Poster Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Viral replicative capacity drives induction of long-lived humoral immunity (#214)

Preethi Eldi 1 , Jacquelyn Horsington 2 , Yee Lian Chew 3 , Robert Brink 4 , Timothy Newsome 3 , Geeta Chaudhri 1 , Guna Karupiah 1
  1. John Curtin School of Medical Research, Canberra, ACT, Australia
  2. CSIRO, Geelong, Victoria, Australia
  3. University of Sydney, Sydney, NSW, Australia
  4. Garvan Institute of Medical Research, Sydney, NSW, Australia

Smallpox eradication through vaccination is one of the most successful public health endeavours of modern medicine. Humoral immunity to smallpox elicited by the live virus vaccine is stable, lasts for decades, and is considered a valuable benchmark of the functional attributes of a good vaccine. We hypothesized that the escalating concentrations of replicating virus (antigens) provide important cues to key immune cell subsets in the germinal centre (GC) responses and these are critical for induction and maintenance of robust, long-lived humoral immunity. To test this, we used mousepox, the disease caused by ectromelia virus (ECTV) in mice and an excellent small animal model for smallpox.

Crosstalk between T follicular helper cells (TFH) and B cells is essential for induction of optimal GC responses and high affinity antibody generation. We found that replication-competent wild type ECTV induced more robust TFH and GC responses, contemporaneous with significantly higher neutralizing antibody titres, compared with a poorly replicating ECTV strain. Similar differences were observed between replicating and non-replicating strains of both vaccinia virus and influenza A virus. Importantly, we have identified biomarkers in blood that are predictive of durable, long-lived neutralizing antibody induction, which should greatly aid the field of vaccine biology. 

Using replication-competent and replication-poor recombinant ECTV expressing mutant versions of HEL (hen egg lysozyme) in combination with SWHEL transgenic B cells, we extended our studies to antigen-specific B cell responses. In mice transferred with SWHEL B cells and infected with recombinant ECTV encoding HEL, replicating virus induced massive proliferation of SWHEL B cells, somatic hypermutations (SHM) in the variable region exon of SWHEL Ig heavy chain, and affinity maturation. In contrast, poorly replicating viruses induced minimal proliferation of SWHEL B cells with little or no SHM events. The molecular signatures associated with replication-competent and replication-poor recombinant ECTV infection will be discussed.