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SUMMARY:The Evolution of B Cell Reactivity Following Sequential Dengue Inf
 ection - Kelsey Lowman\, Department of Veterinary Medicine
DTSTART:20260226T130000Z
DTEND:20260226T140000Z
UID:TALK245233@talks.cam.ac.uk
CONTACT:Fiona Roby
DESCRIPTION:Antigenic similarities between the four distinct dengue virus 
 (DENV) serotypes underlie disease enhancement observed in secondary DENV i
 nfection. Antibodies generated in the first infection weakly cross-react w
 ith the new infecting serotype to facilitate (enhance) viral replication t
 hrough Fc receptor-mediated viral entry. This phenomenon is called antibod
 y-dependent enhancement (ADE)\, and it is the largest obstacle to developi
 ng safe and broadly protective vaccines for DENV. \nThe antibody repertoir
 e after primary DENV infection is quite restricted\, comprising predominan
 tly of weakly cross-reactive antibodies targeting the fusion loop of the s
 urface envelope (E) protein of the virus\, while a small portion are serot
 ype-specific antibodies responsible for conveying protective immunity agai
 nst homotypic infection. Secondary DENV infection induces cross-serotype p
 rotection\, in part mediated by a broadening and strengthening of antibody
  responses after heterotypic infection. However\, it is not completely und
 erstood whether the post-secondary antibody response to the new serotype r
 esults from an extension and diversification of the DENV cross-reactive B 
 cells generated during primary infection or is derived from de novo B cell
  responses.\nTo evaluate how antibody diversity evolves across sequential 
 infection\, I first conducted a comprehensive analysis of the DENV-memory 
 B cell receptor (BCR) repertoire of a highly exposed individual. This reve
 aled that the majority of DENV-specific BCRs interacted with the E protein
  fusion loop and contained BCR physicochemical features opposite to those 
 observed for DENV broadly neutralising antibodies. Despite their target\, 
 I identified fusion loop epitope antibodies with greater neutralisation ac
 tivity than typically described for standard fusion loop epitope antibodie
 s. The BCR signatures identified suggest an underlying selection for speci
 fic BCR features drives the clonal maturation trajectory away from enhanci
 ng\, weakly cross-reactive fusion loop epitope antibodies toward protectiv
 e and more specific antibodies. \nOne of the greatest challenges to direct
 ly mapping this antibody diversification during infection has been our ina
 bility to sample and measure human germinal centre responses. To study thi
 s\, we established a blinded Phase I trial to model sequential DENV infect
 ion in 45 individuals across different DENV immune histories (naïve\, pri
 mary heterotypic\, and polytypic) using a live-attenuated DENV3 vaccine. W
 e successfully implemented a minimally invasive\, ultrasound-guided\, fine
  needle aspirate sampling of draining lymph nodes to capture DENV-responsi
 ve B cells at the site of their activation and affinity maturation. Flow c
 ytometric analyses of circulating and lymph node-resident B cells revealed
  that naïve participants’ germinal centre responses were predominantly 
 DENV3-specific\, whereas individuals with prior immunity demonstrated cros
 s-reactive lymph node activity associated with a broadening and strengthen
 ing of DENV antibody responses as far as 57 days after vaccination. These 
 data provide valuable insight into germinal centre activities that inform 
 our basic understanding of DENV-specific B cell and antibody responses\, a
 s well as greater patterns of B cell imprinting\, that will lay the founda
 tion for the development of next-generation DENV vaccine strategies and th
 erapeutic interventions.\n
LOCATION:LT2\, Department of Veterinary Medicine
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