The new vaccine called 4X-SA-GP protects against S. aureus infection

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Immunization of mice with a new vaccine consisting of fungal particles loaded with Staphylococcus aureus (S. aureus) proteins protects mice against S. aureus infection, according to a study published August 20 2020 in the open-access journal PLOS Pathogens by David Underhill of Cedars-Sinai Medical Center, and colleagues.

S. aureus is one of the most common bacterial infections worldwide, and antibiotic-resistant strains such as methicillin-resistant S. aureus (MRSA) are a major threat and burden to public health. MRSA not only infects immunocompromised patients but also healthy individuals, and has rapidly spread from the healthcare setting to the outside community.

Vaccines aimed at targeting S. aureus have failed in clinical trials, and the reason for this lack of success remains unclear. As this pathogen continues to rapidly spread on a global scale, it is vital that new approaches to S. aureus vaccination are developed.

Immunocompromised individuals such as patients with HIV are highly susceptible to S. aureus infections, and they are also at increased risk of developing fungal infections.

Based on this evidence, Underhill and colleagues tested whether stimulation of antifungal immunity would promote the type of immune responses needed for effective host defense against S. aureus.

The researchers developed a new vaccine called 4X-SA-GP, which consists of fungal β-glucan particles loaded with four S. aureus proteins. Mice were vaccinated once a week for three weeks with 4X-SA-GP, and then injected with S. aureus either four or eight weeks later.

Vaccination induced protective T cell and antibody responses, and the T cell responses in particular were essential for vaccine-induced protection from S. aureus infection. Moreover, the mice had detectable antibody levels and reduced S. aureus levels in the spleen and kidneys eight weeks after immunization.

According to the authors, this work potentially broadens the use of the β-glucan particle vaccine system for a much-needed vaccine targeting S. aureus.

The authors conclude, “We need some creative new approaches to explore towards developing a S. aureus vaccine, and we are excited to share our recent experiences with antigen-loaded fungal particles”.


Natural products useful in disease prevention and treatment have been highly sought after throughout human history. A major problem in the characterization of many natural products is that they represent a complex mixture of ingredients, any one of which may contribute to their bioactivity.

β‐Glucans from fungi, yeast and seaweed are well‐known biologic response modifiers that function as immunostimulants against infectious diseases and cancer.1,2

Unlike most other natural products, purified β‐glu- cans retain their bioactivity, which permits the characterization of how β‐glucans work on cellular and molecular levels. Several decades of intensive research on the biological effects of β‐glucan show they exert strong immunomodulatory properties and are among other substances acting through an organism’s own biological response mechanisms as biological response modifiers.3,4 β‐1,3‐glucans are structurally complex homopolymers of glucose, usually isolated from yeast and fungal cell walls.

Yeast are characterized by a high glucan content (more than 85% β‐1,3‐D‐glucan polymers) with a small admixture of chitin (about 2%) and lipids (<1%).5 The isolation from var- ious types of mushrooms was a logical follow‐up of the folk remedy use of mushrooms in numerous nations.

The number of different glucan structures is almost as great as the number of sources used for their isolation. Different physicochemical parameters, such as solubility, primary structure, molecular weight, branching and polymer charge, influence the biolog- ical activities of β‐glucans. It is therefore imperative to use only highly purified and sufficiently characterized glucans.

GLUCAN AND ITS EFFECTS ON IMMUNITY

Research with β‐glucans has shown that they function through stimulation of granulocytes, monocytes, macrophages and natural killer cells.

Two membrane β‐glucan receptors that trigger responses to β‐glucans have been characterized on a molecular level.

The first to be reported was the iC3b recep- tor known as complement receptor 3 (CR3), and the second was the dectin‐1 receptor.6-8

Despite years of research, it is not clear whether there are two separate receptors for glucan or a single receptor of both CR3 (CD11b/CD18) and dectin‐1 proteins.9 As biological effects of glucans appear to be multifactorial, it is not surprising that glucans also influence the production and secretion of cytokines.

Soluble β‐1,3‐D glucans have been shown to protect against infection with both bacteria and protozoa in several experimental models and to enhance antibiotic efficacy in infections with antibiotic‐resistant bacteria.

The protective effect of glucans has been seen in experimental infection with Leishmania major, L donovani, Candida albicans, Toxoplasma gondii, Streptococcus suis, Plasmodium berghei, Staphylococcus aureus, Escherichia coli, Mesocestoides corti and Trypanosoma cruzi.10-19

It is particularly interesting that glucan has been found to protect against anthrax infection.20 Moreover, glucan‐me- diated protection against lethal infections can be passively transferred.21

In addition to the protection against infection, glucan is a well‐known biological response modifier that has been used as an immunoadjuvant therapy for cancer since 1980, mostly in Japan.7,22-24 Another glucan activity, demonstrated during 1980s, was stimulation of haemo-poiesis in an analogous manner as granulocyte‐monocyte colony‐stimulating factor.25

Both particulate and soluble glucans, when administered intravenously, caused signifi- cantly enhanced recovery of blood cell counts after gamma irradiation.26 Other researchers showed that glucan could reverse the myelosuppression caused by chemotherapeutic treatment.27

Glucan was originally administered solely by injection. Subsequently, the oral immune modulatory activities of glucans have been reported.

However, more research has been devoted to demonstrate that orally given glucan is as active as injected glucan but only a limited number of publications have focused on its mechanism of action.

The available data do suggest that glucan, when given orally, might have similar effects as glucan administered by either intraperitoneal or intravenous route.20,28-31

There is no information about the influence of glucan administered in long‐lasting preven- tive oral delivery on humoral and cell immunity parameters. Generally, preventive oral programmes with immunomodulators are intended for an optimization of anti‐infectious immunity within endangered populations (allergic children, population affected by environmental stress, seniors and pa- tients in post‐operational recovery (well‐being), workers in polluted environments, etc, or as a widely applied prevention before the onset of highly transmissible airway infectious disease incidents.

Further research in preventive oral supplementation is done in agreement with the “WHO Declaration” and the new global health policy “Health for All in the 21st Century”.

Orally administered β‐glucans increased the numbers of intestinal intraepithelial lymphocytes and potentiated the production of cytokines, namely interferon‐γ (IFN‐γ).32 It was found that soluble glucan upregulated leucocyte activity and cytokine secretion.

These properties, together with prolongation of survival in some infections, have led us to question the efficacy of β‐glucans in oral infections caused by intracellular bacterial pathogens, namely Salmonella enterica and Francisella tularensis.

Oral route of infection is most common for these two bacterial species. The protection mediated by locally produced IFN‐γ is the main mech- anism of early natural immunity after infection with these microbes.

An additional advantage of using glucan is its marked ab- sence of toxicity or negative side effects and the GRAS (gen- erally recognized as safe) approval by the FDA.

VACCINES

Vaccination is the most effective intervention in modern medicine and still plays a fundamental role in the prevention, and sometimes eradication, of infectious diseases.

Vaccine development includes not only the development of new vaccines against diseases such as AIDS, tuberculosis and malaria, but also the development of one‐time and needle‐free vaccines.

In addition, therapeutic cancer vaccines using the specificity of the immune system are novel, highly promising strategies for improving cancer therapy. It is not surprising that WHO encourages the speedy development of oral vaccine formulations to simplify their transport, storage and administration.

At present, there are more than 70 licensed vaccines for preventive or therapeutic disposition of almost 30 species of pathogenic viruses, bacteria and fungi. The first vaccines were based on the neutralization or attenuation of pathoge- nicity or toxicity of disease‐causing agents. E

xpanding scientific knowledge, especially in infectious immunology, and new biotechnologies have enabled the development of newer and safer vaccine subunits composed of proteins, peptides
or nucleic acids.33

On the other hand, their reduced immunogenicity has demanded the use of potent substances that strengthen the immune response, principally working as adjuvants. Antigen encapsulation in polymer‐based particles is a primordial tool for superior vaccine delivery to mucosal sites.

Mucosal epithelia represent the main gateway for penetration of pathogenic vectors inside the organism. From this point of view, oral vaccination may be the most important for protection against enteric pathogens and partially against respiratory pathogens.

Orally administered vaccines containing whole attenuated pathogenic micro‐organisms in some circumstances may be less effective (eg, in some immunocom- promised patients) and may provoke outbreaks of infectious diseases similar to the 2000 outbreak of polio in several countries.34

A new and more effective vaccination strategy consists of microparticulate antigen carriers which can be used for delivery and adjuvant integration, increasing the immune response.35

GLUCAN MICROPARTICLES AS A DELIVERY PLATFORM FOR ORAL VACCINATION

Among the numerous categories of particulate antigen de- livery systems, such as immune‐stimulating complexes, liposomes, micro‐ and nanoparticles, or virus‐like particles, the Saccharomyces cerevisiae‐derived β‐glucan microparticles could be regarded as the most promising for an oral delivery platform.85-88

Particulate nanocarriers may exert a high adjuvant potential and could increase the immune response to vaccination due to their size and structural similarity to natural patho- gens.

These preparations are particularly advantageous for nasal delivery of vaccines, which rapidly became favoured vaccines because of the efficient M cell uptake in the nasal‐associated lymphoid tissue.

Various compositions of glucan‐based materi- als for nasal deliveries are described by Cevher et al.89

The use of natural polymers in the preparation of anti- gen delivery systems is one of the contemporary tendencies on the development of innovative and more effective vac- cines.73

From a series of biopolymers, the β‐glucans seem to be the most promising. β‐glucans in the form of microparticles could serve not only as immunostimulants but also as receptor‐targeted antigen carriers advantageously applied to mucosal vaccination.90

Addition of antibodies to G protein‐ conjugated glucan particles further improved the specific targeting to enterocytes and dendritic cells.91

Oral vaccination by gavage is one of the most effective methods for administration of antigen compared with other routes of immunization (intravenous, subcutaneous, intra- muscular) because both systemic and local mucosal immu- nity responses are induced.

Other effective ways of antigen delivery from the point of view of systemic immune response induction occur only when antigens arrive at blood vessels after passing through the liver.

Administration of vaccines through the oral route requires protecting the antigen from degradation prior to absorption in the gastrointestinal tract, where it directly elicits immune response within the gut‐associated lymphoid tissue, which is the largest immune organ of the body.92,93

During formulation of effective mucosal vaccines, limitations, such as the lowered immunogenicity of antigens used for vaccination, may be encountered.94 A

glucan‐based encapsulation system has shown to be an optimal solution. This system protects antigens before their degradation, enhances their immunogenicity and increases their accumulation in the vicinity of mucosal tissue for better absorption.35,95

Moreover, encapsulated antigen is selectively captured in the gut‐associated lymphoid tissue.96,97

reference link : DOI: 10.1111/sji.12833


More information: Paterson MJ, Caldera J, Nguyen C, Sharma P, Castro AM, Kolar SL, et al. (2020) Harnessing antifungal immunity in pursuit of a Staphylococcus aureus vaccine strategy. PLoS Pathog 16(8): e1008733. doi.org/10.1371/journal.ppat.1008733

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