Evolution of Bordetella pertussis post vaccination

Evolution of Bordetella pertussis post vaccination Whooping cough or pertussis is caused by the gram-negative bacterium Bordetella pertussis. It is a highly contiguous disease in the human respiratory tract. Characteristic of pertussis is a paroxysmal cough with whooping sound during gasps of breath after coughing episodes. It is potentially fatal to unvaccinated infants. The best approach to fight pertussis is to vaccinate. Vaccinations against pertussis have been available from the 1940s. Traditionally vaccines were whole-cell pertussis (wP) preparations as part of the combined diphtheria-tetanus-pertussis (DTP) vaccines. More recently acellular pertussis (aP) vaccines have replaced the wP vaccines in many countries. The aP vaccines are less reactogenic and can also be administered to school children and adults. There are several publications reporting variation in the i>B. pertussis virulence factors that are also aP vaccine antigens. This has occurred in the genes coding for pertussis toxin and pertactin about 15 to 30 years after the introduction of pertussis vaccines to immunisation programs. Resurgence of pertussis has also been reported in many countries with high vaccination coverage. In this study the evolution of B. pertussis was investigated in Finland, the United Kingdom, Poland, Serbia, China, Senegal and Kenya. These represent countries with a long history of high vaccination coverage with stable vaccines or changes in the vaccine formulation; countries which established high vaccination coverage late; and countries where vaccinations against pertussis were started late. With bacterial cytotoxicity and cytokine measurements, comparative genomic hybridisation, pulsed-field gel electrophoresis (PFGE), genotyping and serotyping it was found that changes in the vaccine composition can postpone the emergence of antigenic variants. It seems that the change in PFGE profiles and the loss of genetic material in the genome of B. pertussis are similar in most countries and the vaccine-induced immunity is selecting non-vaccine type strains. However, the differences in the formulation of the vaccines, the vaccination programs and in the coverage of pertussis vaccination have affected the speed and timing of these changes.

Development of a Glycocluster Adjuvant Mimicking Natural Yeast beta-(1,2)-Structures

Allergy is characterized by T helper (Th) 2-type immune response after encounter with an allergen leading to subsequent immunoglobulin (Ig) E-mediated hypersensitivity reaction and further allergic inflammation. Allergen-specific immunotherapy (SIT) balances the Th2-biased immunity towards Th1 and T regulatory responses. Adjuvants are used in allergen preparations to intensify and modify SIT. β-(1,2)-oligomannoside constituents present in Candida albicans (C. albicans) cell wall possess Th1-type immunostimulatory properties. The aim of this thesis was to develop a β-(1,2)-linked carbohydrate compound with known structure and anti-allergic properties to be applied as an adjuvant in SIT. First the immunostimulatory properties of various fungal extracts were studied. C. albicans appeared to be the most promising Th1-inducing extract, which led to the synthesis of various mono- or divalent oligomannosides designed on the basis of C. albicans. These carbohydrates did not induce strong cytokine production in human peripheral blood mononuclear cell (PBMC) cultures. In contrast to earlier reports using native oligosaccharides from C. albicans, synthetic -(1,2)-linked mannotetraose did not induce any tumor necrosis factor production in murine macrophages. Next, similarities with synthesized divalent mannosides and the antigenic epitopes of β-(1,2)-linked C. albicans mannan were investigated. Two divalent compounds inhibited specific IgG antibodies binding to below 3 kDa hydrolyzed mannan down to the level of 30–50% showing similar antigenicity to C. albicans. Immunomodulatory properties of synthesized carbohydrate assemblies ranging from mono- to pentavalent were evaluated. A trivalent acetylated dimannose (TADM) induced interleukin-10 (IL-10) and interferon-γ responses. TADM also suppressed birch pollen induced IL-4 and IL-5 responses in allergen (Bet v) stimulated PBMCs of birch pollen allergic subjects. This suppression was stronger with TADM than with other used adjuvants, immunostimulatory oligonucleotides and monophosphoryl lipid A. In a murine model of asthma, the allergen induced inflammatory responses could also be suppressed by TADM on cytokine and antibody levels.