MaltSci 麦伴科研

Appearance

Popular Reports / Immunology

This report is written by MaltSci based on the latest literature and research findings

How do vaccine adjuvants enhance immune responses? ​

Abstract ​

Vaccination is a cornerstone of public health, and the inclusion of adjuvants in vaccine formulations has become increasingly vital for enhancing immune responses. Adjuvants serve to improve the immunogenicity of vaccines, particularly those containing purified antigens that may elicit weak immune responses on their own. This review provides a comprehensive overview of the mechanisms by which vaccine adjuvants enhance immune responses, focusing on the activation of innate immunity and the enhancement of adaptive immunity. Adjuvants can activate antigen-presenting cells (APCs), prolong antigen retention at the injection site, and modulate the quality of the immune response, thus ensuring a more robust and durable protection against pathogens. Traditional adjuvants, such as aluminum salts, have been widely used due to their safety and efficacy, while newer molecular adjuvants, including TLR agonists, are being developed to target specific immune pathways. The review also discusses the clinical applications of these adjuvants in infectious diseases and cancer vaccines, highlighting their real-world impact on vaccine performance. Despite progress, challenges in safety, tolerability, and regulatory considerations persist, necessitating ongoing research into novel adjuvant strategies. Future directions in adjuvant research emphasize personalized approaches and innovative platforms that leverage computational modeling and systems biology to enhance vaccine efficacy across diverse populations. Understanding the intricate interplay between adjuvants and the immune system is essential for advancing vaccine technology and addressing global health challenges.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Mechanisms of Action of Vaccine Adjuvants
    • 2.1 Activation of Innate Immunity
    • 2.2 Enhancement of Adaptive Immunity
  • 3 Types of Vaccine Adjuvants
    • 3.1 Aluminum Salts
    • 3.2 Oil-in-Water Emulsions
    • 3.3 Molecular Adjuvants
  • 4 Clinical Applications and Efficacy
    • 4.1 Case Studies in Infectious Diseases
    • 4.2 Adjuvants in Cancer Vaccines
  • 5 Challenges in Adjuvant Development
    • 5.1 Safety and Tolerability
    • 5.2 Regulatory Considerations
  • 6 Future Directions in Adjuvant Research
    • 6.1 Personalized Adjuvant Strategies
    • 6.2 Novel Adjuvant Platforms
  • 7 Summary

1 Introduction ​

Vaccination remains one of the most effective public health interventions for preventing infectious diseases. The efficacy of vaccines is significantly influenced by their formulation, particularly through the inclusion of adjuvants. Traditionally, vaccines consist of antigens designed to elicit an immune response; however, the incorporation of adjuvants has been shown to markedly enhance both the magnitude and longevity of these responses. Vaccine adjuvants serve as critical components that not only boost the immunogenicity of the antigens but also modulate the immune system's response to ensure a more robust and durable protection against pathogens. As such, understanding the mechanisms by which adjuvants enhance immune responses is essential for the advancement of vaccine technology and the development of effective immunization strategies.

The significance of adjuvants in vaccine development cannot be overstated. With the emergence of new infectious diseases and the challenge of vaccine hesitancy, there is an urgent need for vaccines that elicit strong immune responses across diverse populations. Current vaccines often fail to provide adequate protection, particularly in vulnerable groups such as the elderly or immunocompromised individuals[1]. Adjuvants play a pivotal role in addressing these challenges by enhancing the immune response, improving vaccine efficacy, and potentially allowing for the use of lower doses of antigens, which is particularly beneficial in resource-limited settings[2].

Research on vaccine adjuvants has evolved significantly over the past century. Early adjuvants, such as aluminum salts, were discovered empirically, while recent advances have been driven by a deeper understanding of the immune system, particularly the innate immune response[2][3]. This knowledge has facilitated the development of novel adjuvants, including oil-in-water emulsions and molecular adjuvants like toll-like receptor (TLR) agonists, which have been shown to activate various immune pathways and enhance both innate and adaptive immune responses[4][5]. Furthermore, innovative approaches, such as systems vaccinology, have begun to elucidate the complex interactions between adjuvants and the immune system at the molecular level[4].

This review aims to provide a comprehensive overview of the mechanisms by which vaccine adjuvants enhance immune responses. We will begin by exploring the activation of innate immunity and the enhancement of adaptive immunity, detailing how various adjuvants interact with immune cells to promote a more effective response[6][7]. Next, we will categorize the types of vaccine adjuvants, focusing on traditional adjuvants such as aluminum salts and oil-in-water emulsions, as well as newer molecular adjuvants[2][3]. The clinical applications and efficacy of these adjuvants will be examined through case studies in infectious diseases and cancer vaccines, highlighting their real-world impact on vaccine performance[8][9].

Despite the progress made, challenges remain in the development of adjuvants. Issues related to safety and tolerability, as well as regulatory considerations, pose significant hurdles that must be addressed to facilitate the approval and widespread use of new adjuvants[7][8]. Furthermore, as we look to the future, personalized adjuvant strategies that cater to specific populations and disease contexts will be essential in optimizing vaccine responses[9]. Novel adjuvant platforms, including those utilizing computer-aided design and epigenetic modulation, represent exciting avenues for future research[9][10].

In summary, this review will serve as a comprehensive resource for researchers and practitioners in the field of immunology and vaccinology. By elucidating the intricate interplay between adjuvants and the immune system, we aim to contribute to the advancement of vaccine technology and the development of effective strategies to combat global health challenges. Understanding the role of adjuvants in enhancing immune responses is not only critical for improving vaccine efficacy but also for addressing the broader implications of vaccine hesitancy and emerging infectious diseases.

2 Mechanisms of Action of Vaccine Adjuvants ​

2.1 Activation of Innate Immunity ​

Vaccine adjuvants enhance immune responses primarily by activating the innate immune system, which in turn influences the adaptive immune response. The mechanisms through which adjuvants exert their effects are multifaceted and involve various processes that contribute to the overall efficacy of vaccines.

Adjuvants can serve as direct ligands for pathogen recognition receptors (PRRs), which are crucial components of the innate immune system. For instance, many adjuvants target Toll-like receptors (TLRs), leading to the activation of signaling pathways that result in the production of pro-inflammatory cytokines and chemokines. This activation creates a local immuno-competent environment at the injection site, enhancing the recruitment and activation of immune cells, such as dendritic cells (DCs), monocytes, and macrophages, which are essential for antigen presentation and the initiation of adaptive immune responses[6][11].

The action of adjuvants can also include the formation of a depot effect, which prolongs the retention of the antigen at the injection site, allowing for sustained release and more effective antigen uptake by antigen-presenting cells. This sustained release is critical for maintaining the activation of immune responses over time[2][12].

Moreover, certain adjuvants have been shown to induce cell stress and death, leading to the release of damage-associated molecular patterns (DAMPs). These DAMPs can further stimulate innate immune responses and enhance the immunogenicity of the vaccine by promoting the activation of DCs and the subsequent activation of T and B cells[13][14].

The understanding of how adjuvants modulate innate immunity has advanced significantly, revealing that different adjuvants can activate distinct pathways and receptors, resulting in varying types of adaptive immune responses. For example, some adjuvants may preferentially enhance T helper 1 (Th1) responses, while others may boost Th2 responses, depending on the specific innate signaling pathways they activate[15][16].

In summary, vaccine adjuvants enhance immune responses by activating the innate immune system through various mechanisms, including direct interaction with PRRs, prolonging antigen retention, inducing the release of immunostimulatory signals, and shaping the quality of the adaptive immune response. This multifaceted approach is essential for improving vaccine efficacy and developing next-generation vaccines capable of providing robust and long-lasting protection against infectious diseases.

2.2 Enhancement of Adaptive Immunity ​

Vaccine adjuvants play a crucial role in enhancing immune responses by modulating both the innate and adaptive immune systems. The mechanisms through which they operate are multifaceted and involve several key processes.

Adjuvants enhance the adaptive immune response primarily by stimulating the innate immune system. They achieve this through various mechanisms, including the activation of antigen-presenting cells (APCs), such as dendritic cells, which are pivotal in linking innate and adaptive immunity. By targeting pattern recognition receptors (PRRs) like Toll-like receptors (TLRs), adjuvants can induce the maturation and activation of APCs, leading to enhanced production of antigen signals and co-stimulatory signals necessary for effective T cell activation[11].

One significant mechanism of action is the formation of a depot at the injection site, which prolongs the release of the antigen, allowing for sustained immune stimulation. This depot effect helps in maintaining higher local concentrations of the antigen, facilitating better uptake and presentation by APCs[17]. Furthermore, adjuvants can induce the secretion of cytokines and chemokines that recruit immune cells to the site of injection, creating a local immuno-competent environment conducive to a robust immune response[6].

The enhancement of adaptive immunity also involves the modulation of the quality and quantity of immune responses. Adjuvants can influence the types of T cell responses generated, such as promoting Th1 or Th2 responses depending on the adjuvant used. For instance, some adjuvants are known to activate inflammasomes, which are multiprotein complexes that drive the activation of inflammatory caspases, resulting in the secretion of pro-inflammatory cytokines like IL-1. These cytokines play a crucial role in shaping the adaptive immune response, affecting both cellular and humoral immunity[18].

Moreover, the mechanisms by which adjuvants act can lead to improved antibody responses. For example, the presence of adjuvants can enhance the total antibody titers and induce potent cell-mediated immunity, which is essential for protection against various pathogens[12]. Some adjuvants also stimulate mucosal immunity and provide cross-protection, further contributing to their effectiveness[12].

Recent advances in understanding the molecular mechanisms of adjuvants have also highlighted the potential for rational design of new adjuvant systems that can specifically tailor immune responses. The integration of systems biology approaches, including transcriptomics, allows for a comprehensive analysis of the gene expression profiles influenced by adjuvants, offering insights into their complex interactions within the immune system[4].

In conclusion, vaccine adjuvants enhance immune responses through a variety of mechanisms that involve the activation of innate immune pathways, modulation of APC function, prolonged antigen presentation, and tailored adaptive immune responses. The continued exploration of these mechanisms is vital for the development of more effective vaccines, particularly against challenging pathogens and in populations with poor immune responses.

3 Types of Vaccine Adjuvants ​

3.1 Aluminum Salts ​

Vaccine adjuvants are crucial components in enhancing the immune response to vaccines, particularly in non-living vaccines that typically induce weak adaptive immunity. Among the various types of adjuvants, aluminum salts, commonly referred to as alum, have been extensively utilized for nearly a century due to their safety and efficacy in promoting protective humoral immunity.

Aluminum adjuvants primarily enhance immune responses through several mechanisms. First, they facilitate the adsorption of antigens, leading to a high local concentration at the injection site. This increased antigen availability enhances uptake by antigen-presenting cells (APCs), such as dendritic cells and macrophages. The adsorption of antigens to aluminum salts not only aids in phagocytosis but also slows the diffusion of antigens from the injection site, allowing for a prolonged immune response as inflammatory cells accumulate in the area [19].

Moreover, aluminum adjuvants selectively stimulate a type 2 immune response (Th2) characterized by the production of antibodies. While they are effective in promoting humoral immunity, their capacity to induce cell-mediated immunity is limited, as they do not strongly activate cytotoxic T cells [20]. The mechanism of action involves the activation of dendritic cells, which can be triggered through both direct and indirect pathways. For instance, aluminum adjuvants can activate the NLRP3 inflammasome in dendritic cells, leading to the release of pro-inflammatory cytokines such as IL-1β and IL-18, which are pivotal in shaping the adaptive immune response [21].

In addition to enhancing antigen uptake and promoting a Th2 response, aluminum adjuvants also induce the release of chemokines that recruit additional immune cells to the site of injection. This recruitment is crucial for the development of a robust immune response [10]. Furthermore, the presence of aluminum salts in vaccines has been shown to stimulate the release of danger-associated molecular patterns (DAMPs) from damaged cells, which further activates dendritic cells and enhances their ability to present antigens to T cells [21].

Recent advancements in the understanding of aluminum adjuvants have led to the exploration of novel formulations and combinations with other immunomodulatory molecules. For instance, combining aluminum salts with cationic lipids has been shown to enhance the adjuvanticity of alum by improving antigen processing and cross-presentation by APCs, thus potentially overcoming the limitations associated with aluminum salts alone [22].

In conclusion, aluminum salts serve as effective vaccine adjuvants primarily by enhancing antigen adsorption, promoting local immune responses, activating dendritic cells, and facilitating the recruitment of immune cells. Despite their limitations in inducing strong cell-mediated immunity, ongoing research aims to improve their efficacy through innovative formulations and combinations with other adjuvant systems [23][24][25].

3.2 Oil-in-Water Emulsions ​

Vaccine adjuvants are critical components in enhancing the immunogenicity of vaccines, particularly for non-living vaccines, which often induce weak immune responses on their own. Among the various types of adjuvants, oil-in-water emulsions have emerged as effective enhancers of immune responses, especially in the context of pandemic influenza vaccines.

Oil-in-water emulsions function by creating a depot effect at the injection site, which prolongs the release of the antigen and enhances its uptake by antigen-presenting cells (APCs). This mechanism is crucial for stimulating both humoral and cellular immune responses. For instance, studies have shown that emulsions such as MF59 can significantly improve antibody titers and the diversity of antibody responses. MF59 has been reported to enhance the quantity, diversity, specificity, and affinity maturation of antibody responses, particularly to the hemagglutinin 1 (HA1) globular head of influenza viruses. This enhancement is attributed to the adjuvant's ability to recruit immune cells and induce a robust cytokine response, which facilitates the development of effective immune memory [26].

Moreover, the specific composition of the oil-in-water emulsion can greatly influence its efficacy. Research has indicated that the structure of the oil component is vital; for example, squalene-based emulsions have shown distinct adjuvant activities compared to those based on medium-chain triglycerides. In vivo studies demonstrated that squalene-based emulsions significantly enhanced antibody responses, indicating that the biological activity of the oil composition plays a critical role in the adjuvant's effectiveness [[pmid:23122325],[pmid:36531114]].

The stability of the emulsion is another important factor that contributes to its effectiveness. Emulsions with appropriate droplet sizes and zeta potentials have been shown to maintain their physical stability over time, which is essential for ensuring consistent immune responses. For example, a study found that squalene-based emulsions maintained droplet sizes between 322 to 812 nm and zeta potentials between -30 mV to -10 mV over four weeks, indicating good stability as a vaccine adjuvant [27].

In summary, oil-in-water emulsions enhance immune responses through several mechanisms: they create a sustained release of antigens, promote effective antigen uptake by APCs, and stimulate robust cytokine production, all of which are critical for generating strong humoral and cellular immunity. The choice of oil composition, stability of the emulsion, and the specific formulation can all significantly impact the adjuvant's performance, making it a vital consideration in vaccine development [[pmid:23122325],[pmid:21632986],[pmid:36531114]].

3.3 Molecular Adjuvants ​

Vaccine adjuvants are critical components that enhance the immune responses elicited by vaccines, thereby improving their efficacy. Among the various types of adjuvants, molecular adjuvants represent a specific subclass that directly interacts with immune-modulatory receptors. These adjuvants are designed to augment immune responses by co-stimulating B cell receptors (BCRs) alongside other immune-modulatory receptors. This strategy can enhance downstream signaling pathways, leading to improved antibody titers, increased potency, and enhanced survival in challenge models [28].

One of the most extensively studied molecular adjuvants is C3d, which has been shown to significantly improve immune responses to a variety of antigens. Additionally, other ligands from the tumor necrosis superfamily, such as BAFF and APRIL, as well as molecules like CD40 and CD180, have demonstrated potential as molecular adjuvants by enhancing humoral immunity [28]. However, it is important to note that no single molecular adjuvant has emerged as universally effective across all contexts, indicating the need for systematic exploration of various molecular adjuvants to fully realize their potential in next-generation vaccine technologies [28].

Molecular adjuvants can also influence the adaptive immune response by modulating regulatory T cell (Treg) functions. By depleting or functionally inhibiting Tregs, certain molecular adjuvants have been employed to amplify the immune response to vaccine antigens. This approach has shown promise in enhancing vaccine efficacy, although it also raises concerns about the potential induction of autoimmune diseases [29].

Moreover, the mechanisms through which molecular adjuvants exert their effects are complex and involve the activation of various immune pathways. For instance, they can activate innate immune receptors such as Toll-like receptors (TLRs), which are critical for initiating and shaping adaptive immune responses. By engaging these receptors, molecular adjuvants can enhance the overall immune response, leading to a more robust and durable protection against pathogens [3].

In summary, molecular adjuvants enhance immune responses by directly interacting with immune-modulatory receptors, co-stimulating B cell responses, modulating Treg functions, and activating innate immune pathways. This multifaceted approach underscores the importance of molecular adjuvants in the development of effective vaccines, as they not only improve the quantity of the immune response but also its quality and durability [4][28][29].

4 Clinical Applications and Efficacy ​

4.1 Case Studies in Infectious Diseases ​

Vaccine adjuvants enhance immune responses through various mechanisms that optimize the interaction between the immune system and the vaccine antigens. The primary role of adjuvants is to boost the immunogenicity of vaccines, particularly those containing highly purified antigens that may not elicit a strong immune response on their own. This enhancement is critical for both preventative and therapeutic vaccines against infectious diseases.

One of the fundamental ways adjuvants operate is by stimulating the innate immune system, which subsequently influences the adaptive immune response. Adjuvants can activate antigen presenting cells (APCs), such as dendritic cells, which play a crucial role in initiating and directing the adaptive immune response. For instance, the interaction of adjuvants with pattern recognition receptors (PRRs) on APCs leads to the release of pro-inflammatory cytokines and chemokines, enhancing the activation and maturation of these cells. This process ensures a more robust activation of T and B cells, which are essential for long-term immunity [30].

The effectiveness of adjuvants can be attributed to their ability to influence both the magnitude and quality of the immune response. For example, certain adjuvants can skew the immune response towards a T-helper 1 (Th1) or T-helper 2 (Th2) profile, depending on the desired type of immunity. Th1 responses are generally associated with enhanced cell-mediated immunity, while Th2 responses are linked to strong antibody production [2]. This targeted modulation is particularly important in the context of diseases where a specific immune response is required for protection.

In addition to cytokines, plant-derived products have emerged as promising adjuvants. These natural substances often exhibit low toxicity and high stability, making them suitable for vaccine development. They can enhance immune responses by improving the stability and safety of vaccines while also providing cost-effective solutions for adjuvant use [5].

Moreover, recent advancements in understanding the mechanisms of action of adjuvants have led to the development of novel adjuvant systems that combine multiple adjuvant types to achieve greater efficacy. For instance, systems that target specific immune cells can facilitate more precise immune responses, particularly for chronic infectious diseases and cancer, where traditional vaccines may be less effective [31].

The importance of adjuvants is underscored by their historical and ongoing role in vaccine efficacy. Traditional adjuvants like aluminum salts have been used for decades, primarily to enhance humoral immunity. However, the need for improved adjuvants that can also promote cell-mediated immunity has led to the exploration of new formulations that integrate various immune-stimulating components [32].

In summary, vaccine adjuvants enhance immune responses by activating the innate immune system, modulating the adaptive immune response, and providing tailored immune profiles to improve vaccine efficacy against infectious diseases. Their development continues to be a vital area of research, aiming to overcome the challenges posed by emerging infectious diseases and populations that respond poorly to conventional vaccines [13].

4.2 Adjuvants in Cancer Vaccines ​

Vaccine adjuvants play a crucial role in enhancing immune responses, particularly in the context of cancer vaccines. Their primary function is to amplify the intensity, speed, and duration of immune responses to vaccine antigens. This enhancement is achieved through several mechanisms, which include the activation of antigen-presenting cells (APCs), modulation of immune signaling pathways, and the promotion of adaptive immune responses.

One significant aspect of adjuvants is their ability to stimulate APCs, such as dendritic cells (DCs). Mature DCs are essential for initiating robust T cell responses. For instance, adjuvants can prolong the exposure of antigens to DCs, which facilitates their maturation and subsequent activation of antigen-specific T cells. This process is vital for inducing potent and long-lasting cellular immunity, particularly in cancer immunotherapy, where effective T cell responses are necessary to target and eliminate tumor cells [33].

Adjuvants can also influence the immune environment by enhancing the release of pro-inflammatory cytokines, which further promotes the activation and proliferation of T cells. For example, Montanide ISA-51, a water-in-oil emulsion, has been shown to enhance anti-tumor immune responses by improving antigen release and facilitating immune cell aggregation and activation. When combined with Toll-like receptor (TLR) agonists or other immunomodulatory agents, Montanide ISA-51 can significantly amplify the immune response against various cancers, including melanoma and glioma [34].

Moreover, recent research has highlighted the role of adjuvants in inducing epigenetic changes that can enhance immune responses. These epigenetic modifications can influence gene expression patterns associated with immune pathways, thereby modulating the strength and duration of immune responses to vaccines [9].

In cancer vaccines, the choice of adjuvant is particularly critical due to the unique challenges posed by the tumor microenvironment, which often includes immunosuppressive factors. For instance, adjuvants that can counteract the effects of myeloid-derived suppressor cells (MDSCs), which inhibit T cell responses, are essential for the efficacy of cancer vaccines [35]. The incorporation of adjuvants that stimulate strong T cell responses can help overcome these barriers and improve therapeutic outcomes.

Additionally, novel strategies such as using multifunctional protein conjugates that combine adjuvants and antigens have shown promise in enhancing immune responses. These constructs can facilitate the co-delivery of adjuvants and antigens, leading to significantly higher antibody titers and enhanced T cell responses compared to traditional vaccine formulations [36].

Overall, the incorporation of adjuvants in cancer vaccines is essential for enhancing immunogenicity and achieving effective anti-tumor responses. The ongoing research into novel adjuvants and their mechanisms of action continues to provide valuable insights that could lead to the development of more effective cancer immunotherapies.

5 Challenges in Adjuvant Development ​

5.1 Safety and Tolerability ​

Vaccine adjuvants play a critical role in enhancing immune responses by improving the magnitude, functionality, breadth, and durability of these responses. They achieve this through various mechanisms, primarily by modulating both innate and adaptive immune pathways. The understanding of these mechanisms has been advancing, revealing how adjuvants can influence the type and quality of the immune response, which is crucial for developing effective vaccines against a range of pathogens.

One of the primary functions of adjuvants is to boost the immunogenicity of vaccines that contain purified antigens, which often have suboptimal immunogenic properties on their own. For instance, adjuvants can enhance the activation of antigen-presenting cells (APCs), which in turn promotes a stronger T cell response. Adjuvants can also help in shaping the immune response towards a specific type of immunity, such as humoral (antibody-mediated) or cell-mediated immunity, depending on the nature of the pathogen being targeted [6][37].

However, the development of effective adjuvants faces significant challenges. A major issue is the high safety and efficacy standards that current adjuvants must meet for human vaccines. The limited number of adjuvants approved for clinical use, such as aluminum salts and monophosphoryl lipid A, underscores the challenges in balancing immunogenicity with safety [38][39]. Many adjuvants can lead to adverse reactions, which complicates their use in vaccine formulations. This is particularly concerning for populations that may be more vulnerable to vaccine side effects, such as infants and the elderly [40].

The safety and tolerability of adjuvants are paramount. For instance, while aluminum salts have a long history of use and a strong safety record, there are ongoing concerns regarding their potential links to adverse reactions, including rare but serious conditions [38]. This highlights the need for a thorough understanding of both the efficacy and the potential toxicities associated with different adjuvants. The challenge lies in developing new adjuvants that can enhance immunogenicity without compromising safety. Recent research initiatives aim to explore alternative adjuvant formulations, including plant-derived adjuvants and novel nanoparticles, which may offer improved safety profiles [5][41].

In conclusion, while vaccine adjuvants are essential for enhancing immune responses and ensuring effective vaccination, the challenges of safety and tolerability remain critical in their development. Ongoing research and innovative approaches are necessary to create adjuvants that maximize vaccine efficacy while minimizing adverse effects.

5.2 Regulatory Considerations ​

Vaccine adjuvants are critical components that enhance the immune response to vaccine antigens, playing a vital role in improving vaccine efficacy. They achieve this enhancement through various mechanisms that stimulate the innate immune system, which in turn influences the adaptive immune response. Adjuvants can target specific innate immune receptors and pathways, leading to increased activation of antigen-specific B and T cells, which are essential for long-lasting immunity. Recent studies indicate that adjuvants can induce durable epigenetic reprogramming of the innate immune system, thereby providing heightened resistance against diverse pathogens (Lee et al., 2022) [42].

The enhancement of immune responses by adjuvants can be attributed to several factors. Firstly, adjuvants can amplify the magnitude of the immune response, which is particularly important for antigens that possess low immunogenicity, such as subunit vaccines (Coffman et al., 2010) [6]. They can also alter the quality of the immune response, ensuring that the immune system generates the appropriate type of response (humoral or cell-mediated) depending on the nature of the pathogen (Montomoli et al., 2011) [43].

Despite the critical role of adjuvants in vaccine development, there are significant challenges associated with their development. One major challenge is the limited number of adjuvants that have been approved for human use, which is largely due to the slow process of translating novel adjuvants from preclinical studies to clinical application (Vázquez-Maldonado et al., 2023) [44]. Furthermore, the existing adjuvants may not be optimal for all vaccine types, particularly those requiring strong T cell immunity, which necessitates ongoing research into new adjuvant formulations (Sinani & Şenel, 2025) [41].

Regulatory considerations also play a significant role in the development of vaccine adjuvants. Current regulations tend to focus on traditional adjuvants, such as aluminum salts, which have been used for decades (Montomoli et al., 2011) [43]. However, there is a growing recognition of the need for new adjuvants that can provide enhanced efficacy and safety. Regulatory agencies are beginning to draft guidance on the evaluation of new adjuvants, which is crucial for advancing the development of innovative adjuvant systems (Mutwiri et al., 2011) [45]. The challenge lies in ensuring that these new adjuvants are both effective and safe for human use, requiring extensive preclinical and clinical testing to establish their immunogenicity and potential adverse effects (Cui et al., 2024) [46].

In summary, vaccine adjuvants enhance immune responses by targeting innate immune pathways, thereby amplifying and modulating the adaptive immune response. The development of new adjuvants faces challenges related to regulatory approval and the need for improved formulations. Addressing these challenges is essential for the advancement of vaccine technology and the effective control of infectious diseases.

6 Future Directions in Adjuvant Research ​

6.1 Personalized Adjuvant Strategies ​

Vaccine adjuvants play a crucial role in enhancing immune responses by modulating both innate and adaptive immunity. They achieve this through various mechanisms that include the activation of innate immune receptors, promotion of antigen presentation, and modulation of immune cell signaling pathways.

Adjuvants can enhance the immunogenicity of vaccines by stimulating the innate immune system, which in turn influences the adaptive immune response. For instance, they can act as direct ligands for pathogen recognition receptors or induce cell stress and death, leading to the release of immunostimulatory damage-associated molecular patterns. This activation of innate immunity is essential for developing robust and sustained adaptive immune memory across different populations [13].

One of the primary functions of adjuvants is to improve the presentation of antigens to antigen-presenting cells (APCs). By enhancing the uptake and processing of antigens, adjuvants can significantly increase the quantity and quality of the adaptive immune response, which includes both humoral and cellular immunity. For example, the AS01 adjuvant system, which combines immunostimulatory molecules like MPL and QS-21, has been shown to promote CD4+ T cell-mediated immune responses, making it a suitable candidate for vaccines targeting viruses or intracellular pathogens [8].

Moreover, molecular adjuvants that target B cell receptors have demonstrated the ability to improve antibody titers and potency. This co-stimulation of the B cell receptor and immune-modulatory receptors augments downstream signaling pathways, which is vital for effective antibody production [28].

In recent years, there has been a shift towards the rational design of adjuvants based on an improved understanding of immune mechanisms. Systems biology approaches, such as transcriptomics, allow for a comprehensive analysis of the immune response to vaccines, facilitating the identification of biomarkers of adjuvanticity. This knowledge enables the development of personalized adjuvant strategies tailored to the unique immunological profiles of individuals, taking into account factors such as age, sex, genetics, and microbiota [41].

Future directions in adjuvant research emphasize the need for a more evidence-based approach to the selection of adjuvants. This includes the use of omics and systems biology to create molecular benchmarks for assessing vaccine safety and efficacy. As the understanding of the interplay between adjuvants and the immune system deepens, it is anticipated that novel adjuvants will be developed that can induce tailored immune responses against specific pathogens, particularly for populations that typically respond poorly to conventional vaccines [47].

In summary, vaccine adjuvants enhance immune responses through a multifaceted approach that includes the activation of innate immunity, improved antigen presentation, and targeted modulation of immune signaling pathways. The ongoing research in this field aims to create personalized adjuvant strategies that optimize vaccine efficacy for diverse populations, thereby addressing the global health challenges posed by infectious diseases.

6.2 Novel Adjuvant Platforms ​

Vaccine adjuvants play a crucial role in enhancing immune responses by improving the immunogenicity of vaccines. They achieve this through various mechanisms that target the innate immune system, thereby promoting a more robust adaptive immune response. Adjuvants can be categorized into two main types: immunostimulants and delivery systems. Immunostimulants act as danger signal molecules that activate antigen-presenting cells (APCs) by engaging pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), which leads to the production of co-stimulatory signals and enhances adaptive immune responses. Delivery systems, on the other hand, facilitate antigen presentation by prolonging the bioavailability of antigens and targeting them to lymph nodes or APCs [11].

Recent advances in adjuvant research have focused on developing novel adjuvant platforms that can effectively enhance vaccine efficacy. For instance, the TriAdj platform, which consists of a TLR agonist (either polyI:C or CpG oligodeoxynucleotides), a host defense peptide, and polyphosphazene, has shown promising results in eliciting long-term humoral and cellular immunity across various animal models [48]. This combination adjuvant not only improves immunogenicity in healthy populations but is also effective in vulnerable groups such as neonates, even in the presence of maternal antibodies.

Furthermore, innovative approaches in adjuvant development have incorporated systems biology and computational modeling to better understand the complex interactions between adjuvants and the immune system. This has led to the identification of new adjuvants with enhanced immune activation potency, capable of compensating for the deficiencies of traditional adjuvants [11]. For example, the use of computer-aided design has facilitated the discovery of broad-spectrum adjuvants that can significantly boost vaccine responses against various pathogens [10].

In addition, the mechanisms by which adjuvants promote immunogenicity have been linked to their ability to activate inflammasomes, which are multiprotein complexes that drive the activation of inflammatory responses. This activation leads to the secretion of pro-inflammatory cytokines that modulate both the cellular and humoral arms of the adaptive immune response [18]. Understanding these mechanisms is essential for the rational design of future adjuvants that can provide robust protection against a wide range of infectious diseases.

The ongoing research emphasizes the need for continued innovation in adjuvant technology, particularly in the context of emerging infectious diseases and pandemic preparedness. The development of new adjuvant platforms that are safe, effective, and capable of eliciting strong immune responses will be critical in addressing the challenges posed by future pathogens [49]. Thus, the future directions in adjuvant research will likely focus on refining these novel platforms, optimizing their mechanisms of action, and ensuring their applicability across diverse populations and vaccine formulations [41].

7 Conclusion ​

This review highlights the critical role of vaccine adjuvants in enhancing immune responses, emphasizing their multifaceted mechanisms of action that activate innate immunity and modulate adaptive responses. The findings indicate that adjuvants such as aluminum salts, oil-in-water emulsions, and molecular adjuvants each contribute uniquely to the efficacy of vaccines, with potential applications in infectious diseases and cancer immunotherapy. Despite the significant advancements made in adjuvant research, challenges remain, particularly concerning safety, tolerability, and regulatory hurdles. Future research directions are geared towards developing personalized adjuvant strategies that can optimize vaccine responses for diverse populations, as well as innovative adjuvant platforms that leverage systems biology approaches to create effective and safe vaccine formulations. This continued exploration is essential to address the growing public health challenges posed by emerging infectious diseases and vaccine hesitancy.

References ​

  • [1] Evelyna Derhovanessian;Graham Pawelec. Vaccination in the elderly.. Microbial biotechnology(IF=5.2). 2012. PMID:21880118. DOI: 10.1111/j.1751-7915.2011.00283.x.
  • [2] Alberta Di Pasquale;Scott Preiss;Fernanda Tavares Da Silva;Nathalie Garçon. Vaccine Adjuvants: from 1920 to 2015 and Beyond.. Vaccines(IF=3.4). 2015. PMID:26343190. DOI: 10.3390/vaccines3020320.
  • [3] Jiayin Xing;Xiangxiang Zhao;Xiaotian Li;Ren Fang;Mingrui Sun;Yang Zhang;Ningning Song. The recent advances in vaccine adjuvants.. Frontiers in immunology(IF=5.9). 2025. PMID:40433383. DOI: 10.3389/fimmu.2025.1557415.
  • [4] Diogo Pellegrina;Heather L Wilson;George K Mutwiri;Mohamed Helmy. Transcriptional Systems Vaccinology Approaches for Vaccine Adjuvant Profiling.. Vaccines(IF=3.4). 2025. PMID:39852812. DOI: 10.3390/vaccines13010033.
  • [5] Manshu Zou;Chang Lei;Dan Huang;Lan Liu;Yuanshan Han. Application of plant-derived products as adjuvants for immune activation and vaccine development.. Vaccine(IF=3.5). 2024. PMID:38987109. DOI: 10.1016/j.vaccine.2024.07.016.
  • [6] Robert L Coffman;Alan Sher;Robert A Seder. Vaccine adjuvants: putting innate immunity to work.. Immunity(IF=26.3). 2010. PMID:21029960. DOI: 10.1016/j.immuni.2010.10.002.
  • [7] Ennio De Gregorio;Elena Caproni;Jeffrey B Ulmer. Vaccine adjuvants: mode of action.. Frontiers in immunology(IF=5.9). 2013. PMID:23914187. DOI: 10.3389/fimmu.2013.00214.
  • [8] Arnaud M Didierlaurent;Béatrice Laupèze;Alberta Di Pasquale;Nadia Hergli;Catherine Collignon;Nathalie Garçon. Adjuvant system AS01: helping to overcome the challenges of modern vaccines.. Expert review of vaccines(IF=4.8). 2017. PMID:27448771. DOI: 10.1080/14760584.2016.1213632.
  • [9] Yasmine Megdiche;Rosângela Salerno-Gonçalves. Harnessing adjuvant-induced epigenetic modulation for enhanced immunity in vaccines and cancer therapy.. Frontiers in immunology(IF=5.9). 2025. PMID:40040700. DOI: 10.3389/fimmu.2025.1547213.
  • [10] Juan Ma;Shenqing Wang;Chuanfang Zhao;Xiliang Yan;Quanzhong Ren;Zheng Dong;Jiahuang Qiu;Yin Liu;Qing'e Shan;Ming Xu;Bing Yan;Sijin Liu. Computer-Aided Discovery of Potent Broad-Spectrum Vaccine Adjuvants.. Angewandte Chemie (International ed. in English)(IF=16.9). 2023. PMID:36815280. DOI: 10.1002/anie.202301059.
  • [11] Tingmei Zhao;Yulong Cai;Yujie Jiang;Xuemei He;Yuquan Wei;Yifan Yu;Xiaohe Tian. Vaccine adjuvants: mechanisms and platforms.. Signal transduction and targeted therapy(IF=52.7). 2023. PMID:37468460. DOI: 10.1038/s41392-023-01557-7.
  • [12] Azam Bolhassani;Somayeh Talebi;Ali Anvar. Endogenous and Exogenous Natural Adjuvants for Vaccine Development.. Mini reviews in medicinal chemistry(IF=3.3). 2017. PMID:28245781. DOI: 10.2174/1389557517666170228115801.
  • [13] Ed C Lavelle;Craig P McEntee. Vaccine adjuvants: Tailoring innate recognition to send the right message.. Immunity(IF=26.3). 2024. PMID:38599170. DOI: 10.1016/j.immuni.2024.03.015.
  • [14] Tom Y-H Wu;Manmohan Singh;Andrew T Miller;Ennio De Gregorio;Francesco Doro;Ugo D'Oro;David A G Skibinski;M Lamine Mbow;Simone Bufali;Ann E Herman;Alex Cortez;Yongkai Li;Bishnu P Nayak;Elaine Tritto;Christophe M Filippi;Gillis R Otten;Luis A Brito;Elisabetta Monaci;Chun Li;Susanna Aprea;Sara Valentini;Samuele Calabrό;Donatello Laera;Brunella Brunelli;Elena Caproni;Padma Malyala;Rekha G Panchal;Travis K Warren;Sina Bavari;Derek T O'Hagan;Michael P Cooke;Nicholas M Valiante. Rational design of small molecules as vaccine adjuvants.. Science translational medicine(IF=14.6). 2014. PMID:25411473. DOI: 10.1126/scitranslmed.3009980.
  • [15] Bali Pulendran;Prabhu S Arunachalam;Derek T O'Hagan. Emerging concepts in the science of vaccine adjuvants.. Nature reviews. Drug discovery(IF=101.8). 2021. PMID:33824489. DOI: 10.1038/s41573-021-00163-y.
  • [16] Guang Han Ong;Benedict Shi Xiang Lian;Takumi Kawasaki;Taro Kawai. Exploration of Pattern Recognition Receptor Agonists as Candidate Adjuvants.. Frontiers in cellular and infection microbiology(IF=4.8). 2021. PMID:34692565. DOI: 10.3389/fcimb.2021.745016.
  • [17] Sunita Awate;Lorne A Babiuk;George Mutwiri. Mechanisms of action of adjuvants.. Frontiers in immunology(IF=5.9). 2013. PMID:23720661. DOI: 10.3389/fimmu.2013.00114.
  • [18] Sören Reinke;Aneesh Thakur;Cillian Gartlan;Jelena S Bezbradica;Anita Milicic. Inflammasome-Mediated Immunogenicity of Clinical and Experimental Vaccine Adjuvants.. Vaccines(IF=3.4). 2020. PMID:32971761. DOI: 10.3390/vaccines8030554.
  • [19] Harm Hogenesch. Mechanism of immunopotentiation and safety of aluminum adjuvants.. Frontiers in immunology(IF=5.9). 2012. PMID:23335921. DOI: 10.3389/fimmu.2012.00406.
  • [20] Harm HogenEsch. Mechanisms of stimulation of the immune response by aluminum adjuvants.. Vaccine(IF=3.5). 2002. PMID:12184362. DOI: 10.1016/s0264-410x(02)00169-x.
  • [21] Vishukumar Aimanianda;Jean Haensler;Sébastien Lacroix-Desmazes;Srini V Kaveri;Jagadeesh Bayry. Novel cellular and molecular mechanisms of induction of immune responses by aluminum adjuvants.. Trends in pharmacological sciences(IF=19.9). 2009. PMID:19439372. DOI: 10.1016/j.tips.2009.03.005.
  • [22] Arnaud Wilmar;Caroline Lonez;Marjorie Vermeersch;Mathieu Andrianne;David Pérez-Morga;Jean-Marie Ruysschaert;Michel Vandenbranden;Oberdan Leo;Stéphane T Temmerman. The cationic lipid, diC14 amidine, extends the adjuvant properties of aluminum salts through a TLR-4- and caspase-1-independent mechanism.. Vaccine(IF=3.5). 2012. PMID:22075093. DOI: 10.1016/j.vaccine.2011.10.071.
  • [23] Jingyang Lan;Disong Feng;Xueshan He;Qianru Zhang;Rong Zhang. Basic Properties and Development Status of Aluminum Adjuvants Used for Vaccines.. Vaccines(IF=3.4). 2024. PMID:39460352. DOI: 10.3390/vaccines12101187.
  • [24] Giuseppe Del Giudice;Rino Rappuoli;Arnaud M Didierlaurent. Correlates of adjuvanticity: A review on adjuvants in licensed vaccines.. Seminars in immunology(IF=7.8). 2018. PMID:29801750. DOI: 10.1016/j.smim.2018.05.001.
  • [25] Jiangqi Luo;Yue Wang;Chengzhong Yu;Yannan Yang. Bimetallic nanoadjuvants for cancer vaccines.. Trends in pharmacological sciences(IF=19.9). 2025. PMID:40973570. DOI: 10.1016/j.tips.2025.08.007.
  • [26] Surender Khurana;Nitin Verma;Jonathan W Yewdell;Anne Katrin Hilbert;Flora Castellino;Maria Lattanzi;Giuseppe Del Giudice;Rino Rappuoli;Hana Golding. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines.. Science translational medicine(IF=14.6). 2011. PMID:21632986. DOI: 10.1126/scitranslmed.3002336.
  • [27] Ga-Eul Chae;Dong Woo Kim;Hyo-Eon Jin. Development of Squalene-Based Oil-in-Water Emulsion Adjuvants Using a Self-Emulsifying Drug Delivery System for Enhanced Antigen-Specific Antibody Titers.. International journal of nanomedicine(IF=6.5). 2022. PMID:36531114. DOI: 10.2147/IJN.S379950.
  • [28] Taylor Sicard;Audrey Kassardjian;Jean-Philippe Julien. B cell targeting by molecular adjuvants for enhanced immunogenicity.. Expert review of vaccines(IF=4.8). 2020. PMID:33252273. DOI: 10.1080/14760584.2020.1857736.
  • [29] Alexander Batista-Duharte;Damiana Téllez-Martínez;Deivys Leandro Portuondo Fuentes;Iracilda Zeppone Carlos. Molecular adjuvants that modulate regulatory T cell function in vaccination: A critical appraisal.. Pharmacological research(IF=10.5). 2018. PMID:29175113. DOI: 10.1016/j.phrs.2017.11.026.
  • [30] R Lin;P E Tarr;T C Jones. Present status of the use of cytokines as adjuvants with vaccines to protect against infectious diseases.. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America(IF=7.3). 1995. PMID:8749629. DOI: 10.1093/clinids/21.6.1439.
  • [31] Virgil E J C Schijns;Ed C Lavelle. Trends in vaccine adjuvants.. Expert review of vaccines(IF=4.8). 2011. PMID:21506650. DOI: 10.1586/erv.11.21.
  • [32] Marcin Kwissa;Sudhir Pai Kasturi;Bali Pulendran. The science of adjuvants.. Expert review of vaccines(IF=4.8). 2007. PMID:17931149. DOI: 10.1586/14760584.6.5.673.
  • [33] Nataschja I Ho;Lisa G M Huis In 't Veld;Tonke K Raaijmakers;Gosse J Adema. Adjuvants Enhancing Cross-Presentation by Dendritic Cells: The Key to More Effective Vaccines?. Frontiers in immunology(IF=5.9). 2018. PMID:30619259. DOI: 10.3389/fimmu.2018.02874.
  • [34] Liu Nan;Xiuli Zhang;Li Ziyi;Shaowei Li;Ningshao Xia. Montanide ISA-51: a promising adjuvant in cancer vaccine immunotherapy.. Expert review of vaccines(IF=4.8). 2025. PMID:41102132. DOI: 10.1080/14760584.2025.2576234.
  • [35] Audry Fernández;Liliana Oliver;Rydell Alvarez;Luis E Fernández;Kelvin P Lee;Circe Mesa. Adjuvants and myeloid-derived suppressor cells: enemies or allies in therapeutic cancer vaccination.. Human vaccines & immunotherapeutics(IF=3.5). 2014. PMID:25483674. DOI: 10.4161/hv.29847.
  • [36] Jing-Jing Du;Chang-Wei Wang;Wen-Bo Xu;Lian Zhang;Yuan-Kai Tang;Shi-Hao Zhou;Xiao-Fei Gao;Guang-Fu Yang;Jun Guo. Multifunctional Protein Conjugates with Built-in Adjuvant (Adjuvant-Protein-Antigen) as Cancer Vaccines Boost Potent Immune Responses.. iScience(IF=4.1). 2020. PMID:32146328. DOI: 10.1016/j.isci.2020.100935.
  • [37] Geert Leroux-Roels. Unmet needs in modern vaccinology: adjuvants to improve the immune response.. Vaccine(IF=3.5). 2010. PMID:20713254. DOI: 10.1016/j.vaccine.2010.07.021.
  • [38] Nikolai Petrovsky. Comparative Safety of Vaccine Adjuvants: A Summary of Current Evidence and Future Needs.. Drug safety(IF=3.8). 2015. PMID:26446142. DOI: 10.1007/s40264-015-0350-4.
  • [39] Jingyi Fan;Shengbin Jin;Lachlan Gilmartin;Istvan Toth;Waleed M Hussein;Rachel J Stephenson. Advances in Infectious Disease Vaccine Adjuvants.. Vaccines(IF=3.4). 2022. PMID:35891284. DOI: 10.3390/vaccines10071120.
  • [40] John S Tregoning;Ryan F Russell;Ekaterina Kinnear. Adjuvanted influenza vaccines.. Human vaccines & immunotherapeutics(IF=3.5). 2018. PMID:29232151. DOI: 10.1080/21645515.2017.1415684.
  • [41] Genada Sinani;Sevda Şenel. Advances in vaccine adjuvant development and future perspectives.. Drug delivery(IF=8.1). 2025. PMID:40536024. DOI: 10.1080/10717544.2025.2517137.
  • [42] Audrey Lee;Florian Wimmers;Bali Pulendran. Epigenetic adjuvants: durable reprogramming of the innate immune system with adjuvants.. Current opinion in immunology(IF=5.8). 2022. PMID:35588691. DOI: 10.1016/j.coi.2022.102189.
  • [43] Emanuele Montomoli;Simona Piccirella;Baharak Khadang;Elisa Mennitto;Roberto Camerini;Alfonso De Rosa. Current adjuvants and new perspectives in vaccine formulation.. Expert review of vaccines(IF=4.8). 2011. PMID:21806399. DOI: 10.1586/erv.11.48.
  • [44] Nancy Vázquez-Maldonado;Halonna R Kelly;Wolfgang W Leitner. Comprehensive immunoprofiling and systematic adjuvant comparisons for identifying suitable vaccine: Adjuvant pairings.. Human vaccines & immunotherapeutics(IF=3.5). 2023. PMID:37341528. DOI: 10.1080/21645515.2023.2223503.
  • [45] George Mutwiri;Volker Gerdts;Sylvia van Drunen Littel-van den Hurk;Gael Auray;Nelson Eng;Srinivas Garlapati;Lorne A Babiuk;Andrew Potter. Combination adjuvants: the next generation of adjuvants?. Expert review of vaccines(IF=4.8). 2011. PMID:21162624. DOI: 10.1586/erv.10.154.
  • [46] Ying Cui;Megan Ho;Yongjie Hu;Yuan Shi. Vaccine adjuvants: current status, research and development, licensing, and future opportunities.. Journal of materials chemistry. B(IF=5.7). 2024. PMID:38591323. DOI: 10.1039/d3tb02861e.
  • [47] Derek T O'Hagan;Leonard R Friedland;Emmanuel Hanon;Arnaud M Didierlaurent. Towards an evidence based approach for the development of adjuvanted vaccines.. Current opinion in immunology(IF=5.8). 2017. PMID:28755542. DOI: 10.1016/j.coi.2017.07.010.
  • [48] Ravendra Garg;Lorne Babiuk;Sylvia van Drunen Littel-van den Hurk;Volker Gerdts. A novel combination adjuvant platform for human and animal vaccines.. Vaccine(IF=3.5). 2017. PMID:28599794. DOI: 10.1016/j.vaccine.2017.05.067.
  • [49] Brett H Pogostin;Kevin J McHugh. Novel Vaccine Adjuvants as Key Tools for Improving Pandemic Preparedness.. Bioengineering (Basel, Switzerland)(IF=3.7). 2021. PMID:34821721. DOI: 10.3390/bioengineering8110155.

MaltSci Intelligent Research Services ​

Search for more papers on MaltSci.com ​

vaccine adjuvants · immune responses · adaptive immunity · innate immunity · clinical applications

© 2025 MaltSci