Vaccin | EPFL Graph Search

vignette|Trois ampoules de verre du vaccin contre le choléra, Paris, France, 1924. vignette|Publication marquant en 1896 le centenaire de la découverte de la vaccine par Jenner. Un 'vaccin' est une préparation biologique administrée à un organisme vivant afin d'y stimuler son système immunitaire et d'y développer une immunité adaptative protectrice et durable contre l'agent infectieux d'une maladie particulière. La substance active d’un vaccin est un agent antigénique soit à pathogénicité atténuée par une forme tuée ou affaiblie du micro-organisme pathogène, ou par une de ses toxines, ou par une de ses composantes caractéristiques, par exemple une protéine d'enveloppe, soit un acide nucléique. Plusieurs types de vaccins existent selon le procédé utilisé pour obtenir des anticorps neutralisants : virus entiers atténués ou inactivés, vecteurs viraux génétiquement modifiés réplicatifs ou non réplicatifs (adénovirus, vaccine), sous-unités vaccinales obtenues par recombinaison génétique,

Evaluation of oxidation-sensitive polymersomes as vaccine nanocarriers to enhance humoral responses against arenavirus envelope glycoproteins

Clara Galan Navarro

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 platformâs 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.

EPFL2017

Engineering nanoparticle-based vaccines: Implications for the quality of humoral and cellular immunity

Marcela Rincón-Restrepo

Vaccination is undoubtedly a major success in modern medicine. Yet, today there are pathogens for which no licensed or fully protective vaccines have been created. Development of vaccines based on subunit components has proven to be a safe and cost effective method for eliciting protection against pathogenic infections. It erases safety concern related to immunization with live attenuated viruses, and it offers the flexibility to target a specific antigen as well as to tune the quality of the response by selecting a precise immunostimulatory compound. Still, the ability of subunit vaccines to stimulate an immune response is usually weaker than traditional vaccine preparations. One of the approaches used to enhance immunogenicity of subunit vaccines is antigen loading or presentation by biomaterial-based carriers, especially in particulate shapes. For this purpose, our group has recently developed two nanocarriers, nanoparticles (NPs) and polymersomes (PSs) that differ considerably between each other in their physical and chemical properties. In this thesis, we evaluated the impact of antigen delivery by nanocarriers on the magnitude, and more importantly, on the quality of cellular and humoral responses. We assessed how NPs modified the CD8+ T cell response to a viral MHCI epitope and demonstrated that presentation of antigen by NPs significantly enhances the magnitude of the cellular responses. Moreover, we showed that the quality of the memory CD8+ T cells was considerably altered, with NPs promoting a robust pool of memory CD8+ T cells with an effector-like phenotype. Recent work by our group showed that T cell responses induced by NPs and PSs differ significantly depending on the delivery vehicle, with NPs enhancing cytotoxic T cell responses and PS augmenting CD4+ T cells. Herein, we demonstrated that the preferential T cell activation is the consequence of a distinct intracellular trafficking and a differential organ biodistribution of the antigen, which is promoted by the properties of the nanocarrier. Furthermore, we found that PSs are better at enhancing CD4+ T cell activation and inducing T follicular helper (Tfh) cells, which translated in an increase in germinal center B cells. Considering these results, we decided to evaluate the feasibility of a PS-based vaccine for the delivery of an antigen derived from Lassa virus, the Lassa Glycoprotein 1 (LASV-GP1). Our data showed that PSs promote an enhancement in the quality of the antibodies against LASV-GP1, which display an increased protein binding because of a broader epitope targeting. Finally, we demonstrated that, besides classical antigen-presenting cells, non-hematopoietic stromal cells also scavenge foreign antigens. We showed that lymph node lymphatic endothelial cell (LECs) internalize and process exogenous proteins in inflammatory and non-inflammatory conditions in vivo. Although with our approach we could not detect the implications of LECs presentation in the functional outcome of immune responses, we hypothesize that the elucidation of the roles of LECs on the tuning of immunity will bring novel modes of immunomodulation of vaccines. In summary, this thesis describes a comprehensive study of the adaptive immune responses generated after intradermal delivery of particulate-based subunit vaccines.

EPFL2016

Engineering cancer vaccines using stimuli-responsive biomaterials

Yugang Guo, Li Tang, Yu Zhao

Cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison to other immunotherapies, such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges need to be overcome to develop a highly efficient and safe delivery strategy for targeting cancer vaccines to professional antigen-presenting cells and eliciting optimized immune response against cancers. To meet these challenges, biomaterials, particularly biomaterials that are designed to respond to certain environmental stimuli, termed as stimuli-responsive biomaterials, are being actively developed to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines while focusing on the chemistry and material design with varied responsiveness. We also discuss the present challenges and opportunities in the field and provide a perspective for future directions.

2018