To Include or Occlude: Rational Engineering of HCV Vaccines for Humoral Immunity.
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ABSTRACT:
SUBMITTER: Schlotthauer F
PROVIDER: S-EPMC8146105 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In this review, we will discuss the field of engineered humoral immunity with an emphasis on recent work using viral vectors to produce antibodies in vivo. As an alternative to passive transfer of monoclonal antibody protein, a transgene encoding an antibody is delivered to cells via vector transduction, resulting in expression and secretion by the host cell. This review will summarize the evidence in support of this strategy as an alternative to traditional vaccines against infection and as novel therapeutics for a variety of diseases.Historically, humoral immunity has been engineered through vaccination and passive transfer of monoclonal antibodies. However, recent work suggests that vectors can be used to deliver transgenes encoding broadly neutralizing antibodies to non-hematopoietic tissues and can mediate long-term expression that is capable of preventing or treating infectious diseases. The production of engineered monoclonal antibodies allows for precise targeting and elimination of aberrant self-proteins that are characteristic of certain neurodegenerative disease. This approach has also been successfully used to combat cancer and addiction in several animal models. Despite the wide array of expression platforms that have been described, adeno-associated virus vectors have emerged as the frontrunner for rapid clinical translation.Recent advances in vector-mediated antibody expression have demonstrated the potential for such interventions to prevent infection and treat disease. As such, it offers an alternative to immunogen-based vaccine design and a novel therapeutic intervention by enabling precise manipulation of humoral immunity. Success translating these approaches to patients may enable the development of effective prevention against previously intractable pathogens that evade immunity such as HIV, influenza, malaria or HCV and may also enable new treatment options for neurodegenerative diseases such as Alzheimer's disease.
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Project description:Vaccines aim to elicit a robust, yet targeted, immune response. Failure of a vaccine to elicit such a response arises in part from inappropriate temporal control over antigen and adjuvant presentation to the immune system. In this work, we sought to exploit the immune system's natural response to extended pathogen exposure during infection by designing an easily administered slow-delivery vaccine platform. We utilized an injectable and self-healing polymer-nanoparticle (PNP) hydrogel platform to prolong the codelivery of vaccine components to the immune system. We demonstrated that these hydrogels exhibit unique delivery characteristics, whereby physicochemically distinct compounds (such as antigen and adjuvant) could be codelivered over the course of weeks. When administered in mice, hydrogel-based sustained vaccine exposure enhanced the magnitude, duration, and quality of the humoral immune response compared to standard PBS bolus administration of the same model vaccine. We report that the creation of a local inflammatory niche within the hydrogel, coupled with sustained exposure of vaccine cargo, enhanced the magnitude and duration of germinal center responses in the lymph nodes. This strengthened germinal center response promoted greater antibody affinity maturation, resulting in a more than 1000-fold increase in antigen-specific antibody affinity in comparison to bolus immunization. In summary, this work introduces a simple and effective vaccine delivery platform that increases the potency and durability of subunit vaccines.
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Project description:In light of the increasing number of approved monoclonal antibodies for the treatment of cancer, it seems peculiar that the development of antibody inducing vaccines gets so little attention. In our view there is a tremendous opportunity in the development of cancer vaccines inducing humoral immune responses, involving a couple of major advantages. Firstly, the effectivity of a polyclonal antibody response is expected to exceed the one of monoclonal antibodies. This is supported by preclinical data that show pronounced anti-tumor responses and early clinical trials in which benefit is observed in patients with advanced cancer. Secondly, vaccination strategies are expected to reduce hospital visits, resulting in enhanced quality of life. And last but not least, vaccination strategies are extremely cost effective, alleviating the socioeconomic problems of prohibitively high drug costs. To reach further clinical success, efforts should focus on target identification, optimization of vaccination strategies and adjuvant development.
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Project description:The recent Food and Drug Administration's approval of monoclonal antibodies targeting immune checkpoint receptors (ICRs) for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) offers exciting promise to improve patient outcome and reduce morbidities. A favorable response to ICR blockade relies on an extensive collection of preexisting tumor-specific T cells in the tumor microenvironment (TME). ICR blockade reinvigorates exhausted CD8+ T cells and enhances immune killing. However, resistance to ICR blockade is observed in about 85% of patients with HNSCC, therefore highlighting the importance of characterizing the mechanisms underlying HNSCC immune escape and exploring combinatorial strategies to sensitize hypoimmunogenic cold HNSCC to ICR inhibition. Cancer vaccines are designed to bypass the cold TME and directly deliver cancer antigens to antigen-presenting cells (APCs); these vaccines epitomize a priming strategy to synergize with ICR inhibitors. Cancer cells are ineffective antigen presenters, and poor APC infiltration as well as the M2-like polarization in the TME further dampens antigen uptake and processing, both of which render ineffective innate and adaptive immune detection. Cancer vaccines directly activate APC and expand the tumor-specific T-cell repertoire. In addition, cancer vaccines often contain an adjuvant, which further improves APC function, promotes epitope spreading, and augments host intrinsic antitumor immunity. Thus, the vaccine-induced immune priming generates a pool of effectors whose function can be enhanced by ICR inhibitors. In this review, we summarize the major HNSCC immune evasion strategies, the ongoing effort toward improving HNSCC vaccines, and the current challenges limiting the efficacy of cancer vaccines.
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Project description:BACKGROUND:Gut microbiome plays a crucial role in modulating human and animal immune responses. Rabies is a fatal zoonosis causing encephalitis in mammals and vaccination is the most effective method to control and eliminate rabies. The relationship between the gut microbiome and humoral immunity post rabies vaccination has not been investigated yet. METHODS:Mice orally administrated with a cocktail of broad-spectrum antibiotics were inoculated with rabies vaccines, and humoral immune response was analyzed at indicated time points. The 16S ribosomal RNA (16S rRNA) gene sequencing was performed on fecal samples from groups in vancomycin-treated and untreated mice. Mice were immunized with rabies vaccines and virus-neutralizing antibody (VNA) levels were measured, resulting in VNA high (H) and low (L) groups. Then 16S rRNA gene sequencing was performed on fecal samples from H and L group mice. RESULTS:After antibiotic (Abx) treatment, mice had decreased levels of rabies virus (RABV)-specific IgM, IgG, and virus-neutralizing antibody compared with untreated mice. Abx-treated mice had fewer T follicular helper cells, germinal center B cells, and antibody secreting cells (ASCs) in lymph nodes than did untreated mice. Gut microbiome facilitated secondary immune responses by increasing the generation of ASCs. Treatment with vancomycin alone had a similarly impaired effect on the humoral immune responses compared with Abx-treated mice. From the natural population group of mice received rabies vaccines, VNA titers vary significantly and the abundance of Clostridiales and Lachnospiraceae was positively associated with the antibody titers in mice. CONCLUSIONS:Our results provide the evidence that the gut microbiome impacts humoral immunity post rabies vaccination, and further investigation of the mechanism will help the development of novel adjuvants and vaccines.
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2023-10-27 | GSE240108 | GEO
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