We are not unfamiliar with vaccines, but few people know about vaccine adjuvants. The so-called adjuvant refers to the substance added to the vaccine that can enhance the immunogenicity of the vaccine antigen. Adjuvants are nonspecific immune enhancers that, when injected with or preinjected into the body, enhance the body’s immune response to an antigen or alter the type of immune response.
From the name, it seems that adjuvants are just ingredients for vaccine production, but in fact, adjuvants play a pivotal role in vaccines, especially for recombinant protein vaccines. There are many kinds of adjuvants; for example, aluminum hydroxide adjuvant, Corynebacterium pumilus, lipopolysaccharide, cytokines, alum, etc. Freund’s complete adjuvant and Freund’s incomplete adjuvant are the most commonly used adjuvants in animal experiments.
Recombinant protein vaccines only include the part of the pathogen that immune recognition leads to protection, which improves the purity of the vaccine and reduces side effects, but at the same time reduces the immunogenicity of the vaccine. Only adding adjuvants can solve this problem.
Adjuvants are so important, but adjuvants are very rare. Except for the aluminum adjuvant discovered in 1926, there are only five new adjuvants approved by the FDA.
1. Vital Adjuvants
If a vaccine is compared to a bullet, then the antigen is the warhead of the bullet, and the adjuvant is the gunpowder in the bullet, which is responsible for boosting the bullet and penetrating the barrier of natural immunity.
From a functional point of view, the currently approved adjuvants can be roughly divided into two types: one is an adjuvant that stimulates an immune response, and enhances the immunogenicity of an antigen by connecting to receptors on innate immune cells, such as CpG1018;
The other is adjuvant with vaccine delivery, which presents the necessary amount of vaccine antigen and immunostimulatory agent to the immune system to induce immunity, such as aluminum adjuvant, emulsion.
The mechanism of adjuvant enhancing immune response is to change the physical shape of the antigen, prolong the retention time of the antigen in the body; stimulate the ability of mononuclear phagocytes to present the antigen; stimulate the differentiation of lymphocytes and increase the ability to expand the immune response.
There are also adjuvants that combine the first two effects, such as GlaxoSmithKline’s AS01 and AS02.
Since the adjuvant can enhance the surface area of the antigen and prolong the retention time of the antigen in the body, so that the antigen can have sufficient contact time with the lymphatic system cells, so it has a variety of effects:
– Converting non-antigenic substances into effective antigens;
– Enhance circulating antibody levels or generate more effective protective immunity;
– changing the type of circulating antibodies produced;
– the ability to enhance cell-mediated hypersensitivity;
– Development of experimental autoimmune or other types of allergic diseases;
– Protection of antigens (especially DNA, RNA) from breakdown by enzymes in the body.
For vaccines, adjuvants have become the key to success. In fact, it is not uncommon to rely on adjuvants to come to the forefront.
Take GlaxoSmithKline as an example, although the 2-valent HPV vaccine was crushed by Merck’s 4 and 9-valent HPV vaccines, it added a new self-developed adjuvant to the recombinant shingles vaccine Shingrix, and finally Rolled over Merck’s shingles vaccine and successfully pulled back a round.
Merck’s Zostavax, an attenuated shingles virus vaccine, was the king of the shingles vaccine world before Shingrix.
However, the advent of Shingrix changed that. Shingrix is a recombinant protein vaccine combining the herpes zoster virus gE protein and self-developed AS01B adjuvant.
The addition of AS01B adjuvant significantly enhanced the immune response of the vaccine. Shingrix has compared traditional aluminum adjuvants in preclinical mouse experiments. AS01B adjuvant elicited a level of immune response several times higher than that of traditional aluminum adjuvant:
Although Shingrix and Zostavax did not conduct head-to-head clinical trials, according to data published by GlaxoSmithKline, in pivotal Phase III clinical trials, Shingrix reduced the risk of contracting herpes zoster in people aged 50 and over compared with placebo 97.2%.
The efficacy data of Merck Zostavax in the elderly group of 50-59 years old is only 69.8%, and the efficacy in the elderly group over 60 years old is even lower.
In view of such excellent data, the US Centers for Disease Control and Prevention directly recommends that Shingrix replace Zostavax for immunization of people aged 50 and over.
In 2020, Shingrix’s global sales reached 1.989 billion pounds. Relying on its own developed adjuvant, GlaxoSmithKline successfully replaced Merck’s dominance in the shingles vaccine.
2. Extremely scarce species
Despite the importance of adjuvants, only a handful of products have been approved globally.
Generally, adjuvants are not approved as a single drug, but are approved in their entirety as part of a vaccine. From the discovery of the first aluminum adjuvant in 1926 to the present, in the past 100 years, the FDA has only approved 5 new adjuvants, MF-59, AS01, AS03, AS04, and CpG1018.
The outbreak of the new crown pneumonia epidemic has made the research and development of new crown vaccines a hot spot. In terms of new crown recombinant protein vaccines, there are still only a few players who have the ability to independently develop adjuvant products.
Why is such an important adjuvant so few approved products? It can only be said that the development of adjuvants is too difficult.
First, there is the issue of security.
Adjuvant is a substance that is injected into the human body with the vaccine, and safety is naturally the primary requirement. But the difficulty is also difficult. A safe and effective substance is difficult to find.
In the past, the design of different adjuvant formulations mainly relied on personal research and development experience, which invisibly increased the difficulty.
At this stage, the new generation of adjuvants basically stands on the shoulders of the first generation of adjuvants and improves them. Even so, development is still very difficult.
Second, the mechanism of action of adjuvants is very complex.
For a long time, adjuvant research has been called the “dirty little secrets” of the vaccine industry, mainly because the mechanism of action of adjuvants is poorly understood.
Up to now, the mechanism of action of many adjuvants has not been clearly studied by researchers. For example, the mechanism of QS-21 and immunostimulatory complexes remains poorly understood.
This also leads to the fact that the development of adjuvants can only follow “empirical science”, commonly known as “three points of strength, seven points of luck”. Until recent years, the development of modern immunology, especially the accumulation of knowledge on innate immunity, has accelerated the development of vaccine adjuvants to a certain extent.
Finally, there is the challenge of process scale-up.
These adjuvant formulations often have naturally derived ingredients that are difficult to characterize and standardize, such as squalene oil (from shark liver) in oil-in-water emulsions. This leads to two problems, one is that it is difficult to stabilize and scale up the process, and the other is that the raw materials are hard to come by.
But don’t underestimate this issue. Having technology is the first step, but also having the ability to bring technology from the laboratory to the industry. Due to the scale-up of the adjuvant process and the supply of raw materials, Novavax has repeatedly delayed the date of its new crown vaccine application.
It is these problems one after another that limit the progress of research and development of new adjuvants, making them a scarce species in the vaccine industry.