Vaccine adjuvants play a crucial role by enhancing the immunogenicity of antigens and boosting not only the strength, but also the longevity of the immune response. In essence, they stimulate cytokine production, facilitate the maturation of dendritic cells and antigen presentation, and drive the proliferation and differentiation of T and B cells. By amplifying the vaccine's effectiveness, adjuvants make it possible to use smaller quantities of antigens.
A wide range of adjuvants have been effectively incorporated into veterinary vaccines, with several innovative technologies currently undergoing preclinical evaluation. These adjuvants can be classified into two categories: antigen-presenting adjuvants (such as mineral salts, oil emulsions, and nanoparticles) and immune-enhancing adjuvants (including toll-like receptor agonists, cytokines, saponins, and propolis).¹
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Over the past few decades, hundreds of materials have been tested as potential adjuvants. However, aluminum-based adjuvants remain the most widely used globally. For over 90 years, these adjuvants have played a key role in human medicine, enhancing the immune response to vaccines. They have been included in billions of vaccine doses and administered to millions of people annually. ²
In veterinary medicine, aluminum-based adjuvants are equally significant, incorporated into vaccines for livestock diseases such as Foot and Mouth Disease (FMD, Brucellosis, Blue Tongue, Epizootic Haemorrhagic Disease and many others.¹
The primary aluminum-based compounds used as adjuvants include aluminum hydroxide, aluminum phosphate, and alum, with aluminum hydroxide being the most widely used. Aluminum hydroxide adjuvant is produced by adding sodium hydroxide to a solution of aluminum ions under carefully controlled conditions. Factors such as temperature, concentration, and mixing speed play a critical role in determining the physicochemical properties of the resulting adjuvant.³
Aluminum-based adjuvants have the ability to induce high antibody titers, even after a single immunization, due to the formation of a short-term depot at the injection site, which gradually releases antigens, allowing for efficient phagocytosis and activation of immune mechanisms.⁴ Other advantages include ease of formulation, an excellent safety profile and minimal reactogenicity.
Clostridial diseases in ruminants are a major veterinary concern. They are caused by toxins produced by various Clostridium species. The main clostridial diseases include botulism, tetanus, blackleg, malignant edema, and enterotoxemia. Implementing regular vaccination programs is critical for their prevention.
Clostridial vaccines have demonstrated high efficacy in protecting cattle, sheep, and goats. Different types are commercially available, including whole formalin–inactivated vaccines, bacterin-toxoid vaccines, toxoid vaccines, genetically engineered vaccines, and more recently, nanovaccines.⁵
Most commonly used clostridial vaccines, with the exception of C. chauvoei vaccines – which consist of whole formalin-inactivated bacterial cultures – contain one or more toxoids (exotoxins without pathogenic effect) produced by C. perfringens, C. novyi, C. tetani and C. septicum. These toxoid-based vaccines induce a robust neutralizing antibody response and are formulated with appropriate adjuvants that help enhance the animal immune system.
As noted earlier, aluminum-based adjuvants are highly effective in enhancing immune responses, particularly against pathogens where antibody-mediated immunity is essential for protection, such as in the case of clostridial infections.
However, a notable limitation of these adjuvants is their relatively weak stimulation of cell-mediated immune responses, which are essential for combating certain types of pathogens. However, clostridial diseases do not trigger the cell-mediated immunity ⁶. Therefore, an adjuvant capable of stimulating this type of immunity is of little interest for these diseases.
To improve the efficacy of aluminum compounds against other diseases, including viral infections, the strategy of its co-administration with other adjuvants to stimulate Th1 cell-mediated response has been explored in numerous research studies.⁷
Over the past decade, several new combination adjuvants have been registered for both human and animal health. These adjuvants typically consist of two or three individual components, often at lower doses or formulated into smaller particles. Combining different adjuvants can produce a synergistic effect that can exceed the sum of their individual effects. With a deeper understanding of the immune responses necessary for effective disease protection through vaccination, combination adjuvants can both enhance and direct them to be either Th-1 or Th-2, depending on the desired effect.⁸
Several adjuvant combinations are already at various stages of clinical trials for human vaccines targeting infectious diseases and cancer. The findings from these studies could help guide the development of adjuvants for animal vaccines.⁷
In veterinary medicine, research has focused on evaluating various combinations of adjuvants, such as emulsions and saponins, to enhance the efficacy of vaccines for Avian Influenza or FMD in cattle. Additionally, using saponin as a co-adjuvant in aluminum hydroxide gel vaccines offers a simple, safe, and cost-effective alternative for boosting vaccine potency. This combination helps induce high antibody titers and strengthens cell-mediated immune responses.⁹
Saponin (Quil A) is also used in conjunction with aluminum hydroxide in inactivated vaccines against Blue Tongue Virus (BTV) or Epizootic Haemorraghic Disease Virus (EHDV) to ensure a robust immune response in vaccinated animals.10
Aluminum-based adjuvants remains the gold standard against which new and experimental adjuvants should be assessed. Leveraging their high adsorptive capacity, they are increasingly being used as a platform for the development of novel combination adjuvants that can effectively stimulate immune responses against specific pathogens. Therefore, aluminum-based adjuvants will continue to be a key component in vaccine formulations for the years to come.¹¹
Bibliographic references
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10Paul-Ehrlich Institute. Federal Institute for Vaccines and Biomedicines. https://www.pei.de/EN/home/home-node.html
11Laera D, HogenEsch H, O’Hagan DT. Aluminum Adjuvants—‘Back to the Future’. Pharmaceutics. 2023; 15(7):1884.