Here we describe a novel humoral vaccination strategy where particles are specifically designed to deliver B cell activation signals in a co-ordinated fashion that exploits pre-existing CD4+ T cell help. Liposome-based vaccine nanoparticles were produced to display ‘weak’ target antigens exclusively on the particle surface, while ‘strong’ helper CD4 epitopes are ‘hidden’ inside the particle core. These helper epitopes are released upon internalisation by B cells to be presented on MHC class II for B cell activation by non-cognate CD4+ T cells.
In mice with pre-existing CD4+ T cell immunity to Ovalbumin (OVA) core peptides, Plasmodium falciparum CSP-coated vaccine particles containing OVA peptides can induce rapid, high-titre, isotype-switched, anti-CSP antibody responses – in keeping with the immediate involvement of anti-OVA T helper cells. We demonstrate that responses can be improved by providing the ‘third signal’ for B cell activation by including TLR9 agonists in the core of our vaccine particles. We then investigate whether this strategy can bypass CD4+ T cell tolerance of ‘modified self’ antigens to generate antibody responses against cancer antigens. Lastly, in addition to exploiting vaccine-induced CD4 T cells, we show that we can also exploit pre-existing CD4+ T cells induced by infection with a chronic viral pathogen Murine Cytomegalovirus (MCMV) to augment antibody responses to target antigens.
We conclude that our particle design can engage pre-existing, non-cognate CD4+ T cell help – either against a chronic viral pathogen or induced by immunisation – to significantly enhance humoral responses to target antigens. This platform may be useful in cancer vaccination, where CD4+ T cell mediated tolerance of cancer antigens represents a significant immunological hurdle. Additionally, as it elicits rapid and class-switched antibodies, this could be a useful rapid-response approach to combat threats such as pandemic influenza.