mRNA Vaccine Development for Emerging Animal and Zoonotic Diseases

Abstract

In the prevention and treatment of infectious diseases, mRNA vaccines hold great promise because of their low risk of insertional mutagenesis, high potency, accelerated development cycles, and potential for low-cost manufacture. In past years, several mRNA vaccines have entered clinical trials and have shown promise for offering solutions to combat emerging and re-emerging infectious diseases such as rabies, Zika, and influenza. Recently, the successful application of mRNA vaccines against COVID-19 has further validated the platform and opened the floodgates to mRNA vaccine's potential in infectious disease prevention, especially in the veterinary field. In this review, we describe our current understanding of the mRNA vaccines and the technologies used for mRNA vaccine development. We also provide an overview of mRNA vaccines developed for animal infectious diseases and discuss directions and challenges for the future applications of this promising vaccine platform in the veterinary field.

Keywords: immune response; infectious disease; mRNA vaccine; viruses; zoonoses.

Figure 1

Antigen translation and presentation of mRNA vaccines in host cells. The mRNA encapsulated in the lipid carrier molecules transits to the cytosol via endocytosis, then mRNA is released by endosomal escape. After entering cytosol, cellular translation machinery is utilized to produce an antigen of interest. The ubiquitin-proteasome system then degrades intracellular antigen into peptides that can be presented by major histocompatibility complex (MHC) class I molecules. Lastly, MHC I -epitope complex is recognized by CD8⁺ T cells to trigger the specific immune responses. In addition, the antigen of interest secreted to the extracellular domain is ingested by antigen-presenting cells (APCs), such as dendritic cells, macrophages, and langerhans cells. Following proteolytic degradation and presentation by MHC class II molecules, the MHC II -epitope complex is recognized by CD4⁺ T cells to induce the CD4⁺ mediated immune responses.

Figure 2

The types of mRNA vaccines. (a) The non-amplifying mRNA consists of 5′ cap, 5′ UTR, the gene of interest encoding region, 3′ UTR, and poly(A) tails; (b) The linear saRNA contains the genes of 5′ cap, 5′ UTR, intact RNA replication machinery, the gene of interest encoding region, and 3′ UTR; (c) The trans-amplifying system harbors an RNA-encoding RNA-replication machinery and another RNA-encoding antigen of interest.

Figure 3

The structure of the cationic lipid nanoparticle. Cationic lipid nanoparticle mainly consists of cationic lipid, distearoylphosphatidylcholine (DSPC), lipid-linked polyethylene glycol (PEG), cholesterol, and mRNA molecules. Cationic lipids interact with the negatively charged mRNA to form the particles. DSPC enhances particle stability, delivery efficacy, and biodistribution. Cholesterol can improve LNP stability by modulating membrane integrity and rigidity. PEG-lipids can further improve LNP stability and control particle size.

Figure 4

The innate and adaptive immune responses induced by mRNA vaccines. ① Antigen expression and cytokine induction: With the administration of mRNA vaccine, mRNA can be recognized by RNA sensors, then the innate immune response is activated, resulting in production of cytokines and IFNs. ② Dendritic cell activation: Dendritic cells are induced to maturation by produced IFNs and cytokines, and migrate to lymph for presenting the antigen of interest to T cells. ③ T and B cell priming in the lymph node: T cells are activated by the dendritic cell. The activated CD4+ helper T cells perform the assisted tasks, including promoting the maturation of plasma cells and secretion of antibodies. B cells induced by antigens differentiate into memory B cells and plasma cells with the help of CD4+ helper T cells and cytokines. ④ Activation of cellular and humoral immunity: The CD8+ cytotoxic T cells and antibodies transport to inflamed or infected tissue to clear the infection. The antigens can be cleared by antibodies-mediated neutralization and the death of virus-infected cells mediated by CD8+ cytotoxic T cells. The immune memory will be activated once infected with the same virus.