations for D, T, P vaccines, and a need for updating the manual has been recognized. In these two meetings the current situation of quality control methods in terms of potency, safety and identity tests for DTP vaccines and statistical analysis of data were reviewed. Based on the WHO recommendations and recent validation of testing methods, the content of current manual were reviewed and discussed. The group agreed that the principles to be observed in selecting methods included identifying those critical for assuring safety, efficacy and quality and which were consistent with WHO recommendations/requirements. Methods that were well recognized but not yet included in current Recommendations should be taken into account. These would include in vivo and/or in vitro methods for determining potency, safety testing and identity. The statistical analysis of the data should be revised and updated. It was noted that the mouse based assays for toxoid potency were still quite widely used and it was desirable to establish appropriate standards for these to enable the results to be related to the standard guinea pig assays. The working group was met again to review the first drafts and to input further suggestions or amendments to the contributions of the drafting groups. The revised manual was to be finalized and published by WHO.
    Vaccine 05/2008; 26(16):1913-21. · 3.49 Impact Factor
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    ABSTRACT: Haemophilus influenzae b conjugate vaccines (Hib) are almost entirely evaluated by physico-chemical methods to ensure the consistency of manufacture of batches. As different assays are employed for the quantification of Hib capsular polysaccharide PRP (polyribosyl ribitol phosphate; 5-D-ribitol-(1-->1)-beta-D-ribose-3-phosphate) in final formulations and bulk components, there was deemed a need for an International Standard of Hib PRP polysaccharide to be made available. Ten laboratories from 8 different countries participated in a collaborative study to determine the PRP content and assess the suitability of a candidate International Standard PRP preparation (02/208). The results illustrate that a reduction in between-laboratory variability could be achieved by use of a common reference preparation and data analysis showed no significant differences in the values obtained by the different assays: ribose, phosphorus, and high performance anion exchange chromatography-pulsed amperometric detection (HPAEC-PAD), suggesting the suitability of the proposed reference for use across these assays for quantification of PRP content in Hib vaccines. On the basis of the results of this study, the First International Standard for PRP, NIBSC Code 02/208, has been established by the Expert Committee of Biological Standards of the World Health Organisation, with a content of 4.933+/-0.267mg/ampoule, as determined by the ribose assays carried out by 7 of the participating laboratories.
    Biologicals 10/2007; 35(4):235-45. · 1.62 Impact Factor
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    ABSTRACT: The physico-chemical characteristics and immunogenicity of a candidate vaccine against otitis media, prepared from recombinant lipidated outer membrane proteins (rLP4 and rLP6) from non-typeable Haemophilus influenzae (NTHi) and of the ubiquitous cell surface protein UspA2 from Moraxella catarrhalis, were evaluated. Optical spectroscopy, size exclusion chromatography and gel electrophoresis were used to characterise the purified protein components and assess their purity and molecular sizes. The results showed that the three proteins were highly purified. Possible dimers in rLP4, dimers and multimers in rLP6 and UspA2 were detected. Small amounts of rLP4 and rLP6 dimers and most of UspA2 complexes remained tightly bound even after SDS treatment under reducing conditions. Immunogenicity studies showed that all proteins induced substantial antibody responses in mice immunised with AlPO4-adsorbed rLP4, rLP6 or UspA2 or a combination of these proteins. However, combination of these proteins resulted in a reduced response to rLP4 and rLP6, but not to UspA2, suggesting interference between these proteins which should be taken into consideration during the development and evaluation of this vaccine.
    Vaccine 07/2007; 25(25):4801-8. · 3.49 Impact Factor
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    ABSTRACT: This report reflects the discussion and conclusions of a WHO group of experts from national regulatory authorities, national control laboratories, vaccine industry and other relevant institutions involved in standardisation and control of acellular pertussis vaccines, held on 16-17 March 2006, in St. Albans, UK. Following previous discussions (Bethesda, 2000; Ferney-Voltaire, 2003; Geneva, 2005) and collection of relevant data for quality control, on the one hand, and clinical evaluation of acellular pertussis vaccines, on the other, this meeting was intended to review the scientific basis for the revision of WHO guidelines adopted in 1996 [Guidelines for the production and control of the acellular pertussis component of monovalent or combined vaccines. In: WHO Expert Committee on Biological Standardisation. Forty-seventh report. Geneva, World Health Organisation, 1998 (WHO Technical Report Series, No. 878), Annex 2]. The discussion on animal protection models, immunogenicity and toxicity testing was focused on three main aspects: value of the assay for the purpose of licensing and/or lot release; validity criteria and potential optimisation of the assays. The group agreed that establishment of JNIH-3 as a potential International Standard (IS) for modified intra-cerebral challenge assay should be under consideration. It was suggested that the inclusion of a reference vaccine, such as JNIH-3 in the intra-nasal challenge model could improve the standardisation of this assay. It was proposed that the development of stable reference vaccines for immunogenicity testing should be encouraged. Further collection of the data from the countries with established lot release of acellular pertussis vaccines will be undertaken to prepare a solid basis for recommendations on toxicity tests. In the context of recommendations for clinical assessment of new vaccines, the group emphasised the importance of comparability studies with antigens that have already undergone efficacy trials in the past. The outline for the section on clinical evaluation of acellular pertussis vaccines was presented and after the consultation further additions were made. Post-marketing surveillance was recognised as an important part of overall vaccine evaluation and a unique opportunity to understand vaccine performance in the population and to establish a link with quality control.
    Vaccine 05/2007; 25(15):2749-57. · 3.49 Impact Factor
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    ABSTRACT: Pertussis toxin (PTx) is a major virulence factor produced by Bordetella pertussis. In its detoxified form (PTd), it is an important component of acellular pertussis vaccines although some residual PTx activity may likely be present because of the limitations of the detoxification processes used. Furthermore, different detoxification procedures have been shown to result in different amino acid side-chain modifications for the resulting PTd. The histamine-sensitisation test (HIST) in mice is currently used for the safety testing of these vaccines. However, an alternative test is needed because of large assay variability and ethical concerns. The ADP-ribosylation enzyme activity of PTx is thought to be the major factor responsible for the histamine-sensitising activity detected in vivo. In the present study, the ADP-ribosylation activity in different acellular pertussis-based combination vaccine formulations was measured and compared with reactivity in the HIST. The results indicated that different products showed differences in ADP-ribosylation activity and a level which would be significant in relation to the reactivity seen in the HIST could not be defined, except for vaccines that contain genetically detoxified PTx, which do not have enzymatic activity nor in vivo toxicity. Different detoxification procedures as well as formulation factors could contribute to this variation. Relying solely on the residual enzyme activity of PTx in vaccines containing chemically detoxified PTd may not fully reflect the in vivo reactivity observed by the HIST. Refinement of the in vitro test to include a step which monitors the B-subunit activity of PTx may provide a better correlation with the in vivo HIST.
    Vaccine 05/2007; 25(17):3311-8. · 3.49 Impact Factor
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    ABSTRACT: Following the reduction in efficacy of Hib-TT vaccines in the primary immunization schedule observed in the UK between 1999 and 2003, batches of vaccine manufactured by two different companies were retrospectively examined by the National Institute for Biological Standards and Control. The study evaluated 41 batches of the Hib-TT vaccines manufactured between 1994 and 2003, assaying potency (total PRP saccharide content), integrity (% free saccharide), consistency (molecular sizing), and immunogenicity, as well as reviewing data previously obtained at the time of release. The study indicated the stability of the lyophilized final fill vaccines to extend well past their assigned shelf-lives, and found no trends in the endotoxin content, total saccharide or % free saccharide content. A trend towards slightly larger conjugates was observed over time in Hib-TT A, evidenced in both the manufacturer's data obtained at the time that samples were submitted for testing and in data obtained from the retrospective analysis. The study confirmed that that there had been no significant change in the quality of the Hib vaccines that could possibly account for the change reported in their protective efficacy in the UK. The study also demonstrated the value of independent testing of vaccines from the time of licensure and in the ongoing monitoring and re-examination of selected batches, as necessary, to assure their continuing quality, safety and consistency.
    Human vaccines 01/2007; 3(5):176-82. · 3.14 Impact Factor
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    ABSTRACT: Four recombinant forms of the cell-invasive adenylate cyclase toxin (CyaA) of Bordetella pertussis were compared for the ability to enhance protection against B. pertussis in mice when coadministered with an acellular pertussis vaccine (ACV). The four forms were as follows: fully functional CyaA, a CyaA form lacking adenylate cyclase enzymatic activity (CyaA*), and the nonacylated forms of these toxins, i.e., proCyaA and proCyaA*, respectively. None of these forms alone conferred significant (P > 0.05) protection against B. pertussis in a murine intranasal challenge model. Mice immunized with ACV alone showed significant (P < 0.05) reductions in bacterial numbers in the lungs after intranasal challenge compared with those for control mice. When administered with ACV, both CyaA and CyaA* further reduced bacterial numbers in the lungs of mice after intranasal challenge compared with those for ACV-immunized mice, but the enhanced protection was only significant (P < 0.05) with CyaA*. Coadministration of CyaA* with ACV caused a significant (P < 0.05) increase in immunoglobulin G2a antibody levels against pertactin compared with those in mice immunized with ACV alone. Spleen cells from mice immunized with ACV plus CyaA* secreted larger amounts of interleukin-5 (IL-5), IL-6, gamma interferon (IFN-gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) than did cells from mice immunized with ACV plus CyaA or ACV alone after stimulation in vitro with a mixture of B. pertussis antigens. Spleen cells from mice immunized with ACV plus CyaA* also secreted larger amounts of IFN-gamma and GM-CSF than did cells from mice immunized with CyaA* alone after stimulation in vitro with CyaA*. Macrophages from mice immunized with ACV plus CyaA* produced significantly (P < 0.05) higher levels of nitric oxide than did macrophages from mice immunized with CyaA* alone, ACV alone, or ACV plus CyaA after stimulation in vitro with a mixture of B. pertussis antigens or heat-killed B. pertussis cells. These data suggest that the enhancement of protection provided by CyaA* was due to an augmentation of both Th1 and Th2 immune responses to B. pertussis antigens.
    Infection and Immunity 01/2007; 74(12):6797-805. · 4.07 Impact Factor

Publication Stats

912 Citations
86 Downloads
326.02 Total Impact Points

Institutions

  • 1991–2013
    • National Institute for Biological Standards and Control
      • Biotherapeutics
      Potters Bar, England, United Kingdom
  • 2010
    • Public Health England
      Londinium, England, United Kingdom
  • 2006
    • World Health Organization WHO
      Genève, Geneva, Switzerland
  • 2004
    • University of California, Los Angeles
      • Department of Pediatrics
      Los Angeles, CA, United States
  • 2002
    • University of Glasgow
      Glasgow, Scotland, United Kingdom