Philipp Oster

Publications of Philipp Oster

• Early clinical experience with a candidate meningococcal B recombinant vaccine (rMenB) in healthy adults.

  Authors: Daniela Toneatto, Philipp Oster, A Corine W deBoer, Amy Emerson, George F Santos, Ellen Ypma, Lisa DeTora, Mariagrazia Pizza, Alan Kimura, Peter Dull

  Human vaccines. 07/2011; 7(7):781-91.

  The development of a broadly protective vaccine against meningococcal serogroup B is a well-recognized public health need. Whole-genome sequencing was used to identify meningococcal surface proteinsThe development of a broadly protective vaccine against meningococcal serogroup B is a well-recognized public health need. Whole-genome sequencing was used to identify meningococcal surface proteins that are conserved across strains. These proteins were incorporated into two investigational vaccines. Three randomized studies were performed to evaluate a three-component recombinant meningococcal serogroup B vaccine (rMenB) and rMenB plus outer membrane vesicles from the Norwegian outbreak strain 44/76 (rMenB+OMVNW). Participants were randomized to receive 3 or 4 doses of rMenB or rMenB+OMVNW or control vaccines and provided sera for exploratory immunogenicity testing against a panel of meningococcal serogroup B strains. A booster dose was administered 12 months after the initial primary series in one of the studies. The control cohort received a licensed quadrivalent meningococcal polysaccharide vaccine against serogroups A, C, W-135 and Y as well as hepatitis B vaccine as safety comparators. Solicited reactions within 7 days of any vaccination and adverse events throughout the studies were recorded. One hundred four participants enrolled into the clinical trials. Both rMenB and rMenB+OMVNW induced immune responses to multiple serogroup B strains in the majority of participants. Compared with rMenB, rMenB+OMVNW appeared somewhat more immunogenic and reactogenic; the study was not adequately powered for statistical assessment of these small differences. Both investigational vaccines were more reactogenic than the licensed vaccines. Few vaccinees discontinued any study due to reactogenicity to any study vaccine administered. Based on the immunogenicity and reactogenicity results in these participants, both rMenB and rMenB+OMVNW were promising candidates for further investigation.

• The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans.

  Authors: Daniela Toneatto, Shevqet Ismaili, Ellen Ypma, Kay Vienken, Philipp Oster, Peter Dull

  Human vaccines. 06/2011; 7(6):646-53.

  Neisseria meningitidis serogroup B is a well-recognized cause of bacterial meningitis and sepsis for which no broadly protective vaccine exists. Whole genome sequencing was used to identify threeNeisseria meningitidis serogroup B is a well-recognized cause of bacterial meningitis and sepsis for which no broadly protective vaccine exists. Whole genome sequencing was used to identify three antigens: factor H binding protein (fHbp), Neisserial adhesin A (NadA), and Neisseria heparin binding antigen (NHBA) for an investigational vaccine candidate (rMenB). This was the first trial of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB), containing rMenB and outer membrane vesicles (OMV) from the New Zealand epidemic strain in humans. Seventy adults enrolled and received study vaccine. All vaccines were generally well tolerated. Immune responses were observed to multiple serogroup B strains following all investigational vaccines, suggesting the potential for broad coverage against this serogroup. Immunogenicity was enhanced by the addition of OMV; the 4CMenB displayed the optimal profile for further investigation. In a phase I, observer blind, randomized trial, healthy adults (18-40 years of age) were randomized 2:2:1 to receive 3 doses of 4CMenB, rMenB with OMV from the Norwegian outbreak strain, or rMenB alone. Pre- and postvaccination sera were evaluated in a serum bactericidal assay using human complement (hSBA) against a panel of 15 serogroup B strains, with titers ≥ 4 considered protective. Solicited injection site and systemic reactions were evaluated for 7 days following each vaccination and adverse events were reported throughout the study. In this trial, 4CMenB displayed a favorable profile for further clinical development. 4CMenB demonstrated immunogenicity against multiple heterologous serogroup B strains. All vaccines were generally well tolerated in this study.

• Antibody persistence following MeNZB vaccination of adults and children and response to a fourth dose in toddlers.

  Authors: Catherine Jackson, Diana Lennon, Sharon Wong, Jacqueline Yan, Joanna Stewart, Stewart Reid, Philipp Oster, Ellen Ypma, Diana Martin

  Archives of disease in childhood. 05/2011; 96(8):744-51.

  A New Zealand serogroup B meningococcal epidemic prompted trials of a strain-specific (B:4:P1.7-2,4) outer membrane vesicle vaccine (MeNZB). Adults, school children, and infants provided serum afterA New Zealand serogroup B meningococcal epidemic prompted trials of a strain-specific (B:4:P1.7-2,4) outer membrane vesicle vaccine (MeNZB). Adults, school children, and infants provided serum after three MeNZB doses to evaluate antibody persistence via serum bactericidal assay. Toddler (16-24 months) non-responders and responders received a fourth MeNZB dose 11 and 17 months after dose three respectively. Response was a ≥4-fold rise in bactericidal titre to a titre of ≥8. Geometric mean bactericidal titres (GMTs), with 95% CI, after dose 3: adults: 27 (14-52), 5 (3-11), and 7 (3-15) at 1, 10, and 22 months; school children: 18 (13-25) and 4 (3-6) at 1 and 4 months; infants: 27 (19-39) and 2 (2-3) at 1 and 7 months. The titre achieved after priming significantly influenced persistence. Toddler non-responder GMTs were 4 (3-5) and 1 (1-1) at 1 and 11 months after dose 3 and 69 (46-106) 1 month after dose 4. Responder GMTs were 24 (19-30) and 3 (2-4) at 1 and 17 months after dose 3 and 259 (184-363) 1 month after dose 4. Dose 4 had no safety concerns. Immune response to MeNZB was most sustained in adults. In infants, bactericidal titres decayed almost to baseline by 7 months after dose 3. Toddlers showed marked immune response following a fourth dose suggesting memory. Persisting antibody is likely to be necessary for ongoing protection, as seen with serogroup C meningococci.

• 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.

• Measuring antigen-specific bactericidal responses to a multicomponent vaccine against serogroup B meningococcus.

  Authors: Marzia M Giuliani, Alessia Biolchi, Davide Serruto, Francesca Ferlicca, Kay Vienken, Philipp Oster, Rino Rappuoli, Mariagrazia Pizza, John Donnelly

  Vaccine. 07/2010; 28(31):5023-30.

  Serum bactericidal activity using human complement is the basis for established correlates of protection against invasive meningococcal disease. During the development of multicomponent protein-basedSerum bactericidal activity using human complement is the basis for established correlates of protection against invasive meningococcal disease. During the development of multicomponent protein-based vaccines against meningococcus B, it is necessary to measure antigen-specific bactericidal responses. This is not straightforward because each strain may be killed by antibodies to multiple antigens. We characterized a large panel of strains and, using a competitive inhibition SBA, we identified four strains that are each specifically killed by bactericidal antibodies to one of the major vaccine components. These strains provide a straightforward approach to demonstrate protective responses to each component of the vaccine and demonstrate that each of the antigens in the vaccine is sufficient to provide a potentially protective level of bactericidal activity.

• 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%.

• Vaccine preventability of meningococcal clone, Greater Aachen Region, Germany.

  Authors: Johannes Elias, Leo M Schouls, Ingrid van de Pol, Wendy C Keijzers, Diana R Martin, Anne Glennie, Philipp Oster, Matthias Frosch, Ulrich Vogel, Arie van der Ende

  Emerging infectious diseases. 03/2010; 16(3):465-72.

  Emergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annualEmergence of serogroup B meningococci of clonal complex sequence type (ST) 41/44 can cause high levels of disease, as exemplified by a recent epidemic in New Zealand. Multiplication of annual incidence rates (3.1 cases/100,000 population) of meningococcal disease in a defined German region, the city of Aachen and 3 neighboring countries (Greater Aachen) prompted us to investigate and determine the source and nature of this outbreak. Using molecular typing and geographic mapping, we analyzed 1,143 strains belonging to ST41/44 complex, isolated from persons with invasive meningococcal disease over 6 years (2001-2006) from 2 German federal states (total population 26 million) and the Netherlands. A spatially slowly moving clone with multiple-locus variable-number tandem repeat analysis type 19, ST42, and antigenic profile B:P1.7-2,4:F1-5 was responsible for the outbreak. Bactericidal activity in serum samples from the New Zealand MeNZB vaccination campaign confirmed vaccine preventability. Because this globally distributed epidemic strain spreads slowly, vaccination efforts could possibly eliminate meningococcal disease in this area.

• 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.

• Properties and clinical performance of vaccines containing outer membrane vesicles from Neisseria meningitidis.

  Authors: Johan Holst, Diana Martin, Richard Arnold, Concepcion Campa Huergo, Philipp Oster, Jane O'Hallahan, Einar Rosenqvist

  Vaccine. 06/2009; 27 Suppl 2:B3-12.

  Meningococcal outer membrane proteins have been used for over 20 years in more than 80 million doses; either as carrier protein in a Haemophilus influenzae type b (Hib) polysaccharide conjugateMeningococcal outer membrane proteins have been used for over 20 years in more than 80 million doses; either as carrier protein in a Haemophilus influenzae type b (Hib) polysaccharide conjugate vaccine or as vesicle vaccine formulations against meningococcal disease. Conventional wild-type outer membrane vesicle (wtOMV) vaccines are the only formulations that have shown efficacy against serogroup B meningococcal disease. This has been demonstrated in Cuba, Norway and New Zealand; where epidemics, dominated by one particular strain or clone, were causing high rates of disease and wtOMV vaccines have been used for epidemic control. The most significant limitation for widespread use of wtOMV is that the immune response is strain-specific in infants, mostly directed against the immuno-dominant porin protein, PorA. The natural orientation of surface-exposed membrane antigens and the preservation of good physico-chemical stability are key features of OMV vaccines. The efficacy, tolerability and safety of wtOMV vaccines have been well proven. The most recent experience from New Zealand demonstrated a vaccine effectiveness of 80% for children less than 5 years of age, over a period of 24 months. Such results are encouraging for the further use of "tailor-made" OMV vaccines for epidemic control. Moreover, it provides opportunities for development of OMV vaccines with various additional cross-protective potential. There is good reason to believe that in the coming few years the "OMV-concept" will be exploited further and that a number of cross-protective "universal" antigens will be included in vaccines against serogroup B meningococcal disease. The desire to have a global vaccine strategy that enables susceptible individuals to be protected against all the relevant serogroups of meningococcal disease may become a reality.

• Immunogenicity and Tolerability in Infants of a New Zealand Epidemic Strain Meningococcal B Outer Membrane Vesicle Vaccine.

  Authors: Sharon Wong, Diana Lennon, Catherine Jackson, Joanna Stewart, Stewart Reid, Ellen Ypma, Jane O'Hallahan, Philipp Oster, Kim Mulholland, Diana Martin

  The Pediatric infectious disease journal. 05/2009;

  BACKGROUND:: An outer membrane vesicle meningococcal vaccine (MeNZB), was developed for the New Zealand epidemic strain of Neisseria meningitidis B:4:P1.7-2,4. METHODS:: A phase II, randomized,BACKGROUND:: An outer membrane vesicle meningococcal vaccine (MeNZB), was developed for the New Zealand epidemic strain of Neisseria meningitidis B:4:P1.7-2,4. METHODS:: A phase II, randomized, observer blind, controlled study evaluating the safety, reactogenicity, and immunogenicity of MeNZB administered with routine New Zealand immunizations at 6 weeks, 3 months, and 5 months of age (n = 375). Group 1 (n = 250) received 25 mug MeNZB and routine immunizations with a fourth MeNZB dose given at 10 months (n = 51). Group 2 (n = 125) received routine immunizations only. Sero-response was a >/=4-fold rise in vaccine strain serum bactericidal antibody titer compared with baseline or a titer of at least 1:8 for baselines <1:4. Reactogenicity was monitored for 7 days after vaccination. RESULTS:: Sero-response in Group 1 was achieved in 53% (95% Confidence interval [CI]: 46-59, n = 239) and 69% (95% CI: 54-80, n = 45) with geometric mean antibody titers of 9 (95% CI: 7-10) and 22 (95% CI: 12-39) after the third and fourth doses, respectively. No negative interference by MeNZB on routine immunizations was detected. There were no serious adverse events judged to be vaccine related. CONCLUSIONS:: In this group of New Zealand infants, 4 MeNZB doses were required to demonstrate titers comparable with those achieved after 3 doses in older children. MeNZB was safe when used concomitantly with routine New Zealand immunizations to 5 months of age.

• Phase II Meningococcal B Vesicle Vaccine Trial in New Zealand Infants.

  Authors: Catherine M Jackson, Diana R Lennon, Viliame Tk Sotutu, Jacqueline Yan, Joanna M Stewart, Stewart Reid, Sue Crengle, Philipp Oster, Ellen Ypma, Ingeborg Aaberge, Kim Mulholland, Diana R Martin

  Archives of disease in childhood. 10/2008;

  A tailor-made serogroup B outer membrane vesicle vaccine was evaluated in the context of an serogroup B meningococcal epidemic dominated by Neisseria meningitidis strain B:4:P1.7b,4. OBJECTIVE: ToA tailor-made serogroup B outer membrane vesicle vaccine was evaluated in the context of an serogroup B meningococcal epidemic dominated by Neisseria meningitidis strain B:4:P1.7b,4. OBJECTIVE: To determine the safety, reactogenicity, and immunogenicity in infants aged 6 to 8 months of a Meningococcal B vaccine developed against the New Zealand epidemic strain. Design, Setting, and PARTICIPANTS: Observer-blind, randomised, controlled trial conducted in 296 healthy infants in Auckland, New Zealand. INTERVENTION: Infants were randomised 4:1 to receive three doses of New Zealand candidate vaccine (epidemic strain NZ98/254, B:4:P1.7b,4) or Meningococcal C conjugate vaccine at six weekly intervals. MAIN OUTCOME MEASURES: Immune response was determined by human complement mediated serum bactericidal assay. Sero-response was a four-fold or greater rise in titre compared to baseline, with baseline titres < 4 required to increase to >/=8. Blood samples were taken pre-vaccination, 6 weeks after dose two, and 4 weeks after dose three. Local and systemic reactions were recorded for 7 days after vaccination. RESULTS: Sero-response to the candidate vaccine strain, NZ98/254, was demonstrated in 74 % (95%CI: 68-80% intention-to-treat; 67-79% per protocol) after three doses of New Zealand candidate vaccine. No Meningococcal C conjugate vaccine recipients were sero-responders to NZ98/254 after three doses. Both vaccines were well tolerated with no vaccine related serious adverse events. CONCLUSIONS: Our data indicate that the New Zealand candidate vaccine administered in three doses to this group of 6-8 month old infants was safe and immunogenic against the candidate vaccine strain NZ98/254 (Neisseria meningitidis B:4:P1.7b,4).

• 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.

• Immunogenicity, reactogenicity, and safety of a P1.7b,4 strain-specific serogroup B meningococcal vaccine given to preteens.

  Authors: Jamie Hosking, Kumanan Rasanathan, Florina Chan Mow, Catherine Jackson, Diana Martin, Jane O'Hallahan, Philipp Oster, Ellen Ypma, Stewart Reid, Ingeborg Aaberge, Sue Crengle, Joanna Stewart, Diana Lennon

  Clinical and vaccine immunology : CVI. 12/2007; 14(11):1393-9.

  New Zealand (NZ) has experienced a Neisseria meningitidis serogroup B epidemic since 1991. MeNZB, a strain-specific outer membrane vesicle vaccine made using an NZ epidemic strain isolate, NZ98/254New Zealand (NZ) has experienced a Neisseria meningitidis serogroup B epidemic since 1991. MeNZB, a strain-specific outer membrane vesicle vaccine made using an NZ epidemic strain isolate, NZ98/254 (B:4:P1.7b,4), from two manufacturing sites, the Norwegian Institute of Public Health (NIPH) and Chiron Vaccines (CV; now Novartis), was evaluated for safety, immunogenicity, and reactogenicity in this observer-blind trial with 8- to 12-year-old children. In year 1, cohort A (n = 302) was randomized 4:1 for receipt of NIPH-MeNZB or MenBvac (Norwegian parent vaccine strain 44/76; B:15:P1.7,16). In year 2, cohort B (n = 313) was randomized 4:1 for receipt of CV-MeNZB or NIPH-MeNZB. Participants all received three vaccinations 6 weeks apart. Local and systemic reactions were monitored for 7 days. Seroresponse was defined as a fourfold or greater rise in the serum bactericidal antibody titer from the baseline titer as measured by a serum bactericidal assay. Those with baseline titers of <1:4 required titers of >/=1:8 to serorespond. Intention-to-treat (ITT) and per protocol (PP) analyses are presented. In cohort A, 74% (ITT) and 73% (PP) of NIPH-MeNZB recipients demonstrated seroresponses against NZ98/254 after three doses, versus 32% (ITT and PP) of MenBvac recipients. In cohort B, seroresponses against NZ98/254 after three doses occurred in 79% (ITT and PP) of CV-MeNZB versus 75% (ITT) and 76% (PP) of NIPH-MeNZB recipients. Vaccines were tolerable, with no vaccine-related serious adverse events. In conclusion, the NZ strain meningococcal B vaccine (MeNZB) from either manufacturing site was immunogenic against New Zealand epidemic vaccine strain meningococci with no safety concerns when given in three doses to these 8- to 12-year-old children.

• Immunogenicity and safety of a combination of two serogroup B meningococcal outer membrane vesicle vaccines.

  Authors: Synne Sandbu, Berit Feiring, Philipp Oster, Oddveig S Helland, Hilde S. W. Bakke, Lisbeth M Naess, Audun Aase, Ingeborg S Aaberge, Anne-Cathrine Kristoffersen, Kjersti M. Rydland, Sandrine Tilman, Hanne Nøkleby, Einar Rosenqvist

  Clinical and vaccine immunology : CVI. 10/2007; 14(9):1062-9.

  MenBvac and MeNZB are safe and efficacious vaccines against serogroup B meningococcal disease. MenBvac is prepared from a B:15:P1.7,16 meningococcal strain (strain 44/76), and MeNZB is prepared fromMenBvac and MeNZB are safe and efficacious vaccines against serogroup B meningococcal disease. MenBvac is prepared from a B:15:P1.7,16 meningococcal strain (strain 44/76), and MeNZB is prepared from a B:4:P1.7-2,4 strain (strain NZ98/254). At 6-week intervals, healthy adults received three doses of MenBvac (25 microg), MeNZB (25 microg), or the MenBvac and MeNZB (doses of 12.5 microg of each vaccine) vaccines combined, followed by a booster 1 year later. Two-thirds of the subjects who received a monovalent vaccine in the primary schedule received the other monovalent vaccine as a booster dose. The immune responses to the combined vaccine were of the same magnitude as the homologous responses to each individual vaccine observed. At 6 weeks after the third dose, 77% and 87% of the subjects in the combined vaccine group achieved serum bactericidal titers of > or = 4 against strains 44/76 and NZ98/254, respectively, and 97% and 93% of the subjects achieved a fourfold or greater increase in opsonophagocytic activity against strains 44/76 and NZ98/254, respectively. For both strains, a trend of higher responses after the booster dose was observed in all groups receiving at least one dose of the respective strain-specific vaccine. Local and systemic reactions were common in all vaccine groups. Most reactions were mild or moderate in intensity, and there were no vaccine-related serious adverse events. The safety profile of the combined vaccine was not different from those of the separate monovalent vaccines. In conclusion, use of either of the single vaccines or the combination of MenBvac and MeNZB may have a considerable impact on the serogroup B meningococcal disease situation in many countries.

• Inadequacy of colominic acid as an absorbent intended to facilitate use of complement-preserved baby rabbit serum in the Neisseria meningitidis serogroup B serum bactericidal antibody assay.

  Authors: Jamie Findlow, Ann Holland, Diana Martin, Philipp Oster, Paul Balmer, Ray Borrow

  Clinical and vaccine immunology : CVI. 06/2007; 14(5):556-61.

  The surrogate of protection against Neisseria meningitidis serogroup B (MenB) is the serum bactericidal antibody (SBA) assay, which measures the functional activity of antibody by using an exogenousThe surrogate of protection against Neisseria meningitidis serogroup B (MenB) is the serum bactericidal antibody (SBA) assay, which measures the functional activity of antibody by using an exogenous complement source. Despite baby rabbit complement having been used in meningococcal serogroup A, C, Y, and W135 SBA assays, it is not recommended for use in the MenB SBA assay due to elevated SBA titers caused by low-avidity anti-MenB capsular antibody in test sera. Therefore, the possibility of absorbing anti-MenB capsular antibody from test sera to enable the use of baby rabbit complement in the MenB SBA assay was investigated by comparing the results with those gained using human complement. Colominic acid from Escherichia coli K1, which shares the same linkage residue as MenB polysaccharide, was used as an absorbent due to the commercial unavailability of purified MenB polysaccharide. Inclusion of soluble colominic acid as an absorbent with baby rabbit complement resulted in a general reduction in SBA titers compared with those obtained using baby rabbit complement alone. However, these were not comparable to human SBA titers for all samples. Further optimization and investigations demonstrated that for some samples, colominic acid reduced titers to less than those achieved with human complement, and for others, it was not possible to inhibit titers by using colominic acid. The results suggested that the use of colominic acid will not result in the ability to use baby rabbit complement in the MenB SBA assay, thus not alleviating the difficulties in procuring human complement. However, alternative absorbents, such as purified MenB polysaccharide, may warrant further evaluation.

• New zealand epidemic strain meningococcal B outer membrane vesicle vaccine in children aged 16-24 months.

  Authors: Sharon Wong, Diana Lennon, Catherine Jackson, Joanna Stewart, Stewart Reid, Sue Crengle, Sandrine Tilman, Ingeborg Aaberge, Jane O'Hallahan, Philipp Oster, Kim Mulholland, Diana Martin

  The Pediatric infectious disease journal. 04/2007; 26(4):345-50.

  BACKGROUND: New Zealand has experienced an epidemic of Neisseria meningitidis dominated by strain B:4:P1.7b,4 since 1991. Children younger than 5 years are at highest risk. Previous serogroup B outerBACKGROUND: New Zealand has experienced an epidemic of Neisseria meningitidis dominated by strain B:4:P1.7b,4 since 1991. Children younger than 5 years are at highest risk. Previous serogroup B outer membrane vesicle (OMV) strain specific vaccines have shown variable efficacy in this age group. OBJECTIVE: To evaluate the immunogenicity, reactogenicity and safety in 16-24-month-old children of an OMV vaccine developed against the New Zealand epidemic strain. METHODS: Children (332) aged 16-24 months were randomized to receive the New Zealand candidate vaccine made using strain NZ98/254 (B:4:P1.7b,4) or the Norwegian parent vaccine made using strain 44/76 (B:15:P1.7,16). Vaccines (25 microg/dose) were administered at 0, 6 and 12 weeks in this observer-blind trial. Immune response was measured by serum bactericidal assay and enzyme-linked immunosorbent assay. Sero-response was defined as a 4-fold or greater rise in serum bactericidal antibody titer compared with baseline, with titers <1:4 required to increase to >or=1:8 to be considered a sero-response. Local and systemic reactions were monitored for 7 days after vaccination. RESULTS: Sero-response against NZ98/254 was achieved after 3 doses in 75% (95% CI: 69-80%) receiving the New Zealand candidate vaccine by both intention to treat (ITT) and per protocol (PP) analyses. In Norwegian parent vaccinees this was seen in 3% (0-12%) (ITT) and 4% (0-13%) (PP). Vaccines were well tolerated with no vaccine-related serious adverse events. CONCLUSION: The New Zealand candidate vaccine administered to these 16-24-month-old children in 3 doses was safe and elicited a promising immune response against the candidate vaccine strain NZ98/254 (N. meningitidis B:4:P1.7b,4) contributing to vaccine licensure for this age group.

• Comparison and correlation of neisseria meningitidis serogroup B immunologic assay results and human antibody responses following three doses of the Norwegian meningococcal outer membrane vesicle vaccine MenBvac.

  Authors: Jamie Findlow, Stephen Taylor, Audun Aase, Rachel Horton, Robert Heyderman, Jo Southern, Nick Andrews, Rita Barchha, Ewan Harrison, Ann Lowe, Emma Boxer, Charlotte Heaton, Paul Balmer, Ed Kaczmarski, Philipp Oster, Andrew Gorringe, Ray Borrow, Elizabeth Miller

  Infection and immunity. 09/2006; 74(8):4557-65.

  The prediction of efficacy of Neisseria meningitidis serogroup B (MenB) vaccines is currently hindered due to the lack of an appropriate correlate of protection. For outer membrane vesicle (OMV)The prediction of efficacy of Neisseria meningitidis serogroup B (MenB) vaccines is currently hindered due to the lack of an appropriate correlate of protection. For outer membrane vesicle (OMV) vaccines, immunogenicity has primarily been determined by the serum bactericidal antibody (SBA) assay and OMV enzyme-linked immunosorbent assay (ELISA). However, the opsonophagocytic assay (OPA), surface labeling assay, whole blood assay (WBA), and salivary antibody ELISA have been developed although correlation with protection is presently undetermined. Therefore, the aim of the study was to investigate further the usefulness of, and relationships between, MenB immunologic assays. A phase II trial of the OMV vaccine, MenBvac, with proven efficacy was initiated to compare immunologic assays incorporating the vaccine and six heterologous strains. Correlations were achieved between the SBA assay, OMV ELISA, and OPA using human polymorphonuclear leukocytes and human complement but not between an OPA using HL60 phagocytic cells and baby rabbit complement. Correlations between the surface labeling assay, the SBA assay, and the OMV ELISA were promising, although target strain dependent. Correlations between the salivary antibody ELISA and other assays were poor. Correlations to the WBA were prevented since many samples had results greater than the range of the assay. The study confirmed the immunogenicity and benefit of a third dose of MenBvac against the homologous vaccine strain using a variety of immunologic assays. These results emphasize the need for standardized methodologies that would allow a more robust comparison of assays between laboratories and promote their further evaluation as correlates of protection against MenB disease.

• Persisting immune responses indicating long-term protection after booster dose with meningococcal group B outer membrane vesicle vaccine.

  Authors: Berit Feiring, Jan Fuglesang, Philipp Oster, Lisbeth M Naess, Oddveig S Helland, Sandrine Tilman, Einar Rosenqvist, Marianne A. R. Bergsaker, Hanne Nøkleby, Ingeborg S Aaberge

  Clinical and vaccine immunology : CVI. 07/2006; 13(7):790-6.

  MenBvac is an outer membrane vesicle vaccine against systemic meningococcal disease caused by serogroup B Neisseria meningitidis. In this placebo-controlled double-blind study including 374 healthyMenBvac is an outer membrane vesicle vaccine against systemic meningococcal disease caused by serogroup B Neisseria meningitidis. In this placebo-controlled double-blind study including 374 healthy adolescents, the safety and immunogenicity of a schedule of three primary doses 6 weeks apart followed by a fourth dose a year later were evaluated. Antibody responses to the vaccine strain and heterologous strains (non-vaccine-type strains) and the persistence of these antibodies were measured by the serum bactericidal assay (SBA) and enzyme-linked immunosorbent assay up to 1 year after the last dose. The proportion of subjects with SBA titers of > or = 4 against the vaccine strain increased from 3% prevaccination to 65% after the third dose. Ten months later, this proportion had declined to 28%. The fourth dose induced a booster response demonstrated by 93% of subjects achieving a titer of > or = 4. One year after the booster dose, 64% still showed SBA titers of > or = 4. Cross-reacting antibodies were induced against all heterologous strains tested, although the magnitude of SBA titers differed widely between the different strains. All four doses of MenBvac were safe. Both MenBvac and the placebo had reactogenicity profiles of mild to moderate local and systemic reactions. Pain, the most common reaction, was reported with similar frequencies in both groups. No serious adverse events occurred in the MenBvac group. This study confirmed the good immunogenicity of the primary course of MenBvac and demonstrated prolonged persistence and increased cross-reactivity of functional antibodies elicited by a booster dose.

• Interlaboratory standardization of the measurement of serum bactericidal activity by using human complement against meningococcal serogroup b, strain 44/76-SL, before and after vaccination with the Norwegian MenBvac outer membrane vesicle vaccine.

  Authors: Ray Borrow, Ingeborg S Aaberge, George F Santos, T Lynn Eudey, Philipp Oster, Anne Glennie, Jamie Findlow, E Arne Høiby, Einar Rosenqvist, Paul Balmer, Diana Martin

  Clinical and diagnostic laboratory immunology. 08/2005; 12(8):970-6.

  There is currently no standardized serum bactericidal antibody (SBA) assay for evaluating immune responses to meningococcal outer membrane vesicle or protein vaccines. Four laboratories, ManchesterThere is currently no standardized serum bactericidal antibody (SBA) assay for evaluating immune responses to meningococcal outer membrane vesicle or protein vaccines. Four laboratories, Manchester Health Protection Agency (MC HPA), New Zealand Institute of Environmental Science and Research Limited (NZ ESR), Norwegian Institute of Public Health (NIPH), and Chiron Vaccines (Chiron), measured SBA titers in the same panel of human sera (n=76) from laboratory staff (n=21) vaccinated with MenBvac. Blood samples were collected prevaccination, prior to each of the three doses of MenBvac given at 6-week intervals, and 6 weeks following the third dose. Initial results showed a number of discrepancies in results between the four participating laboratories. The greatest effect on titers appeared to be due to differences among laboratories in the maintenance of the meningococcal serogroup B test strain, 44/76-SL. A repeat study was conducted using the same frozen isolate (meningococcal serogroup B test strain 44/76-SL), freshly distributed to all four laboratories. Using SBA titers from the tilt method for all samples, and using MC HPA as the comparator, the results were as follows for NZ ESR, NIPH, and Chiron, respectively, using log(10) titers: correlation coefficients (r) were 0.966, 0.967, and 0.936; intercepts were 0.08, 0.15, and 0.17; and slopes were 0.930, 0.851, and 0.891. In both prevaccination and postvaccination samples from 15 subjects assayed by all four laboratories, similar increases in SBA (fourfold or greater) were observed (for 11, 11, 9, and 9 subjects for MC HPA, NZ ESR, NIPH, and Chiron, respectively), and similar percentages of subjects with SBA titers of>or=4 p revaccination and 6 weeks following each dose were found. The SBA assay has been harmonized between the four different laboratories with good agreement on seroconversion rates, n-fold changes in titers, and percentages of subjects with SBA titers of >or=4.