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Vaccinology, the scientific discipline focused on vaccines, has evolved from combating infectious diseases to addressing a wide array of a broad spectrum of health concerns, including autoimmune disorders, neurodegenerative diseases, and allergies, with promising therapeutic vaccines for cancer utilizing tumor-infiltrating lymphocytes (TILs) and adoptive cell therapy, like chimeric antigen receptor T-cell (CAR-T-cells), CAR-natural killer cells (CAR-NK cells), and CAR-macrophages (CAR-M), as well as necrotic and necroptotic cancer cells. Additionally, ongoing research endeavors aim to develop anti-addiction vaccines. This chapter offers a comprehensive exploration of vaccinology, encompassing fundamental immunity concepts, the role of adjuvants, and various vaccine types. It traces the evolution of vaccine development from traditional methods to modern innovations like messenger ribonucleic acid (mRNA) vaccines, exemplified by those developed for coronavirus disease 2019 (COVID-19), which offer rapid adaptability to emerging variants. The significance of measuring neutralizing antibodies in assessing vaccine efficacy and effectiveness, which is crucial for guiding epidemic responses, is underscored. By delving into historical and contemporary developments, addressing current challenges, and envisioning future directions, this chapter fosters a deeper understanding of vaccinology and encourages critical reflection on innovative solutions to global health challenges.
Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, Algeria
*Address all correspondence to: mourad.aribi@univ-tlemcen.dz
1. Introduction
Vaccinology, the discipline dedicated to vaccines, encompasses crucial research on immunogens, host immune responses, delivery methods, manufacturing, and clinical evaluation. Vaccines offer a potent strategy for disease prevention and eradication, with notable contributions from historical figures such as Edward Jenner and Louis Pasteur. While initially concentrated on infectious diseases, these advances now encompass a broader spectrum, including non-infectious conditions such as cancer, autoimmune disorders, neurodegenerative diseases, allergies, and addiction [1]. Additionally, veterinary vaccines are indispensable for ensuring animal health and human food safety.
Vaccination, by exposing the body to non-pathogenic forms or microbial components, aims to stimulate adaptive immune responses against targeted pathogens, whether bacteria, viruses, or toxins [2]. This approach has been effective in controlling many infectious diseases, as evidenced by the eradication of smallpox [3], the only disease eradicated by vaccination, achieved through the global efforts led by the World Health Organization in the twentieth century [4]. This monumental success underscores the transformative power of vaccines in eliminating deadly diseases.
However, the major challenge lies in developing effective vaccines that stimulate cellular immunity against intracellular microbes and developing vaccines against high antigenic variation pathogens, such as human immunodeficiency virus (HIV). Research is ongoing on the use of viral vectors and deoxyribonucleic acid (DNA) [5] to induce cellular immune responses, although their clinical effectiveness is still limited.
In addition to active vaccination, passive immunization also confers protective immunity by transferring specific antibodies or pooled immunoglobulins (IgG) from blood donors. This approach is often used to rapidly treat potentially life-threatening diseases caused by toxins, such as tetanus [6], and to protect against a variety of diseases caused by respective pathogens, including rabies, hepatitis [7], and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [8]. However, passive immunization has limitations, including its short duration of protection and lack of immune memory. Nevertheless, new attempts at long-term passive immunization, using viral vectors to introduce genes encoding neutralizing antibodies into humans, have been initiated in hopes of providing prolonged protection.
Concurrently, the initiation of T-cell-dependent immune responses against protein antigens often requires the use of adjuvants. These substances, by increasing the expression of co-stimulators and cytokine production, promote T-cell growth and differentiation [9]. Some adjuvants, such as aluminum hydroxide gel and monophosphoryl lipid A, have been approved for clinical use, while others, such as CG-rich oligonucleotides, are under exploration. Additionally, natural substances stimulating T-cell responses can also be used, offering promising alternatives to traditional adjuvants.
The aim of this chapter is to provide a comprehensive exploration of the field of vaccines, with a specific focus on human vaccines. It covers a range of topics, from fundamental concepts of immunity to the evolution of vaccine development approaches, as well as the challenges and advancements within this domain. The objective is to provide readers with a thorough grasp of essential concepts, recent advancements, and related challenges in vaccination, while also encouraging critical consideration of future developments in the field.
2. An overview of innate and acquired—adaptive—immunity
The immune response is a complex process orchestrated by the immune system to defend the body against pathogens and foreign substances, consisting of two main categories: innate immunity and adaptive immunity (Box 1). Innate immunity encompasses physical and chemical barriers, such as the skin, mucous membranes, and bodily secretions, along with phagocytic cells, which ingest and destroy pathogens. Additionally, innate immunity involves the local inflammatory response [10], triggered by the detection of infection, leading to the release of proinflammatory cytokines to recruit other immune cells and enhance the immune response.
Understanding the fundamentals of immune responses is crucial in grasping the body’s defense mechanisms against pathogens. Here are some key concepts:
Passive immunity: Provides immediate protection through the transfer of pre-formed antibodies or immune cells from an immune individual to a non-immune individual. It offers rapid but short-term defense against pathogens.
Active immunity: Involves the activation of the host’s immune system, leading to the production of antibodies or immune memory cells in response to exposure to antigens. While active immunity takes time to develop, it provides long-lasting protection against future infections.
Initial antibody response: The first wave of antibody production that occurs upon the initial exposure to an antigen.
Lasting immunity: Long-term protection against pathogens, achieved through the production of memory cells and sustained antibody levels.
Secondary immune response: The rapid and enhanced immune reaction upon re-exposure to a pathogen, characterized by quicker and more robust antibody production compared to the primary response.
Plasmablasts: Early, short-lived antibody-secreting cells that are rapidly produced during the initial stages of an immune response.
Produce intense early antibody response to initial activation.
Short lifespan, typically lasting days to weeks.
Participate in the initial phase of the immune response.
Can secrete all immunoglobulin isotypes, depending on the stimulus that induces their formation.
Plasmablasts, unlike naive B-cells, immature plasma cells, and mature plasma cells, possess the capacity to proliferate.
Short-lived effector cells: Cells that provide immediate but temporary immune protection during the initial phase of an immune response.
Broader set of immune effector cells, including plasmablasts.
May include other types of effector cells such as cytotoxic T-cells and activated macrophages.
Short-lived plasma cells (SLPCs): Plasma cells with a limited lifespan that are generated during the initial immune response.
Subset of plasmablasts that differentiate into short-lived antibody-secreting cells.
Produce antigen-specific antibodies during the initial phase of the immune response.
Rapidly disappear after antigen clearance, typically lasting days to weeks.
Long-lived (memory) plasma cells (LLPCs): Plasma cells with an extended lifespan that persist in the body after the resolution of the initial immune response.
Generated from plasmablasts or plasma cells during the immune response.
Persist in the bone marrow or other tissue niches for months to years.
Produce long-term antigen-specific antibodies, providing durable immunity against the antigen.
T-independent (TI) antibody responses: Antibody responses generated without the help of T-cells, typically in response to repetitive antigens such as polysaccharides and lipopolysaccharides. They can also yield short-lived germinal centers (GCs) without inducing somatic hypermutation (SHM) or affinity maturation [13].
T-dependent (TD) antibody responses: Antibody responses that require assistance from T helper cells, typically in response to protein antigens, leading to high-affinity, class-switched antibodies and the formation of memory B-cells.
Follicular B-cell response dependent on T helper cells: B-cell activation and antibody production within lymphoid follicles that require help from T helper cells, resulting in high-affinity antibodies and memory B-cells.
Extrafollicular B-cell response dependent on T helper cells: Rapid antibody production occurring outside the follicles with assistance from T helper cells, typically producing SLPCs.
Follicular B-cell: B-cells located within lymphoid follicles that participate in T-dependent responses and undergo affinity maturation. Common locations include lymph nodes, spleen, tonsils, Peyer’s patches, and other secondary lymphoid organs.
Marginal zone B-cell: B-cells found in the marginal zone of the spleen and other secondary lymphoid tissues, involved in T-independent responses, particularly to blood-borne pathogens. Common locations include the spleen, lymph nodes, tonsils, and Peyer’s patches.
B1 B-cell: A subset of B-cells primarily located in body cavities such as the peritoneum and pleura, involved in producing natural antibodies and early defense against pathogens. Other common locations include mucosal tissues.
Box 1.
Key concepts in immune responses.
In contrast, acquired or adaptive immunity involves the more specialized responses of B-cells and T-cells. B-cells produce antibodies specific to antigens on pathogens, facilitating their elimination, while activated T-cells can kill infected cells or regulate the immune response by producing cytokines. Moreover, adaptive immunity establishes immune memory [11], with memory B-cells and memory T-cells persisting in the body after infection, enabling a quicker and more effective response upon re-exposure to the same pathogen. The coordination of the immune response includes antigen presentation, where antigen-presenting cells (APCs) like dendritic cells (DCs) capture antigens and present them in a degraded form as antigenic peptides to T-cells, and in their native form to B-cells (follicular dendritic cells [FDC]) in lymph nodes, initiating specific and adaptive immune responses. DCs excel as APCs due to their efficient internalization of extracellular antigens through different processes like receptor-mediated endocytosis, phagocytosis, and micropinocytosis [12]. Furthermore, cellular communication via cytokines plays a crucial role in coordinating the activities of various immune cells and regulating the immune response to ensure an appropriate level of defense against pathogens, while avoiding excessive tissue damage. Such acquired immunity plays a crucial role in the epidemiology of communicable diseases. It manifests in two main ways: through natural infection, where the immune system develops a specific response following exposure to a pathogen, and through vaccination, a form of artificially acquired immunity induced by administering vaccines. Both approaches significantly contribute to individual and collective protection against infectious diseases.
3. Secondary response and immune memory: Key characteristics, quantitative parameters, and implications for vaccination
Understanding the intricacies of the secondary response, synonymous with immune memory, is essential for advancing vaccination strategies. This understanding enables us to refine vaccination approaches, ensuring optimal immune responses and long-term immunity.
3.1 Characteristics of the secondary—anamnestic—immune response
Although the primary immune response occurs during the initial encounter of the immune system with an infectious agent, subsequent encounters with the same pathogen are referred to as the secondary immune response or anamnestic immune response, enabling vaccine development [14]. This response is characterized by several distinctive features:
Rapidity: The secondary immune response is more rapid than the primary immune response. This is due to the presence of memory lymphocytes that are already specifically programmed to recognize the antigen, allowing for a quicker activation of effector immune cells.
Magnitude: Thanks to the presence of memory cells generated during the primary immune response, the secondary immune response demonstrates increased speed and strength, resulting in more efficient pathogen elimination compared to the primary immune response. Vaccines mimic infections, initiating a primary immune response that primes the organism for a secondary immune response upon exposure to the actual infectious agent [15].
Specificity: The secondary immune response is more specific because memory lymphocytes selected during the first exposure to the antigen are already present and ready to selectively recognize and respond specifically to this antigen.
Durability and long-term memory protection: Since memory lymphocytes produced during the primary immune response persist for long periods, the secondary response provides long-term protection against recurring infections by the same pathogen.
3.2 Adaptive immune response and immune memory
The adaptive response and immune memory are two fundamental aspects of the immune system that play a crucial role in protection against infections. Here is an overview of these two concepts:
Adaptive immune response: The adaptive immune response, formerly called the specific immune response, is characterized by its ability to specifically target pathogens. It is orchestrated by B-cells and T-cells, which recognize and target specific antigens present on pathogens. The adaptive response divides into two main branches: the humoral response, involving antibodies produced by plasma cells derived from antigen-activated B-cells in secondary lymphoid organs (SLOs) such as the spleen and lymph nodes (for review, see [16]), and the cellular response, involving cytotoxic/cytolytic T-cells (CTLs) that eliminate infected cells. Specificity and memory are key features of the adaptive immune response.
Immune memory: The processes involved in forming and maintaining immune memory, as well as the mechanisms supporting long-term immunity, especially concerning the crucial roles of memory T-cells and memory B-cells, are highly intricate. However, they are presented here in a straightforward and concise manner.
3.2.1 Memory T-cells
Distinguished into central memory T-cells (TCM), stem cell-like memory T-cells (TSCM), effector memory T-cells (TEM), and resident memory T-cells (TRM) subtypes, memory T-cells contribute distinctively to immune surveillance and the orchestration of secondary immune responses [17, 18]. TCM and TSCM, distinguished by their expression of lymph node homing markers such as CD62L and CCR7, exhibit remarkable proliferative potential upon reactivation. Acting as reservoirs for generating effector and memory T-cell subsets, they play a critical role in mounting robust immune defenses. On the other hand, TEM, armed with tissue-specific homing markers such as C-C chemokine receptor type 5 (CCR5) and C–X–C motif chemokine receptor 3 (CXCR3), swiftly migrate into non-lymphoid tissues to engage invading pathogens with immediate effector functions, including cytotoxicity and cytokine production. Meanwhile, TRM, established at the original site of infection, persist long-term and provide frontline defense against secondary invasions, forming a crucial part of the body’s immune surveillance system. This dynamic collaboration between memory T-cell subsets ensures a layered defense strategy, with TRM offering localized protection, TEM reinforcing defense through recruitment, and TCM orchestrating comprehensive pathogen control and elimination within lymphoid tissues [18]. Such intricate interactions highlight the adaptive nature of the immune system and its ability to mount effective responses against recurring threats.
3.2.2 Memory B-cells and memory plasma cells
Through antibody secretion, B-cells and their progeny contribute significantly to vaccination strategies and host defense against pathogens. B-cell immunity entails primary antibody production for direct protection and the rapid, amplified response enabled by memory B-cells upon secondary exposure [19].
During the T-dependent (TD) immune response, activated B-cells, guided by T follicular helper (Tfh) cells within follicles, form germinal centers (GCs), which serves as a specialized microenvironment where B-cells experience rapid proliferation, immunoglobulin class switching, and affinity maturation via somatic hypermutation (SHM) [20]. In addition to high-affinity antibodies, GC B-cells produce long-lived plasma cells (LLPCs, also termed memory plasma cells) and memory B-cells, contributing to effective future protection [21] (for review, see [22]). Of note, it has been reported that LLPCs can develop in both TI and TD responses, independently of B-cell maturation in GCs [13], and that naive B-cells can develop into memory B-cells within follicles, outside GCs [23]. Also of note, the development of memory B-cells relies heavily on the interaction between CD40 on B-cells and CD40L (CD40 ligand, CD154) expressed by T-cells and follicular dendritic cells (FDCs) [24], as well as the presence of specific transcription factors such as broad complex-tramtrack-bric a brac and Cap’n’collar (BTB and CNC) homology 2 (Bach2), homeobox protein (Hhex), transducin-like enhancer of split-3 (Tle3) [25], B-cell lymphoma 6 protein (Bcl-6), paired box 5 (PAX5), purine-rich box 1 (PU.1), interferon regulatory factor 8 (IRF8), and IRF4low, induced upon antigen receptor activation [21]. On the other hand, other transcription factors promote differentiation into plasma cells, including B lymphocyte-induced maturation protein-1 (Blimp-1, also called PRDM1 [PR domain zinc finger protein 1]) [26, 27], IRF4, proto-oncogene MYC (c-Myc) [28], and X-box binding protein 1 (XBP-1) (Figure 1) [32].
Figure 1.
Coordination and dynamics of T-B-cell interactions in T-dependent humoral immune responses. The process of T-B-cell interaction and T-dependent humoral responses begins with the recognition of different epitopes of the same protein antigen by both cell types and occurs in several phases. While T-cells recognize only peptide fragments of antigens, B-cells can identify both protein and non-protein antigens, even in their native conformation. In SLOs, T-cells and B-cells are segregated into distinct anatomical compartments. B-cells congregate within follicles, while T-cells reside in the paracortex. This organization enables an effective immune response upon antigen exposure. B-cells are attracted into follicles by chemokines, while T-cells are directed to the paracortex via specific chemokine receptors. Initial activation of Th cells requires antigen recognition and costimulation, typically by proteins derived from extracellular microbes, presented as peptides bound to major histocompatibility complex class II (pMHC II) molecules on DCs in T-cell-rich zones of peripheral lymphoid tissues. Activated Th cells switch into Teff cells, producing cytokines and CD40 ligand (CD40L, CD154). Some migrate toward the lymphoid follicle edges of the B-cell zone and interact with antigen-stimulated B-cells in the parafollicular zones. Before this interaction, naive B-cells must recognize an epitope on the native protein, transported into the follicle, through the membrane B-cell receptor (mIg, BCR). They then undergo receptor-mediated endocytosis and become activated within the follicles of the same lymphoid organ. ABCs exit these follicles and migrate to T-cell zone to encounter activated Th cells. This migration relies on changes in chemokine receptor expression: T-cells downregulate C-C chemokine receptor type 7 (CCR7) and upregulate C-X-C chemokine receptor type 5 (CXCR5), while B-cells exhibit the opposite pattern. Consequently, B-cells and T-cells migrate and meet at follicle borders or interfollicular zones, facilitating the next phase of their interaction. B-cells present peptide fragments to extrafollicular Teff cells via MHC class II molecules. This initial interaction leads to the generation of short-lived extrafollicular plasma cells producing early protective antibodies (and few memory B-cells). Alternatively, some activated B-cells migrate back into the B-cell follicle center, where they divide and mutate their BCR genes, forming a specialized structure known as GC. These centroblasts transition into centrocytes, gather antigen from FDCs, and present processed peptides to Tfh cells. Tfh and Tfr cells differentiate during T-cell priming, influenced by B-cell lymphoma protein 6 (Bcl-6) expression, and migrate into the GC to respectively support or suppress B-cell activity. During humoral immune responses, FDCs play a crucial role in selecting high-affinity B-cells, a process facilitated by GC formation, ensuring that only those with higher affinity BCRs survive and proliferate, while lower affinity B-cells undergo apoptosis. The GC provides a microenvironment for the generation of long-lived plasma cells and memory B-cells, key components of the adaptive immune response [29, 30]. SHM, aided by the enzyme activation-induced cytidine deaminase (AID), further enhances the affinity of B-cell receptors for antigens (affinity maturation), contributing to the diversification and refinement of the antibody repertoire [31]. The transcription factors associated with each stage of B-cell development are shown to provide additional context (Box 3, for review, see [21]). The full understanding of T-B cell interactions and the humoral response is vital for improving vaccine design and effectiveness, as it emphasizes the need for efficient antigen presentation and B-cell activation to induce strong, long-lasting immunity. ABC: activated B-cell, AID: activation-induced cytidine deaminase, Bach2: broad complex-tramtrack-bric a brac and Cap’n’collar (BTB and CNC) homology 2, BCL-6: B lymphoma 6, Blimp-1: B lymphocyte-induced maturation protein-1 (also known as PRDM1, PR domain zinc finger protein 1), DC: dendritic cell, FDC: follicular dendritic cells, GC: germinal center, IRF: interferon regulatory factor, PU.1: Purine-rich box 1, a nuclear protein encoded by spleen focus-forming virus (SFFV) proviral integration site 1 (SPI1), and a member of the E26 transformation-specific (ETS) family of transcription factors, essential for immune cell development and function, PAX5: paired box 5, SHM: somatic hypermutation, Teff: effector T-cells, Tfh: T follicular helper cells, Tfr: T follicular regulatory cells, Th: helper T-cells, XBP-1: X-box binding protein 1.
In humans, memory B-cells persist for decades, maintaining long-term memory for specific antigens without constant stimulation. Abundant in the spleen, they constitute a significant portion of the B-cell population and exhibit somatic mutations in immunoglobulin (Ig) variable genes, indicative of their antigen experience. In murine models, memory B-cells exhibit heterogeneous localization and functions, influenced by the isotypes they express; IgM+ cells are distributed throughout follicles, while IgG1+ cells tend to localize near senescent GCs. Studies using fate mapping techniques reveal distinct behaviors between IgM+ and IgG+ memory B-cells upon antigen rechallenge, with IgM+ cells initiating new GCs and IgG+ cells differentiating into antibody-secreting cells, primarily located in the splenic red pulp. Similar to memory T-cells, memory B-cells possess the ability to home back to the tissues of their origin or migrate to SLOs. This phenomenon is particularly evident in mucosal immune reactions, where memory B-cells preferentially accumulate at sites of initial infection, contributing to long-term immune protection and responses to recurrent infections [33].
3.2.2.1 Short-lived plasma cells
Short-lived plasma cells/plasmablasts (SLPCs, proliferating cells) are generated during the acute phase of the immune response and are responsible for the rapid production of specific antibodies during the first exposure to an antigen. They predominantly originate in extrafollicular areas within SLOs, where they produce IgM antibodies with low affinity [34]. Their lifespan is relatively short, usually ranging from a few days (3–5 days) to a few weeks.
3.2.2.2 Long-lived (memory) plasma cells
The generation of LLPCs (memory plasma cells, non-proliferating cells) and memory B-cells from the naive B-cell repertoire during the primary response to an antigen predominantly occurs in SLOs within B-cell follicles and GCs, following a two-phase process. In the first phase, antigenic stimulation through B-cell antigen receptors (BCRs) induces naive B-cells to differentiate into SLPCs and GC B-cells within the B-cell follicles. In the second phase, antigens drive GC B-cells to differentiate into LLPCs and memory B-cells within the GCs. During subsequent recall responses to antigens, memory B-cells respond by differentiating into LLPCs or by re-entering the GC reaction, thereby contributing to a robust and sustained immune response [23]. Unlike SLPCs, LLPCs can persist for long periods (from several months to lifetime) in various lymphoid tissues, including the bone marrow and lymph nodes. They are responsible for maintaining long-term immunity against the specific antigen by slowly producing antibodies over time (Box 2).
T-dependent B-cell responses can give rise to two types of plasma cells based on their lifespan:
Extrafollicular focus: T-dependent B-cell response and short-lived plasma cells (SLPCs)Here, activated T helper cells, stimulated by DCs, become effector lymphocytes. These effector cells initially interact, in an extrafollicular setting, with antigen-activated B-cells (also known as B lymphoblasts) within follicles, giving rise to SLPCs/plasmablasts. This scenario characterizes an extrafollicular focus where the involvement of extrafollicular T helper lymphocytes is pivotal.
GC focus: T-dependent B-cell response and long-lived (memory) plasma cells (LLPCs)In this scenario, activated B-cells undergo the GC reaction, where they encounter follicular helper T (Tfh) cells and FDCs. This interaction leads to the generation of LLPCs and memory B-cells.
Antibody responses: extrafollicular vs. follicular pathwaysAntibody responses can manifest through two main routes: extrafollicular and follicular pathways. In the extrafollicular pathway, class switching is restricted, and somatic mutation rates are minimal, yielding antibodies with comparatively lower affinity. Plasma cells derived from this pathway have a brief lifespan, typically around 3–5 days (to a few weeks). In contrast, the follicular pathway entails extensive class switching and higher rates of somatic mutation, resulting in antibodies with heightened affinity. Plasma cells originating from this pathway are long-lived, enduring for years.
Early humoral immunity and plasma cell lifespan: Most plasma cells from the initial immune response are short-lived, undergoing apoptosis after a few days, ensuring controlled early humoral immunity.
Box 2.
B-cell T-dependent responses and plasma cell types.
Late B-cell differentiation involves diverse mature B-cell subsets expressing specific transcription factors. Upon antigen activation, B-cells proliferate, switch immunoglobulin classes, and differentiate into distinct cell types like plasmablasts. Follicular B-cells contribute to GC reactions, producing memory B-cells and LLPCs. It is worth noting that the roles of marginal zone B-cells and B1 cells in plasma cell generation are suspected but remain unclear [21]. Mature B-cells
Paired box protein 5 (PAX5)
Purine-rich box 1 (PU.1)
Interferon-regulatory factor 8 (IRF8)
BTB and CNC homolog 2 (BACH2)
IRF4low
Activated B-cells (B lymphoblasts)
IRF4high
X-box-binding protein 1 (XBP1)
Intermediate levels of B lymphocyte-induced maturation protein 1 (BLIMP1)
GC B-cells
Upregulation of B-cell lymphoma protein 6 (BCL-6)
Repression of IRF4
Memory B-cells
Similar to mature B-cells (PAX5, PU.1, IRF8, BACH2, and IRF4low)
LLPCs
BLIMP1high
IRF4high
XBP1high
Box 3.
Transcription factors involved in late B-cell development stages.
3.2.3 Innate immune memory
Recent research has highlighted the existence of innate immune memory, also known as trained immunity [35]. This phenomenon involves the ability of innate immune cells, such as monocytes and macrophages, to develop a heightened response to secondary infections following exposure to certain pathogens or stimuli. Trained immunity is mediated by epigenetic changes that enhance the responsiveness of innate immune cells, resulting in a more rapid and robust immune response upon re-encounter with the same or similar pathogens. This concept expands our understanding of immune memory beyond the adaptive immune system, demonstrating the complexity and versatility of the body’s defense mechanisms against infectious threats.
3.3 Optimizing immune memory: insights from vaccination
Quantitative parameters such as lymphocyte numbers, durability, renewal rate, and tissue distribution play a crucial role in determining the strength of immune memory after vaccination. For instance, higher frequencies of antigen-specific memory lymphocytes enable the immune system to respond rapidly upon re-exposure to the pathogen. Additionally, the durability and sustained renewal rates of these lymphocytes ensure long-term protection. Equally important is the distribution of memory lymphocytes across various tissues, which supports localized surveillance and quick responses. Moreover, the intensity and duration of the initial effector response are key factors that influence the formation and longevity of immune memory. Therefore, understanding these interconnected parameters is essential for evaluating the efficacy of vaccine-induced immunity.
4. Rethinking immunity: the significance of the danger theory in vaccination strategy
The danger theory, pioneered by Polly Matzinger in the 1990s [36], presents a paradigm shift in our comprehension of the immune system’s operation. Departing from the conventional framework of self and non-self-recognition, this theory underscores the immune system’s responsiveness to signals of danger and stress. It posits that immune cells are not solely triggered by foreign pathogens but also by diverse cellular stressors and disruptions in homeostasis. By incorporating the detection of damage and peril to the entire organism, this perspective expands our insight into immunity. This broader understanding has significant implications for vaccination strategies, as it underscores the importance of considering not only pathogen presence but also the host’s physiological state and responses to effectively induce protective immune responses.
Edward Jenner, a British physician, pioneered vaccination in 1796 with the first successful smallpox vaccine. Observing that milkmaids exposed to cowpox were protected from smallpox, he inoculated a boy named James Phipps with cowpox and then exposed him to smallpox [37]. Remarkably, the boy did not develop smallpox, thereby proving that the cowpox inoculation conferred immunity against the more deadly disease. This groundbreaking experiment not only demonstrated the potential of vaccination as a preventive measure but also laid the foundation for modern immunology.
Building on Jenner’s foundational work, Louis Pasteur, a French chemist and microbiologist, advanced vaccination by developing techniques to attenuate pathogens while preserving their ability to trigger immune responses. In 1885, Pasteur created a rabies vaccine using a method that involved drying spinal cord material from rabid rabbits to decrease its virulence. On July 6, 1885, Pasteur used this vaccine to inoculate Joseph Meister, a boy bitten by a rabid dog [38]. Over ten days, Pasteur administered progressively more virulent doses of the virus, ultimately proving the vaccine’s effectiveness as Meister survived both the rabies exposure and subsequent inoculations with virulent virus. This achievement represented a major milestone in shaping modern vaccination principles, revolutionizing public health and laying the groundwork for the creation of vaccines targeting a range of infectious diseases.
The immune response of a vaccine relies on its immunogenic power, which determines its ability to trigger an active adaptive immune response and induce anamnestic response. Human vaccines come in various forms, including live-attenuated vaccines and inactivated vaccines, which may contain whole bacteria or viruses, as well as components of bacteria or viruses such as polysaccharides, proteins, or recombinant proteins. Some vaccines are also based on bacterial products, such as purified toxins called toxoids. Acellular vaccines, on the other hand, contain specific fragments of the outer shell of bacteria rather than whole bacteria, providing protection against bacterial diseases such as pertussis, diphtheria, and meningitis with fewer side effects than traditional vaccines. DNA or mRNA vaccines introduce specific DNA or RNA strands into the body’s cells to prompt the production of antigenic proteins, thereby stimulating an adaptive immune response against specific pathogens. As a result, it is inappropriate to classify them as acellular vaccines, given their mechanism of action.
Vaccines can be classified in various ways based on different criteria. A common classification can based on two fundamental types of vaccines: live-attenuated vaccines and inactivated vaccines (Table 1, Box 4) [51]. Alternatively, a broader classification is based on a range of vaccine formulations, including live-attenuated vaccines, whole inactivated vaccines, protein subunit inactivated vaccines, polysaccharide inactivated vaccines, polysaccharide conjugate inactivated vaccines, DNA and mRNA vaccines, recombinant protein inactivated vaccines, and inactivated vaccines with viral vectors expressing a protein (Table 2).
Vaccine type
Description
Specific characteristics
Examples of vaccines
References
Live-attenuated vaccine
Derived from “wild” viruses or bacteria, weakened in a laboratory; replicate in the body to stimulate an immune response.
They are usually effective after a single dose; can cause severe infections in immunocompromised individuals; must be stored and handled carefully.
Classification of vaccines based on two basic types of vaccines: live-attenuated vaccine, and inactivated vaccine.
HPV: human papillomavirus, MMR: measles, mumps, and rubella.
In our exploration of vaccines, it is essential to understand their diverse nature and the distinct advantages and disadvantages they offer. This box provides a concise overview of the characteristics of each vaccine type. Live-attenuated vaccines
They typically cause asymptomatic or mild infections.
They confer protection similar to that induced by natural infection; they more effectively stimulate the production of antibodies and cytotoxic T lymphocytes.
Immunity is rapidly acquired (usually within less than 14 days after vaccination) and persistent (a single dose is often sufficient).
They have the capability to replicate within the host but are rendered harmless as their virulence is compromised.
They can sometimes lead to infectious disease due to reversion of the vaccine virus (as in the case of oral polio, BCGitis, or vaccinia), especially in individuals with particular risks (immunodeficiency, pregnancy, etc.).
Their biological stability is lower, posing challenges for transportation and storage, especially in certain regions.
They are devoid of any infectious power as they are incapable of multiplying.
Very stable and easily distributable in all regions of the globe.
They do not always generate sufficient immune memory after the first dose; antigens may lose some of their immunogenicity during inactivation.
The conferred immunity is short-lived, necessitating boosters.
They often require the addition of an adjuvant.
They primarily trigger humoral immunity.
Their cost is higher as a large concentration of antigens is required. For bacteria, heating at a non-permissive temperature is often sufficient for inactivation.
Subunit vaccines utilize specific parts of pathogens, such as proteins or polysaccharides, to induce an immune response.
These vaccines offer targeted immunity against particular components of pathogens, reducing the risk of adverse reactions.
Immunity typically requires multiple doses and may necessitate booster shots to maintain effectiveness.
Subunit vaccines do not contain live pathogens, minimizing the risk of causing disease or reverting to a virulent form.
Challenges include the need for adjuvants to enhance immune response and the potential for decreased efficacy against evolving pathogens.
Examples: hepatitis B vaccine, human papillomavirus vaccine, toxoid vaccines (tetanus vaccine, diphtheria vaccine).
DNA and mRNA vaccines
Utilize the organism’s own replication and expression mechanisms to produce antigens.
DNA vaccines use plasmids rich in unmethylated CpG nucleotides containing complementary DNA (cDNA) to encode protein antigens, stimulating immune responses.
mRNA vaccines utilize mRNA encoding microbial antigens for rapid development and cost reduction.
Both vaccines prompt the production of antigenic proteins, triggering immune responses.
They offer quick adaptability to emerging threats.
Immunity is primarily antibody-mediated and may require booster doses.
Challenges include specialized delivery systems and long-term safety concerns.
Examples: mRNA vaccines for COVID-19, experimental DNA vaccines.
Classification of vaccines based on vaccine types.
The protein used is an anatoxin, which is a bacterial toxin that, through physical (heat) or chemical (formalin) action, has lost its toxic properties but retained its immunogenic property (Adapted from [84, 85]). COVID-19: coronavirus 2019, ETEC: cholera and enterotoxigenic Escherichia coli, Hib: Haemophilus, influenzae type b, HPV: human papillomavirus, IPD: invasive pneumococcal disease, MenACWY: Meningococcal serogroups A, C, W, Y, MenB: serogroup B meningococcal, MenC: meningococcal serogroup C, mRNA: messenger ribonucleic acid, SARS-CoV-2: severe acute respiratory syndrome coronavirus 2.
Live-attenuated vaccines are developed from wild viruses or bacteria that have been weakened in a laboratory setting. These vaccines induce an immune response closely resembling natural infection and are typically effective after a single dose. However, they require replication within the body to trigger an immune response, posing risks for individuals with weakened immune systems and require careful storage and handling. It is worth noting that these vaccines could theoretically undergo reversion to virulence due to various factors such as back-mutation of attenuating mutations, compensatory mutations, recombination, reassortment, or changes in quasispecies diversity [86].
Whole-cell inactivated vaccines involve the inactivation of bacteria or viruses using either physical or chemical methods. They, on the other hand, are not live and cannot replicate. They primarily stimulate antibody production, with limited or no cellular immunity activation. Over time, antibody titers against inactivated antigens may decline, necessitating periodic booster doses to bolster antibody levels. However, they are safer for immunocompromised individuals and include vaccines such as the polio vaccine, the hepatitis A vaccine, and rabies vaccines. While multiple doses may be required for lasting immunity, and periodic boosters to maintain antibody levels, they play a crucial role in preventing the spread of infectious diseases.
Subunit vaccines contain specific portions of pathogens necessary to induce an immune response [87], with conjugate subunit vaccines enhancing effectiveness through chemical linking of polysaccharides and proteins. Pure polysaccharide vaccines typically induce T-cell-independent immune responses [88], while toxoid vaccines provide protection against some diseases such as tetanus and diphtheria by inactivating bacterial toxins. Recombinant vaccines utilize genetic engineering to produce antigens from various sources, including hepatitis B, human papillomavirus (HPV), and influenza [89], effectively stimulating the immune system to prevent targeted diseases. In the development of these vaccines, immunoinformatics methods play a crucial role by addressing pivotal challenges, including immune-related concerns in vulnerable populations, emerging infectious diseases, and antigenic variability [90]. These methods utilize computational tools to predict antigenic epitopes [91], optimize vaccine design, and enhance immunogenicity [92]. By leveraging immunoinformatics, modern recombinant, protein-based, and epitope-based vaccines are refined and tailored with precision to ensure efficacy and safety [93, 94].
DNA vaccines utilize plasmids containing complementary DNA (cDNA) encoding protein antigens to elicit specific humoral and cellular immune responses, facilitated by bacterial plasmids rich in unmethylated CpG nucleotides recognized by TLR9 in DCs [95]. While promising, efficacy challenges in clinical trials have prompted ongoing research into new vectors.
mRNA vaccines represent a recent approach utilizing mRNA encoding microbial antigens, offering rapid development, cost reduction, and the ability to combine multiple antigens into a single vaccine. Advances in mRNA stability and translatability have overcome initial hurdles, making mRNA vaccination practical. These vaccines retain innate immunity activation and utilize lipid nanoparticles for cellular uptake [96], with promising approaches involving mRNA tethering to modified alphavirus RNA genomes for self-replication within recipient cells (Table 3).
Characteristics
Types of vaccines
Live-attenuated vaccines
Inactivated vaccines
Acellular vaccines
Pathogen nature
Attenuated live microorganisms
Inactivated microorganisms
Specific part of pathogenic agents
Adjuvants
Rarely necessary
Often necessary
Often necessary
Common adjuvants
Rarely used
Aluminum hydroxide, aluminum phosphate
Aluminum hydroxide, aluminum phosphate
Replication-capable
Ability to multiply but no longer cause disease due to impaired virulent traits
Absent
Absent
Induction of immune response
Cellular and humoral immune response
Primarily humoral immune response
Primarily humoral immune response
Duration of immunity
Generally long, sometimes lifelong
Variable, often requires booster doses to maintain immunity
Variable, often requires boosters
Reversion risk
Low
Absent
Absent
Preparation cost
Relatively low
Relatively high
Relatively high
Stability
Less stable
More stable
More stable
Risks for specific populations
Risks for immunocompromised individuals
Minimal to no risk
Minimal to no risk
Advantages
Typically confers durable, sometimes lifelong immunity
Stimulates robust immune response, including cellular response
Low-cost preparation
Lower risk of reversion to virulent form
Can be safely administered to immunocompromised individuals
Reduces risk of adverse effects associated with live or inactivated pathogens
Can be safely administered to immunocompromised individuals
Disadvantages
Risk of vaccine-associated disease in some sensitive individuals
Less biologically stable, requiring specific storage and transportation conditions
Risk of allergic reaction to certain vaccine components
Sometimes requires booster doses to maintain immunity
Often higher preparation cost
Often requires booster doses to maintain immunity
May be less effective than live-attenuated vaccines for certain pathogens
Often higher preparation cost
Examples
BCG, MMR vaccine, varicella vaccine
Influenza vaccine, inactivated polio vaccine, hepatitis A vaccine
Pertussis vaccine, HPV vaccine, DTaP vaccine
Table 3.
Comparison of different types of vaccines: live-attenuated vaccines, inactivated vaccines, and acellular vaccines.
BCG: Bacille de Calmette et Guérin, DTaP: diphtheria, tetanus, and acellular pertussis, HPV: human papillomavirus, MMR: measles, mumps, and rubella.
8. Determinants of antigen immunogenicity and vaccine efficacy
The immunogenicity of an antigen depends on several parameters that influence its reactivity (Box 5). Firstly, the size of the antigen plays a crucial role, as soluble antigens are often less immunogenic than larger or membrane-bound ones. Additionally, the chemical nature of the antigen is a determining factor, as polysaccharides and haptens, such as heavy metals or benzene derivatives, may not elicit the same immune response as peptide antigens. For example, some antigens may present suppressor determinants, like amino acids 1 to 17 of egg lysozyme [97], which can modulate the immune response. Moreover, the antigen dose is a crucial consideration, as excessive concentrations may lead to immune tolerance rather than activation. Finally, the antigen’s ability to be recognized by APCs and/or complement is also essential for initiating an adequate immune response. Thus, the immunogenicity of an antigen is determined by a complex combination of factors that interact to shape the immune response. These elements are also crucial for understanding vaccine efficacy, as they influence the antigen’s ability to induce an adaptive immune response and confer protection against infections. This effectiveness can be improved with an adjuvant.
Vaccines exhibit diverse immune characteristics that play a crucial role in their effectiveness and ability to elicit a protective immune response. These characteristics include:
Type of induced immunity: Vaccines stimulate both innate and adaptive immune responses. Adaptive immunity, primarily induced by vaccines, entails specific and long-term immune responses mediated by T-cells and B-cells, leading to antibody production and immunological memory.
Antigen composition: Vaccines allow for tailored immune responses depending on the targeted pathogen and the required protective mechanism, influenced by factors such as the specific antigen included in the vaccine formulation and the nature or type of adjuvant, if utilized.
Adjuvants: Certain vaccines incorporate adjuvants that enhance the immune response by stimulating cytokine production and immune cell maturation.
Stability and shelf life: The stability of vaccine components and their ability to remain immunogenic during storage are vital for ensuring vaccine efficacy.
Mode of administration: The route of vaccine administration can influence the nature and strength of the induced immune response.
Safety: Vaccines must be safe and should not cause severe adverse effects. Vaccine safety is carefully monitored throughout the development and deployment phases.
9. Vaccine adjuvants: key support for immunity and vaccine efficacy
Adjuvants, whose name originates from the Latin “adjuvare” meaning “to help or aid” [98], are critical in enhancing vaccine efficacy by intensifying the immune response when administered with an antigen, enabling vaccines to evoke potent and enduring immune responses while reducing dosage and injection frequency and increasing stability.
The efficacy of adjuvants in boosting vaccine efficacy varies according to their type and specific properties. Many of them are immunostimulants that target pattern recognition receptors (PRRs) to activate innate immune responses. Some promote the production of cytokines or directly activate specific signaling pathways, stimulating inflammation independently of PRRs [99]. Additionally, they can facilitate the presentation of soluble antigens to immune cells and prolong antigen exposure. Adjuvants also enhance antigen presentation by stimulating phagocytic cells like macrophages and by acting as ligands for co-stimulation receptors to boost lymphocyte proliferation. Thus, incorporating adjuvants is a critical strategy to improve the immunogenicity and protective efficacy of vaccines against infections.
The main types of adjuvants used in human vaccines include aluminum salts, squalene-based compounds such as MF59™ and AS03™, and monophosphoryl lipid A (MPL) [100, 101]. While some adjuvants, such as CpG oligonucleotides and lipid nanoparticles, are under study, others such as saponins and alpha-galactosylceramide (αGalCer) derivatives are also being explored for their potential in modulating the immune response, improving both humoral and cellular immunities, and enhancing protection in various infection and toxin models [102]. Evaluation of candidate adjuvants involves assessing their ability to induce an effective immune response while ensuring safety for human use, often through in vitro and in vivo tests. Emulsion adjuvant technology, which encapsulates antigens in oil and water emulsions, is widely employed to enhance vaccine immunogenicity and durability, offering various types tailored to specific antigen characteristics and vaccination requirements.
The preparation of traditional vaccines involves a diverse array of methods and techniques tailored to the unique characteristics of target pathogens, spanning classical culture and attenuation to modern genetic engineering approaches. These include the utilization of recombinant DNA technology, virus-like particles, and novel adjuvants to enhance immunogenicity and safety profiles. These methods, aimed at enhancing efficacy, safety, and accessibility, reflect both historical advancements and contemporary innovations in vaccine production.
In the late 1920s and 1930s, primary cell cultures were instrumental in vaccine research against certain viruses including vaccinia, poliovirus, and yellow fever virus, emphasizing the importance of living cells for virus propagation and highlighting the challenge of distinguishing true virus replication from mere particle survival in slow-growing cultures, as demonstrated by experiments such as those with vaccinia virus in rabbit testis cultures in 1925 [103]. Between 1930 and 1950, particularly during World War II, military requirements were a key factor motivating vaccine development, supported by influential organizations like the World Health Organization and the Rockefeller Institute, leading to the creation of vaccines for adenovirus, poliovirus, Japanese B encephalitis virus, and influenza virus during this era [104].
The development of specific vaccines also illustrates the evolution of vaccine preparation methods. This can be exemplified by the development of the Bacille de Calmette et Guérin (BCG) vaccine for tuberculosis, which underscores the vital need for immunization against M. tuberculosis and related species within the M. tuberculosis complex. Alongside M. tuberculosis itself, other complex members such as M. africanum, M. microti, and M. bovis contribute to the disease burden. Derived from M. bovis and attenuated through 230 consecutive cultures over 13 years [105, 106], resulting in the deletion of the region of difference 1 (RD1) and subsequent attenuation, the development of the BCG vaccine highlights the critical need for continuous scientific progress in combating tuberculosis, as it stands as the only defense against this formidable pathogen.
Moreover, genetic engineering methods have revolutionized vaccine development. Gene deletion attenuation involves deleting specific genes from microorganisms to reduce virulence while retaining their ability to induce a protective immune response. Reassortant vaccines, introduced in the 1960s [107], are created by combining genomic segments of two different segmented RNA viruses, allowing for genetic recombination and the creation of new reassortant viruses with combined characteristics. Notable examples include vaccines against avian H5N1 influenza virus and pentavalent vaccines against rotavirus.
Rotavirus vaccines, a significant development in pediatric vaccination following its discovery in 1973 as a major cause of childhood acute gastroenteritis, come in two main types: live-attenuated and inactivated vaccines [108]. Live, oral, attenuated rotavirus vaccines, like the monovalent (RV1) human rotavirus vaccine (Rotarix®, developed by Merck) and the pentavalent (RV5) bovine-human reassortant vaccine (RotaTeq®, developed by GlaxoSmithKline), have demonstrated very good safety and efficacy profiles in large clinical trials in Western-industrialized countries and in Latin America [109]. Inactivated rotavirus vaccines (IRVs) were developed in response to concerns over rare but severe adverse events associated with live oral vaccines and their limited efficacy against the full range of rotavirus serotypes. Additionally, live oral vaccines have shown reduced immunogenicity, especially in impoverished children in Africa and Asia, necessitating an alternative approach. IRV offers a solution, supported by studies demonstrating its protective role through serum antibody response and efficacy in animal models following parenteral immunization [110].
Subunit vaccines, also known as acellular vaccines, are another key advancement. These vaccines utilize selected antigens, such as proteins, toxoids, or polysaccharides, formulated with adjuvants to enhance immunogenicity. Polysaccharide conjugation, a method used to augment the immunogenicity of subunit vaccines, involves linking polysaccharides to carrier proteins like tetanus toxoid using adipic acid as a conjugation agent [111, 112], enabling the shift from a T-cell-independent to a T-cell-dependent immune response and the IgM-to-IgG switching. This process contributes to the development of effective vaccines against bacterial pathogens and selected virus, like rotaviruses, particularly in vulnerable populations such as infants and young children [113]. Additionally, modern subunit vaccines now feature genetically enhanced variants where proteins synthesized in host cells yield recombinant protein or peptide vaccines, highlighting the critical role of immunoinformatics in optimizing these advancements. Moreover, progress in reverse vaccinology has facilitated the development of recombinant subunit vaccines, extracting antigenic proteins directly from pathogen genomic sequences, thereby refining vaccine design with precision and specificity [2].
11. Artificial intelligence in immunoinformatics: enhancing modern vaccine development
Immunoinformatics, or computational immunology, harnesses computational methods to predict immune responses, identify critical epitopes, and streamline vaccine design processes through reverse vaccinology. By predicting antigenic epitopes directly from pathogen genomic sequences [114], immunoinformatics enables the identification of conserved pathogen targets [115], essential for effective vaccine development (Figure 2). This discipline has gained prominence alongside the rapid development of mRNA vaccines, exemplified by Pfizer and Moderna, underscoring its agility in responding to emerging pathogens. Computational models enable rational vaccine design by simulating antigen-immune system interactions, enhancing formulation stability, immunogenicity, and safety through advanced algorithms.
Figure 2.
Overview of a pipeline for constructing a multi-epitope peptide vaccine using immunoinformatics. This schematic outlines the comprehensive approach used to develop a peptide vaccine, highlighting key steps from initial antigen selection through to experimental validation.
Emerging health challenges, including infectious diseases such as SARS-CoV-2, Nipah, Zika, Lassa, Monkeypox, West Nile, and Ebola, and beyond, drive current trends in drug discovery such as molecular target screening, natural source exploration, and drug repurposing. In response, computational immunology harnesses artificial intelligence (AI) and machine learning to streamline candidate identification, accelerate development timelines, and reduce costs, while molecular docking and dynamics methods are pivotal in addressing a wide range of health threats, including emerging viral infections [116]. This synergy accelerates vaccine discovery by analyzing extensive datasets to predict immune responses with unparalleled accuracy. Machine learning models, trained on vast immunological data [117], enhance our ability to swiftly respond to new health threats, facilitating agile vaccine development strategies. The rapid deployment of mRNA vaccines against COVID-19 illustrates how immunoinformatics [118] and AI [119] collaboratively design effective vaccines.
12. Role of neutralizing antibodies in vaccine protection
The role of neutralizing antibodies (NAbs) in vaccine protection is paramount, as they prevent infection and damage by neutralizing bacteria, viruses, parasites, and toxins [120]. Following vaccination, the immune system produces these specific antibodies targeting antigens on the surface of pathogens, thereby blocking their ability to infect target cells. Some neutralizing antibodies also bind to heparan sulfate [121], enhancing their effectiveness by increasing their concentration near target cells. Additionally, they maintain a stable interaction with cellular receptors, thereby limiting the pathogen’s ability to penetrate host cells. By activating other components of the immune system, such as NK cells and phagocytic cells, neutralizing antibodies enhance its ability to eliminate pathogens and resolve infection.
12.1 Methods for measuring NAb activity
Although the methods presented here primarily focus on viral neutralization, it is worth noting that there is a wide variety of techniques for measuring NAb activity, which are essential for assessing immune responses in different contexts and evaluating vaccine efficacy. These methods encompass various techniques tailored to specific research or clinical settings:
Serum/plasma virus neutralization assay: This method involves incubating the target virus with samples containing antibodies, then assessing the antibodies’ ability to neutralize viral infection by measuring the reduction in viral infectivity. The assay is highly sensitive and specific, assessing neutralizing antibody titers following infection or vaccination. Traditional techniques conducted in vitro rely on inhibiting virus infectivity within cell cultures in the presence of NAbs. Titers are determined based on the presence or absence of cytopathic effects (CPE) or through immunoreactive techniques indicating viral infection [122].
Microneutralization assay: The microneutralization (MN) assay is a method used to assess the ability of serum or antibodies to neutralize virus infectivity. It is similar to the virus neutralization assay but is conducted on a smaller scale in 96 microtiter plates, allowing for testing of a larger number of samples simultaneously [123]. In this assay, plates seeded with target cells are incubated with serially diluted antibodies and the virus. After several days, CPE is observed, and viable cells are stained especially with like crystal violet [124].
Hemagglutination inhibition (HI) assay: Primarily used for enveloped viruses like influenza, this method relies on antibodies’ ability to prevent red blood cell (RBC) agglutination by binding to the viral antigen, resulting in hemagglutination inhibition. In the HI assay, the serum samples are diluted twofold in 96-well plates. A known virus titer is added, followed by a 30-minute incubation at room temperature. Subsequently, RBCs are introduced, and the plate is further incubated for 30 minutes at room temperature. If the serum contains antibodies that react with the virus, these antibodies will bind to the virus, preventing it from causing hemagglutination of the RBCs. This process allows for the precise determination of antibody titers in the serum [125].
Antibody-dependent-cell-mediated cytotoxicity (ADCC)-based NAb assay [126]: During ADCC, cytotoxic antibodies specifically bind to antigens on target cells through their fragment antigen-binding (Fab fragment) domains, while their Fc region interacts with the FcγRIIIa (CD16) receptor present on effector cells such as NK cells and some myeloid cells. This interaction triggers the release of cytokines such as IFNγ and cytotoxic granules containing perforin and granzymes, ultimately leading to ADCC. In the NAb-based ADCC assay, the presence of NAbs may influence ADCC results by reducing the number of available infected target-cells for cellular cytotoxicity, potentially resulting in decreased measured ADCC activity.
Cell-cell fusion neutralization assay: Some viruses have the capability to propagate via cell-cell fusion, which occurs when viral-encoded fusion proteins on cell surfaces are activated by receptor binding, leading to membrane fusion. This assay measures antibodies’ ability to prevent fusion of virus-infected cells with adjacent uninfected cells, thus inhibiting syncytia (bi- or multinucleated cells) formation and limiting viral infection spread [127].
Pseudovirus neutralization assay: In this method, a pseudovirus carrying foreign viral glycoproteins is used to assess antibodies’ ability to neutralize viral entry into host-cells. Its advantages include the potential for use in lower biosafety containment levels, scalability for high-throughput measurements at reduced costs, and the ability to tailor the viral glycoprotein to match emerging virus variants. This method can be applied to various potentially lethal viruses such as influenza (H7N9), Middle East Respiratory Syndrome-coronavirus (MERS-CoV), hepatitis C virus (HCV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the causative agent of COVID-19) and its recent variants [128].
ELISA-based neutralizing antibody detection assay: This method relies primarily on an enzyme-linked immunosorbent assay (ELISA), which operates on the principle that the interaction between an antigen or a recombinant portion of an antigen, coupled with an enzyme such as horseradish peroxidase (HRP), and a specific receptor adsorbed onto a solid surface can be inhibited by NAbs present in a serum or plasma sample. In other words, when a sample containing NAbs from an infected patient is added, these antibodies can block or neutralize this interaction, and this neutralization often correlates with the concentration of antibodies in the sample. This approach has been successfully demonstrated using specific antigens such as the receptor-binding domain (RBD) of the SARS-CoV-2 where NAbs can inhibit the interaction between the RBD and its cellular receptor, human angiotensin-converting enzyme 2 (hACE2), thereby demonstrating dose-dependent neutralizing activity. An example of this test is the surrogate virus neutralization test (sVNT) [129].
Lateral flow immunoassay: The lateral flow immunoassay (LFIA) is a rapid point-of-care method for detecting NAbs by leveraging immune interactions between antigens and antibodies. Similar to ELISA, LFIA is based on this principle but offers faster results, typically within 5–30 minutes. During outbreaks, LFIA is crucial for large-scale virus detection, mitigating resource disparities and societal burdens of undetermined infection statuses. Originally developed in the 1980s for qualitative detection of human chorionic gonadotropin, LFIA has since evolved with various chromogenic materials such as colloidal gold, colloidal carbon, colloidal selenium, magnetic nanomaterials, and quantum dots. Technological advancements have led to automated and semi-quantitative immunochromatography instruments, expanding LFIA’s applications in biomedicine, environmental monitoring, and food engineering. In the context of the COVID-19 pandemic, LFIA has been proposed as a tool for rapid detection of NAbs. It operates on the basis of an antigen-antibody interaction, while the assessment of NAbs against SARS-CoV-2 relies on protein-protein interactions, specifically involving the interaction between the RBD or the S protein and ACE2 [130].
Virus release inhibition-based NAbs assay: This assay assesses the effectiveness of antibodies in inhibiting the release of viral particles from infected cells, thus impeding the spread of viral infection. One example of such assays has been conducted in antibody inhibition of Influenza A virus Assembly and Release. This evaluation relies on monoclonal antibodies targeting key surface proteins of the influenza virus, including hemagglutinin, neuraminidase, and the M2 protein. The test is coupled with a fluorescence imaging-based approach to visualize and quantify viral release inhibition by enumerating virions [131].
12.2 Significance of NAb measurements across public health contexts
Neutralizing antibody measurements play a pivotal role in various contexts, ranging from vaccine development and clinical trials to disease surveillance and outbreak investigations. These measurements are essential for evaluating the effectiveness or efficacy of vaccines, ensuring the quality of vaccine lots, monitoring immune responses in clinical trials, tracking population-level immunity, and guiding public health interventions during outbreaks and pandemics. Therefore, they are indispensable in several critical scenarios, including the following:
Vaccine development: Assessing the efficacy of candidate vaccines by determining their ability to induce NAbs against the target pathogen.
Vaccine lot release: Ensuring consistency and potency of vaccine lots before distribution to the public by verifying the presence of NAbs.
Clinical trials: Monitoring immune responses in vaccine recipients during clinical trials to evaluate vaccine safety, effectiveness, and efficacy.
Disease surveillance: Tracking population-level immunity to infectious diseases by measuring NAb titers over time.
Outbreak investigation, vaccination strategies, and convalescent plasma/serum therapy: Rapidly assessing NAb levels in individuals during disease outbreaks is crucial for informing public health responses and vaccination strategies. This is particularly vital during pandemics, such as the COVID-19 pandemic, or epidemics, where understanding the population’s level of immunity can guide targeted interventions and vaccine distribution efforts. In vaccine development, evaluating the neutralizing capacity of antibodies generated by candidate vaccines helps assess their efficacy in preventing infection. Similarly, in convalescent plasma or serum therapy, measuring NAbs is essential for determining the potency of donated plasma or serum in providing passive immunity to recipients. Additionally, in convalescent individuals, monitoring NAb levels guides the selection of suitable donors with high antibody titers, ensuring that the plasma or serum used for therapy contains sufficient NAbs to effectively combat the target pathogen.
13. Administration modalities of vaccines
The administration modalities of vaccines encompass various techniques, each tailored to optimize immunogenicity and patient comfort. Intradermal and subcutaneous injections are commonly employed, with intradermal injections activating skin DCs to enhance immunogenicity [132], particularly beneficial for influenza, rabies, and hepatitis B vaccines, while subcutaneous injections are preferred in young adults, offering effective protection with potentially reduced antigen doses. Intramuscular injection, favored for inactivated vaccines, promotes rapid absorption into the bloodstream, though it may induce temporary local reactions. Mucosal vaccination targets mucosal linings, stimulating local immunity and offering increased protection against pathogens entering through mucosal surfaces, with examples including oral rotavirus vaccines and nasal spray flu vaccines.
14. Measurement of vaccine efficacy or effectiveness
Effectiveness η measures the real-world performance of a vaccine, in contrast to efficacy that can be defined as the performance of an intervention under ideal and controlled circumstances. It is usually determined through controlled and randomized clinical studies. Vaccine efficacy is typically expressed as a percentage and represents the reduction in the risk of contracting the disease among vaccinated individuals compared to non-vaccinated ones [133]. This measure can also be adjusted for various factors such as age, gender, and other demographic characteristics. Once established, vaccine efficacy is used to evaluate the vaccine’s impact on disease prevention at both individual and population levels, guiding decisions in public health policy and vaccination programs [134].
14.1 Factors influencing vaccine efficacy
Vaccine efficacy can vary depending on various factors, including vaccine type, target population, individual immune response, and pathogen evolution. It can also be influenced by other factors such as pathogen mutation, population vaccine coverage, and the duration of protection provided by the vaccine.
14.2 Methods of calculating vaccine efficacy or effectiveness
Formulas for calculating vaccine efficacy or effectiveness can be influenced by a myriad of factors, including vaccine and pathogen characteristics, population-related aspects, vaccination coverage and compliance rates, environmental and societal influences, surveillance and monitoring efforts, study design and statistical analysis methodologies, vaccine deployment and implementation strategies, population adherence and behavior patterns, pathogen evolution and variants, duration of protection, population characteristics and dynamics, healthcare infrastructure and capacity, as well as public health interventions and policies. Additionally, their assessments can also be impacted by methodological choices, such as observational studies, case-control studies, cohort studies, and community or cluster trials.
The methods and formulas provided herein for assessing vaccine efficacy or effectiveness, tailored to each study type, were derived from a recent systematic review [135]. This review meticulously combed through databases including PubMed, Google Scholar, and Web of Science, employing specific search terms encompassing vaccine efficacy and relative effectiveness. Additional keywords such as “waning” were included to capture studies assessing effectiveness over various time frames. Adhering to PRISMA guidelines, the review rigorously screened articles for relevance and adherence to inclusion criteria. The included studies offered estimates for comparative vaccine effectiveness, either directly or indirectly, employing methods like network meta-analysis. Data extraction involved meticulous documentation of factors such as season, study design, sample size, endpoint, rVE definition, and statistical models. Vaccine comparisons were systematically categorized based on component, dose, and timing or history. Bias assessment was conducted using established tools such as the ROBINS-I for observational studies and the ROB-2 for randomized trials. This comprehensive review identified 63 articles meeting the inclusion criteria, with the majority focusing on relative vaccine effectiveness studies over the past decade, highlighting a recent surge in research interest in this field.
Other conventional approaches to assess vaccine efficacy in both media and medical literature involve employing relative risk reduction (RRR) [137]. In the realm of clinical trial risk assessments, certain equations are provided as follows:
RR (relative risk) = EER/CER
RRR = 1 – relative risk, or RRR = ARR/CER
ARR = CER – EER
NNT = 1/ARR
Abbreviations: ARR: absolute risk reduction, CER: control event rate, EER: experimental event rate, IRR: incidence rate ratio (comparing vaccinated to non-vaccinated individuals), IVadj: instrumental variable-adjusted rate ratio, NNT: number needed to treat, OR&IRRpool: combined odds ratio and rate ratios pooled, ORpool: pooled odds ratio, PERR: prior event rate ratio, RRpool: pooled rate ratio, RRR: relative risk reduction.
15. Harnessing individual and herd immunity, and herd protection
Both individual and herd immunity are crucial in combating infectious diseases (Figure 3). Individual immunity develops following exposure to a pathogen or vaccination, providing personal immune response [148]. Simultaneously, herd immunity emerges when a sufficient portion of the population becomes immune to an infection, effectively reducing the transmission of infectious diseases. It encompasses three main aspects: the threshold for epidemic decline, the proportion of immune individuals, and the indirect protection for those with lower immunity levels [141]. Vaccination offers individual protection, while herd immunity extends its benefits to the entire population, including unvaccinated individuals and those with waning immunity. Protocols for assessing individual immunity utilize serological tests, while collective immunity, crucial in managing epidemics like COVID-19, necessitates ongoing evaluation despite challenges such as genetic variations and variations in seropositivity rates. Sustaining collective immunity remains paramount, highlighting the significance of public health measures in reducing the transmission rate of infectious diseases. Recognizing this collective immunity is critical for efficiently managing their dissemination within communities.
Figure 3.
Individual and herd immunity, and herd protection. Immunization is a comprehensive process that provides immunity through vaccination or natural pathogen exposure [138]. Its main effect is to prevent and combat infection. This figure succinctly illustrates its importance in controlling the spread of infectious diseases across various scenarios. In the first case, without immunization, infection spreads rapidly in the non-immunized population [139, 140]. In the second case, partial immunization reduces infection spread but it persists [141]. Conversely, in the third case, high immunization levels contain the infection with minimal disease spread [142] (for review, see [143]). Furthermore, the umbrella/herd protection effect [144, 145] of collective immunization demonstrates that widespread vaccination not only protects vaccinated individuals but also the entire population by reducing infection transmission [146]. Similarly, individual immunization contributes to personal disease prevention and diminishes disease spread within the community [147].
The concept of the epidemic isocline, for instance, illustrates how the transmission rate of an infectious disease infection correlates with the proportion of immunized individuals in a population, further emphasizing the necessity of vaccination efforts and community health measures. The higher this proportion, the lower the transmission rate of the disease. The threshold of immunized individuals, also known as the herd immunity threshold or collective immunity threshold, is the minimum proportion of immunized individuals required in a population to prevent the sustained spread of an infectious disease. Once this threshold is exceeded, herd immunity acts as a barrier, limiting the transmission of the disease and protecting even non-immunized individuals.
16. Advancements in vaccination therapies
Progress in vaccination therapies extends across various domains, presenting hopeful avenues for diverse health dilemmas. In cancer vaccination, pioneering approaches include therapeutic vaccines that stimulate the immune system to target cancer cells directly [149], adoptive cell therapy involving the harvesting and modification of immune cells such as T lymphocytes in the laboratory to recognize and attack cancer cells, and then reinfusing them into the patient. This method encompasses therapies such as genetically modified T-cells (CAR-T-cells) [150] and tumor-infiltrating lymphocytes (TILs) [151]. Additionally, CAR-NK therapy is emerging as a promising method of tumor immunotherapy [152], offering safety and efficacy advantages over CAR-T therapy, with a particular focus on hematological tumors. CAR-M represent a new avenue in the treatment of solid tumors [153], with promising preclinical and clinical results, especially through approaches combining induced pluripotent stem cells with second-generation CARs to extend their use to solid cancers. Prophylactic vaccines like the HPV vaccine guard against cervical cancer [154]. Moreover, the investigation into the immunogenicity of killed cancer cells for cancer therapy inspires innovative approaches, including the induction of potent anti-tumor immunity through vaccination with necrotic [155] and necroptotic cancer cells [156]. Similarly, therapeutic vaccines for autoimmune disorders seek to regulate immune responses in various conditions such as multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and systemic lupus erythematosus (SLE) by targeting autoantigens to restore immune equilibrium [157]. Allergen immunotherapies [158], including sublingual and subcutaneous methods, aim to diminish immune reactivity to allergens, providing relief to allergy sufferers. Moreover, ongoing investigations explore vaccines for other conditions such as migraines [159] and Alzheimer’s disease [160], striving to address underlying disease mechanisms through immune modulation. These initiatives hold potential to transform disease management by leveraging the immune system’s capabilities, though ongoing research is essential to ensure their safety and effectiveness.
17. The future of vaccines
Advancements in vaccine technology promise a new era in the prevention of infectious diseases and the enhancement of public health. mRNA vaccines, like those developed against COVID-19, allow for rapid adaptation to new variants or other diseases. Researchers are working on universal vaccines that protect against a wide range of pathogen strains, potentially reducing the need for strain-specific vaccines. Therapeutic vaccines target the treatment of various conditions, boosting cellular immunity to fight cancer, treat autoimmune diseases, and combat addictions (e.g., cocaine and nicotine). Clinical trials are ongoing to improve the effectiveness of NicVax for tobacco addiction. Innovations such as nanoparticles, viral vectors, and synthetic biology open new possibilities for designing more effective and safe vaccines. Non-injection vaccines, such as those administered orally or topically, could make vaccination more convenient and accessible. Rapid vaccine development is focused on addressing emerging diseases such as Zika, Ebola, Nipah, and Avian Influenza, which have recently reemerged [161, 162], as prioritized by the WHO for research and development in emergency contexts [163]. Personalized vaccines tailored to individual genetic profiles and medical histories could enhance efficacy and safety. Improvements to existing vaccines include using Vero cells instead of mouse brains to reduce contamination risks, developing acellular vaccines like those for pertussis to reduce adverse reactions, adding adjuvants like water-in-oil formulations to boost immune responses, and creating universal flu vaccines targeting conserved parts of the virus for broader protection. New vaccines are also being developed against various viruses such as dengue, HIV, and coronavirus, bacteria like Mycobacterium tuberculosis and Staphylococcus aureus, and some parasites responsible for diseases such as malaria and leishmaniasis. These advancements not only improve the prevention of infectious diseases but also explore new therapeutic areas, offering significant solutions for public health and individual well-being. Moreover, the integration of AI in immunoinformatics heralds a transformative approach to vaccine development, accelerating the discovery of optimal vaccine candidates [90, 119, 164], while enhancing our capacity to respond swiftly to emerging health threats.
18. Complexities of vaccine development and challenges
Vaccine development poses significant challenges, including stringent safety standards and the difficulty of defining immune correlates of protection. Animal models used in research may not accurately represent human immune responses, complicating preclinical studies. Furthermore, clinical trials are often at large scale and complex, adding logistical challenges to the process. Despite these obstacles, ongoing research is crucial due to limitations associated with vaccination. These include partial efficacy, the limited duration of immunity, and variability in effectiveness among individuals. Side effects, reduced herd immunity due to vaccine hesitancy, and the need for periodic updates to vaccines to address viral mutations are also concerns. Specificity of vaccines to certain strains can pose challenges, as seen in cases like the H1N1 vaccine’s association with narcolepsy. These complexities highlight the importance of ongoing surveillance, research, and public education to ensure the safety and efficacy of vaccines in preventing infectious diseases.
19. Cultural impacts of vaccines: early resistance movements and transformative public health
Vaccines have been pivotal in not just preventing diseases but also in shaping societal attitudes and cultural norms. Early resistance movements against vaccines emerged during pivotal historical moments, such as the introduction of smallpox vaccination by Edward Jenner in the late eighteenth century. These movements often reflected broader societal concerns about safety, individual rights, and the perceived overreach of governmental health mandates [165].
For instance, the Anti-Vaccination Society of America, founded in the nineteenth century, protested mandatory smallpox vaccinations, arguing against government intrusion into personal medical decisions. Such movements catalyzed debates that influenced public health policies and vaccination strategies globally. In mid-nineteenth-century England, compulsory health legislation expanded state authority over civil liberties in the name of public health. This was evident in two key areas: mandatory smallpox vaccination and compulsory measures for screening, isolating, and treating prostitutes with venereal disease. The Vaccination Acts of 1853 mandated smallpox vaccination, initially overseen by Poor Law Guardians, despite free vaccination for the poor. This was met with resistance due to its compulsory nature, seen as a violation of personal freedom. Similarly, the Contagious Diseases Acts aimed to control venereal diseases but faced opposition for perceived government overreach and infringement on individual rights [166].
Resistance to vaccination was not unique to smallpox. Louis Pasteur’s development of the rabies vaccine in the 1880s also encountered skepticism and opposition, as acknowledged by Roux, who recognized both successes and failures in the vaccine’s risk-benefit analysis. Critics like Michel Peter pointed to cases such as Réveillac, who died of rabies post-vaccination, and accused Pasteur of inflating rabies mortality rates to enhance the vaccine’s perceived benefits. Another notable failure was Lord Doneraile’s death from rabies despite treatment in Paris after being bitten by a rabid fox in 1887. Anton von Frisch, a former trainee of Pasteur, further questioned the reliability and effectiveness of Pasteur’s vaccine method in 1887 [167]. These criticisms underscored broader societal concerns about safety, autonomy, and the role of government in public health. Despite these controversies, Pasteur’s pioneering work laid the groundwork for modern microbiology and immunology, showcasing vaccines’ transformative impact in preventing infectious diseases [168, 169].
The eradication of smallpox, achieved through widespread vaccination campaigns led by the World Health Organization [170], stands as one of the greatest triumphs in medical history. This success not only saved millions of lives but also demonstrated the transformative power of vaccines in eliminating deadly diseases and reshaping global health priorities. It sparked a paradigm shift toward preventive medicine and laid the groundwork for subsequent vaccination efforts against diseases such as polio, measles, and rubella.
In recent times, the COVID-19 pandemic has highlighted both the critical importance of vaccines and the persistent challenges of vaccine resistance [171]. The development and deployment of vaccines against SARS-CoV-2 encountered significant opposition, influenced by safety concerns, political factors, and widespread institutional mistrust, reflecting broader psychological dispositions that shape vaccine hesitancy and resistance [172]. Social media played a significant role in shaping public perception [173], while concerns about the rapid development of mRNA vaccines fueled hesitancy [174]. Resistance movements echoed those of the past, raising issues about personal freedom and governmental mandates [175, 176]. Despite these challenges, the vaccination efforts have been pivotal in controlling the pandemic, showcasing the continued transformative impact of vaccines on public health.
Through these historical examples, vaccines have not only safeguarded individual health but have also driven societal changes, underscoring their role as a cornerstone of modern public health. By exploring the cultural impacts of vaccines, we gain insights into how medical advancements have intersected with cultural values, influencing policies and perceptions to shape the landscape of global health today.
20. Conclusions and future prospects
In conclusion, human vaccines encompass a diverse array of forms and classifications, all playing a crucial role in eliciting immune responses. Their classification based on composition, ranging from live-attenuated vaccines to inactivated vaccines, along with subunit and nucleic acid-based vaccines, reflects the diversity of mechanisms they employ to induce protection against pathogens. Furthermore, advancements in research pave the way for novel approaches such as universal, therapeutic, and personalized vaccines, alongside the utilization of emerging technologies such as nanoparticles and viral vectors to enhance their efficacy and safety. In this context, the measurement of NAbs holds paramount importance, in both vaccine development and evaluation, disease surveillance, and epidemic response. This measurement provides valuable insights into individual and collective immunity, facilitating the assessment of vaccine efficacy and effectiveness, monitoring population immunity, and guiding vaccination and epidemic response strategies. By integrating NAb measurement into research and clinical practice, we are better equipped to address the challenges posed by infectious diseases and to promote global public health.
Looking ahead, advances in vaccine technology are poised to revolutionize disease prevention and public health. Future developments include mRNA vaccines offering flexibility for rapid adaptation to new variants, and universal vaccines designed to protect against a wide range of pathogen strains. Therapeutic vaccines represent a breakthrough in preventive medicine, targeting the treatment of various conditions such as cancer, autoimmune diseases, and other inflammatory and autoinflammatory disorders, as well as conditions or behaviors affecting people’s quality of life. Emerging technologies such as nanoparticles and viral vectors offer new avenues for vaccine design, while orally or topically administered vaccines promise greater convenience and accessibility. Research also focuses on vaccines against emerging diseases such as Zika and Ebola, as well as personalized vaccines tailored to individual genetic profiles and improvements to existing vaccines for enhanced safety and efficacy. Additionally, ongoing efforts aim to develop new vaccines against viruses, bacteria, and parasites, offering promising solutions for public health and individual well-being.
However, vaccine development presents significant challenges, including stringent safety standards and the difficulty of defining immune correlates of protection. Animal models used in research may not accurately represent human immune responses, complicating preclinical studies. Furthermore, clinical trials are often at large scale and complex, adding logistical challenges to the process. Despite these obstacles, ongoing research is crucial due to limitations associated with vaccination, such as partial efficacy, limited duration of immunity, and variability in effectiveness among individuals. Side effects, reduced herd immunity due to vaccine hesitancy, and the need for periodic updates to vaccines to address viral mutations are also concerns. The specificity of vaccines to certain strains can pose challenges, as seen in cases like the H1N1 vaccine’s association with narcolepsy. These complexities underscore the importance of continuous surveillance, research, and public education to ensure the safety and efficacy of vaccines in preventing infectious diseases.
In perspective, advances in vaccine science offer promising potential to address persistent public health challenges. Ongoing progress in vaccine research could lead to innovative solutions for combating infectious diseases, including those caused by emerging or treatment-resistant pathogens. Furthermore, the exploration of new technological platforms, such as mRNA vaccines and viral vectors, paves the way for faster and more effective vaccine development approaches. Concurrently, a better understanding of immune response and protective mechanisms could enable the development of more targeted and personalized vaccines, tailored to individual needs and specific populations. Moreover, strengthened international collaboration, coupled with a commitment to equity in vaccine access, is essential to ensure an effective global response to public health challenges.
Additionally, the integration of immunoinformatics and AI in vaccine development represents a significant advancement. These technologies facilitate the prediction of antigenic epitopes, enhance vaccine design processes, and optimize immunogenicity. By harnessing computational methods and machine learning algorithms, researchers can expedite vaccine development timelines and improve vaccine efficacy against evolving pathogens. This interdisciplinary approach holds promise for accelerating the discovery and deployment of vaccines worldwide, thereby reinforcing global health security.
Moreover, understanding the social and cultural impacts of vaccines is crucial. From early resistance movements to the eradication of diseases like smallpox, vaccines have transformed public health and societal norms. This journey, from risky initial experiments to modern innovations, stands as one of humanity’s greatest accomplishments in conquering deadly diseases. By continuing on this trajectory, it is conceivable that vaccines will become even more crucial in preventing and controlling not only infectious diseases but also non-infectious diseases on a global scale.
Acknowledgments
I am deeply grateful to the members of the Laboratory of Applied Molecular Biology and Immunology (BIOMOILIM, ID W0414100), University of Tlemcen (Algeria), for their invaluable support in harmonizing my research commitments with academic responsibilities. Their unwavering assistance has been pivotal in navigating this endeavor. The author acknowledges the use of basic AI and online tools for language polishing of the manuscript, which in no way affects the authenticity or originality of the author’s work.
Conflict of interest
The author declares that there are no conflicts of interest regarding the research, funding sources, or any other matter that could inappropriately influence the content of this chapter.
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Written By
Mourad Aribi
Submitted: 20 May 2024Reviewed: 15 July 2024Published: 19 September 2024
Open access peer-reviewed chapter - ONLINE FIRST
