Harnessing Human Antibodies to Deliver Effective Immunoprophylaxis against Difficult Disease Targets. (360G-Wellcome-106917_Z_15_Z)

Antibodies underpin effective vaccine-induced immunity, whilst monoclonal antibodies (mAbs) have come of age as effective biologicals. Nevertheless, effective antibody-mediated immunity can still fail to arise against numerous disease targets. This proposal seeks to understand the human antibody response against target antigens to enable the development of new vaccines or immunoprophylactic approaches that can deliver effective immunity against the most challenging of human diseases. The approac hes explored here will be applicable to a range of difficult disease areas, but proof-of-concept will be established against the blood-stage human malaria parasites. This work will address four key questions: 1. Can highly effective next-generation vaccines be developed by elucidating the most quantitatively susceptible epitopes identified from the repertoire of human antibodies following vaccination? 2. Can a highly effective and synergistic combination of human mAbs be developed against th e malaria parasite? 3. Can the affinity of vaccine-induced antibodies be influenced by the means of vaccine delivery in humans? 4. Can effective immunity based on a mixture of mAbs or their defined epitopes be i) delivered using vectored technologies, or ii) induced by traditional vaccination? Human mAbs will be produced from B cells isolated from volunteers vaccinated with leading antigens from the human malaria parasites Plasmodium falciparum and P. vivax. The mAbs will be characterised and used in structural studies to aid design of improved vaccine immunogens and to assess affinity maturation. In parallel technologies will be developed that seek to bypass the adaptive immune system and deliver effective immunoprophylaxis through vectored mAb delivery.