Next-Generation Vaccine Adjuvants: Explore the advancements in adjuvant technology

Vaccines are one of the most powerful tools to prevent and control infectious diseases. They
work by stimulating the body’s immune system to recognize and fight off specific pathogens.
However, not all vaccines are equally effective or safe. Some vaccines may require multiple
doses, have limited protection against variants, or cause unwanted side effects. That’s where
adjuvants come in.

Adjuvants are substances that are added to vaccines to enhance the body’s immune response
to the vaccine. They can help increase the quantity, quality, and duration of immunity, as well
as reduce the amount of antigen or number of doses needed. Adjuvants can also modulate the
type of immune response, such as inducing cellular or humoral immunity or stimulating
mucosal or systemic immunity.

The development of safer, more effective adjuvants could significantly improve vaccine
performance and expand the range of diseases that can be prevented by vaccination. However,
finding the right adjuvant for a given vaccine is not easy. It requires a deep understanding of the
immunological mechanisms, the pathogen characteristics, and the safety profile of each
adjuvant.

The evolution of vaccine adjuvants

The history of vaccine adjuvants dates back to the early 20th century when aluminium salts
(alum) were first used to enhance the immune response to diphtheria and tetanus toxoids. Alum
remains the most widely used

adjuvant in human vaccines today, due to its low cost, ease of manufacture, and acceptable
safety record. Alum works by forming a depot at the injection site, which prolongs antigen
exposure and attracts immune cells.

Alum also activates innate immune receptors, such as Toll-like receptors (TLRs), which trigger
inflammatory signals and cytokine production.

 

However, alum has some limitations. It mainly induces a Th2-type humoral response,
which is effective against extracellular pathogens, but not against intracellular pathogens or cancer cells. Alum also has low potency and stability at high temperatures, which
poses challenges for vaccine storage and distribution in resource-limited settings.

In the second half of the 20th century, several oil-in-water emulsion adjuvants were developed,
such as MF59 (Novartis), AS03 (GSK), and AF03 (Sanofi Pasteur). These adjuvants consist of
oil droplets suspended in an

aqueous phase, which create a depot effect and stimulate local inflammation. They also enhance
antigen uptake and presentation by antigen-presenting cells (APCs), such as dendritic cells and
macrophages. Emulsion adjuvants can induce both Th1- and Th2-type responses, as well as
cytotoxic T-cell responses. They have been used in licensed vaccines against influenza (Fluad®,
Pandemrix®, Focetria®) and herpes zoster (Shingrix®).

However, emulsion adjuvants also have some drawbacks. They can cause local reactions, such
as pain, swelling, or redness at the injection site. They can also induce systemic reactions, such
as fever or headache. Moreover, they may not be suitable for all antigens or diseases, as they
may interfere with antigen stability or specificity.

The emergence of next-generation vaccine adjuvants

The 21st century has witnessed a surge of innovation in vaccine adjuvant technology, driven
by advances in immunology, biotechnology, and nanotechnology. The newer generation
adjuvants are essentially combination adjuvants that consist of a particulate/delivery vehicle
carrying antigen and/or immune potentiator.

Particulate/delivery vehicles are designed to protect antigens from degradation, facilitate
antigen delivery to APCs, and target specific tissues or organs. Examples of particulate/delivery
vehicles include liposomes, virosomes, virus-like particles (VLPs), nanoparticles,
microparticles, microspheres, nano gels, dendrimers, and polymeric matrices.

Immune potentiators are molecules that activate specific immune receptors or pathways to
enhance or modulate the immune response. Examples of immune potentiators include TLR
agonists (such as CpG oligodeoxynucleotides or monophosphoryl lipid A), NOD-like
receptor agonists (such as muramyl dipeptide), RIG-I-like receptor agonists (such as
poly(I:C)), STING agonists (such as cyclic dinucleotides), cytokines (such as interleukin-12
or interferon-gamma), chemokines (such as CCL19 or CCL21), and costimulatory molecules
(such as CD40L or OX40L).

The combination of particulate/delivery vehicles and immune potentiators can create
synergistic effects, such as enhancing antigen stability, uptake, and presentation; stimulating innate and adaptive immunity; inducing mucosal and systemic immunity; and generating
long-lasting memory and protection.

Some examples of next-generation vaccine adjuvants that are in clinical development or
have been approved include:

• AS04: a combination of alum and monophosphoryl lipid A (MPL), a TLR4 agonist
  derived from Salmonella Minnesota. AS04 is used in licensed vaccines against human
  papillomavirus (Cervarix®) and hepatitis B (Fendrix®). AS04 can induce strong
  Th1-type responses and cytotoxic T-cell responses, as well as cross-protection against
  HPV variants.
• AS01: a combination of MPL and QS-21, a saponin extracted from the bark of Quillaja
  saponaria. AS01 is used in licensed vaccines against malaria (Mosquirix®) and herpes
  zoster (Shingrix®). AS01 can induce potent Th1-type responses and cytotoxic T-cell
  responses, as well as long-term memory and protection.
• CpG 1018: a synthetic CpG oligodeoxynucleotide that acts as a TLR9 agonist. CpG
  1018 is used in an approved vaccine against hepatitis B (Heplisav-B®). CpG 1018
  can induce robust Th1-type responses and high antibody titers, as well as protection
  in older adults and immunocompromised individuals.
• Matrix-M™: a saponin-based adjuvant that contains purified fractions of Quillaja
  saponaria. Matrix- M™ is used in an approved vaccine against COVID-19
  (Novavax®). Matrix-M™ can induce balanced Th1- and Th2-type responses, as well
  as neutralise antibodies and cellular immunity, against SARS-CoV-2.

The future of vaccine adjuvants

The field of vaccine adjuvants is rapidly evolving, with new discoveries and challenges
emerging every day. Some of the current trends and directions include:

• Developing adjuvants for novel vaccine platforms, such as mRNA, DNA, or viral vector
  vaccines. These platforms may require different types of adjuvants to optimize their
  immunogenicity, stability, and safety. For example, mRNA vaccines may benefit from
  adjuvants that can enhance mRNA delivery, protect mRNA from degradation, or
  modulate mRNA translation.
• Developing adjuvants for mucosal vaccines, such as nasal, oral, or rectal vaccines.
  These vaccines may offer advantages over injectable vaccines, such as ease of
  administration, better compliance, and induction of mucosal immunity. However,
  mucosal vaccines may face challenges such as low antigen uptake, high antigen
  degradation, or low immune response. Therefore, mucosal adjuvants may need to overcome these barriers by enhancing antigen absorption, stability, or stimulation.
• Developing adjuvants for universal vaccines, such as universal influenza or HIV
  vaccines. These vaccines aim to provide broad and durable protection against diverse
  and evolving pathogens. However, achieving this goal may require adjuvants that can
  elicit cross-reactive and cross-protective immune responses, such as broadly
  neutralizing antibodies or T-cell responses.
• Developing adjuvants for therapeutic vaccines, such as cancer or autoimmune disease
  vaccines. These vaccines aim to treat existing diseases by modulating the immune
  system to target specific antigens or cells. However, achieving this goal may require
  adjuvants that can overcome immune tolerance or suppression, enhance immune
  effector functions, or induce immune regulation.

 

Conclusion

Vaccine adjuvants are essential components of modern vaccinology. They can improve the
efficacy and safety of existing vaccines, as well as enable the development of new vaccines for
emerging or challenging diseases. The next-generation vaccine adjuvants are based on novel
combinations of particulate/delivery vehicles and immune potentiators that can tailor the
immune response to specific needs. The future of vaccine adjuvants is promising, with new
opportunities and challenges arising from novel vaccine platforms, mucosal vaccines, universal
vaccines, and therapeutic vaccines.

 

References

https://www.frontiersin.org/articles/10.3389/fimmu.2023.1043109/full

 

https://www.nature.com/articles/d43747-023-00035-x

 

https://www.pharmafocusasia.com/articles/vaccine-adjuvants