Jamie Findlow

Publications of Jamie Findlow

• Immunogenicity of a Single Dose of Meningococcal Group C Conjugate Vaccine Given at 3 Months of Age to Healthy Infants in the United Kingdom.

  Authors: Helen Findlow, Ray Borrow, Nick Andrews, Pauline Waight, Elizabeth Sheasby, Mary Matheson, Anna England, David Goldblatt, Lindsey Ashton, Jamie Findlow, Elizabeth Miller

  The Pediatric infectious disease journal. 02/2012;

  BACKGROUND:: From 1999, in the UK, meningococcal C conjugate (MCC) vaccines from 3 manufacturers, were introduced to the infant immunization schedule at 2,3 and 4 months of age. In 2006, the scheduleBACKGROUND:: From 1999, in the UK, meningococcal C conjugate (MCC) vaccines from 3 manufacturers, were introduced to the infant immunization schedule at 2,3 and 4 months of age. In 2006, the schedule was refined to a two dose primary schedule at 3 and 4 months of age, with a combined MCC/Haemophilus influenzae type b (MCC/Hib-TT) booster at 12 months of age. Recent data have demonstrated that two of the three MCC vaccines showed potential for use as a single priming dose in infancy. METHODS:: A randomized trial was undertaken with two MCC vaccines; one using tetanus toxoid carrier protein (MCC-TT) and one using CRM197 carrier protein (MCC-CRM197). Infants were immunized with MCC at 3 months of age followed by a MCC/Hib-TT booster at 12 months of age. RESULTS:: The serum bactericidal antibody (SBA) geometric mean titers (GMT) one month following a single dose of MCC-TT or MCC-CRM197 were 223.3 (95% CI 162.9-306.1) and 95.8 (95% CI 66.4-138.2) with 100% and 95.5% of infants having SBA titers ≥ 8, respectively. Before boosting, antibody titers had declined and 1 month following MCC/Hib-TT booster, SBA GMTs rose to 2251.0 (95% 1535.3-3300.3) and 355.9 (95% CI 235.4-538.1) for children primed with MCC-TT and MCC-CRM197, respectively. CONCLUSION:: In conclusion, a single priming dose of either MCC-TT or MCC-CRM197 administered at 3 months of age can be used together with the Hib/MCC-TT booster in the second year of life.

• Invasive meningococcal capsular group y disease, England and Wales, 2007-2009.

  Authors: Shamez N Ladhani, Jay Lucidarme, Lynne S Newbold, Stephen J Gray, Anthony D Carr, Jamie Findlow, Mary E Ramsay, Edward B Kaczmarski, Raymond Borrow

  Emerging infectious diseases. 01/2012; 18(1):63-70.

  Enhanced national surveillance for invasive meningococcal disease in England and Wales identified an increase in laboratory-confirmed capsular group Y (MenY) disease from 34 cases in 2007 to 44 inEnhanced national surveillance for invasive meningococcal disease in England and Wales identified an increase in laboratory-confirmed capsular group Y (MenY) disease from 34 cases in 2007 to 44 in 2008 and 65 in 2009. For cases diagnosed in 2009, patient median age at disease onset was 60 years; 39% of patients had underlying medical conditions, and 19% died. MenY isolates causing invasive disease during 2007-2009 belonged mainly to 1 of 4 clonal complexes (cc), cc23 (56% of isolates), cc174 (21%), cc167 (11%), and cc22 (8%). The 2009 increase resulted primarily from sequence type 1655 (cc23) (22 cases in 2009, compared with 4 cases each in 2007 and 2008). cc23 was associated with lpxL1 mutations and meningitis in younger age groups (<25 years); cc174 was associated with nonmeningitis, particularly pneumonia, in older age groups (>65 years). The increase in MenY disease requires careful epidemiologic and molecular monitoring.

• Correlation of group C meningococcal conjugate vaccine response with B- and T-lymphocyte activity.

  Authors: James B Wing, Lynne Smart, Ray Borrow, Jamie Findlow, Helen Findlow, Andrew Lees, Robert C Read, Andrew W Heath

  PloS one. 01/2012; 7(2):e31160.

  Despite the success of conjugate vaccination against meningococcal group C (MenC) disease, post-vaccination, some individuals still exhibit rapid waning of initially protective bactericidal antibodyDespite the success of conjugate vaccination against meningococcal group C (MenC) disease, post-vaccination, some individuals still exhibit rapid waning of initially protective bactericidal antibody levels. The mechanism of this relative loss of humoral protection remains undetermined. In this report we have investigated the relationship between T- and B-cell activation and co-stimulation and the loss of protective antibody titers. We have found that healthy volunteers who lose protective MenC antibody levels one year after receipt of glycoconjugate vaccine exhibit no detectable cellular defect in polyclonal B- or T-cell activation, proliferation or the B-memory pool. This suggests that the processes underlying the more rapid loss of antibody levels are independent of defects in either initial T- or B-cell activation.

• Structural characterisation, stability and antibody recognition of chimeric NHBA-GNA1030: An investigational vaccine component against Neisseria meningitidis.

  Authors: Angela Martino, Claudia Magagnoli, Giuseppe De Conciliis, Sandro D'Ascenzi, Mark J Forster, Lauren Allen, Charlotte Brookes, Stephen Taylor, Xilian Bai, Jamie Findlow, Ian M Feavers, Alison Rodger, Barbara Bolgiano

  Vaccine. 12/2011; 30(7):1330-42.

  A new generation multi-component vaccine, principally directed against serogroup B Neisseria meningitidis (4CMenB), has recently been developed. One of its components, identified through reverseA new generation multi-component vaccine, principally directed against serogroup B Neisseria meningitidis (4CMenB), has recently been developed. One of its components, identified through reverse vaccinology, is the neisserial heparin-binding antigen (NHBA) which is included in the formulation as a novel NHBA-GNA1030 fusion protein (NHBA-FP). We describe here the biophysical characteristics of this vaccine antigen to understand better its structural properties in solution and concurrent immunogenicity prior to formulation. By deliberately stressing the protein to lose its immune responses, we were able to study the protein's structural changes at the molecular level. The unmodified NHBA-FP was found to be mainly monomeric with mass of 67kDa and secondary structure dominated by β-sheets and turns (57% average). The antigen was very stable in storage buffer. It could be forced to unfold in a low-salt buffer resulting in the exposure of one of its two tryptophan residues at 50°C. Long-term stress studies (10-15 days at 37°C) showed modification in the chromatographic and electrophoretic profiles with progressive degradation and aggregation. Since there was little change in secondary structure (as monitored by circular dichroism and tryptophan fluorescence spectroscopy), the loss of functional immunogenicity of the thermal stressed protein could be mainly attributed to the observed fragmentation and aggregation. We therefore conclude that the maintenance of the intact, non-fragmented state of the NHBA-FP is important to preserve its functional immunogenicity. This may thus be utilised as an assay for the control testing of the protein.

• Recombinant protein meningococcal serogroup B vaccine combined with outer membrane vesicles.

  Authors: Xilian Bai, Jamie Findlow, Ray Borrow

  Expert opinion on biological therapy. 07/2011; 11(7):969-85.

  INTRODUCTION: Meningococcal infection is a major cause of morbidity and mortality worldwide. Infection with Neisseria meningitidis is most common in young children, teenagers and people with certainINTRODUCTION: Meningococcal infection is a major cause of morbidity and mortality worldwide. Infection with Neisseria meningitidis is most common in young children, teenagers and people with certain medical conditions. Effective polysaccharide and glycoconjugate vaccines for serogroups A, C, W135 and Y have been developed. A similar capsular polysaccharide approach for serogroup B (MenB) has by most been judged as unsuitable, hence, no broad coverage vaccine has been licensed to date. The novel vaccine Bexsero (previously 4CMenB) has been developed and proven safe and immunogenic in clinical trials. AREAS COVERED: The authors outline the constituents of Bexsero and immunogenicity and safety data from preclinical and clinical trials published in peer-reviewed literature, meeting proceedings and publicly-available clinical trial websites from 2000 to 2010. EXPERT OPINION: Bexsero is well tolerated with a proven safety profile, and has demonstrated a robust immune response across different age groups against a range of diverse MenB strains. These data suggest that Bexsero has the ability to provide protection in infants, who are at the greatest risk of developing meningococcal disease.

• Characterization of Neisseria meningitidis isolates that do not express the virulence factor and vaccine antigen factor H binding protein.

  Authors: Jay Lucidarme, Lionel Tan, Rachel M Exley, Jamie Findlow, Ray Borrow, Christoph M Tang

  Clinical and vaccine immunology : CVI. 06/2011; 18(6):1002-14.

  Neisseria meningitidis remains a leading cause of bacterial sepsis and meningitis. Complement is a key component of natural immunity against this important human pathogen, which has evolved multipleNeisseria meningitidis remains a leading cause of bacterial sepsis and meningitis. Complement is a key component of natural immunity against this important human pathogen, which has evolved multiple mechanisms to evade complement-mediated lysis. One approach adopted by the meningococcus is to recruit a human negative regulator of the complement system, factor H (fH), to its surface via a lipoprotein, factor H binding protein (fHbp). Additionally, fHbp is a key antigen in vaccines currently being evaluated in clinical trials. Here we characterize strains of N. meningitidis from several distinct clonal complexes which do not express fHbp; all strains were recovered from patients with disseminated meningococcal disease. We demonstrate that these strains have either a frameshift mutation in the fHbp open reading frame or have entirely lost fHbp and some flanking sequences. No fH binding was detected to other ligands among the fHbp-negative strains. The implications of these findings for meningococcal pathogenesis and prevention are discussed.

• Kinetics of immune responses to nasal challenge with meningococcal polysaccharide one year after serogroup-C glycoconjugate vaccination.

  Authors: James B Wing, Lynne Smart, Ray Borrow, Jamie Findlow, Helen Findlow, Andrew W Heath, Robert C Read

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 06/2011; 52(11):1317-23.

  Recipients of serogroup-C glycoconjugate meningococcal vaccine (MCC) exhibit waning of serum bactericidal antibody (SBA) titers, but the rate of decline and the speed of their immunological memory inRecipients of serogroup-C glycoconjugate meningococcal vaccine (MCC) exhibit waning of serum bactericidal antibody (SBA) titers, but the rate of decline and the speed of their immunological memory in response to new meningococcal nasopharyngeal colonization are unknown. In a prospective challenge study, we measured persistence of SBA and anti-Neisseria meningitidis serogroup-C (MenC) immunoglobulin (Ig) G and IgA in adults aged 18-39, 28 days and 12 months after receiving MCC. Volunteers were then challenged intranasally with 50 μg MenC polysaccharide to mimic meningococcal colonization, and systemic and mucosal antibody responses were measured. All subjects had protective SBA titers (≥8) 28 days after MCC vaccination, but 12.3% and 20.2% had unprotective (<8) or low (<128) levels, respectively, after 12 months. Following rechallenge (12 months postvaccination) and measurement of antibody responses after 4, 7, and 10 days, rises in SBA titers were only observed in subjects with low (<128) or nonprotective (<8) prerechallenge SBA titers. In subjects with pre rechallenge SBA titers <8, the majority did not reach a protective SBA titer until 7 days post-rechallenge. MenC-specific IgG levels rose in both serum and saliva in correlation with SBA titers. No detectable rise in salivary IgA was observed. In those individuals who fail to retain protective SBA 12 months after MCC, immunological memory fails to generate protective systemic and mucosal antibodies until 7 days post intranasal challenge with cognate meningococcal polysaccharide. This is likely too slow to protect from natural meningococcal infection. MCC vaccinees rely on persistence of antibody levels rather than immunological memory for sustained protection.

• Molecular targets in meningococci: efficient routine characterization and optimal outbreak investigation in conjunction with routine surveillance of the meningococcal group B vaccine candidate, fHBP.

  Authors: Jay Lucidarme, Lynne S Newbold, Jamie Findlow, Stefanie Gilchrist, Stephen J Gray, Anthony D Carr, James Hewitt, Edward B Kaczmarski, Ray Borrow

  Clinical and vaccine immunology : CVI. 02/2011; 18(2):194-202.

  In 2007, recommendations were proposed for the molecular typing of meningococci. Multilocus sequence typing (MLST) was recommended to guide national and international disease management andIn 2007, recommendations were proposed for the molecular typing of meningococci. Multilocus sequence typing (MLST) was recommended to guide national and international disease management and facilitate studies of population biology and evolution. Sequencing of porA variable regions (VRs) 1 and 2 and the fetA VR was recommended for monitoring antigenic distribution and investigating potential outbreaks. porB characterization was recommended if further resolution was required. Several investigational "group B" meningococcal vaccines, including two in the advanced stages of development, incorporate factor H-binding protein (fHBP). The requirement for routine surveillance of fhbp places additional pressure on reference laboratories, both financially and in terms of labor. This study investigated the optimal and most efficient molecular typing schemes for (i) routine meningococcal characterization and (ii) the investigation of potential outbreaks, in conjunction with routine surveillance of fhbp. All invasive disease isolates received by the Health Protection Agency Meningococcal Reference Unit between July 2007 and June 2008 (n = 613) were characterized in terms of capsular group, porA, fetA VR, fhbp, and sequence type (ST). Following capsular grouping and porA genosubtyping, several predominant capsular group-porA combinations were identified. The levels of additional resolution afforded by fetA and fhbp were comparable and partially complementary. fhbp constitutes an effective substitute for fetA as a routine marker of antigenic distribution, thereby reducing costs in conjunction with fhbp surveillance. MLST afforded markedly superior resolution overall and is the optimal scheme for investigating outbreaks in which (i) typing data are unavailable for the index case or (ii) the index case possesses a known, predominant capsular group-porA repertoire.

• Nasopharyngeal colonization by Neisseria lactamica and induction of protective immunity against Neisseria meningitidis.

  Authors: Cariad M Evans, Catherine B Pratt, Mary Matheson, Thomas E Vaughan, Jamie Findlow, Ray Borrow, Andrew R Gorringe, Robert C Read

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 01/2011; 52(1):70-7.

  Natural immunity to Neisseria meningitidis may result from nasopharyngeal carriage of closely related commensals, such as Neisseria lactamica. We enrolled 61 students with no current carriage ofNatural immunity to Neisseria meningitidis may result from nasopharyngeal carriage of closely related commensals, such as Neisseria lactamica. We enrolled 61 students with no current carriage of Neisseria species and inoculated them intranasally with 10,000 colony-forming units of Neisseria lactamica or sham control. Colonization was monitored in oropharyngeal samples over 6 months. We measured specific mucosal and systemic antibody responses to N. lactamica and serum bactericidal antibody (SBA) and opsonophagocytic antibodies to a panel of N. meningitidis serogroup B strains. We also inoculated an additional cohort following vaccination with N. lactamica outer-membrane vesicles (OMV) produced from the same strain. Twenty-six (63.4%) of 41 inoculated individuals became colonized with N. lactamica; 85% remained colonized at 12 weeks. Noncarriers were resistant to rechallenge, and carriers who terminated carriage were relatively resistant to rechallenge. No carriers acquired N. meningitidis carriage over 24 weeks, compared with 3 control subjects (15%). Carriers developed serum IgG and salivary IgA antibodies to the inoculated N. lactamica strain by 4 weeks; noncarriers and control subjects did not. Cross-reactive serum bactericidal antibody responses to N.meningitidis were negligible in carriers, but they developed broad opsonophagocytic antimeningococcal antibodies. OMV vaccinees developed systemic and mucosal anti-N. lactamica antibodies and were relatively resistant to N. lactamica carriage but not to natural acquisition of N. meningitidis. Carriers of N. lactamica develop mucosal and systemic humoral immunity to N. lactamica together with cross-reacting systemic opsonophagocytic but not bactericidal antibodies to N. meningitidis. Possession of humoral immunity to N. lactamica inhibits acquisition of N. lactamica but not of N. meningitidis. Some individuals are intrinsically resistant to N. lactamica carriage, independent of humoral immunity.

• Immunogenicity of two investigational serogroup B meningococcal vaccines in the first year of life: a randomized comparative trial.

  Authors: Matthew D Snape, Tom Dawson, Philipp Oster, Anita Evans, Tessa M John, Brigitte Ohene-Kena, Jamie Findlow, Ly-Mee Yu, Ray Borrow, Ellen Ypma, Daniela Toneatto, Andrew J Pollard

  The Pediatric infectious disease journal. 11/2010; 29(11):e71-9.

  An investigational vaccine against serogroup B meningococcal (MenB) disease containing 3 main recombinant proteins (factor H-binding protein, Neisserial adhesion A, and Neisserial heparin-bindingAn investigational vaccine against serogroup B meningococcal (MenB) disease containing 3 main recombinant proteins (factor H-binding protein, Neisserial adhesion A, and Neisserial heparin-binding antigen) has been developed. We evaluated the immunogenicity and reactogenicity of a 3-dose course of this vaccine administered alone (recombinant MenB [rMenB]) or combined with the outer membrane vesicle (OMV) component of the vaccine used in New Zealand (rMenB+OMV). A randomized, single-blind, comparative study of 60 healthy infants enrolled at 6 to 8 months of age and immunized with rMenB or rMenB+OMV at day 0, day 60, and at age 12 months. Blood samples obtained at baseline and 1 month following the second and third doses of vaccine were analyzed for serum bactericidal antibody (SBA) using human complement (hSBA) against 7 MenB strains. The putative correlate of protection was an hSBA titer of ≥4. The per-protocol analysis included 24 of 30 participants randomized to each group. After 3 doses of rMenB+OMV, 90% or more of participants had an hSBA titer ≥4 for 5 MenB strains, with 70% of participants having an hSBA titer ≥4 for a sixth strain. rMenB alone was immunogenic for only 3 strains. Both vaccines were well tolerated. Three doses of rMenB+OMV in the second half of infancy induce bactericidal antibodies against strains expressing vaccine antigens, demonstrating the potential for broader vaccine prevention of MenB disease. This vaccine is now in phase III clinical trials.

• Multicenter, open-label, randomized phase II controlled trial of an investigational recombinant Meningococcal serogroup B vaccine with and without outer membrane vesicles, administered in infancy.

  Authors: Jamie Findlow, Ray Borrow, Matthew D Snape, Tom Dawson, Ann Holland, Tessa M John, Anita Evans, Karen L Telford, Ellen Ypma, Daniela Toneatto, Philipp Oster, Elizabeth Miller, Andrew J Pollard

  Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 10/2010; 51(10):1127-37.

  In the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. AnIn the absence of an efficacious broadly protective vaccine, serogroup B Neisseria meningitidis (MenB) is the leading cause of bacterial meningitis and septicemia in many industrialized countries. An investigational recombinant vaccine that contains 3 central proteins; Neisserial adhesin A (NadA), factor H binding protein (fHBP) and Neisserial heparin binding antigen (NHBA) has been developed. These antigens have been formulated with and without outer membrane vesicles (rMenB+OMV and rMenB, respectively) from the New Zealand epidemic strain (B:4:P1.7-2,4). In this trial, we assessed the immunogenicity of these formulations in infants, who are at greatest risk of contracting MenB disease. A total of 147 infants from the United Kingdom were enrolled and randomly assigned to receive rMenB or rMenB+OMV at 2, 4, 6, and 12 months of age or a single dose at 12 months of age. Serum samples taken before and after vaccination were assayed in a standardized serum bactericidal antibody assay against 7 MenB strains. Local and systemic reactogenicity were recorded for 7 days after each vaccination. Analysis was according to protocol. After 3 doses, both vaccines were immunogenic against strains expressing homologous or related NadA and fHBP. rMenB+OMV demonstrated greater immunogenicity than did rMenB and was immunogenic against strains expressing homologous PorA. Both vaccines elicited anamnestic responses after the fourth dose. For both vaccines, responses were lower against strains expressing heterologous fHBP variants and after a single dose at 12 months. The rMenB+OMV vaccine has the potential to protect infants from MenB disease, although the breadth of protection afforded to heterologous antigens requires additional investigation.

• Characterization of fHbp, nhba (gna2132), nadA, porA, and sequence type in group B meningococcal case isolates collected in England and Wales during January 2008 and potential coverage of an investigational group B meningococcal vaccine.

  Authors: Jay Lucidarme, Maurizio Comanducci, Jamie Findlow, Stephen J Gray, Edward B Kaczmarski, Malcolm Guiver, Pamela J Vallely, Philipp Oster, Mariagrazia Pizza, Stefania Bambini, Alessandro Muzzi, Ray Borrow

  Clinical and vaccine immunology : CVI. 04/2010; 17(6):919-29.

  Invasive disease caused by meningococcal capsular groups A, C, W-135, and Y is now preventable by means of glycoconjugate vaccines that target their respective polysaccharide capsules. The capsule ofInvasive disease caused by meningococcal capsular groups A, C, W-135, and Y is now preventable by means of glycoconjugate vaccines that target their respective polysaccharide capsules. The capsule of group B meningococci (MenB) is poorly immunogenic and may induce autoimmunity. Vaccines based on the major immunodominant surface porin, PorA, are effective against clonal epidemics but, thus far, have a limited scope of coverage against the wider MenB population at large. In an alternative approach, the first-generation, investigational, recombinant MenB (rMenB) plus outer membrane vesicle (OMV) (rMenB-OMV) vaccine contains a number of relatively conserved surface proteins, fHBP, NHBA (previously GNA2132), and NadA, alongside PorA P1.4-containing OMVs from the New Zealand MeNZB vaccine. MenB currently accounts for approximately 90% of cases of meningococcal disease in England and Wales. To assess potential rMenB-OMV vaccine coverage of pathogenic MenB isolates within this region, all English and Welsh MenB case isolates from January 2008 (n = 87) were genetically characterized with respect to fHBP, NHBA, NadA, and PorA. Alleles for fHbp, nhba, and porA were identified in all of the isolates, of which 22% were also found to harbor nadA alleles. On the basis of genotypic data and predicted immunological cross-reactivity, the potential level of rMenB-OMV vaccine coverage in England and Wales ranges from 66% to 100%.

• Kinetics of antibody persistence following administration of a combination meningococcal serogroup C and Haemophilus influenzae type b conjugate vaccine at 12 to 15 months of age in healthy UK infants primed with two doses of one of three monovalent meningococcal serogroup C vaccines.

  Authors: Ray Borrow, Nick Andrews, Helen Findlow, Pauline Waight, Joanna Southern, Annette Crowley-Luke, Lorraine Stapley, Anna England, Jamie Findlow, Elizabeth Miller

  Clinical and vaccine immunology : CVI. 11/2009;

  The kinetics of antibody persistence following the administration of a combination meningococcal serogroup C and Haemophilus influenzae type b (Hib) conjugate vaccine (Menitorix) in the second yearThe kinetics of antibody persistence following the administration of a combination meningococcal serogroup C and Haemophilus influenzae type b (Hib) conjugate vaccine (Menitorix) in the second year of life in children primed with two doses of one of three monovalent meningococcal serogroup C (MCC) vaccines was investigated. Study subjects were either administered Menitorix at 12 to 15 months of age followed by the 7-valent pneumococcal conjugate (PCV7) and measles, mumps and rubella (MMR) vaccine 4 to 6 weeks later or all three vaccines concomitantly at 12 to 15 months of age. Blood samples were collected before and 1, 2, 12 and 24 months after boosting. Sera were analyzed for meningococcal serogroup C serum bactericidal antibody (SBA) and IgG as well as Hib-polyribosylribitol phosphate (PRP) specific antibodies. Antibody persistence data from this study were compared to a prior study of Southern et al. (2007) (17) in which children were given three primary doses of both MCC and Hib containing vaccine but were boosted with only a Hib conjugate vaccine. The magnitude of the meningococcal SBA GMT was higher for those subjects primed with NeisVac-C as opposed to Menjugate or Meningitec up to one year following boosting. Two years after boosting, the percentages of subjects with putatively protective SBA titers >/= 8 for children primed with NeisVac-C, Menjugate and Meningitec were 43%, 22% and 23%, respectively. Further booster doses of MCC may be required in the future to maintain good antibody levels, however, there is no immediate need for an adolescent booster as mathematical modelling has shown that persisting herd immunity is likely to control disease for a number of years.

• Characterisation of fHbp, nhba (gna2132), nadA, porA, Sequence Type and the genomic presence of IS1301 in group B meningococcal ST269 clonal complex case-isolates from England and Wales.

  Authors: Jay Lucidarme, Maurizio Comanducci, Jamie Findlow, Stephen J Gray, Edward B Kaczmarski, Malcolm Guiver, Elisabeth Kugelberg, Pamela J. Vallely, Philipp Oster, Mariagrazia Pizza, Stefania Bambini, Alessandro Muzzi, Christoph M Tang, Ray Borrow

  Journal of clinical microbiology. 09/2009;

  Highly effective glycoconjugate vaccines exist against 4 of the 5 major pathogenic groups of meningococci - A, C, W-135 and Y. An equivalent vaccine against group B meningococci (menB) has remainedHighly effective glycoconjugate vaccines exist against 4 of the 5 major pathogenic groups of meningococci - A, C, W-135 and Y. An equivalent vaccine against group B meningococci (menB) has remained elusive due to the poorly immunogenic capsular polysaccharide. A promising alternative, the investigational rMenB+OMV vaccine, contains fHBP, NHBA (previously GNA2132), NadA and outer membrane vesicles from the New Zealand MeNZB vaccine. MenB currently account for 90% of meningococcal disease in England and Wales where the Multilocus Sequence Type (ST)269 clonal complex (cc269) has recently expanded to account for a third of menB cases. To assess potential cc269 coverage of the rMenB+OMV vaccine, English and Welsh cc269 isolates from the past decade were genetically characterised with respect to fHBP, NHBA and NadA. All of the isolates harboured fHbp and nhba alleles, whilst 98% of cc269 isolates were devoid of nadA. Sub-variant profiling of fHbp, nhba and porA against ST revealed the presence of two broadly distinct and well-defined clusters of isolates, centred around ST269 and ST275, respectively. An additional molecular marker, the insertion sequence IS1301 was found to be present in 100% and <2% of isolates of the respective clusters. Based on genetic data, potential rMenB+OMV coverage of cc269 in England and Wales is high (up to 100%) within both clusters. Expression studies and serum bactericidal antibody assays will serve to enhance predictions of coverage and will augment ongoing studies regarding the significance of IS1301 within the ST269-cluster.

• Sequence Diversity of the Factor H Binding Protein Vaccine Candidate in Epidemiologically Relevant Strains of Serogroup B Neisseria meningitidis.

  Authors: Ellen Murphy, Lubomira Andrew, Kwok-Leung Lee, Deborah A Dilts, Lorna Nunez, Pamela S Fink, Karita Ambrose, Ray Borrow, Jamie Findlow, Muhamed-Kheir Taha [......] Claudio T Sacchi, Xin Wang, Diana Martin, Anne von Gottberg, Mignon du Plessis, Keith P Klugman, Annaliesa S Anderson, Kathrin U Jansen, Gary W Zlotnick, Susan K Hoiseth

  The Journal of infectious diseases. 07/2009;

  Background. Recombinant forms of Neisseria meningitidis human factor H binding protein (fHBP) are undergoing clinical trials in candidate vaccines against invasive meningococcal serogroup B disease.Background. Recombinant forms of Neisseria meningitidis human factor H binding protein (fHBP) are undergoing clinical trials in candidate vaccines against invasive meningococcal serogroup B disease. We report an extensive survey and phylogenetic analysis of the diversity of fhbp genes and predicted protein sequences in invasive clinical isolates obtained in the period 2000-2006. Methods. Nucleotide sequences of fhbp genes were obtained from 1837 invasive N. meningitidis serogroup B (MnB) strains from the United States, Europe, New Zealand, and South Africa. Multilocus sequence typing (MLST) analysis was performed on a subset of the strains. Results. Every strain contained the fhbp gene. All sequences fell into 1 of 2 subfamilies (A or B), with 60%-75% amino acid identity between subfamilies and at least 83% identity within each subfamily. One fHBP sequence may have arisen via inter-subfamily recombination. Subfamily B sequences were found in 70% of the isolates, and subfamily A sequences were found in 30%. Multiple fHBP variants were detected in each of the common MLST clonal complexes. All major MLST complexes include strains in both subfamily A and subfamily B. Conclusions. The diversity of strains observed underscores the importance of studying the distribution of the vaccine antigen itself rather than relying on common epidemiological surrogates such as MLST.

• Phase I safety and immunogenicity study of a candidate meningococcal disease vaccine based on Neisseria lactamica outer membrane vesicles.

  Authors: Andrew R Gorringe, Stephen Taylor, Charlotte Brookes, Mary Matheson, Michelle Finney, Moyra Kerr, Michael Hudson, Jamie Findlow, Ray Borrow, Nick Andrews, George Kafatos, Cariad M Evans, Robert C Read

  Clinical and vaccine immunology : CVI. 06/2009;

  Natural immunity to meningococcal disease in young children is associated epidemiologically with carriage of commensal Neisseria species including Neisseria lactamica. We have previously demonstratedNatural immunity to meningococcal disease in young children is associated epidemiologically with carriage of commensal Neisseria species including Neisseria lactamica. We have previously demonstrated that outer membrane vesicles (OMVs) from N. lactamica provide protection against lethal challenge in a mouse model of meningococcal septicaemia. We evaluated the safety and immunogenicity of an N. lactamica OMV vaccine in a phase I placebo-controlled double blinded clinical trial. Ninety seven healthy young adult male volunteers were randomised to receive 3 doses of either OMV vaccine or Alhydrogel control. Subsequently some subjects who had received the OMV vaccine also received a fourth dose of OMV vaccine 6 months after the third dose. Injection site reactions were more frequent in the OMV-receiving group but all reactions were mild or moderate in intensity. The OMV vaccine was immunogenic, eliciting rises in IgG ELISA titers against the vaccine OMVs, together with a significant booster response. Additionally the vaccine induced modest cross-reactive immunity to 6 diverse strains of serogroup B Neisseria meningitidis including IgG against meningococcal OMVs, serum bactericidal antibodies and opsonophagocytic activity. The percentages of subjects showing >/=4-fold or greater rises in bactericidal antibody titer obtained were similar to those previously reported for the Norwegian meningococcal OMV vaccine against the same heterologous meningococcal strain panel. In conclusion this N. lactamica OMV vaccine is safe and induces a weak but broad humoral immune response to N. meningitidis.

• Prevention of meningococcal serogroup C disease by NeisVac-C.

  Authors: Ray Borrow, Jamie Findlow

  Expert review of vaccines. 04/2009; 8(3):265-279.

  NeisVac-C has been demonstrated to be safe, immunogenic and efficacious when administered to infants, toddlers, older children and adults. It is one of the licensed meningococcal serogroup CNeisVac-C has been demonstrated to be safe, immunogenic and efficacious when administered to infants, toddlers, older children and adults. It is one of the licensed meningococcal serogroup C conjugate vaccines and a single dose in infancy may be sufficient for protection until a booster dose is given in the second year of life. Persistence of serum bactericidal antibody, rather than immune memory, is now known to be a more appropriate correlate of long-term protection for serogroup C meningococcal disease. NeisVac-C was demonstrated to enhance responses to Haemophilus influenzae type b (Hib) polyribosylribitol phosphate when coadministered with Hib-tetanus toxoid conjugate vaccines. NeisVac-C also enhances tetanus toxid responses and a dose of NeisVac-C in older children induces responses similar to a dose of tetanus toxoid vaccine.

• Immunogenicity of a reduced schedule of meningococcal group C conjugate vaccine given concomitantly with a 7-valent pneumococcal conjugate vaccine and a combination DTaP5/Hib/IPV vaccine in healthy UK infants.

  Authors: Jo Southern, Ray Borrow, Nick Andrews, Rhonwen Morris, Pauline Waight, Michael Hudson, Paul Balmer, Helen Findlow, Jamie Findlow, Elizabeth Miller

  Clinical and vaccine immunology : CVI. 12/2008;

  This study investigated the use of 2 doses of 3 different meningococcal group C conjugate (MCC) vaccines when given for primary immunization with 7-valent pneumococcal conjugate (PCV7) vaccine andThis study investigated the use of 2 doses of 3 different meningococcal group C conjugate (MCC) vaccines when given for primary immunization with 7-valent pneumococcal conjugate (PCV7) vaccine and Pediacel(TM), a combination product containing 5 acellular pertussis components, diphtheria and tetanus toxoids, Haemophilus influenzae type b (Hib) conjugate and inactivated poliovirus vaccine (DTaP5/Hib/IPV). The immune response after a single dose of MCC is also presented. Infants were randomized to receive two doses of one of the MCC vaccines and PCV7 at 2 and 3 months or at 2 and 4 months of age. Meningococcal group C serum bactericidal antibody (SBA) geometric mean titers (GMTs), Hib-polyribosylribitol phosphate (PRP) IgG geometric mean concentrations (GMCs) and diphtheria and tetanus antitoxin GMCs, together with the proportions of infants achieving putative protective levels, were determined. A total of 393 infants were recruited. Following the first dose of NeisVac-C(TM) (MCC conjugated to tetanus toxoid) 97% of infants achieved protective levels (SBA>/= 8) compared with 80% and 53% respectively for Menjugate(R) and Meningitec(TM) (both of which are conjugated to CRM197). SBA responses to MCC vaccines were not significantly different when administered at 2, 3 or 2, 4 months of age. Following two doses of each MCC, 98-100% achieved protective levels. Both PRP IgG and tetanus responses were significantly enhanced when Pediacel was coadministered with the NeisVac-C. This study demonstrated that NeisVac-C and Menjugate generate good immunogenicity after the first dose at 2 months of age when coadministered with PCV7 and Pediacel and merit further investigation in single dose priming strategies.

• Seroprevalence of antibodies against serogroup C meningococci in England in the post-vaccination era.

  Authors: Caroline L Trotter, Ray Borrow, Jamie Findlow, Ann Holland, Sarah Frankland, Nick J Andrews, Elizabeth Miller

  Clinical and vaccine immunology : CVI. 10/2008;

  The UK introduced meningococcal serogroup C conjugate (MCC) vaccines in 1999, resulting in substantial declines in serogroup C disease and carriage. Here, we measured the age-specific prevalence ofThe UK introduced meningococcal serogroup C conjugate (MCC) vaccines in 1999, resulting in substantial declines in serogroup C disease and carriage. Here, we measured the age-specific prevalence of serum bactericidal antibodies (SBA) to Neisseria meningitidis serogroup C and immunoglobulin G (IgG) concentrations to serogroups A, C, W-135 and Y in 2,673 serum samples collected in England between 2000 and 2004. We compared the seroprevalence of SBA titers >/=8 in the post-vaccination era, with an earlier, pre-vaccination study conducted using the same methods. We found that the percentages of individuals with protective SBA titers were higher in 2000-2004 in all of the age groups targeted for MCC vaccination. In the post-vaccine era the prevalence of protective titers was high (75%) in children who had recently been offered routine immunization, but this fell to 36% more than 18 months after scheduled immunization. In the cohorts targeted in the catch-up campaign, the percentage achieving SBA titers >/=8 was higher in children offered vaccine at age 5-17 years compared to age 1-4 years. Geometric mean concentration (GMC) IgG for serogroup C followed a similar pattern, corresponding to the age at and time since scheduled MCC vaccination. Serogroup-specific IgG GMCs for W-135 and Y were low and showed little variation by age. Serogroup A IgG GMCs were higher, possibly reflecting exposure to cross-reacting antigens. Although the incidence of serogroup C disease remains low due to persisting herd effects, population antibody levels to serogroup C meningococci should be monitored, so that potentially susceptible age-groups can be identified should herd immunity wane.

• Mucosal immunity in healthy adults after parenteral vaccination with outer-membrane vesicles from Neisseria meningitidis serogroup B.

  Authors: Victoria Davenport, Eleanor Groves, Rachel E Horton, Christopher G Hobbs, Terry Guthrie, Jamie Findlow, Ray Borrow, Lisbeth M Naess, Philipp Oster, Robert S Heyderman, Neil A Williams

  The Journal of infectious diseases. 09/2008; 198(5):731-40.

  Nasopharyngeal carriage of meningococcus or related species leads to protective immunity in adolescence or early adulthood. This natural immunity is associated with mucosal and systemic T cellNasopharyngeal carriage of meningococcus or related species leads to protective immunity in adolescence or early adulthood. This natural immunity is associated with mucosal and systemic T cell memory. Whether parenteral Neisseria meningitidis serogroup B (MenB) vaccination influences natural mucosal immunity is unknown. To determine whether parenteral MenB vaccination affects mucosal immunity in young adults and whether this immunity differs from that induced in the blood. Otherwise healthy volunteers were immunized with MenB outer membrane vesicle vaccine before and after routine tonsillectomy. Mucosal and systemic immunity were assessed in 9 vaccinees and 12 unvaccinated control subjects by measuring mononuclear cell proliferation, cytokine production, Th1/Th2 surface marker expression, and antibody to MenB antigens. Parenteral vaccination induced a marked increase in systemic T cell immunity against MenB and a Th1 bias. In contrast, although mucosal T cell proliferation in response to MenB neither increased nor decreased following vaccination, mononuclear cell interferon gamma, interleukin (IL)-5, and IL-10 production increased, and the Th1/Th2 profile lost its Th1 bias. Parenteral MenB vaccination selectively reprograms preexisting naturally acquired mucosal immunity. As new-generation protein-based MenB vaccine candidates undergo evaluation, the impact of these vaccines on mucosal immunity in both adults and children will need to be addressed.