The Role of Vaccine Adjuvants in Modern Immunization Strategies

Dr. Kapil Maithal, President & Head - of Vaccines & Diagnostics at Zydus Lifesciences in a recent interaction with India Pharma Outlook, discusses innovations in vaccine adjuvants, particularly nanoparticle-based adjuvants and TLR agonists that enhance efficacy and safety. He also addressed challenges in India's diverse population and manufacturing landscape. Dr Maithal is a prominent leader in Vaccines & Biologicals R&D, with over two decades of experience. He specializes in product development and project management and has received accolades for developing ZyCoV-D, the world’s first human DNA vaccine against COVID-19.

To begin with, how are innovations like nanoparticle-based adjuvants and Toll-like receptor (TLR) agonists addressing challenges in vaccine efficacy and safety in the development of novel adjuvants?

COVID pandemic was a game changer and led to numerous innovations across the healthcare sector including adjuvants. Innovative vaccine candidates were developed rapidly during the pandemic and some of them warranted new adjuvants capable of enhancing antigen stability, antigen dose sparing and more importantly activating various immune pathways leading to improved efficacy and longevity of immune response with much lower adverse effects.

Two categories which made significant progress during this period were nanoparticle-based adjuvants and Toll-like receptor (TLR) agonists.

Nanoparticle-based adjuvants gained prominence as many mRNA vaccines used lipid nanoparticles both as stabilizers and improving antigen delivery to antigen-presenting cells (APCs) to boost the immune response. Nanoparticle-based adjuvants are also being used for controlled release of antigens to induce more mature B-cell mediated response for longer lasting immunity. Besides lipid nanoparticles, many inorganic and other biodegradable materials like clay, gold, chitosan etc. have also been used in numerous research studies.

On the other hand, Toll-like receptors (TLRs) agonists are now being used in a number of vaccines as they can recognize conserved pathogen-associated molecular patterns (PAMP) and stimulate targeted and balanced immune responses. These adjuvants are known to stimulate effective cellular immune responses, which are vital for protection against intracellular pathogens and cancer. Many TLRs are known of which few are present on the endosomal membranes within the cell while others are expressed on the cell surface. A variety of TLR agonists has been used in vaccines like dsRNA analogues (TLR3), Lipid A analogues (TLR4), Flagellin (TLR5), imidazoquinolines (TLR7 and TLR8), CpG ODN (TLR9) etc. Some of these are already part of licensed vaccines however, many are still in developmental stages with long-term profiles yet to be fully established.

Considering diverse immune responses in India, what are the key challenges in selecting suitable adjuvants for vaccines that ensure broad immunity while minimizing reactogenicity?

Given the fact that India has varied climatic conditions across the length and breadth of the country, this may lead to the ecological diversity of the pathogen strains/serotypes with varying levels of infectivity and severity of the disease. This can contribute to differences in the level of immune response to vaccines. Similarly, differences in the rate of vaccine coverage in different regions of the country and the movement of large migrant populations between rural and urban areas can also impact levels of immune protection. Furthermore, the increasing levels of co-morbidity associated with lifestyle diseases; varying nutritional index and ageing population due to increasing life expectancy in India are also attributed to variable immune response in the population.

Although most of these factors are largely addressed as part of large Phase III clinical trials where vaccines along with adjuvants (if added) are tested across different geographies of the country with clearly defined exclusion and inclusion criteria to arrive at vaccine efficacy or non-inferiority to an approved vaccine. Furthermore, post-licensure, continuous pharmacovigilance data is also evaluated to ensure that the marketed vaccines are efficacious and safe.

In India’s expanding vaccine manufacturing ecosystem, what bottlenecks exist in scaling adjuvant-containing vaccines?

Factors which become bottlenecks in scaling up adjuvant-containing vaccines relate to, the limited availability of domestically produced high-quality adjuvants, limited expertise in novel adjuvant development and formulation, ring-fenced innovator patents, need for specialized equipment, cGMP facilities for adjuvant production and complex quality testing requirements for novel multi-component adjuvants. Furthermore, conventionally Indian manufacturers have relied on the procurement of well-established and characterized adjuvants from external vendors rather than investing in the development of novel adjuvants.

Although, moving forward the development of novel and potent adjuvants will become a necessity not only due to the emergence of new diseases and pathogen diversity but also to be able to compete with vaccines developed by innovators with proprietary adjuvants.

In fact, there are many academic and industrial R&D centres that have developed specialized programs in areas like liposome-based adjuvants, biodegradable chitosan-based adjuvants, plant-based adjuvants and nanoparticle-based adjuvants and hopefully, next decade we will be one of the major players in producing adjuvants besides being the largest producer of vaccines in the World.

How are new adjuvant formulations addressing cold chain challenges for vaccine storage in remote Indian areas, and what emerging solutions enhance adjuvant stability under these conditions?

Vaccine wastage due to cold chain failure is one of the major programmatic challenges any healthcare system faces. It is quite detrimental as it leads to a decrease in the availability of vaccines and challenges in stock management, which can impact vaccine coverage besides the major financial burden associated with this wastage. Thus, a need for thermostable vaccines has been warranted for many decades but now with advancements in adjuvants and vaccine delivery technologies, this is becoming a near reality.

Some adjuvants are known to protect vaccine antigens from degradation caused by heat exposure by either creating a protective environment around the antigen or altering the physical state of the antigen, which helps in thermo-stabilization.

Some noteworthy, examples include Conventional aluminum salt-based adjuvants (Alum) are widely used and provide some thermal stability to antigens by surface adsorption, Oil in water emulsions contribute to improving thermal stability as reported for MF59 adjuvanted influenza vaccine and ASO3 adjuvant has also been reported to provide stabilizing effect on antigens during temperature fluctuations, Liposomal adjuvants have been used to encapsulate the antigen and provide protective environment for many new vaccines under development, and Polymer-based adjuvants like those using poly (lactic-co-glycolic acid) (PLGA), are being studied for their potential to create thermally stable antigen-adjuvant complexes.

With the advancement in the field, one hopes to better understand the molecular mechanism of adjuvant-mediated thermal stabilization, which will enable the development of better and customized adjuvants with the potential to stabilize multiple antigens in combination with vaccines and elicit superior immunological responses.

What scientific and regulatory trends are key in combining multiple adjuvants in vaccines to improve immune response breadth and durability?

For more complex and challenging disease targets where highly efficacious vaccines have eluded us for decades, it becomes important to have advanced adjuvants besides better antigen design.  For eliciting a superior breadth of immune responses combination of adjuvants, known as adjuvant systems is being explored.

These adjuvant systems contribute to providing suitable immune responses in special populations (e.g., elderly, immunocompromised or malnourished) to overcome reduced vaccine efficacy. At the same time, they can also be designed for selectively activating the desired arm of the host’s immune system based on the pathogen and target population. For example, mucosal immunity, which is important as the first line of defence for respiratory, sexually transmitted and enteric diseases can be enhanced while systemic response can be elicited for prolonged and persistent protection.

In fact, some adjuvant systems are already part of commercialized vaccines like ASO adjuvants, which use a variety of ingredients like MPL (a TLR4 agonist) and QS-21 (a saponin), which elicit superior immune response. During the COVID pandemic, the Algel-IMDG adjuvant, which was used in Covaxin contained imidazoquinolinone, a TLR7/8 agonist chemisorbed on Alum (NLRP3 inflammasome), which promoted better antibody affinity maturation and elicited a good immune response. Similarly, Matrix-M, a saponin-based adjuvant that enhances both humoral and cellular immune responses was used in Covovax.

From a regulatory perspective, combination adjuvants undergo more stringent review as expected, specifically in terms of both short-term and long-term safety profiles. This is important as the clearance of these potent adjuvants from the host system is necessary considering the fact that they target different immune pathways and one would not want any autoimmune response to be triggered in the host. Another important aspect is manufacturing consistent lots of adjuvant combinations and subsequent formulations with antigens, which would be required for reproducible biological response, thus demanding a strong quality control testing of both standalone adjuvant systems and as part of the final vaccine formulation.

Looking ahead, what are the anticipated future directions for vaccine adjuvant research, and how might upcoming innovations transform immunization strategies in the next decade?

I think the future of adjuvant research is very bright and will revolutionize the field of vaccinology in the coming decades. Novel adjuvants with a better understanding of their mechanism of action and with the availability of personalized medicines are expected to address the safety and longevity of immune response across populations with diverse genetic backgrounds.

Crystal gazing one would anticipate the development of designer adjuvants using AI-driven technologies to target specific pathogens and selective populations. One would expect advances in material sciences to be extended to adjuvant development and one may be able to develop programmable, controlled release of antigen(s) and also degradation of adjuvants by the host.

The availability of various classes of adjuvants targeting various immunological pathways will lead to the development of tailored combination adjuvants as well as offer vaccine delivery through non-invasive administration like intranasal and oral routes and also advance the delivery of vaccines through transdermal routes.

Some very innovative platforms being explored currently include microbiome-based adjuvants, plant-based adjuvants and stimuli-responsive adjuvants to name a few.