Understanding the Immune Response to Two Different Meningitis Vaccines
Condition: Meningitis; Meningococcal Disease; Septicaemia
MeSH terms: Meningococcal Infections; Sepsis; Meningitis
Study type: Interventional
Phase: Phase 4

Summary: 
      The bacterium (germ) Neisseria meningitidis causes meningitis and blood poisoning. N
      meningitidis is classified into different serogroups (types), based on its outer
      polysaccharide (carbohydrate) capsule. Serogroups A,B,C,W & Y are responsible for the vast
      majority of meningococcal disease worldwide.

      Older vaccines against types A,C,W & Y contain part of the polysaccharide capsule of the
      germ. However, these polysaccharide vaccines do not provide long-term protection against
      disease and are less effective in young children, the group most at risk of meningococcal
      disease. Newer "conjugate" ACWY vaccines attach a polysaccharide to a protein carrier - these
      provoke a good response in young children and can provide long-term protection.

      White blood cells called B cells produce antibodies, which are the main components of
      protection against meningococcal disease. Although many studies have investigated the immune
      response to these vaccines in different age groups by measuring specific antibodies, there is
      limited information about the B cells underlying such an immune response. Several different
      subsets (populations) of B cells exist in the blood. Previous studies by the investigators
      group suggest that different numbers of B cells are produced in response to each vaccine
      type. However, little is understood about which subset of B cell is important for antibody
      production in response to these polysaccharide or conjugate vaccines.

      This study aims to provide detailed information on the immune response to meningococcal
      vaccines by investigating the appearance of B cells and their subsets in the blood after
      vaccination with the polysaccharide and conjugate vaccines. These observations will help us
      understand how polysaccharide and conjugate vaccines stimulate the immune system in different
      ways. This knowledge will help in the development of new vaccines that are effective across
      all age groups.

      The investigators aim to recruit 20 adults aged 30-70 from Oxfordshire. The study will be
      funded by the Oxford Vaccine Group.
    

Detailed description: 
      EPIDEMIOLOGY

      Neisseria meningitidis is a globally important cause of meningitis and septicaemia. The
      polysaccharide capsule is an important virulence factor in causing invasive disease. The
      serogroup of a meningococcal strain is determined by the biochemical composition of the
      polysaccharide capsule. There are 13 diverse polysaccharide capsules but only A, B, C, W and
      Y commonly cause invasive infections. In particular serogroups A,C,W, & Y account for >70% of
      meningococcal disease in North America, serogroups B & C are responsible for the vast
      majority of disease in Europe and Serogroup A causes cyclical meningitis epidemics in the
      African meningitis belt, including the recent outbreak in 2009/2010.

      Given the rapid progression and serious sequelae of meningococcal disease, primary prevention
      is vital and this is most effectively achieved by vaccination. In the absence of a serogroup
      B vaccine, quadrivalent vaccines against serogroups ACW & Y represent the broadest mechanism
      of control of meningococcal disease worldwide. Protection induced by these vaccines relies on
      anti-capsular polysaccharide antibodies.

      MENINGOCOCCAL POLYSACCHARIDE AND CONJUGATE VACCINES

      Polysaccharide ACWY vaccines consist of pure capsular polysaccharide from each of the four
      serogroups and have been in widespread use since the late 1970's. However, in common with
      polysaccharide vaccines against other encapsulated bacteria, meningococcal polysaccharide
      vaccines are poorly immunogenic in young children, do not provoke long lasting immune
      responses[5] and may not reduce nasopharyngeal carriage. Newer conjugate vaccines consist of
      capsular oligosaccharides chemically linked to a protein carrier. Conjugation of a
      polysaccharide to a protein carrier allows the recruitment of cognate T cell help with
      subsequent exposure to antigen provoking a potentiated antibody response and immunological
      memory.

      This study aims to investigate novel aspects of the B cell immune responses to meningococcal
      polysaccharide and conjugate vaccines. To achieve this, we will administer a quadrivalent
      ACWY polysaccharide vaccine (MenACWY-PS), and a quadrivalent ACWY conjugate vaccine
      (MenACWY-CRM) containing capsular oligosaccharides of serogroups A, C, W-135 & Y conjugated
      to a CRM197 mutant diphtheria toxoid carrier to adult volunteers. Each of these vaccines
      contains different amounts of capsular antigen (see Table 1). The polysaccharide vaccine has
      50µg of polysaccharide from each of the 4 serogroups, while the conjugate has 10µg of A and
      5µg of each of C, W & Y.

      A recent trial using MenACWY-PS and MenACWY-CRM conducted by the Oxford Vaccine Group
      (Understanding the Immune Response to Meningitis Vaccines, OXREC 09/H0606/20, Eudract
      2007-001349-17) showed preliminary evidence of a difference in B cell responses to
      polysaccharide and conjugate meningococcal vaccines. However, a confounding factor in
      interpreting the data from this trial has been the difference in the amount of capsular
      antigen contained in each of the two types of vaccine used in the study.

      Full dose MenACWY-PS Polysaccharide vaccine has 50µg each of MenA, MenC,MenW and MenY
      capsular antigen. MenACWY-CRM Conjugate vaccine contains 10µg of MenA capsular antigen and
      5µg each of MenC, MenW and MenY.

      The current study is designed to compare both the full dose MenACWY-PS and a 1/5th dose of
      MenACWY-PS (which contains 10µg of each serogroup) to a full dose of MenACWY-CRM. This will
      differentiate between a polysaccharide dose-dependent response and a true polysaccharide
      vaccine vs. conjugate vaccine response. In particular, we aim to investigate the thymus
      dependent or thymus independent nature of the immune response to polysaccharide and conjugate
      meningococcal vaccines respectively.

      THYMUS INDEPENDENT AND THYMUS DEPENDENT IMMUNE RESPONSES

      Thymus independent (TI) antigens are defined by their ability to induce immune responses in
      T-cell deficient or athymic mice. In common with other high molecular weight molecules with
      repetitive structures, polysaccharide vaccine antigens are further classified as Type 2 TI
      antigens. The repetitive polysaccharide epitopes cross-link the BCR of antigen specific B
      cells, triggering activation signals and stimulating proliferation and differentiation into
      antibody-secreting plasma cells. The absence of T cell help precludes the generation of
      memory B cells.

      TI responses are thought to be largely mediated by marginal zone B cells (MZB), which mature
      in the marginal zone of the spleen. This compartment is poorly developed in children under
      two years of age, which results in an ineffective anti-polysaccharide immune response in this
      age group. Murine studies have revealed an important role for a further subset of mature B
      cells, B1b cells, in adaptive immunity . Unlike the development of conventional B cell
      memory, which requires the formation of germinal centres and T cells, the development of B1b
      cell-mediated long-lasting antibody responses occur independently of T cell- help.

      In contrast, conjugate vaccines act as thymus dependent (TD) antigens. Binding of the
      polysaccharide moiety to antigen specific B cell receptors allows uptake of the
      polysaccharide protein conjugate and processing via the classical MHC class II pathway.
      Peptides derived from the carrier protein are presented to cognate CD4+ T helper cells, which
      provide signals for further B cell differentiation.

      TD responses are mediated by follicular B cells (FOB), with generation of antibody secreting
      plasma cells and memory B cells, capable of responding to further specific antigenic
      challenge[10]. Recent work conducted at the Oxford Vaccine Group suggests that pneumococcal
      polysaccharide and conjugate vaccines induce B1b and FOB cells, respectively. This study will
      investigate whether this also holds true for meningococcal conjugate and polysaccharide
      vaccines. This will be done by analysing the different populations of B cells produced in
      response to the full dose polysaccharide vaccine, 1/5th polysaccharide vaccine and conjugate
      vaccine using novel immunological techniques developed in our laboratories.

      HYPORESPONSIVENESS

      Vaccine-induced hyporesponsiveness is the inability to mount a booster response of at least
      the same magnitude as that produced to the priming dose. Previous vaccination with
      meningococcal polysaccharide vaccine has been shown to impair antibody responses to
      subsequent meningococcal polysaccharide or conjugate vaccines. The design of this study will
      allow investigation of the phenomenon of polysaccharide induced hyporesponsiveness in
      quadrivalent meningococcal vaccines at the level of memory B cell and plasma cell responses.

      SEROGROUP A

      Unlike the sialic acid based polysaccharide capsules of serogroups B, C, W-135 & Y, serogroup
      A meningococcal capsules are composed of N-acetyl mannosamine phosphate. Plain serogroup A
      polysaccharide vaccines show unexpected immunogenicity in young infants.These results suggest
      that perhaps due to its chemical structure, group A polysaccharide may not be handled by the
      immune system as a classic TI antigen. This study will test the hypothesis that follicular B
      cells are produced in response to the serogroup A component of MenACWY-PS, and by contrast,
      marginal zone or B1b cells are produced in response to the serogroup C component of the same
      vaccine. This study will also test the hypothesis that follicular B cells are produced in
      response to serogroups A and C components of MenACWY-CRM.

      ANTIBODY REPERTOIRE

      The human humoral response is anticipatory; potential specific antibody exists prior to
      encountering the extensive collection of antigen encountered over the lifetime of an
      individual. The basis for this diverse repertoire is the multiple gene segments comprising
      the variable region of the antibody molecule. The potential for each V D & J segment to
      combine randomly introduces combinatorial diversity to the repertoire. During rearrangement,
      further nucleotides may be added to or removed from the junction of the gene segments, termed
      junctional diversity. Furthermore, during maturation of the antibody response, somatic
      hypermutation of the variable region occurs during B cell proliferation in the germinal
      centres. This underlies the increase in antibody affinity in secondary responses to antigen.
      These mechanisms help create a potential repertoire of up to 1016 antibody molecules.

      Previous studies have shown that the human humoral response to specific antigens is
      restricted in diversity within the individual and across populations with a limited number of
      antibody encoding variable region genes being utilised. These studies have relied on
      traditional vector cloning and Sanger sequencing of rearranged heavy chain loci of single
      cells, and are limited in the scope of their analysis of potential repertoire.

      Massive parallel sequencing and emulsion PCR are powerful new tools enabling large scale DNA
      sequencing with the potential to simultaneously sequence up to one million reads per run.
      These techniques have been applied to look at the potential antibody repertoire in zebrafish,
      the human antibody repertoire in specific B cell subsets[20] and to assess clonality of
      leukaemoid cells. This study aims to compare the VDJ repertoire in memory B cell populations
      before and after polysaccharide and conjugate ACWY vaccination.

      ANALYSIS OF GENETIC INFLUENCES ON THE IMMUNE RESPONSE

      A further aspect to be assessed in this study is the impact of genetic factors on the
      response to immunisation. Twin studies on several vaccines including measles, mumps and
      rubella, have shown high heritability of vaccine antibody responses. Some genetic
      associations have already been identified between genes of the adaptive and innate immune
      response and some vaccines, for example human leukocyte antigen (HLA) alleles and measles
      antibody responses and IL-1β polymorphisms and hepatitis B vaccine responses. These studies
      have been small scale and based on single candidate genes and the extent to which genetic
      variation contributes to vaccine responses remains poorly understood. Insight into which
      genetic variants affect responses to specific vaccines will help identify the critical immune
      pathways leading to protection after vaccination and lead to the production of more effective
      vaccines. In addition, the identification of genes that may play important roles in wild-type
      infection will allow a better understanding of disease pathogenesis, which in turn may lead
      to the development of novel therapies

      The blood samples obtained in this study provide a source of DNA can then contribute to a DNA
      bank pooling samples from multiple different Oxford Vaccine Group studies. These DNA samples
      can then be used for genome wide analysis of the genetic factors influencing the host
      response to the vaccines received in the relevant studies. This DNA extraction and storage
      will only occur with the specific consent of participants, and DNA will not be analysed for
      any other purpose than to assess factors influencing the immune response to vaccines. Serum
      left over from separation of the cellular plug for DNA extraction will also be stored and
      further immunological assays such as the quantification of functional antibody by serum
      bactericidal activity may also be performed on them.

      SUMMARY

      This study aims to investigate in detail aspects of the B cell response to conjugate and
      polysaccharide quadrivalent meningococcal vaccines in healthy adults using a variety of novel
      laboratory methods.
    

Intervention name(s): MenACWY-CRM conjugate vaccine (Menveo, Novartis); MenACWY-PS polysaccharide vaccine, ( ACWYVax, GSK) and MenACWY-CRM conjugate vaccine (Menveo, Novartis); MenACWY-PS polysaccharide vaccine, ( ACWYVax, GSK) and MenACWY-CRM conjugate vaccine (Menveo, Novartis); 1/5th dose MenACWY-PS polysaccharide vaccine, ( ACWYVax, GSK) and MenACWY-CRM conjugate vaccine (Menveo, Novartis); Polysaccharide (subcutaneously)-conjugate
Intervention type(s): Biological; Biological; Biological; Biological; Biological
Intervention description(s): The MenACWY-CRM conjugate vaccine (Menveo, Novartis) is obtained by extemporaneous mixing just before injection of the lyophilized MenA component to be reconstituted with the MenCWY component. This vaccine is to be administered intramuscularly.; The MenACWY-PS polysaccharide vaccine, ( ACWYVax, GSK) is obtained by reconstituting the purified ACWY polysaccharides with the 0.5 ml water for injection. This vaccine should be administered subcutaneously.The MenACWY-CRM conjugate vaccine (Menveo, Novartis) is obtained by extemporaneous mixing just before injection of the lyophilized MenA component to be reconstituted with the MenCWY component. This vaccine is to be administered intramuscularly.; The MenACWY-PS polysaccharide vaccine, ( ACWYVax, GSK) is obtained by reconstituting the purified ACWY polysaccharides with the 0.5 ml water for injection. This vaccine should be administered subcutaneously.The MenACWY-CRM conjugate vaccine (Menveo, Novartis) is obtained by extemporaneous mixing just before injection of the lyophilized MenA component to be reconstituted with the MenCWY component. This vaccine is to be administered intramuscularly.; To obtain the one-fifth dose of MenACWY-PS, 0.5ml of a full dose of MenACWY-PS will be reconstituted, and then 0.4ml will be discarded prior to subcutaneous injection. The MenACWY-CRM conjugate vaccine (Menveo, Novartis) is obtained by extemporaneous mixing just before injection of the lyophilized MenA component to be reconstituted with the MenCWY component. This vaccine is to be administered intramuscularly.; The MenACWY-PS polysaccharide vaccine, ( ACWYVax, GSK) is obtained by reconstituting the purified ACWY polysaccharides with the 0.5 ml water for injection.The MenACWY-CRM conjugate vaccine (Menveo, Novartis) is obtained by extemporaneous mixing just before injection of the lyophilized MenA component to be reconstituted with the MenCWY component. This vaccine is to be administered subcutaneously
Intervention MeSH terms: Lactitol; Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Vaccines; Meningitis; Meningococcal