Antigens for Vaccination

Antigens for vaccination generally come in three types: engineered live pathogens with reduced toxicity, individual pathogen components (such as proteins or polysaccharides), and genetic material (i.e., "naked" DNA / RNA) of the pathogen. These molecules can trigger innate or adaptive immune responses and induce organisms to synthesize corresponding antibodies to achieve the treatment and prevention of diseases.

Identifying and Producing Vaccine Antigens

The complexity of identifying vaccine antigens may vary depending on whether the vaccine antibodies are whole pathogens or pathogen-derived materials. Intact pathogens usually involve the use of intact viruses or bacteria in the form of recombinant, attenuated or inactivated microorganisms. Attenuated pathogens still retain their activity and a certain ability to replicate, but will change their virulence in the target host in a specific way; inactivated pathogens have died or lost their ability to replicate; recombinant pathogens typically contain at least two different sources of antigen components, this complex framework can give it more desirable physiological characteristics.

Where whole-pathogen approaches are not feasible, other approaches, such as the use of split, subunit or recombinant antigens, will be considered. Existing antigen vaccine preparation generally combines two aspects of safety and immunogenicity. The commonly used methods are recombinant DNA technology and vaccine peptide synthesis. The core principle is to maintain the integrity of the antigen structure, while eliminating unrelated components to the greatest extent and reducing reactogenicity. Especially for DNA vaccines, only the genetic material selected from the pathogen can be used, giving a pure and highly specific antigen. The benefit of such an approach is that it facilitates the generation of recombinant peptides that contain elements of antigenic proteins' conformational epitopes in a concatenated form (recognized by B cells) and linear epitopes (recognized by T cells).

Figure 1. Development of pathogen vaccine technology. (Strugnell, 2011)

Development of Complete Pathogen Vaccines

The most direct way to develop a vaccine is to use intact pathogens that can be killed, inactivated or attenuated (survival but harmless). These complete organisms contain all relevant pathogen-specific proteins and carbohydrate antigens and can be effectively vaccinated. Similar to the case of natural infections, live pathogen vaccines can replicate in vivo and spread to their target tissues, possessing extremely high innate immune strength, high antigen content after replication, and long duration. Besides, if the pathogen can grow rapidly in cell culture, its production cost will be very low. However, for specific pathogens or specific populations, intact pathogens are not applicable. Here are some situations that need to pay attention to:

• Loss of attenuation of live vaccines. Some attenuated vaccines are controlled by CD4⁺ T cells in the body, and for patients with human immunodeficiency virus (HIV) / acquired immunodeficiency syndrome (AIDS), normal attenuated organisms may also cause serious infections or diseases. Therefore, the use of live attenuated vaccines is prohibited in most immunocompromised populations.
• High reactogenicity. Some inactivated whole pathogen vaccines are associated with high frequency local or systemic reactivity. This reactogenicity may be due to the potency of other microbial molecules that trigger an innate immune response.
• Unwanted immune response. Due to the low affinity of protective epitopes, it may cause some harmful immune responses.
• Risk of reversion. Some random mutations or genetic recombination with related microorganisms may lead to the restoration of toxicity of attenuated pathogens.
• Pathogen complexity. Pathogens may also have complex pathogenic pathways involving multiple host tissues. In some diseases, different stages of the pathogen's life cycle produce many different antigens. This makes it difficult to target all of the critical phases of the infective process using the whole pathogen from any single stage of development.
• Latency and immune evasion. Some pathogens usually exist in the host in a latent state in the host's life, or maybe protected or hidden from the immune system, and therefore cannot be used for vaccine-induced immune responses.
• Reduced immunogenicity. Procedures to attenuate or inactivate pathogens may remove important defense triggers or necessary protective immunogenic components (epitopes), in which case the remaining antigens may not induce an immune response that protects the vaccine.

Development of Subunit Antigen

The split pathogen and subunit antigens are derived from the physical separation and/or fractionation of the entire pathogen into smaller components, and the antigen mixture contains the viral envelope and surface antigens. We can make it through mechanical and chemical methods. Toxoid-based vaccines in the early twentieth century were the first subunit vaccines, although they were based on the production of antibodies against pathogenic products of the pathogen rather than the structural components of the pathogen. The use of a combination of different subunit antigen components can provide more complete vaccine protection, and it has been proven that multiple subunits can be combined to make an effective, well-tolerated vaccine.

Development of Engineered Biomolecular Antigen

• Antigens Generated by Recombinant DNA Technology

Improvements in industrial processes and sophisticated analytical screening methods have allowed us to further expand the scope of subunit vaccines. Specific antigen proteins can be produced by recombinant DNA technology for viruses (such as HBV and HPV) that do not grow in cell lines. For example, a gene encoding a specific protein of interest can be inserted into a protein expression system for production, such as baculoviral, which is used to infect insect cells or yeast cells. This method can produce and purify large amounts of recombinant proteins. Since pure antigens generally do not contain components that can activate defensive triggers of the innate immune system, the antigens produced by this method are well-tolerated, but usually require the addition of adjuvants to achieve high immunogenicity and long-term protection.

• Direct Synthesis of Short Peptide Antigens

Identifying and directly synthesizing specific peptides that cause adaptive immune responses through a variety of methods is an effective way to develop vaccine antigen. The peptide selected for vaccine development must contain an epitope capable of inducing sufficient primary T cell activation to achieve effective cellular and humoral immunity.

Reference

1. Strugnell, R.; et al. (2011). Vaccine antigens. Perspect Vaccinol. 1(1): 61-88.