Ray Borrow

Publications of Ray Borrow

• Immunogenicity and safety of a meningococcal quadrivalent conjugate vaccine in Saudi Arabian adolescents previously vaccinated with one dose of bivalent and quadrivalent meningococcal polysaccharide vaccine: phase III, controlled, randomized, modified blind-observer study.

  Authors: Yagob Al-Mazrou, Mohamed Khalil, Helen Findlow, Helen Chadha, Valerie Bosch Castells, David R Johnson, Ray Borrow

  Clinical and vaccine immunology : CVI. 05/2012;

  Reduced immune responses to repeated polysaccharide vaccination have been previously reported but there are limited immunogenicity data on the use of meningococcal polysaccharide vaccine (PSV)Reduced immune responses to repeated polysaccharide vaccination have been previously reported but there are limited immunogenicity data on the use of meningococcal polysaccharide vaccine (PSV) followed by meningococcal conjugate vaccine. Saudi Arabian adolescents (aged 16-19 years) who had previously been vaccinated with ≥ 1 dose of bivalent meningococcal polysaccharide vaccine and 1 dose of quadrivalent meningococcal polysaccharide (MPSV4) were enrolled in a controlled, randomized, modified observer-blind study (collectively the PSV-exposed). The PSV exposed group was randomized to receive either quadrivalent meningococcal conjugate vaccine (MCV4) (n= 145, PSV-exposed/MCV4 group) or MPSV4 (n= 142, PSV-exposed/MPSV4 'group), and a PSV-naïve group received MCV4 (n= 163). Serum samples collected pre- and 28 days post-vaccination were measured by baby rabbit serum bactericidal antibody (rSBA) assay, and vaccine tolerability and safety were also evaluated. For each serogroup, the post-vaccination geometric mean titers (GMTs) were significantly higher in the PSV-naïve group than in either group comprised of the PSV-exposed. The post-vaccination serogroup C rSBA GMT was significantly higher in the PSV-MCV4 group than in the PSV-MPSV4 group, after adjusting for prevaccination GMTs. Although not statistically significant, similar differences were observed for serogroups A, Y, and W-135. No worrisome safety signals were detected. This study demonstrated MCV4 to be safe and immunogenic in those who had previously received polysaccharide vaccination, and suggests that conjugate vaccine may partially compensate for hyporesponsiveness seen with repeated doses of polysaccharide vaccine.

• Use of pneumococcal polysaccharide vaccine in children: what is the evidence?

  Authors: Ray Borrow, Paul T Heath, Claire-Anne Siegrist

  Current opinion in infectious diseases. 04/2012;

  PURPOSE OF REVIEW: Pneumococcal glycoconjugate vaccines (PCVs) are now widely used in infant immunization schedules. These vaccines are also recommended for those at increased risk of pneumococcalPURPOSE OF REVIEW: Pneumococcal glycoconjugate vaccines (PCVs) are now widely used in infant immunization schedules. These vaccines are also recommended for those at increased risk of pneumococcal infection and to provide optimal serotype coverage to those at increased risk of disease. The 23-valent polysaccharide vaccine (PPV23) is often advised from the second birthday to provide broader serotype coverage. The use of pneumococcal polysaccharide vaccines (PPVs) has in recent years become a topic of much debate, especially for use in children. RECENT FINDINGS: Although no effect of PPV23 on carriage has been reported, some protection against invasive pneumococcal disease (IPD) is possible. There is a theoretical risk of memory B-cell depletion to PCV serotypes following PPV23 vaccination, even in PCV-primed children, but the clinical significance is currently unknown. This risk is increased by PPV23 revaccination. SUMMARY: Whether the immune response to PPV23, non-PCV13 serotypes is sufficient to confer clinical benefit to at-risk children depends on their age, underlying disease and the immunogenicity of individual serotypes. Given the theoretical risk of memory B-cell depletion following PPV23 vaccination, it is not clear how best to maintain protection in those at-risk children who remain susceptible to IPD.

• Invasive meningococcal disease in England and Wales: Implications for the introduction of new vaccines.

  Authors: Shamez N Ladhani, Jessica S Flood, Mary E Ramsay, Helen Campbell, Stephen J Gray, Edward B Kaczmarski, Richard H Mallard, Malcolm Guiver, Lynne S Newbold, Ray Borrow

  Vaccine. 03/2012;

  A number of meningococcal vaccines have either been recently licensed or are in late-phase clinical trials. To inform national vaccination policy, it is important to define the burden of disease andA number of meningococcal vaccines have either been recently licensed or are in late-phase clinical trials. To inform national vaccination policy, it is important to define the burden of disease and the potential impact of any new vaccine. This study describes the epidemiology of invasive meningococcal disease across all age groups in England and Wales for recent epidemiological years between 2006 and 2010. The Health Protection Agency (HPA) conducts enhanced national meningococcal surveillance through a combination of clinical and laboratory reporting. Between 2006/09 and 2010/11, the average annual incidence of invasive meningococcal disease across all age groups was 2.0/100,000. Capsular group B (MenB) accounted for 87% (4777/5471), with an overall incidence of 1.8/100,000, with the highest MenB incidence observed among infants (36.2/100,000) where cases increased from birth to 5months of age then gradually declined. An annual average of 245 MenB cases occurred in infants (135 in those aged ≤6months) representing 26% (and 14%) of all MenB cases, respectively. After infancy, MenB rates declined until the age of 12years, rising to a second smaller peak at 18years. MenB case fatality ratio (CFR) was 5.2% (247/4777 cases) overall and was highest among ≥65year-olds (28/161; 17.4%). The largest number of deaths (n=125), however, occurred among <5year-olds. Clonal complexes cc269 and cc41/44 each accounted for around a third of cases across the age groups. Other capsular groups rarely caused invasive disease, although capsular group Y cases more than doubled from 35 in 2006/07 to 86 in 2010/11. Thus, universal meningococcal vaccination with an effective broad-spectrum formulation has potential to prevent most disease, particularly if the vaccine is immunogenic early in infancy, but, there is little justification for routine quadrivalent ACWY conjugate vaccination in the UK, although the increase in MenY disease warrants continued surveillance.

• 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.

• 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.

• Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia.

  Authors: Soonie R Patel, Jessica Bate, Ray Borrow, Paul T Heath

  Archives of disease in childhood. 01/2012; 97(1):46-8.

  Children treated for acute leukaemia are at increased risk of infection with Streptococcus pneumoniae. The basis for this may include low levels of pneumococcal antibody but this has not been wellChildren treated for acute leukaemia are at increased risk of infection with Streptococcus pneumoniae. The basis for this may include low levels of pneumococcal antibody but this has not been well studied. The authors measured serotype-specific pneumococcal IgG antibody concentrations in children treated for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) ≥6 months after completion of standard-dose chemotherapy. Pneumococcal serotype-specific IgG antibody concentrations were low. None of the subjects had protective concentrations against all the heptavalent-pneumococcal conjugate vaccine serotypes. There was no significant difference in antibody concentrations between subjects with ALL and AML (p≥0.05). Children treated for ALL and AML generally have non-protective antibody concentrations against S pneumoniae. There is significant morbidity associated with pneumococcal disease in this patient group and strategies for vaccination are required.

• Seroprevalence of serum bactericidal antibodies against group W135 and Y meningococci in England in 2009.

  Authors: Caroline L Trotter, Helen Findlow, Ray Borrow

  Clinical and vaccine immunology : CVI. 12/2011; 19(2):219-22.

  Serological surveillance has been used in the United Kingdom to inform vaccine policy for several infections, including those with group C meningococci. Meningococcal conjugate vaccines, containingSerological surveillance has been used in the United Kingdom to inform vaccine policy for several infections, including those with group C meningococci. Meningococcal conjugate vaccines, containing capsular groups A, W135, and Y in addition to C, are now available, but their use in the United Kingdom is restricted to at-risk groups and travelers to areas of endemicity. The aim of this study was to establish a baseline for natural immunity for groups W135 and Y. Serum samples collected in 2009 from individuals of all ages were obtained from the Health Protection Agency Seroepidemiology Unit, which collects residual sera from participating laboratories across the country. Serum bactericidal antibody (SBA) activity against two reference strains, representing groups Y (strain M03 241125) and W135 (strain M01 240070), was determined with 1,191 sera using a standardized complement-mediated SBA assay, with complement derived from baby rabbits (rSBA). The age-specific geometric mean titers (GMTs) and percentages of individuals with rSBA titers of ≥ 8 were calculated, together with 95% confidence intervals (CI). Overall, 18.4% and 19.6% had rSBA titers of ≥ 8 for groups W135 and Y, respectively. Antibody prevalence varied by age. In general, rSBA titers were low for younger children, with serum samples from 7% and 13% of children under 5 years achieving titers of ≥ 8 against groups W135 and Y, respectively. GMTs peaked for 20- to 24-year-olds for group W135 (GMT, 7.1; 95% CI, 4.7, 10.9) and for 30- to 44-year-olds for group Y (GMT, 8.6; 95% CI, 5.9, 12.7). Unlike seroprevalence against group B meningococci, there was not an obvious peak in SBA titers in samples from teenagers. Natural immunity against group W135 and Y meningococci in England appears to be low.

• Glycoconjugate vaccines and immune interactions, and implications for vaccination schedules.

  Authors: Ray Borrow, Ron Dagan, Fred Zepp, Hans Hallander, Jan Poolman

  Expert review of vaccines. 11/2011; 10(11):1621-31.

  Conjugate vaccines using diphtheria toxoid variant (CRM(197)), diphtheria toxoid and tetanus toxoid (TT) as carrier protein may induce immune interactions (interference or impairment as measured byConjugate vaccines using diphtheria toxoid variant (CRM(197)), diphtheria toxoid and tetanus toxoid (TT) as carrier protein may induce immune interactions (interference or impairment as measured by lower antibody levels, or enhancement [higher antibody levels]) when coadministered with other vaccines. Immune enhancement occurs when two TT conjugates are coadministered. CRM(197) conjugate vaccines induce immune bystander interference when given with diphtheria-tetanus-acellular pertussis vaccines, which reduces responses to coadministered Haemophilus influenzae type b vaccine conjugated to TT. These bystander effects are greater as the amount of CRM(197) administered increases. When large amounts of either TT or CRM(197) are coadministered, dose-related carrier-induced epitopic suppression may occur, affecting immune responses to meningococcal or pneumococcal polysaccharides. These observations have implications for vaccine scheduling. The range of available alternative vaccines means that specific vaccine coadministrations can avoid or reduce CRM(197)-induced interference. Potential interactions arising from new CRM(197) or TT conjugates will need to be thoroughly examined.

• Meningococcal group C and w135 immunological hyporesponsiveness in african toddlers.

  Authors: Helen Findlow, Samba Sow, Ray Borrow, Milagritos Tapia, Fadima Cheick Haidara, Adebayo K Akinsola, Olubukola T Idoko, Fatoumata Diallo, Richard Adegbola, Yuxiao Tang [......] Lesley Mabey, Daniel Holme, Kelly Townsend, Julie Chaumont, F Marc Laforce, Prasad S Kulkarni, Elisa Marchetti, Simonetta Viviani, Musa Hassan-King, Marie-Pierre Preziosi

  Clinical and vaccine immunology : CVI. 07/2011; 18(9):1492-6.

  A phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWYA phase II clinical study was conducted in African toddlers (aged 12 to 23 months), with subjects receiving either investigational meningococcal group A conjugate (PsA-TT), meningococcal ACWY polysaccharide (PsACWY), or Haemophilus influenzae type b (Hib-TT) vaccine. Ten months following vaccination, the 3 study groups were further randomized to receive a dose of PsA-TT, a 1/5 dose of PsACWY, or a dose of Hib-TT vaccine. Group A serum bactericidal antibody (SBA) results have been reported previously, with PsA-TT demonstrating superior immunogenicity versus PsACWY vaccine. Immunogenicity for serogroups W135 and C was assessed by SBA assay to investigate the impact of multiple doses in this age group. Blood samples were taken prior to vaccination, 28 days and 40 weeks post-primary vaccination, and 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY. Subjects who had previously received a full dose of PsACWY had W135 SBA geometric mean titers (GMTs) of 26.1 and 4.4 at 7 and 28 days post-booster vaccination with a 1/5 PsACWY dose, respectively, whereas the W135 SBA GMTs of naïve subjects at these time points following vaccination with a 1/5 dose of PsACWY were 861.1 and 14.6, respectively. Similar differences were observed for serogroup C, with SBA GMTs of 99 and 5.9 at 7 and 28 days post-booster vaccination with a 1/5 dose of PsACWY, respectively, for naïve subjects, compared to 4.1 and 3.2 for previously vaccinated subjects. Immunologic hyporesponsiveness for groups C and W135 was observed following a full dose of PsACWY vaccine at 12 to 23 months of age and a 1/5 dose of PsACWY 10 months later compared to the case for PsACWY-naïve subjects receiving a 1/5 dose of PsACWY vaccine.

• 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.

• Immunogenicity and safety of a meningococcal A conjugate vaccine in Africans.

  Authors: Samba O Sow, Brown J Okoko, Aldiouma Diallo, Simonetta Viviani, Ray Borrow, George Carlone, Milagritos Tapia, Adebayo K Akinsola, Pascal Arduin, Helen Findlow [......] Julie Chaumont, Lionel Martellet, Fatoumata Diallo, Olubukola T Idoko, Yuxiao Tang, Brian D Plikaytis, Prasad S Kulkarni, Elisa Marchetti, F Marc LaForce, Marie-Pierre Preziosi

  The New England journal of medicine. 06/2011; 364(24):2293-304.

  Group A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. We conducted two studies in Africa toGroup A meningococci are the source of major epidemics of meningitis in Africa. An affordable, highly immunogenic meningococcal A conjugate vaccine is needed. We conducted two studies in Africa to evaluate a new MenA conjugate vaccine (PsA-TT). In study A, 601 children, 12 to 23 months of age, were randomly assigned to receive PsA-TT, a quadrivalent polysaccharide reference vaccine (PsACWY), or a control vaccine (Haemophilus influenzae type b conjugate vaccine [Hib-TT]). Ten months later, these children underwent another round of randomization within each group to receive a full dose of PsA-TT, a one-fifth dose of PsACWY, or a full dose of Hib-TT, with 589 of the original participants receiving a booster dose. In study B, 900 subjects between 2 and 29 years of age were randomly assigned to receive PsA-TT or PsACWY. Safety and reactogenicity were evaluated, and immunogenicity was assessed by measuring the activity of group A serum bactericidal antibody (SBA) with rabbit complement and performing an IgG group A-specific enzyme-linked immunosorbent assay. In study A, 96.0% of the subjects in the PsA-TT group and 63.7% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline; in study B, 78.2% of the subjects in the PsA-TT group and 46.2% of those in the PsACWY group had SBA titers that were at least four times as high as those at baseline. The geometric mean SBA titers in the PsA-TT groups in studies A and B were greater by factors of 16 and 3, respectively, than they were in the PsACWY groups (P<0.001). In study A, the PsA-TT group had higher antibody titers at week 40 than the PsACWY group and had obvious immunologic memory after receiving a polysaccharide booster vaccine. Safety profiles were similar across vaccine groups, although PsA-TT recipients were more likely than PsACWY recipients to have tenderness and induration at the vaccination site. Adverse events were consistent with age-specific morbidity in the study areas; no serious vaccine-related adverse events were reported. The PsA-TT vaccine elicited a stronger response to group A antibody than the PsACWY vaccine. (Funded by the Meningitis Vaccine Project through a grant from the Bill and Melinda Gates Foundation; Controlled-Trials.com numbers, ISRCTN78147026 and ISRCTN87739946.).

• Immunoglobulin G deficiency in United kingdom children with invasive pneumococcal disease.

  Authors: Elaine Stanford, Shamez Ladhani, Ray Borrow, Pauline Waight, Mary Slack, Robert George, Paul Balmer, Elizabeth Miller, Matthew Helbert

  The Pediatric infectious disease journal. 06/2011; 30(6):462-5.

  This study aimed to determine whether nonprotective, convalescent pneumococcal serotype-specific immunoglobulin G (IgG) concentrations in children with invasive pneumococcal disease (IPD) might beThis study aimed to determine whether nonprotective, convalescent pneumococcal serotype-specific immunoglobulin G (IgG) concentrations in children with invasive pneumococcal disease (IPD) might be associated with an underlying IgG deficiency. The first 200 convalescent blood samples from children with IPD that were submitted for pneumococcal antibody testing also had total serum IgG concentrations measured. Pneumococcal IgG testing was performed for 12 serotypes (1, 3, 5, 7, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F); serotype-specific pneumococcal IgG concentrations <0.35 μg/mL were considered nonprotective. IgG deficiency was defined as total serum IgG ≥2 standard deviations below the mean for age. Nineteen of 172 children (11.0%) with sufficient serum had IgG deficiency although serum IgG concentrations were only marginally below the lower limit for age and all 19 had IgG concentrations >2.0 g/L. IgG deficiency was associated with younger age at disease (median, 5.2 [interquartile range, 2.3-13.5] vs. 12.5 [7.4-17.0] months; P = 0.005) and nonprotective convalescent antibody concentrations against the infecting serotype (10/13 [77%] vs. 51/105 [49%]; P = 0.05). There was a correlation between IgG deficiency and the number of serotypes against which children had nonprotective pneumococcal antibody concentrations, particularly among vaccinated cases (P < 0.05). Vaccine failure was also twice as common among those with IgG deficiency (3/19 [16%] vs. 11/53 [7%], P = 0.20), although this association was not statistically significant. Three children with IgG deficiency who were retested 3 to 5 months later had normal serum IgG concentrations. Although 11% of children with IPD had IgG deficiency, total serum IgG concentrations were reassuringly only marginally below the reference range and were within the normal range in those who were retested, suggesting a transient deficiency rather than a serious underlying primary immunodeficiency.

• 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.

• The Global Meningococcal Initiative: recommendations for reducing the global burden of meningococcal disease.

  Authors: Lee H Harrison, Stephen I Pelton, Annelies Wilder-Smith, Johan Holst, Marco A P Safadi, Julio A Vazquez, Muhamed-Kheir Taha, F Marc LaForce, Anne von Gottberg, Ray Borrow, Stanley A Plotkin

  Vaccine. 03/2011; 29(18):3363-71.

  The Global Meningococcal Initiative (GMI) is composed of an international group of scientists, clinicians and public health officials with expertise in meningococcal immunology, epidemiology andThe Global Meningococcal Initiative (GMI) is composed of an international group of scientists, clinicians and public health officials with expertise in meningococcal immunology, epidemiology and prevention. The primary goal of the GMI is the promotion of the global prevention of invasive meningococcal disease through education and research. The GMI members reviewed global meningococcal disease epidemiology, immunization strategies, and research needs. Over the past decade, substantial advances in meningococcal vaccine development have occurred and much has been learned about prevention from countries that have incorporated meningococcal vaccines into their immunization programs. The burden of meningococcal disease is unknown for many parts of the world because of inadequate surveillance, which severely hampers evidence-based immunization policy. As the field of meningococcal vaccine development advances, global surveillance for meningococcal disease needs to be strengthened in many regions of the world. For countries with meningococcal vaccination policies, research on vaccine effectiveness and impact, including indirect effects, is crucial for informing policy decisions. Each country needs to tailor meningococcal vaccination policy according to individual country needs and knowledge of disease burden. Innovative approaches are needed to introduce and sustain meningococcal vaccination programs in resource-poor settings with a high incidence of meningococcal disease.

• Results from a randomized clinical trial of coadministration of RotaTeq, a pentavalent rotavirus vaccine, and NeisVac-C, a meningococcal serogroup C conjugate vaccine.

  Authors: Timo Vesikari, Aino Karvonen, Ray Borrow, Nick Kitchin, Martine Baudin, Stéphane Thomas, Anne Fiquet

  Clinical and vaccine immunology : CVI. 03/2011; 18(5):878-84.

  RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis.RotaTeq (Merck & Co. Inc./Sanofi Pasteur MSD) is a three-dose, oral pentavalent rotavirus vaccine for the immunization of infants from 6 weeks of age for the prevention of rotavirus gastroenteritis. The primary objective of the present trial was to demonstrate that RotaTeq can be coadministered with meningococcal serogroup C conjugate vaccine (MenCC; NeisVac-C; Baxter Healthcare) to healthy infants without impairing the protective immune responses to MenCC. This was an open-label, randomized, comparative study conducted in Finland. The study was designed to assess concomitant versus sequential administration of RotaTeq and MenCC on the immune response to both vaccines. Healthy infants (n = 247), aged 6 to 7 weeks, were recruited. Coadministration of MenCC with RotaTeq was noninferior to sequential administration for the seroprotection rate against meningococcal serogroup C (the proportion of infants with a serum bactericidal antibody titer using baby rabbit complement of ≥ 8 was 100% in both groups). The other responses to MenCC (titer of ≥ 1:128, ≥ 4-fold increase in titer, and geometric mean titers [GMTs]) and the responses to RotaTeq (IgA and SNA response to G1 to G4 and P1A[8], GMTs, and ≥ 3-fold increase in titer) were comparable between groups, including a ≥ 3-fold IgA increase in >96% of the infants in both groups. Concomitant administration of the first doses of MenCC, diphtheria and tetanus toxoids and acellular pertussis vaccine, inactivated poliovirus vaccine, and Haemophilus influenzae type b conjugate vaccine (DTaP-IPV-Hib), and RotaTeq was associated with a higher rate of vomiting and diarrhea than concomitant administration of MenCC and DTaP-IPV-Hib, but that was not observed after the second concomitant administration. The convenience of concomitant administration of RotaTeq and MenCC may, however, outweigh the additive effect of mostly mild adverse events reported after the individual administration of each vaccine. These results support the coadministration of RotaTeq and MenCC.

• Hyporesponsiveness and its clinical implications after vaccination with polysaccharide or glycoconjugate vaccines.

  Authors: Jan Poolman, Ray Borrow

  Expert review of vaccines. 03/2011; 10(3):307-22.

  Hyporesponsiveness (immune tolerance) follows vaccination with meningococcal polysaccharide and many pneumococcal polysaccharide serotypes. Hyporesponsiveness after Haemophilus influenzae type bHyporesponsiveness (immune tolerance) follows vaccination with meningococcal polysaccharide and many pneumococcal polysaccharide serotypes. Hyporesponsiveness after Haemophilus influenzae type b polysaccharide vaccination has not been directly observed, but may follow exposure during disease in some individuals. Use of currently licensed conjugate vaccines has not been associated with hyporesponsiveness to date, with the possible exception of pneumococcal serotype 3. Introduction of polysaccharide vaccines anywhere into a conjugate vaccination schedule may result in reduced immune responses on subsequent exposure. This review of vaccine-induced hyporesponsiveness and its potential clinical implications considers recent evidence suggesting that hyporesponsiveness may occur for specific components of combined conjugate vaccines, such as pneumococcal serotype 3. These data have implications for the development of new multivalent vaccines.

• 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.

• Using the indirect cohort design to estimate the effectiveness of the seven valent pneumococcal conjugate vaccine in England and Wales.

  Authors: Nick Andrews, Pauline A Waight, Ray Borrow, Shamez Ladhani, Robert C George, Mary P E Slack, Elizabeth Miller

  PloS one. 01/2011; 6(12):e28435.

  The 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2, 3 and 13 month schedule, and has led to large decreases in invasive pneumococcal diseaseThe 7-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the United Kingdom in 2006 with a 2, 3 and 13 month schedule, and has led to large decreases in invasive pneumococcal disease (IPD) caused by the vaccine serotypes in both vaccinated and unvaccinated cohorts. We estimated the effectiveness of PCV-7 against IPD. We used enhanced surveillance data, collated at the Health Protection Agency, on vaccine type (n = 153) and non vaccine type (n = 919) IPD cases eligible for PCV-7. The indirect cohort method, a case-control type design which uses non vaccine type cases as controls, was used to estimate effectiveness of various numbers of doses as well as for each vaccine serotype. Possible bias with this design, caused by differential serotype replacement in vaccinated and unvaccinated individuals, was estimated after deriving formulae to quantify the bias. The results showed good effectiveness, increasing from 56% (95% confidence interval (CI): -7-82) for a single dose given under one year of age to 93% (95% CI: 70-98) for two doses under one year of age plus a booster dose in the second year of life. Serotype specific estimates indicated higher effectiveness against serotypes 4, 14 and 18C and lower effectiveness against 6B. Under the assumption of complete serotype replacement by non vaccine serotypes in carriage, we estimated that effectiveness estimates may be overestimated by about 2 to 5%. This study shows high effectiveness of PCV-7 under the reduced schedule used in the UK. This finding agrees with the large reductions seen in vaccine type IPD in recent years in England and Wales. The formulae derived to assess the bias of the indirect cohort method for PCV-7 can also be used when using the design for other vaccines that affect carriage such as the recently introduced 13 valent pneumococcal conjugate vaccine.