The newly filed patent applications for vaccines against staphylococcus aureus

ABSTRACT

Staphylococcus aureus (S. aureus) frequently causes life threatening disease. To release the threat, vaccine has been proposed as a preventive intervention against the cause. However, the development of the vaccines is still in early stages. Thus, highlighting the related newly filed patent applications would stimulate further developments.

KEYWORDS:

• patent application
• staphylococcus aureus
• vaccine

For the first time, the World Health Organization has released a list of drug-resistant bacteria, including Staphylococcus aureus (S. aureus), that pose the greatest threat to human health.¹ Indeed, S. aureus frequently causes life threatening diseases.² Moreover, S. aureus is also associated with postoperative surgical-site and prosthetic joint infections.³ To solve the unmet medical need, vaccine has been proposed as a preventive intervention against the diseases and infections caused by S. aureus. However, most developments of the vaccines are still in early stages.^2,3 Furthermore, a phase III efficacy trial did not show significant decrease of S. aureus bacteremia after one year follow up; while another phase III trial was terminated due to safety and efficacy reasons.²

Since S. aureus vaccines are still under investigations, the newly filed patent applications would reveal the trend of the development. Thus, we search the US patent application database and then highlight the related investigations in the most recent 2 y. The focus would provide information to stimulate further investigations.

A vaccine platform⁴ was proposed to efficiently deliver vaccine through nasal mucosa. To develop the vaccines against pathogens that infect via the mucosal route, the platform would comprise a DNA and/or recombinant fusion protein (FP) vaccine. Since DNA vaccines are stable at room temperature, elimination of the requirement for a cold chain and stockpiling of the vaccine would promote rapid and inexpensive production. Furthermore, FP vaccine does not require an adjuvant; and thus toxicities and adverse events associated with nasal vaccines containing live viral vectors or adjuvants would be significantly reduced or eliminated. In an embodiment, the platform provides a method of inducing an immune response, comprising administering to a subject in need of an immunologically-effective amount of a fusion protein. The immunogenic fusion protein comprises one antigen infectious disease organism and one FcRn-binding domain.

Another group⁵ identified the staphylococcal target of cross-reactive antibody as 1-pyrroline-5-carboxylate dehydrogenase (P5CDH) and the homologous immunogen in S. pneumoniae as SP_1119. The antigens are necessary and sufficient to inhibit the acquisition of S. aureus colonization in a mouse model. Thus, the inventors cloned SP_1119 and P5CDH proteins and claimed a vaccine composition comprising recombinant proteins with the amino acid sequences.⁶

Due to the complex pathogenesis of S. aureus, the chance of finding single antibodies that cross-react between α hemolysin and the bi-component toxins of S. aureus would be low. To increase the potency of anti-S. aureus therapy, an invention⁷ provides a monoclonal antibody with nanomolar affinity to different toxin molecules. The cross-neutralizing antibody comprised at least one polyspecific binding site that binds to α-toxin and at least one of the bi-component toxins of Staphylococcus aureus, which antibody comprises at least 3 complementarity determining regions (CDR1 to CDR3) of the antibody heavy chain variable region. An example of the invention indicated that cross-reactive Hla monoclonal antibody were effective in preventing lethality induced by S. aureus in a pneumonia model.

Another invention⁸ provided a vaccine including an isolated Als protein family member having cell adhesion activity or an immunogenic fragment. An animal model showed both the rAls1p-N and rAls3p-N vaccines mediated improved long-term survival in the mice infected with S. aureus. Furthermore, the mechanism of protection would be an enhancement of Th1 rather than Th2 because no correlation between antibody titers and survival of mice vaccinated with either rAls1p-N or rAls3p-N was observed.

A group of inventors⁹ removed toxigenic potential of S. aureus protein A (SpA) variants to stimulate immune responses that protect against staphylococcal disease. The immunization studies in mice and rabbits indicated that the production of SpA antibodies blocked the association between Protein A and its ligands to generate immunity against staphylococcal infections.

Based on the mechanism that delta toxin related to the regulation of S. aureus quorum sensing system, a patent application¹⁰ included a recombinant delta toxin peptide to produce a vaccine against S. aureus infection. The applicants further demonstrated antibody response by mice vaccinated with the fusion constructs.

Recognizing the fact that a single antigen vaccine to S. aureus would not provide sufficient protection against hematic spread, pneumonia and skin infection, an invention¹¹ proposed a vaccine formulation with S. aureus antigens acting synergistically. The inventors further demonstrated the possibility with mouse models.

A patent application¹² proposed a compound to inhibit expression of the vraSR operon and thus to potentiate the action of antibiotics, because that S. aureus would rely on a vraSR operon for signal transduction.

Another application¹³ discovered that metalloprotease ADAM10 would be related to the pathway of acute lung injury and penetration of toxic-shock syndrome toxin 1 into the vaginal mucosal. Thus, the invention disclosed small molecule inhibitors of ADAM10 to treat pneumonia or inhibit disruption to epithelial barrier in a subject, having or at risk of developing staphylococcal infection.

An invention¹⁴ disclosed that caspase inhibitor would reduce the susceptibility of bone marrow dendritic cells to cell death and decrease the ability to activate gamma delta T cells. Thus, administering a caspase inhibitor would promote an antigen specific immune response to against an infectious disease.

Conclusion

Vaccines would be a solution against the drug resistant infections caused by S. aureus. However, most developments of the vaccines are in early stages and 2 phase III trials were either ended without significant result or terminated due to safety and efficacy reasons. Thus, further developments are highly needed, and the highlight of the related investigations in US patent application database would provide information to promote investigations.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Funding

This work is supported in part by the Taipei Veterans General Hospital (V106C-015) Taiwan.