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Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens
Örebro University, School of Health and Medical Sciences.
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neisseria meningitidis, also referred to as meningococcus, is a Gram-negative diplococcal bacterium best known as an important cause of meningitis and septicaemia worldwide. Meningococcal disease is a rare but life-threatening illness that may progress to death despite optimal medical care including appropriate antibiotic therapy. Case fatality remains high and survivors may suffer from significant sequelae because of impaired circulation and/or damages to the central nervous system. Prevention through vaccination remains a most effective approach to control disease. The main problem, however, is the absence of an effective vaccine against disease caused by a broad spectrum of group B isolates.

Understanding how the meningococcus can be both a common commensal and a devastating human pathogen is a major task for researchers in the area of meningococcal disease. In paper I, we investigated and described the characteristics of fatal meningococcal isolates and compared these with non-fatal invasive meningococcal isolates. The diversity was high within the isolates from both patient groups. Group Y, serotypes 14 and 15 and genosubtypes P1.7,16-29,35 and P1.5-1,10-4,36-2 were more common in fatal cases as were being elderly and female.

The second major task in the area of meningococcal disease is to develop a group B vaccine. Six genes encoding antigens identified as promising vaccine candidates were examined in papers II & III. Based on our results, the prevalence of these genes and their sequence variation have the potential to constitute a meningococcal vaccine of broad range that also cover group B isolates in Sweden and other countries with a similar distribution of disease causing meningococci.

In paper IV, we investigated the levels of IgG antibodies in serum directed against fHbp and NadA, two of the antigens included in papers II & III. Overall, the immune response to fHbp seems to be higher than the immune response to NadA, with a clear rise of anti-fHbp in the young adult groups (20-29 years).

Place, publisher, year, edition, pages
Örebro: Örebro universitet , 2009. , 92 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 31
Keyword [en]
Neisseria meningitidis, meningococcal disease, risk factors, vaccine, genome-derived neisserial antigens (GNA), polymerase chain reaction (PCR), sequencing
National Category
Medical and Health Sciences
Research subject
Medicine; Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-6638ISBN: 978-91-7668-670-6 (print)OAI: oai:DiVA.org:oru-6638DiVA: diva2:214684
Public defence
2009-06-05, Wilandersalen, Universitetssjukhuset Örebro, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2011-05-03Bibliographically approved
List of papers
1. Characteristics of Neisseria meningitidis isolates causing fatal disease
Open this publication in new window or tab >>Characteristics of Neisseria meningitidis isolates causing fatal disease
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2008 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, Vol. 40, no 9, 734-744 p.Article in journal (Refereed) Published
Abstract [en]

The objectives of the present study were to describe a selection of characteristics of all available fatal meningococcal isolates (n=62) and to compare these with all the other invasive isolates (non-fatal, n=474) collected in Sweden from 1995 to 2004 (fatality rate of 12%). The coverage of the fatal isolates by presently discussed outer membrane vesicle (OMV) vaccines was also estimated. The isolates were characterized by serogroup, serotype, genosubtype, multilocus sequence type and antibiogram. Basic epidemiological data were gathered. The results of the fatal isolates showed 55% serogroup B, 27% C, 15% Y and 3% W-135, with a fatality rate of 11% for B, 12% for C, 17% for Y and 8% for W-135. Characteristics associated with higher mortality were age, gender, serogroup Y, serotype 14 and 15 and genosubtypes P1.7,16-29,35 and P1.5-1,10-4,36-2. In contrast, non-14/non-15 serotypes, the genosubtypes P1.5-1,10-8,36-2; P1.7-2,4,37 and P1.7,16,35, as well as reduced sensitivity for penicillin G were associated with decreased mortality. The presently discussed OMV vaccines could, based solely on the complete genosubtype, theoretically cover up to 44% of the fatal serogroup B cases and up to 100% if every variable region by itself is capable to induce protective immunity.

Place, publisher, year, edition, pages
London: Taylor & Francis, 2008
National Category
Medical and Health Sciences Infectious Medicine
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:oru:diva-3456 (URN)10.1080/00365540802029565 (DOI)18609211 (PubMedID)
Available from: 2008-12-08 Created: 2008-12-08 Last updated: 2010-09-27Bibliographically approved
2. Sequence constancies and variations in genes encoding three new meningococcal vaccine candidate antigens
Open this publication in new window or tab >>Sequence constancies and variations in genes encoding three new meningococcal vaccine candidate antigens
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2006 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 24, no 12, 2161-2168 p.Article in journal (Refereed) Published
Abstract [en]

By the strategy “reverse vaccinology” a number of new antigens have been identified in Neisseria meningitidis, which are potential candidates for a highly needed broad-spectrum meningococcal vaccine. In the present study we examined the prevalence, sequence constancies and variations of the genes encoding three of these new antigens designated, genome-derived neisserial antigen (GNA) 1870, GNA1946 and GNA2132. All three genes were present in all     N. meningitidis isolates tested. Concerning gna1870, three major variants of the gene sequences and deduced amino acid sequences were identified and 56% of the deduced amino acids were conserved in all isolates. In gna1946, 98% of the deduced amino acids were conserved and in gna2132, 54% of the deduced amino acids were conserved. Based on gene prevalence and conservation, all three antigens are promising candidates for an effective meningococcal vaccine against all N. meningitidis irrespective of serogroup.

Keyword
Neisseria meningitidis; Vaccine; Genome-derived neisserial antigen (GNA).
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-6634 (URN)10.1016/j.vaccine.2005.11.006 (DOI)
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2012-01-25Bibliographically approved
3. Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease
Open this publication in new window or tab >>Prevalence and sequence variations of the genes encoding the five antigens included in the novel 5CVMB vaccine covering group B meningococcal disease
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2009 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 27, no 10, 1579-1584 p.Article in journal (Refereed) Published
Abstract [en]

During the recent years, projects are in progress for designing broad-range non-capsular-based meningococcal vaccines, covering also serogroup B isolates. We have examined three genes encoding antigens (NadA, GNA1030 and GNA2091) included in a novel vaccine, i.e. the 5 Component Vaccine against Meningococcus B (5CVMB), in terms of gene prevalence and sequence variations. These data were combined with the results from a similar study, examining the two additional antigens included in the 5CVMB (fHbp and GNA2132).

nadA and fHbp v. 1 were present in 38% (n=36), respectively 71% (n=67) of the isolates, whereas gna2132, gna1030 and gna2091 were present in all the Neisseria meningitidis isolates tested (n=95). The level of amino acid conservation was relatively high in GNA1030 (93%), GNA2091 (92%), and within the main variants of NadA and fHbp. GNA2132 (54% of the amino acids conserved) appeared to be the most diversified antigen. Consequently, the theoretical coverage of the 5CVMB antigens and the feasibility to use these in a broad-range meningococcal vaccine is appealing.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2009
Keyword
Neisseria meningitidis; 5CVMB vaccine; Genome-derived neisserial antigen (GNA); sequencing; MLST
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-6635 (URN)10.1016/j.vaccine.2008.12.052 (DOI)
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2017-03-27Bibliographically approved
4. Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis
Open this publication in new window or tab >>Seroprevalence of antibodies against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The IgG antibody levels directed against fHbp and NadA, two potential vaccine antigens for Neisseria meningitidis, were examined in order to investigate the extent of natural immunisation against these antigens in different age groups. As a comparison, the IgG antibody levels against Haemophilus influenzae type b were examined.

In the two youngest age groups, below 10 years of age, relatively low levels of both anti-fHbp and anti-NadA were measured. A 9-fold higher concentration of anti-fHbp was noted in the age groups up to 29 years of age to its peak at 30-39 years, followed by decreased levels with age. Anti-NadA showed a certain increase up to 9 years followed by an even increase up to 49 years.

Keyword
Neisseria meningitidis, factor H binding protein (fHbp), Neisseria adhesin A (NadA), seroprevalence, vaccine
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-6636 (URN)
Available from: 2009-05-06 Created: 2009-05-06 Last updated: 2016-12-06Bibliographically approved

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