The Role of Vaccine Adjuvants in Modern Immunization Strategies

Dr. Kapil Maithal, President & Head - 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?

The Covid pandemic was a game changer and led to numerous innovations across the healthcare sector including adjuvants. Rapid and innovative vaccine candidates were developed during the pandemic and 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 to improve antigen delivery to antigen-presenting cells (APCs), which boosts the immune response. Other advantages of nanoparticles-based adjuvants include improving antigen stability and they can be tailored for controlled release to provide a more mature B-cell mediated response for durability of immune response. Besides lipid nanoparticles, many inorganic and other biodegradable materials are used for antigen entrapment. Materials, like clay, gold, chitosan, etc have been used in numerous research studies.

On the other hand, Toll-like receptors (TLRs) agonists are now being used in several vaccines as they can recognize conserved pathogen-associated molecular patterns (PAMP) and stimulate targeted and balanced immune responses, potentially leading to more effective vaccines. These adjuvants are known to stimulate effective cellular immune responses, which are vital for protection against intracellular pathogens and cancer. There are ten TLRs of which 7, 8, and 9 are present on the endosomal membranes within the cell while others are expressed on the cell surface. A variety of TLR agonists have been used in vaccines like dsRNA analogs (TLR3), Lipid A analogs (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. Despite this, they represent significant advancements in vaccine development, offering potential solutions to current challenges in vaccine efficacy and safety.

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

This is a very pertinent question and varied immune responses in India can be attributed to three major factors according to me. Firstly, given the fact that India has a highly diverse population with various genetic backgrounds, there may be variation in the level of immune response to vaccines and adjuvants. This is further compounded by the fact that we have varied climates across the length and breadth of the country, which contributes to diversity in pathogen strains and serotypes with varying levels of infectivity and severity of the disease.

Secondly, environmental factors like pollution, nutrition index, and risk of co-infections significantly vary across our country and this is further accentuated by a large migrant population, which moves between different regions of the country besides rural and urban areas, which can contribute to varying vaccine coverage and herd immunity leading to differentiated immune protection.

Thirdly and lastly, the increasing levels of co-morbidity associated with lifestyle diseases; a large number of immunocompromised populations, and increasing life expectancy leading to the more elderly population in India also contribute to varied immune responses.

Most of these factors are largely addressed as large Phase III clinical trials are conducted on novel adjuvants and vaccines across different regions 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 evaluated to ensure that the vaccines and adjuvants used are efficacious and safe.

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

It is a dichotomy that India produces almost 60% of global vaccine production but has very limited manufacturing capacity for adjuvants. There are some manufacturers, who produce in-house alum-based adjuvants although next generation adjuvants are mostly in the research and development phase.

This is primarily attributed to the fact that traditionally, Indian manufacturers have relied on procurement of well-established adjuvants from external vendors due to stringent regulatory requirements and the need for additional studies for novel adjuvants, which acted as a deterrent. So the factors that become bottlenecks in scaling up adjuvant-containing vaccines relate to limited availability of domestic production of 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.

However, 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 centers working on liposome-based adjuvants, biodegradable chitosan-based adjuvants, plant-based adjuvants, and nanoparticle-based adjuvants to name a few and hopefully by the next decade we will be one of the major players in producing adjuvants, which will cater to local manufacturing of adjuvant-containing vaccines.

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 decreasing vaccine coverage besides huge financial losses. 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.

Thermal stabilization of antigens by adjuvants refers to the ability of certain adjuvants 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.

Some noteworthy, examples include Conventional aluminum salt-based adjuvants (Alum) are widely used and provide thermal stability to antigens by surface adsorption, Oil in water emulsions contribute to improving thermal stability as reported for MF59 adjuvant in influenza vaccine and ASO3 adjuvants have been shown to provide a stabilizing effect on antigens during temperature fluctuations, Liposomal adjuvants have been used to encapsulate the antigen and provide a 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.

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

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 superior adjuvants besides better antigen design to elicit a strong breadth of immune response.  Such immune response may be difficult to achieve with a single adjuvant and thus combination of adjuvants, known as adjuvant systems are being explored.

These adjuvant systems also 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 to elicit desired types of immune responses based on the pathogen and target population. For example, mucosal immune response, which will be critical for respiratory, sexually transmitted, and enteric diseases can be enhanced as the first line of defense while systemic response can be elicited for prolonged and persistent protection.

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 that 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 the Covovax vaccine.

From a regulatory perspective combination adjuvants undergo more stringent review as expected specifically in terms of both short-term and long-term safety profile. This is important as well as the clearance of these potent adjuvants from the host system is quite necessary because they target different immune pathways and one would not want any autoimmune response to be triggered in the host. Another important aspect is generating a consistent adjuvant combination and subsequent formulation with antigen, which would be required for expected biological response, thus demanding a strong quality control testing of both standalone combination adjuvants 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 medical care are expected to address the safety and durability of immune response across different population types.

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 from the body.

The availability of various classes of adjuvants targeting various immune pathways will lead to the development of tailored combination adjuvants as well as offer vaccine delivery through non-invasive routes 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.