Which Factors affects Immunogenicity? – Factors affecting Immunogenicity

What is Immunogenicity?

• Immunogenicity is a fundamental concept in immunology that describes the ability of a foreign substance, known as an antigen, to stimulate an immune response within the body of a human or another animal. This immune response can be either desired or undesired, depending on the context in which it occurs.
• In the context of vaccines, immunogenicity plays a crucial role. When a vaccine is administered, it contains specific antigens that mimic parts of a pathogen, such as a virus or bacterium. These antigens are carefully selected to provoke an immune response in the body. The immune system recognizes the antigens as foreign and mounts a defensive reaction, producing antibodies and activating immune cells. This immune response is highly desirable as it primes the immune system to recognize and fight off the actual pathogen if the individual is exposed to it in the future. Therefore, wanted immunogenicity is essential for the effectiveness of vaccines in providing immunity and preventing infectious diseases.
• On the other hand, unwanted immunogenicity refers to an immune response that occurs against a therapeutic antigen. In some cases, when a therapeutic antigen, such as a protein-based drug, is introduced into the body, the immune system recognizes it as foreign and generates antibodies against it. These antibodies are called anti-drug antibodies (ADAs). The presence of ADAs can neutralize the therapeutic effects of the drug, rendering it less effective or completely ineffective. Additionally, ADAs can lead to adverse effects or allergic reactions. Unwanted immunogenicity is a significant concern in the field of biotherapy, as it can hinder the success of therapeutic interventions and impact patient outcomes.
• One of the challenges in biotherapy is predicting the immunogenic potential of novel protein therapeutics. It is important to assess the likelihood of inducing an immune response before developing and administering these therapeutic agents. Immunogenicity data obtained from high-income countries may not necessarily apply to low-income and middle-income countries due to genetic and environmental factors that can influence immune responses. Furthermore, the immunogenicity of vaccines can vary with age, making it necessary to consider age-related differences in immune responses. Consequently, the World Health Organization emphasizes the importance of investigating immunogenicity in the target population, as animal testing and in vitro models do not always accurately predict immune responses in humans.
• It is worth noting that the term antigenicity was commonly used in the past to refer to what is now known as immunogenicity. Although the two terms are often used interchangeably, there is a subtle distinction between them. Antigenicity describes the ability of a chemical structure, whether it is an antigen or a hapten, to specifically bind to T cell receptors or antibodies. In contrast, immunogenicity specifically refers to the capacity of an antigen to induce an adaptive immune response. Therefore, while an antigen can bind to T or B cell receptors without triggering an immune response, an immunogenic antigen, also known as an immunogen, is capable of stimulating an adaptive immune response.
• In summary, immunogenicity encompasses both the desired immune response triggered by vaccines and the undesired immune response against therapeutic antigens. Understanding and predicting immunogenicity are crucial for the development of effective vaccines and biotherapeutic interventions. By studying immunogenicity in the target population and considering various factors that influence immune responses, researchers can strive to enhance the safety and efficacy of immunological interventions in diverse populations.

A. Properties of Immunogen

1. Foreignness

• The concept of “foreignness” is crucial in understanding the immune response elicited by antigens. In order to provoke an immune response, an antigen must be perceived as foreign by the animal’s biological system or recognized as non-self. However, there are exceptions and complexities in this recognition process.
• For example, the immunogenicity of an antigen can vary between different animal species. One such example is bovine serum albumin, a commonly used experimental antigen. When injected into a cow, which is the same species from which the antigen is derived, it does not elicit a strong immune response. However, when the same antigen is injected into a rabbit, a different species, it strongly stimulates the immune system. This discrepancy in immunogenicity highlights the importance of species-specific recognition and immune response to foreign substances.
• Despite the general expectation that foreign antigens would be highly immunogenic, there are instances where certain macromolecules exhibit weak immunogenicity. This is particularly observed in macromolecules such as collagen and cytochrome c, which have been conserved throughout evolution. These conserved molecules may be less readily recognized as foreign by the immune system, leading to a weaker immune response compared to other antigens.
• Conversely, there are self-components that are strongly immunogenic, even when injected into the animal from which they originated. Examples of such self-components include sperm and corneal tissues. These self-components are sequestered from the immune system under normal circumstances, and the immune system is not exposed to them. However, when introduced into a different part of the body or directly injected, they can be recognized as foreign by the immune system and elicit a robust immune response.
• The recognition of foreignness by the immune system is a complex process influenced by various factors, including the evolutionary conservation of antigens, species-specific immune responses, and the sequestration of self-components. Understanding these nuances is important in the fields of immunology and antigen design, as it helps researchers predict and manipulate immune responses to develop effective vaccines, therapeutics, and diagnostic tools.
• In summary, the immunogenicity of an antigen is often dependent on its perceived foreignness by the immune system. While foreign antigens typically elicit an immune response, there are exceptions and variations in immunogenicity. Factors such as species-specific recognition, conservation of antigens, and the sequestration of self-components contribute to the complexity of immune responses to different antigens. By studying and comprehending these mechanisms, scientists can enhance their understanding of immune recognition and develop strategies to modulate immune responses for various applications.

2. Molecular Size

• Molecular size plays a significant role in determining the immunogenicity of substances. Immunogens, which are substances capable of eliciting an immune response, are often characterized by a specific range of molecular masses.
• The most potent immunogens typically fall within a molecular mass range of 14,000 to 600,000 Daltons (Da), with a majority exceeding 100,000 Da. Examples of highly antigenic substances within this range include tetanus toxoid, egg albumin, and thyroglobulin. These molecules are known to provoke robust immune responses and are commonly utilized in immunological research and vaccine development.
• In contrast, substances with molecular masses below a certain threshold generally exhibit poor immunogenicity. Typically, substances with molecular masses less than 5,000 to 10,000 Da are considered weak immunogens or even non-antigenic. For instance, insulin, which has a molecular mass of approximately 5,700 Da, is generally considered to be either non-antigenic or weakly antigenic. Although it can interact with the immune system to some extent, its smaller size limits its ability to stimulate a potent and sustained immune response.
• The relationship between molecular size and immunogenicity can be attributed to several factors. Larger molecules offer a greater diversity of epitopes, which are the specific regions recognized by the immune system. This increased epitope diversity allows for a more comprehensive interaction with immune cells and facilitates the generation of a robust immune response. Additionally, larger molecules often have more complex three-dimensional structures, which can enhance their interaction with immune receptors and promote immune activation.
• However, it is important to note that molecular size is just one of several factors that contribute to immunogenicity. Other factors, such as the presence of adjuvants, the route of administration, and the individual’s genetic makeup, can also influence the immune response to a particular substance.
• In summary, the molecular size of a substance is closely associated with its immunogenicity. Substances within the molecular mass range of 14,000 to 600,000 Da, with a preference for those exceeding 100,000 Da, tend to be highly antigenic and capable of eliciting robust immune responses. On the other hand, substances with smaller molecular masses, usually below 5,000 to 10,000 Da, are generally considered weak immunogens or non-antigenic. However, it is important to consider other factors that contribute to immunogenicity, as the relationship between molecular size and immune response is not absolute.

3. Chemical Nature and Heterogeneity

• The chemical nature and heterogeneity of antigens play a crucial role in determining their immunogenicity. Antigens are predominantly composed of proteins, although some are polysaccharides. The complexity of the chemical structure of an antigen is generally correlated with its immunogenic potential.
• In general, substances that are chemically more complex tend to exhibit higher immunogenicity. This complexity can arise from the presence of multiple epitopes within the antigen, allowing for a greater variety of interactions with the immune system. Proteins, with their intricate folding patterns and diverse amino acid sequences, often possess a higher degree of chemical complexity compared to simpler substances.
• Synthetic homopolymers, which consist of multiple copies of a single sugar or amino acid, generally lack immunogenicity regardless of their size. This is because the repetitive nature of their structure fails to provide the necessary diversity of epitopes required for effective immune recognition and response. In contrast, heteropolymers, which contain different sugars or amino acids, tend to be more immunogenic. The inclusion of diverse components in the antigen structure increases the likelihood of stimulating a broader range of immune responses.
• Interestingly, the presence of an aromatic radical, such as a benzene ring, is considered essential for the rigidity and antigenicity of a substance. Aromatic radicals provide structural stability to the antigen, allowing it to maintain a conformation that is capable of effectively interacting with immune receptors. This rigidity contributes to the ability of the antigen to be recognized by the immune system and triggers an appropriate immune response.
• Overall, the chemical nature and heterogeneity of antigens are critical determinants of their immunogenicity. Chemically complex substances, particularly those composed of proteins and heteropolymers, tend to exhibit higher immunogenic potential due to their diverse epitopes. Conversely, synthetic homopolymers lack immunogenicity, regardless of their size. The presence of an aromatic radical within the antigen structure contributes to its rigidity and antigenicity, facilitating effective immune recognition.
• It is important to note that while these general principles hold true in many cases, there can be exceptions and variations depending on the specific antigen and the immune system of the individual. The field of immunology continues to explore and unravel the complex interplay between the chemical nature of antigens and the resulting immune responses, leading to advancements in vaccine development, immunotherapy, and diagnostics.

4. Physical form

• The physical form of an antigen is an important factor that influences its immunogenicity. Generally, particulate antigens are more immunogenic compared to soluble antigens. Additionally, the denatured form of an antigen tends to be more immunogenic than its native form. Furthermore, large, insoluble, or aggregated molecules tend to be more immunogenic than small, soluble ones.
• Particulate antigens, such as those present in vaccines or particles derived from pathogens, are highly effective at inducing immune responses. The particulate nature of these antigens allows for efficient uptake and presentation by antigen-presenting cells (APCs). The size and shape of the particles contribute to their immunogenicity, as they can enhance interactions with immune cells and facilitate the activation of both B-cells and T-cells. The repetitive nature of particulate antigens can also provide multiple epitopes, leading to a more robust and sustained immune response.
• Denatured antigens, which have undergone a structural change resulting in the loss of their native conformation, often exhibit increased immunogenicity compared to their native form. Denaturation can occur through various processes such as heat, chemical treatment, or pH changes. The altered structure of denatured antigens can expose previously hidden or inaccessible epitopes, making them more accessible to immune recognition. This exposure of new epitopes can trigger a stronger immune response, leading to enhanced immunogenicity.
• The size and solubility of antigens also play a role in determining their immunogenicity. Large molecules, insoluble particles, or aggregated antigens tend to be more immunogenic than small, soluble ones. The larger size provides more surface area for interactions with immune cells and facilitates the activation of immune responses. Insoluble or aggregated antigens can be efficiently phagocytosed by APCs, leading to effective antigen presentation and subsequent immune activation.
• On the other hand, small, soluble antigens may have limited immunogenicity. Their rapid diffusion and clearance from the body can reduce their interaction with immune cells and limit the activation of immune responses. However, soluble antigens can still induce immune responses when presented in the appropriate context, such as when coupled with adjuvants or when delivered using specific delivery systems.
• Understanding the influence of physical form on immunogenicity is essential in vaccine design, as it allows researchers to optimize the formulation and presentation of antigens to enhance immune responses. By utilizing particulate antigens, denatured forms, or larger insoluble or aggregated molecules, scientists can develop more effective vaccines and immunotherapies that elicit robust and targeted immune responses.
• In summary, the physical form of an antigen significantly impacts its immunogenicity. Particulate antigens, denatured antigens, and larger insoluble or aggregated molecules tend to be more immunogenic compared to soluble, native, or smaller antigens, respectively. Consideration of the physical form of antigens is crucial in designing effective vaccines and immunotherapies that elicit potent and targeted immune responses.

5. Susceptibility to antigen processing and presentation

• Susceptibility to antigen processing and presentation is a crucial factor in determining the immunogenicity of antigens. The development of an effective immune response, both humoral (antibody-mediated) and cell-mediated, relies on the interaction between T-cells and antigens that have been appropriately processed and presented together with major histocompatibility complex (MHC) molecules.
• Antigens that cannot be effectively processed and presented by MHC molecules are generally poor immunogens. MHC molecules are responsible for presenting antigens to T-cells, allowing them to recognize and initiate an immune response against the specific antigen. If an antigen cannot be properly processed and presented, the immune system may fail to mount a robust response. This can occur when the antigen structure is not compatible with the antigen-processing machinery within antigen-presenting cells (APCs), such as macrophages or dendritic cells.
• Antigens that are easily phagocytosed, or engulfed by APCs, tend to be more immunogenic. Phagocytosis allows APCs to internalize antigens and break them down into smaller peptide fragments that can be presented by MHC molecules. The efficient uptake and processing of antigens by APCs facilitate the activation of T-cells, leading to a stronger immune response.
• For instance, D-amino acids are stereoisomers of naturally occurring L-amino acids. However, antigen-presenting cells can only process and present L-amino acids, not D-amino acids. Therefore, antigens composed of D-amino acids are generally poor immunogens since they cannot be effectively processed and presented by the antigen-presenting cells. This limitation highlights the importance of structural compatibility between antigens and the antigen-processing machinery within APCs for successful immunogenicity.
• Understanding the susceptibility of antigens to antigen processing and presentation is crucial in vaccine development and immunotherapy. Researchers aim to design antigens that are readily phagocytosed by APCs and can be effectively processed and presented to the immune system. By optimizing the antigen structure and promoting its compatibility with the antigen-processing machinery, scientists can enhance the immunogenicity of antigens and stimulate more potent immune responses.
• In summary, the susceptibility of antigens to antigen processing and presentation plays a vital role in their immunogenicity. Antigens that can be efficiently processed and presented by MHC molecules are more likely to elicit a strong immune response. Antigens that are easily phagocytosed by antigen-presenting cells tend to be more immunogenic. Conversely, antigens that cannot be processed or presented effectively, such as those containing D-amino acids, are generally poor immunogens. By considering the compatibility of antigens with the antigen-processing machinery, researchers can optimize immunogenicity and develop more effective immunotherapies and vaccines.

B. Biological System of Host

• The biological system of the host is a critical factor that influences the immunogenicity of antigens. Several factors within the host’s biological system determine its immune responsiveness and can impact the immune response towards antigens.
• The genotype of the recipient animal plays a major role in determining immune responsiveness. Different species or individuals within a species may exhibit varying levels of immunogenicity towards specific substances. This is influenced by the genes encoding the major histocompatibility complex (MHC) molecules, which are responsible for processing and presenting antigens to immune cells. The MHC gene products play a crucial role in determining the compatibility between antigens and the immune system. Additionally, genes encoding B-cell and T-cell receptors, as well as proteins involved in various regulatory mechanisms, can influence immunogenicity.
• The dosage and route of administration of an immunogen are also important factors. Insufficient dosage may fail to elicit an immune response or lead to a state of tolerance, where the immune system becomes unresponsive to the antigen. Conversely, excessively high doses can also lead to unresponsiveness or tolerance. There exists an optimal dosage range for an immune response to be elicited. Additionally, the timing and frequency of antigen administration play a role. A single dosage may not be sufficient to develop a robust immune response, but repeated booster doses over a period of time can enhance immunogenicity. The route of administration strongly influences the immune response. For example, subcutaneous administration is often more effective than intravenous or intragastric routes in eliciting an immune response.
• Adjuvants are substances that, when mixed and injected with an antigen, enhance its immunogenicity. Adjuvants work through various mechanisms to enhance the immune response. For example, aluminium potassium sulphate (Alum) is an adjuvant that increases the persistence of the antigen at the injection site, allowing for a more prolonged exposure to the immune system. It also enhances the phagocytosis of the antigen and stimulates a local inflammatory response, leading to increased immune activation. Adjuvants can provide co-stimulatory signals, prolong the presence of antigens, and enhance non-specific proliferation of lymphocytes, all of which contribute to improved immunogenicity.
• However, the use of adjuvants may come with undesirable side effects such as fever and inflammation. Therefore, the selection and optimization of adjuvants require careful consideration to balance immunogenicity enhancement and potential adverse effects.
• In conclusion, the biological system of the host significantly impacts immunogenicity. The genotype of the recipient animal, dosage and route of administration of the immunogen, and the use of adjuvants all influence the immune response. Understanding these factors is crucial in designing effective immunization strategies and optimizing vaccine development to elicit robust and targeted immune responses while minimizing adverse effects.

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