Vaccines to combat skin diseases associated with the skin microbiome.

The power and potential of vaccines

Most individuals have personal experience of vaccination. It is very likely that you have been vaccinated against diseases such as Polio, Rubella or, more recently, Covid-19. The main purpose of these vaccines is to ward off a disease rather than to cure sickness. In doing so, vaccines help individuals fight diseases and, more importantly, through widespread immunization and surveillance, they enable populations to avoid epidemics and pandemics.

The impact of vaccines on human health is incalculable and dates as far back as 1838. By pioneering work on the first vaccine, which used cowpox to protect humans from smallpox, Edward Jenner (1749-1823) is said to have saved more lives than any other individual throughout history [1,2]. The resulting vaccines were the most powerful weapon used in the eradication of smallpox by 1980. The World Health Organisation (WHO) today lists over 35 deadly human diseases for which vaccines already exist or are expected soon [3]. Recently, the RTS,S vaccine against malaria was prequalified by WHO in July 2022 and is already saving lives.

A natural next step in vaccine development is to harness the immense power of vaccines to protect us from conditions that although less life threatening are proven to be life changing, including acne, atopic dermatitis and other hard-to-treat skin diseases. In principle, it should be possible for children to be safely vaccinated pre-puberty to protect them from severe acne in their teens and later in their lives. But where do we start with this vaccine development? What antigens are likely to be good targets? What other factors need to be considered? And what work has been done so far?

Progress to date

There are currently numerous vaccines in development for Staphylococcus aureus infections, including those that are methicillin-resistant (MRSA). Although not all these vaccines are intended primarily for skin diseases, once available they may give protection against atopic dermatitis, cellulitis and impetigo (a highly contagious skin infection involving both S. aureus and S. pyogenes). Furthermore, targeted research is underway to specifically explore the potential of vaccines and immunotherapies for acne and skin allergies, such as contact dermatitis. Companies such as GlaxoSmithKline, NovaDigm Therapeutics, and Integrated BioTherepeutics have already run clinical trials on vaccines designed to prime the immune system against S. aureus to help prevent severe atopic dermatitis [4].

Note: at the time of writing of this article, despite significant interest, multiple clinical trials, and Sanofi’s RIAce-001 mRNA vaccine likely to progress to Phase II trials, no vaccine for common skin diseases such as acne or atopic dermatitis had received full regulatory approval.

Finding the right antigens

Vaccines work by priming your immune system to enable infection to be thwarted by a quick immune response. To achieve this, a vaccine contains one or more antigenic substances that safely induce an immune response that is strong enough to protect you from the disease the next time you are exposed to that pathogen [5]. There are a number of ways to achieve this.

Active prophylactic vaccines contain or generate within the host (you) key antigenic substances associated with the disease. Simple pathogens such as cowpox (vaccinia virus) and smallpox (variola virus) have only ~200 genes and therefore relatively few key antigens. As a result, by utilising just a small number of antigens, the immune system can be primed to achieve long-term immunity with just a primary and booster dose of vaccine.

Unfortunately, it is not as straightforward to achieve long-term immunity against the larger and more complex bacterial genomes which are associated with skin diseases. S. aureus, for example, has ~1,441 core genes [6], and Cutibacterium acnes’ genome typically contains ~1,194 core genes [7]. The sheer number of different antigens produced by bacteria makes it harder to identify which antigens will generate the desired long-lasting immune response needed for an effective vaccine. In addition, thanks to their complex biochemistry, the bacteria can switch between many different virulence factors and antigens, enabling them to even evade primed immune systems.

Complementing microbiome effects

Readers of the Secret Life of Skin will be familiar with the dynamic interplay that is constantly taking place between the skin and its microbiota, and how these interactions help develop our innate and adaptive immunity, which then goes on to shape the microbiome. This ‘microbe-host, microbe-microbe warfare’ helps prevent dysbiosis, which if left unchecked can lead to skin diseases such as acne and psoriasis [8].

Cell-mediated adaptive immunity results from microbiota-generated antigenic substances engaging with immune T cells. These antigens are ‘remembered’ and when the ‘remembered’ antigen is next encountered, T helper cells quickly activate B cells and antigen-specific antibodies are produced. T cell recognition of antigens from the microbiome underpins tolerance and helps maintains the healthy steady state between skin and its microbiota [9].

Vaccines aimed at preventing skin diseases need to be sympathetic to the delicate balance between the skin and its microbiota and be complementary to existing adaptive immunity. They need to supplement and not disrupt the natural antigen-interplay. Otherwise, rather than protecting from skin diseases, antibodies that target antigens common to pathogenic and commensal microbes could, through causing dysbiosis, lead to skin problems.

Virulence factors as vaccine targets

One approach which is proving to have some merit in developing vaccines for opportunistic pathogens is to target virulence factors. Skin microbes only produce significant quantities of these virulence factors when they begin to change from their commensal state. Effective vaccines must inhibit factors expressed by all strains of the opportunistic pathogen. Otherwise, strains with additional virulence factors may be able to perpetuate the disease. Ideally the vaccine should also trigger sufficient antibodies to kill the pathogenic-form while leaving the commensal-form unaffected. An immune system primed by such a vaccine would respond the moment the opportunistic pathogen starts to change from friend to foe and thereby prevent the disease.

In 2018, Wang et al. investigated the virulence factor secreted by C. acnes, known as Christie-Atkins-Munch-Peterson factor 2 (CAMP), for their mouse antiacne vaccine. The studies showed that CAMP factor enlarges the area of haemolysis caused by S. aureus β-hemolysin and plays a key role in acne cytotoxicity. It has proinflammatory properties that can be inhibited by antibodies and is produced in greater quantities when C. acnes is grown in anaerobic conditions, as found in acne inflamed pilosebaceous units. Their ex-vivo acne model, derived from acne lesions taken from human sufferers, produced higher than normal levels of C. acnes CAMP factor. Finally, their studies in mice showed that the growth of C. acnes was reduced significantly in the vaccinated animals, and these mice expressed less mouse MIP-2, (a chemokine that attracts neutrophils) [10].

Mice are not the best animal models for human skin conditions and more research is therefore needed to fully understand the precise role of CAMP factor 2 in acne. However, these findings suggest that CAMP factor could be a suitable target for vaccines and other therapies aimed at modulating the immune responses in acne-prone skin.

Vaccines for atopic dermatitis

Like acne, atopic dermatitis is initiated and aggravated by microbes living on the skin and needs several different factors to come together at the same time.  Through a weakened stratum corneum, allergens and irritants can enter the skin more easily and trigger exaggerated local and systemic immune responses. Immune cells, particularly the T cell subset TH2 pathway, become activated and there is a general increase in inflammatory molecules, which results in redness, itching and inflammation, and cause the characteristic dry, scaly patches.

S. aureus surface proteins aggravate the condition by increasing the TH2 response, stimulating a greater expression of adhesion molecules (fibronectin and fibrinogen), and reducing the expression of antimicrobial peptides (human β-defensin 2 and cathelicidin) and barrier proteins (filaggrin and loricrin) [11].  As S. aureus plays a key role in atopic dermatitis (and reducing numbers can help alleviate symptoms), Clowry et al., reviewed six S. aureus vaccines, which were already in clinical trials for managing atopic dermatitis:

1. NovaDigm Therapeutics’ had a vaccine in clinical trials that used a recombinant Candida albicans Als3p adhesion protein, (which is homologous to S. aureus surface proteins).
2. GlaxoSmithKline’s vaccine was based on the two common type 5 capsular polysaccharides (CP5 and CP8), conjugated to carrier protein tetanus toxoid. This vaccine also contained two virulence factors: (1) mutated detoxified α-toxin (which is essential for infections where the epithelial barrier is disrupted); and (2) S. aureus surface protein clumping factor A (which under sheer stress is responsible for attachment) [12].
3. Integrated BioTherapeutics’ vaccine contained recombinant Staphylococcal enterotoxin B with alum adjuvant.
4. Chengdu Olymvax Biopharmaceuticals Inc.’s vaccine contains five conserved antigens, including the secreted factors α-hemolysin, staphylococcal enterotoxin B and the three surface proteins, staphylococcal protein A, iron surface determinant B N2 domain, and manganese transport protein C and aluminium phosphate adjuvants.
5. Pfizer had two multi-antigen vaccines on clinical trial. The first, S. aureus three-antigen (SA3Ag), which includes bacterial type 5 capsular polysaccharides (CP5 and CP8) and S. aureus surface protein clumping factor A.
6. And the second, S. aureus four-antigen (SA4Ag) vaccine, which comprises of the same antigens as in SA3Ag plus an extra recombinant manganese transporter protein C known as rP305A [4].

The S. aureus four-antigen (SA4Ag) and three-antigen (SA3Ag) vaccines were shown to have good immunogenicity and tolerance. Meta-analysis evaluating systemic and local adverse events concluded that SA4Ag and SA3Ag also have acceptable safety in adults [13, 14].

Safety of any vaccine is paramount and postoperative deaths following S. aureus infections during trials of recombinant subunit vaccine V710 have raised concerns about the safety of the staphylococcal vaccines in development [15]. A possibly safer approach to inducing immunity to skin diseases might be to engineer bacterial strains within the microbiome to express antigens to key disease-supporting virulence factors.

This type of approach is being trialled with some success to treat melanoma. S. epidermidis is present at significant levels in the skin microbiota and can induce a highly specific adaptive immune response. Chen et al. therefore engineered a strain of S. epidermidis to express melanoma tumour antigens. They showed that tumour-specific T cells were generated, and the growth of localised and metastatic melanoma were reduced [16].

Disappointingly, none of the published research on vaccines for skin ailments associated with the skin microbiome monitored changes in the skin microbiome during their trials.

A disruptive technology

During an interview for Kevin Kunzmann titled “How Likely Is A Vaccine for Acne?”, Christopher Bunick, MD, mentioned Sanofi’s RIAce-001 vaccine and predicted that a vaccine for acne could be available in 2027. He explained that acute acne ruins lives and can cause life-long disfiguring scars. As a dermatologist, he would like to be able to bring sufferers relief from acne so they can live their lives without worrying about their acne [17]. Another (unnamed) expert who works in cosmetics, highlighted that a vaccine capable of preventing skin blemishes could also have a profound impact on the skin care market. Both experts agreed that vaccines targeting common skin ailments would be disruptive technology for their professions.

To conclude

As we have discussed in this blog, vaccines already save lives and prevent epidemics and it is hoped that in just a few years’ time they could also prevent some skin diseases. Of particular interest to pharma is the use of vaccines to treat common skin conditions such as acne, atopic dermatitis, rosacea, and psoriasis.

For many people, the dynamic balance between the skin and it’s microbiota is able to protect against these skin diseases. However, for the less fortunate individuals who struggle with the conditions, the possibility of a vaccine that could help regain control of the opportunistic pathogens that bring on these skin diseases would be life changing.

If children could be vaccinated pre-puberty and then be protected from severe acne, that would be a significant medical milestone. Vaccines are also a particularly attractive solution as they reduce the need for antibiotics and have the potential to be effective even against antibiotic resistant microbes such as MRSA.

Safety of any vaccine is of paramount importance. Edward Jenner used live viruses in his smallpox vaccine, which made his patients mildly sick. This might have been acceptable at the time, but our understanding of vaccines has come a long way in the past 200 years. The antigenic substances involved in modern vaccines should not cause disease in healthy people.

Future vaccines for skin diseases must be safe and not disrupt the balance of the skin microbiome. It is likely that they will target several of the key virulence factors expressed only when opportunistic pathogens change from friend to foe, which therefore should not impact commensal forms of the pathogens and not make us sick.

These advances in vaccine technology have the potential to significantly disrupt the dermatology and the cosmetic industries by challenging the traditional approach to managing blemished and otherwise compromised skin. They have the potential to be life-changing for millions today and in the future.

References

1. Baron, J. The Life of Edward Jenner M.D. LL.D. F.R.S. Vol. 2. (1838) London: Henry Colburn, p. 100
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3. WHO 2023 https://www.who.int/teams/immunization-vaccines-and-biologicals/diseases.
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8. https://thesecretlifeofskin.com/2022/02/28/immunity-and-the-microbiome/#:~:text=Bacteria%20found%20on%20our%20skin,bacteria%20%5B7%2C8%5D.
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17. Kunzmann, K. How Likely Is A Vaccine for Acne? HCPlive, Oct 21, (2022)  https://www.hcplive.com/view/how-likely-vaccine-for-acne