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The First Dose of a Haemophilus influenzae Type b Conjugate Vaccine Reactivates Memory B Cells: Evidence for Extensive Clonal Selection, Intraclonal Affinity Maturation, and Multiple Isotype Switches to IgA2¹

Lotte Hougs^2,*, Lars Juul^*, Henrik J. Ditzel^*,, Carsten Heilmann, Arne Svejgaard^* and Torben Barington^*

^* Department of Clinical Immunology and Pediatric Clinic II, The National University Hospital, Rigshospitalet, Copenhagen, Denmark; and Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

The Ab response of a healthy adult to the first dose of a Haemophilus influenzae type b capsular polysaccharide (HibCP) conjugate vaccine was studied at the level of Ig gene usage by circulating Ab-secreting cells. Forty-one IgA and 17 IgG mRNA sequences were obtained. The major part of the response was confined to IgA Ab-secreting cells, and 72% of the IgA sequences were derived from the progeny of a single rearranged B cell. These sequences could be arranged in a genealogical tree showing multiple somatic mutations and at least two intraclonal isotype switches to IgA2. Fourteen somatic mutations were shared by this clonal progeny, indicating that extreme clonal selection had occurred early in the clonal development. Taking into account the frequency of somatic mutations and the clone size, it was evident that the responding cell population must have originated from a mutated, highly selected, and expanded population of cells existing before vaccination, i.e., memory B cells. The dominating heavy and light chains of the response were combined in a Fab that bound HibCP. It was shown that the shared heavy and light chain mutations increased the affinity for HibCP considerably, indicating that the clonal selection had been driven by affinity. Pre-existing memory cells in unvaccinated adults may explain several features of Ab responses to polysaccharide vaccines and may play a role in acquiring the ability to respond to pure polysaccharides during infancy.

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