Improving vaccination against type-2 T-independent antigens

Summary Infections with encapsulated bacteria are responsible for the death of millions of children and the elderly each year. Capsular polysaccharides behave as T-independent antigens (TI) and vaccination based on these carbohydrates provides protection against these infections. The efficacy of vaccines against TI antigens is severely limited by their inability to induce recall responses upon revaccination or infection. This phenomenon depends on inhibition of memory B cells by antigen-specific IgG generated in the primary response. The mechanism behind this inhibitory activity however, remains unclear. The efficacy of vaccines critically depends on adjuvants that can promote strong memory and influence Ig class switch recombination (CSR). However, effective adjuvants for TI antigens vaccination are not available. The goal of our proposal is to answer two outstanding questions regarding the response to TI antigens: what is the mechanism of the inhibition of recall responses? and how can CSR and generation of memory B cells can be manipulated to improve vaccination? For these studies we will use a mouse model of tularemia and will use Francisella tularensis LPS, a model TI antigen that we showed activates B1 cells. In aim 1 we will test the hypothesis that IgG-LPS immune complexes inhibit memory B1 cells reactivation and IgM production through complement activation. We will test whether complement depletion or absence could restore the recall response to vaccination with TI antigens and result in a more effective vaccine for tularemia. In aim 2 we will test the hypothesis that novel adjuvants can improve recall responses to TI antigen by manipulating CSR in B1 cells and/or improving generation of memory B1. Based on our preliminary results we will test a number of potential adjuvant treatments with the goal of achieving sustained IgM and increased LPS-specific IgA production but reduced IgG (responsible for inhibition of recall response). These adjuvants are also expected to increased numbers of memory B1 cells. If successful, our studies will create proof of concepts that can inform future development of more effective vaccination strategies for TI antigens.