Guide to Vaccine Adjuvants

Guide To Vaccine Adjuvants

You may have heard about vaccine adjuvants and the potential problems they may or may not pose.

The subject is quite technical and, as a result, it’s not hard to get lost in the weeds.

In this article, we provide a user-friendly guide to vaccine adjuvants to make sense of the subject – and provide definitive answers to the questions swirling around the topic of vaccine adjuvants.

What are The Vaccine Adjuvants?

Vaccine Bottle And Injection

The worldwide adoption of vaccine programs has proven to be one of the most profound advances in healthcare that the world has ever seen.

Early vaccines that are made of inactivated pathogens are effective. However, cultivating large cultures of a virus can be impractical, unsafe and, sometimes, unethical.

As a result, subunits, made up of microbial proteins or carbohydrates, are used as vaccine antigens.

However, subunit antigens are not that effective at stimulating the body’s innate immunity. 

Vaccine adjuvants are molecules, compounds or supramolecular complexes that are included in a vaccine in order to boost the potency of vaccine antigens.

In scientific terms, these adjuvants boost the immunogenicity of the vaccine. That simply means that they are able to increase the body’s immune response. 

Vaccine antigens are also able to:

  • Modulate the type of immune response
  • Reduce the number of antigens in the vaccine
  • Reduce the number of immunizations required
  • Improve the efficacy of a vaccine in vulnerable populations, such as the elderly or newborn babies

Adjuvants: A Brief History

The first adjuvant was used in 1926. This was alum which was used in a diphtheria vaccine. Alum proved safe and was seen to significantly increase the effectiveness of vaccines.

However, there was little work done on understanding the mechanism of action of alum adjuvants or in developing next-generation adjuvants until the beginning of the 21st century.

During the first decade of the 21st century, researchers developed the Cervarix vaccine human papillomavirus (HPV) which includes a combination adjuvant comprised of alum and the TLR4 agonist monophosphoryl lipid.

It was approved by the FDA in 2009. This marked a turning point in the development of vaccine adjuvants.  

AS04 is the first FDA-licensed adjuvant to include a known PAMP (potent pathogen-associated molecular pattern).

The FDA granted the license when it was proven that AS04 brought bout a more effective innate immune response than alum alone.

Adjuvant Development

Adjuvant Development

The first adjuvants were developed to boost the natural immunity in cases where antigens delivered a weak immunogenic response.

Of the first generation adjuvants, only aluminum salts—including aluminum oxyhydroxide and aluminum phosphate (collectively, alum)—and squalene based oil-in-water (o/w) emulsions (eg, AS03 or MF59)  have been included as part of FDA-licensed vaccines. 

The number of adjuvants with acceptable efficacy and safety profiles is very small and is produced by a limited number of companies.

Because of the limitations imposed by the FDA on access to different types of adjuvants and a general lack of knowledge regarding the formulation and use of adjuvants, the development of new vaccines is impaired. 

A key part of the body’s affective response to a virus is the kicking in of the body’s innate immune system.

This requires the activating of innate pattern recognition receptors (PRR) such as the toll-like receptors (TLRs) or the RIG-I-like receptors (RLRs) that recognize pathogen-associated molecular patterns (PAMPs), leading to the production of cytokines and chemokines.

In turn, these activate antigen-presenting cells (APC), in particular, dendritic cells (DCS), that initiate a cascade of signals to cells of the adaptive immune response, preparing them for the development of specific immunity.

As a result, the stimulating of the body’s innate immunity is a key strategy to improve the effectiveness of a vaccine.

New adjuvants are being developed all the time. However, many of them fail due to one or more of the following factors:

  • Lack of manufacturability
  • Lack of stability
  • Lack of efficacy
  • Unacceptable levels of tolerability
  • Safety concerns

What Adjuvants are Currently Being Used in Vaccines?

Taking Vaccine From Bottle With Injection

Alum is used as an adjuvant in the following vaccines:

  • Diphtheria–Spertus-tetanus tetanus (DPT)
  • Diphtheria–tetanus (DT)
  • DT combined with hepatitis B virus (HBV)
  • Haemophilus influenza B or inactivated poliovirus (IPV)
  • hepatitis A (HAV)
  • Streptococcus pneumonia
  • Meningococcal
  • HPV

Monophosphoryl lipid A (MPL) + aluminum salt (AS04) is used in the following vaccine:

  • Cervarix

Oil in water emulsion composed of squalene (MF59) is used in the following vaccine:

  • Fluad

Monophosphoryl lipid A (MPL) and QS-21 are used in the following vaccine:

  • Shingrix

Cytosine phosphoguanine (CpG), a synthetic form of DNA that mimics bacterial and viral genetic material (CpG 1018) is used in the following vaccine:

  • Heplisav-B

There is no adjuvant in the following vaccines:

  • ActHIB, chickenpox
  • live zoster (Zostavax)
  • measles, mumps & rubella (MMR)
  • meningococcal (Menactra, Menveo)
  • Rotavirus
  • seasonal influenza (except Fluad)
  • single antigen polio (IPOL)
  • yellow fever

The Adjuvants Up Close

Alum

Illustration Of Alum Adjuvant

Alum has been used as an adjunct to vaccines since the mid-1920s. Tiny levels of aluminum are added to the vaccine in order to boosts the body’s own innate immune system.

Aluminum is commonly found all around us, including in the atmosphere.

Extensive research has shown that the amounts of alum contained in vaccines are extremely low and, furthermore, it is not easily absorbed by the human body.

AS04

The monophosphoryl lipid A (MPL) has been sued in the Cervarix vaccine since 2009. It is not currently valuable in the United States, however, due to low demand.

MF59

Fluad is an influenza vaccine that specifically targets people aged 65+. This vaccine contains MF59, which is n oil-water emulsion that consists of squalene.

This is a naturally occurring oil that comes from plant and animal cells. 

MF59 has been used in flu vaccines throughout Europe since 1997. It has been available in the United States since 2016. There have been no safety issues with regard to MF59.

AS01B

The Shingrix vaccine contains an adjuvant called AS01B. The vaccine is designed for people aged 50+.

AS01B is made up of monophosphoryl lipid A (MPL), which is a compound that is isolated from the surface of the bacteria to boost innate immunity, along with QS-21, which is a natural compound that is extracted from the Chilean soapbark tree (Quillaja Saponaria Molina). 

There are currently trials taking place for potential vaccines for malaria and HIV  that include AS01B. 

CpG 1018

Heplisav B Vaccine

The Heplisav-B vaccine contains an adjuvant called CpG 1018. It contains cytosine phosphoguanine (CpG) motifs, which is a synthetic form of DNA that mimics bacterial and viral genetic material.

CpG 1018 has been shown to boost the body’s innate immune response. 

Next-Generation Vaccine Adjuvants

The development of vaccine adjuvants is based upon enhancing the immune response without compromising safety.

This is done with the addition of well-defined molecules. The development of adjuvants has been largely focused on boosting the humoral immune system.

Alum and emulsion adjuvants achieve this result by driving the production of endogenous danger-associated molecular pattern (DAMP) molecules that activate inflammasome cascades to produce IL-1β, or Interleukin 1β, which is is a potent pro-inflammatory cytokine that is crucial for host-defense responses to infection and injury.

The next generation of adjuvants is to be included in vaccines against such challenging viruses as TB, HIV, and Malaria will very probably require the addition of cellular immunity boosters to boost the humoral immune response.

In fact, the development of cellular immunity boosters represents one of the greatest needs in the advancement of vaccine adjuvants. 

A promising strategy to meet the need for cellular immunity boosters is the inclusion of PAMPs in vaccine adjuvants.

A number of PAMPs have been tested as vaccine candidates, with the TLR ligand class of molecules being the most clinically advanced, including the TLR4  ligand MPL incorporated into several vaccines.

The bringing to market of AS04 in 2009 showed that PAMPs, including TLR4 agonists, can also boost the efficacy of the humoral immune response over first-generation adjuvants like alum. 

Adjuvants for HIV and TB

HIV Vaccination

At the time of this writing, the only vaccine for Tuberculosis is the BCG vaccine. BCG does a great job of limiting the severity of TB in childhood.

However, it does not prevent infection of adult cases of pulmonary TB. As a result, there is an urgent need to develop a new, better vaccine against TB.

There is also a race to develop an effective vaccine against malaria.

These two dire needs have driven the research and development of vaccine adjuvants over the past decade. 

When it comes to TB, the focus has been to drive Th1 CD4+ T-cell responses. This has been shown to be the best protection against tuberculosis.

To achieve this response, the body needs to produce cytokines such as gamma interferon (IFN-γ), which is responsible for macrophage activation; tumor necrosis factor (TNF), which is important for granuloma development and maintenance; and interleukin 2 (IL-2),  which is responsible for the clonal expansion of T lymphocytes.

Researchers are studying a number of adjuvant candidates to bring about the above results.

These include AS01 and AS02, MPL formulated in liposomes or an o/w emulsion developed by Glaxo Smith Kline; GLA-SE,  a synthetic TLR4 agonist in an o/w emulsion developed by the  Infectious Disease Research Institute; CAF01, consisting of trehalose dibehenate (a ligand for the C-type lectin receptor Mincle) formulated in liposomes and developed by Statens Serum Institut; and IC3, a cationic peptide and TLR9 agonist  oligodeoxynucleotide. 

In each of the above cases, immunostimulatory PRR agonist and formulation have been maximized in order to drive the TH1 response to specific antigens. 

The development of vaccine adjuvants to combat HIV has fallen behind those for TB.

The vaccines that are being researched either not have adjuvant additives or make use of alum or emulsions.

HIV vaccine researchers have identified that antibody durability is a vital aspect.

Adjuvants that promote cellular immunity, especially T follicular helper cells needed to sustain germinal centers, may be critical to the development of an effective HIV vaccine.

The Science Behind Vaccine Adjuvants

Scientist Looking At Petri Dish

It was originally thought that alum was able to increase the body’s innate immune response by slowing down the release of the antigen from the immunization site.

This theory has been recently disproven, with it being shown that the immune-boosting response of alum is due to the production of IL-1β downstream of the release of DAMPs such as uric acid and host DNA which are released by damaged cells and recognized by specific receptors.

The effectiveness of a vaccine adjuvant can be enhanced by appropriate particulate delivery systems to increase cell uptake and provide sustained release of antigen and the active pharmaceutical ingredients in the vaccine.

The adjuvant formulation is, therefore, very important to the innate immune-boosting ability of the adjuvant. 

Are Vaccine Adjuvants Safe?

The greatest concern regarding vaccine adjuvant safety centers around the use of aluminum.

Children around the world receive relatively high levels of aluminum from multiple injections over a number of vaccinations.

Aluminum is neurotoxic, meaning that it has the potential to kill neurons that are needed for proper brain functioning. Once it is injected into the body it is able to travel to other parts of the body.

There have been a number of studies that provide us with evidence that aluminum adjuvants in vaccines significantly increase the risk of autoimmune disease and neurological disorders, including macrophagic myofasciitis, chronic fatigue, muscle weakness,  cognitive deficits such as memory loss, sleep disturbances, and multiple sclerosis-like demyelinating central nervous system disorders. 

Here are overviews of several studies into the effects of alum vaccine adjuncts on the human body:

Study One 

Illustration Of Central Nervous System

Aluminum in the central nervous system (CNS): toxicity in humans and animals, vaccine adjuvants, and autoimmunity. Immunol Res 2013 Jul; 56(2-3): 304-16.

This paper examined the evidence on aluminum neurotoxicity, particularly when added to vaccines as an adjuvant and injected into humans to stimulate an immune response.

It concluded that there is a significant correlation between the number of aluminum-containing vaccines that children receive and the rate of autism spectrum disorders.

It also pointed out that Injected aluminum is worse than ingested aluminum (from dietary sources) because it bypasses the protective barriers of the gastrointestinal tract, requiring a lower dose to induce a toxic reaction.

Study Two

Aluminum vaccine adjuvants: are they safe? Curr Med Chem 2011; 18(17): 2630-37.

This paper summarizes what is currently known about aluminum toxicity. Here are the key points . . .

Aluminum is a neurotoxin and may be a co-factor in several neurodegenerative disorders and diseases, including Alzheimer’s, Parkinson’s, amyotrophic lateral sclerosis (ALS), multiple sclerosis, autism, and epilepsy.

No studies have been conducted to confirm the safety of combining aluminum with other toxic substances in vaccines, such as mercury, formaldehyde, phenoxyethanol, polysorbate 80, and glutaraldehyde.  

The FDA allows scientists conducting clinical trials to compare the safety of an aluminum-containing vaccine to an aluminum-containing “placebo.” This underestimates the true rate of adverse vaccine reactions.

Study Three

Holding For Hand

Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA syndrome) in commercial sheep. Immunol Res 2013 Jul; 56(2-3): 317-24.

This paper identifies a new form of autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome) in sheep, linked to vaccinations containing aluminum adjuvants. 

The condition appears in some sheep 2-6 days after they are vaccinated. Symptoms of the acute phase include poor response to external stimuli and acute meningoencephalitis.

The chronic phase causes muscular atrophy, neurodegeneration of the gray matter of the spinal cord, and death.

Study Four

Peptide cross-reactivity: the original sin of vaccines.  Front Biosci (Schol Ed) 2012 Jun 1; 4: 1393-1401.

This paper describes several problems with current vaccine technology, such as the ability of microbes to evade the immune system, and the use of adjuvants which can cause autoimmunity.

It notes that Adjuvants can induce hyperactivation of the immune system, initiating autoimmune processes.

Autoimmune attacks against myelin may cause demyelinating diseases, while attacks against proteins and antigens affecting cognition and behavior may cause autism and behavior disorders.

Conclusion

Vaccine adjuvants have proven to be a useful tool to boost the efficacy of vaccines.

They allow for a boosting of the body’s innate immune system to fight off a virus, while also modulating the type of immune response, reducing the amount of antigens in the vaccine, limiting the number of immunizations required and improving the efficacy of a vaccine in vulnerable populations, such as the elderly or newborn babies.

On the other hand, some serious potential risks have been identified, especially with regard to alum based vaccine adjuncts.

We’ve laid out the facts so that you can make your own informed choice and make the decisions that are best for the long-term safety of yourself and your loved ones.

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