Vaccine Technologies and Platforms for Infectious Diseases: Current Progress, Challenges, and Opportunities

Abstract

Vaccination is a key component of public health policy with demonstrated cost-effective benefits in protecting both human and animal populations. Vaccines can be manufactured under multiple forms including, inactivated (killed), toxoid, live attenuated, Virus-like Particles, synthetic peptide, polysaccharide, polysaccharide conjugate (glycoconjugate), viral vectored (vector-based), nucleic acids (DNA and mRNA) and bacterial vector/synthetic antigen presenting cells. Several processes are used in the manufacturing of vaccines and recent developments in medical/biomedical engineering, biology, immunology, and vaccinology have led to the emergence of innovative nucleic acid vaccines, a novel category added to conventional and subunit vaccines. In this review, we have summarized recent advances in vaccine technologies and platforms focusing on their mechanisms of action, advantages, and possible drawbacks.

Keywords: DNA vaccine; Virus-like Particles; inactivated vaccine; live attenuated vaccine; mRNA vaccine; next generation vaccines; polysaccharide vaccine; toxoid vaccine; vaccine; vaccine platforms; vaccine types; viral vectored vaccine.

Figure 1

Schematic representation of common vaccine components, showing the typical vaccine components, including the active ingredients, stabilizers, adjuvants, preservatives, antibiotics, and trace components.

Figure 2

Basics of the immune response to vaccines following intramuscular administration. Vaccine components (e.g., antigen, and/or adjuvant) are recognized and phagocytosed (or uptaken) by tissue resident innate immune cells, or antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages (Mϕs). The process of antigen and/or adjuvant recognition, phagocytosis, and intracellular processing of antigens induce APCs to mature (e.g., increased expression of clusters of differentiation (CDs) such as CD80, CD40, MHC…), and migrate to secondary lymphoid organs (SLO; e.g., draining lymph nodes (dLN), and the spleen). Incoming APCs encounter and interact with T lymphocytes through molecular recognition between the APCs major histocompatibility complex (MHC) and the T cell receptor (TCR); also known as signal 1. This interaction is stabilized through an additional set of interactions between receptors, or co-receptors, on both cell types (i.e., CD40-CD40L); also known as signal 2. Interaction between MHC-II and the TCR, co-receptors, and APC secreted cytokines (also known as signal 3) induces the activation of helper T cells (T_h or CD4⁺ T cells). In some cases, antigens may be cross-presented on class I MHC in addition to the canonical class II MHC presentation. The former interacts with the TCR of CD8⁺ T cells, leading to their differentiation into effector (cytotoxic) T cells and memory CD8⁺ T cells. CD4⁺ T cells differentiate into one of the subclasses (e.g., Th2, Tfh, Th17, Th9…).

Figure 3

Schematic representation of the different vaccine platforms for infectious diseases, showing different vaccine technologies against (A) viral, and (B) bacterial pathogens.

Figure 4

Schematic representation of the production and purification process during manufacturing of Virus-like Particles (VLPs), shows (A) the manufacturing process of VLPs and (B) their expression in cell systems.

Figure 5

Schematic representation of viral and bacterial structures, showing the typical components of enveloped and non-enveloped viruses (Left), and bacteria (Right).

Figure 6

Schematic representation of the production and purification process during manufacturing of viral vectors. Modified viral plasmids that code for the vector components and the vaccine immunogen (transgene) are designed to co-transfect packaging cells. Within the cells, the plasmids are expressed, resulting in viral particles containing the vaccine immunogen. Particles assemble in the cytoplasm and are released into the media via cellular lysis before further purification, concentration, diafiltration, and characterization.

Figure 7

Schematic representation of the production and purification process during manufacturing of DNA and mRNA vaccines. (Top): Plasmid DNA production: Designing the sequence is the first step in developing a genomic vaccine followed by high cell-density fermentation, gene synthesis, and subcloning. Cells are harvested, lysed, and purified using chromatography. DNA plasmids are then sequenced for quality assurance before being concentrated, filtered, and sterilized for DNA vaccine formulations. (Bottom): mRNA production: mRNA synthesis for RNA-based vaccines requires the linearization of the DNA plasmid to ensure a run-off transcription. Synthesis of mRNA from the DNA plasmid template is catalyzed by an in vitro transcription (IVT) enzymatic process. RNA polymerase (ex. T7 Polymerase), nucleotide triphosphates (NTPs) substrates, polymerase cofactor MgCl₂, a pH buffer containing polyamine, and antioxidants are all components of the IVT procedure. Following QC check, the mRNA is concentrated, filtered, and sterilized.

Figure 8

Conventional, self-amplifying, trans-amplifying, and circular RNA vaccine designs. 5′ 7-methylguanosine triphosphate (m7G), 5′ Untranslated region (5′UTR), 3′ untranslated region (3′UTR), and poly A tail are common in all RNA designs. (A) Conventional unmodified, and nucleoside modified mRNA encoding vaccine immunogen. (B) Self-amplifying RNA encoding replicase gene, a subgenomic promoter, and the vaccine immunogen. Replicase genes (e.g., Alphavirus nsP1-4) code for RNA dependent RNA polymerase complex (RdRP) that recognizes the subgenomic promoter sequences and amplifies vaccine immunogen. (C) Trans-amplifying mRNA relies on the same concept of the self-amplifying mRNA but uses two different RNA transcripts: a conventional RNA encoding replicase genes and, an RNA encoding subgenomic promoter along with the vaccine immunogen. (D) Circular RNA engineered to enable protein expression through the addition of internal ribosomal entry sites (IRES) (e.g., encephalomyocarditis virus IRES) and/or the incorporation of specific nucleoside modifications in the 5′ UTR.