Files

Abstract

Vaccines currently represent one of the most effective means to control and prevent infectious diseases affecting humans and animals and have dramatically improved public health, quality of life, and life expectancy. Over the last years several conceptual and technological advances in the field of bioengineering and immunology have allowed the development of new vaccines designs. Expanding novel domains such as structural biology, human monoclonal antibody isolation, high throughput sequencing, and design of new nanocarrier delivery platforms have changed the landscape of vaccinology. These new vaccine formulations allow the design of tailor-made antigens and particulate vehicles which allow better and fine-tuned protective immune responses against known and newly emerging pathogens. Over the past decades emerging human pathogens with the potential to cause severe epidemics have become a major public health problem. The last Ebola and Zika virus epidemics demonstrated in a dramatic manner that there is an urgent need to develop prophylactic and therapeutic approaches against pathogenic emerging viruses. Most successful vaccines rely on attenuated live microorganisms to induce protective immunity. However, changed demographics and associated safety concerns makes the development of a safer alternative a priority. Subunit vaccines composed of microbial components and proteins have emerged as a suitable alternative, however they are generally less immunogenic. To address this problematic our laboratory works on the development of immunization platforms which allow 1) the development of safe recombinant subunit vaccines and 2) the rapid generation of specific monoclonal antibodies using biosynthetic immunogens without the need for prior isolation and culture of the agent. The approach evaluated in the present studies is based on a novel polymersome (PS) platform serving as nanocarrier for efficient antigen delivery and the induction of humoral immunity. The potential of PS was assessed in the context of two important human emerging pathogens form the arenavirus family that cause severe hemorrhagic fevers and of which there are neither FDA-approved vaccines not prophylactic treatments: Lassa virus (LASV), endemic in Western Africa, and Machupo virus (MACV), the causative agent of Bolivian hemorrhagic fever. In a first part, we evaluated the PS platform’s capacity to enhance humoral immunity against the envelope glycoprotein 1 of LASV, (LASV GP1) that is notorious for its weak immunogenicity and poor antibody response. Immunization of mice with adjuvanted PS (LASV GP1) enhanced the quality of the humoral response to LASV GP1, eliciting antibodies with higher binding affinity to virion GP1, increased levels of polyfunctional anti-viral CD4 T cells, and the frequency of IgG-secreting B cells. PS (LASV GP1) elicited a more diverse epitope repertoire of anti-viral IgG. In a second part, we employed the PS platform in combination with single cell B cell sorting and cloning of recombinant IgG to generate a first set of species-specific mAbs against MACV. These new mAbs show exquisite specificity and negligible cross-reactivity to closely related arenaviruses in relevant techniques making them a unique and powerful tool for research and diagnostics purposes.

Details

Actions

Preview