Abstract
The need for CD4+ T cell responses to arise de novo following vaccination can limit the speed of B cell responses. Populations of pre-existing vaccine-induced or anti-viral CD4+ T cells recognising distinct antigens could be exploited to overcome this limitation. We hypothesise that liposomal vaccine particles encapsulating epitopes that are recognised, after processing and B cell MHCII presentation, by pre-existing CD4+ T cells will exploit this pre-existing T cell help and result in improved antibody responses to distinct target antigens displayed on the particle surface. Liposomal vaccine particles were engineered to display the malaria circumsporozoite (CSP) antigen on their surface, with helper CD4+ epitopes from distinct vaccine or viral antigens contained within the particle core, ensuring the B cell response is raised but focused against CSP. In vivo vaccination studies were then conducted in C57Bl/6 mice as models of either vaccine-induced pre-existing CD4+ T cell immunity (using ovalbumin—OVA) or virus-induced pre-existing CD4+ T cell immunity (murine cytomegalovirus—MCMV). Following the establishment of pre-existing by vaccination (OVA in the adjuvant TiterMax® Gold) or infection with MCMV, mice were administered CSP-coated liposomal vaccines containing the relevant OVA or MCMV core CD4+ T cell epitopes. In mice with pre-existing anti-OVA CD4+ T cell immunity, these vaccine particles elicited rapid, high-titre, isotype-switched CSP-specific antibody responses—consistent with the involvement of anti-OVA T helper cells in confirming activation of anti-CSP B cells. Responses were further improved by entrapping TLR9 agonists, combining humoral vaccination signals ‘one’, ‘two’ and ‘three’ within one particle. Herpes viruses can establish chronic infection and elicit significant, persistent cellular immune responses. We then demonstrate that this principle can be extended to re-purpose pre-existing anti-MCMV immunity to enhance anti-CSP vaccine responses—the first description of a strategy to specifically exploit anti-cytomegalovirus immunity to augment vaccination against a target antigen.
Highlights
Vaccines are arguably our most effective medical technology, combining scientific innovation with a worldwide medical need
To determine whether pre-existing non-cognate T cells could be harnessed to support immune responses to new target antigens on the surface of vaccine particles, liposomal vaccine particles were produced with spatially segregated B and CD4+ T cell antigens
Immunodominant CD4 + T cell epitopes of the model antigen ovalbumin (OVA323-339) were incorporated into the liposome core, while the B cell epitope from Plasmodium falciparum malaria circumsporozoite protein—five repeats of NANP terminated with a cysteine residue (CSP)–was conjugated to the particle surface (Fig 2a)
Summary
Vaccines are arguably our most effective medical technology, combining scientific innovation with a worldwide medical need. By associating strong MHCII helper epitopes as part of the same vaccine particle as the target antigen, it is possible to confirm antigen-specific B cell activation by pre-existing non-cognate CD4+ T cells that recognise an epitope from a different immunological target. Conjugate vaccines—where carbohydrate B cell antigens are coupled to strong protein carriers—are the archetypal example of a vaccine strategy exploiting this mechanism to enhance antibody responses to weak antigens. Conjugating helper peptides or proteins to target antigens does not reliably enhance anti-target antibody responses. This approach can result in the immune response to the protein carrier dominating over that generated against the target antigen [6] [7] [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
