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CN-116940574-B - Compounds and their use as vaccine adjuvants

CN116940574BCN 116940574 BCN116940574 BCN 116940574BCN-116940574-B

Abstract

Provided herein are a range of compounds and their use as adjuvants. Provided herein are compounds, compositions comprising compounds, and uses thereof. These compounds can be used as adjuvants for vaccines, which can significantly improve the cellular and humoral immune response to the vaccine compared to conventional aluminum adjuvants. The compounds as adjuvants can increase broad-spectrum protection against various coronaviruses such as SARS virus, influenza virus and HIV virus and significantly enhance the persistence of vaccine immunoprotection.

Inventors

  • LU LU
  • JIANG SHIBO
  • LIU ZEZHONG
  • XIE MING
  • ZHANG YILONG
  • ZHOU JIE
  • WANG QIAN
  • WANG XINLING
  • XU WEI

Assignees

  • 福君基因公司
  • 复旦大学

Dates

Publication Date
20260505
Application Date
20220520
Priority Date
20210524

Claims (16)

  1. 1. A compound of the formula or a pharmaceutically acceptable thereof use of a salt in the preparation of an adjuvant for a vaccine: , wherein the vaccine comprises an antigen from one or more of SARS-CoV, varicella zoster virus, HIV NHR trimer, SARS-CoV-2 and influenza subtypes H1N1, H3N2, B/Yamagata and B/Victoria.
  2. 2. The use of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is used in combination with at least one of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and a pharmaceutically acceptable diluent.
  3. 3. The use of claim 1, wherein the antigen is an antigen from a SARS-CoV-2 omnikom mutant.
  4. 4. The use of claim 1, wherein the antigen is SARS-CoV-2 RBD-Fc protein or the gE protein of varicella zoster virus.
  5. 5. The use of claim 1, wherein the vaccine is an inactivated vaccine, a live attenuated vaccine, a subunit vaccine or a nucleic acid vaccine.
  6. 6. The use of claim 5, wherein the nucleic acid vaccine is an mRNA vaccine or a DNA vaccine.
  7. 7. The use of claim 1, wherein the vaccine is an intramuscular vaccine, an intradermal vaccine or an inhalation vaccine.
  8. 8. A vaccine comprising: (1) A compound of the formula a pharmaceutically acceptable salt: And (C) sum (2) Antigens are antigens from one or more of SARS-CoV, varicella zoster virus, HIV NHR trimer, SARS-CoV-2 and influenza subtypes H1N1, H3N2, B/Yamagata and B/Victoria.
  9. 9. The vaccine of claim 8, wherein the vaccine is an intramuscular vaccine, an intradermal vaccine, or an inhalation vaccine.
  10. 10. The vaccine of claim 8, wherein the antigen is an antigen from a mutant SARS-CoV-2 omnikom.
  11. 11. The vaccine of claim 8, wherein the antigen is SARS-CoV-2 RBD-Fc protein or the gE protein of varicella zoster virus.
  12. 12. The vaccine of claim 8, wherein the vaccine is an inactivated vaccine, a live attenuated vaccine, a subunit vaccine, or a nucleic acid vaccine.
  13. 13. The vaccine of claim 12, wherein the nucleic acid vaccine is an mRNA or DNA vaccine.
  14. 14. A method for producing the vaccine of any one of claims 8-13, comprising mixing the compound or pharmaceutically acceptable salt thereof and the antigen.
  15. 15. Use of the vaccine of any one of claims 8-13 for the manufacture of a medicament for the treatment or prevention of an infectious disease, wherein the infectious disease is selected from the group consisting of Severe Acute Respiratory Syndrome (SARS), COVID-19, varicella zoster and influenza.
  16. 16. A kit comprising the vaccine of any one of claims 8-13 and instructions for treating or preventing an infectious disease.

Description

Compounds and their use as vaccine adjuvants Priority The present application claims priority from PCT application No. PCT/CN2021/095498, filed on 24 5 months 2021, entitled "compounds and their use as vaccine adjuvants", which is incorporated herein by reference in its entirety. Technical Field The present disclosure relates to the field of biological medicine, in particular to a series of small molecule STING agonists. Background Vaccines are considered to be the most powerful weapon for preventing the transmission of infectious diseases. After the outbreak of coronavirus disease 2019 (COVID-19), various vaccines against coronavirus SARS-CoV-2 rapidly enter clinical trials, including mRNA vaccines, DNA vaccines, inactivated vaccines, viral vector vaccines, and the like. The main component of these vaccines is the Spike protein (Spike protein) or receptor binding domain (Receptor binding domain, RBD) of coronaviruses. Currently, many COVID-19 vaccines have demonstrated protection against SARS-CoV-2 infection in both human ACE2 transgenic mice and non-human primate models. although currently, more than ten vaccines are approved worldwide, there are still some issues that need to be addressed. For example, coronaviruses continue to mutate as the virus spreads in the population. The new mutant strains present a significant challenge to the current marketed vaccines. Recent studies have shown that SARS-CoV-2 mutant in the United kingdom and SARS-CoV-2 mutant in south Africa have developed some immune escape phenomena against some existing vaccines on the market (Wang et al Mrna vaccine-elicited antibodies to SARS-CoV-2and circulating variants,medRxiv,2021. Furthermore, three highly pathogenic coronaviruses including SARS-CoV, SARS-CoV-2 and MERS-CoV appear and outbreak successively in the last 20 years. Some coronaviruses from bats similar to SARS have been found, such as RS3367 and WIV strain, indicating that future SARS-related coronaviruses may still appear suddenly and spread in the population like SARS-CoV-2. Currently, only a few studies have shown that vaccines based on SARS-CoV-2 antigen can produce weak cross-neutralizing antibody protection (Liu Z et al.RBD-Fc-based COVID-19vaccine candidate induces highly potent SARS-CoV-2neutralizing antibody response,Signal Transduct Target Ther,2020). against SARS-CoV and SARS-associated coronavirus infection whether the serum of patients who have recovered from SARS-CoV infection can neutralize SARS-CoV-2 is also controversial. Studies have shown that serum from patients infected with SARS-CoV can cross-neutralize SARS-CoV-2, but another study with weak neutralization (Zhu,Y.et al.Cross-reactive neutralization of SARS-CoV-2by serum antibodies from recovered SARS patients and immunized animals.Sci Adv,2020). showed that serum from patients recovered from SARS-CoV infection could not effectively neutralize the SARS-CoV-2 virus (Wang,Y.et al.Kinetics of viral load and antibody response in relation to COVID-19severity.J Clin Invest,2020)., which suggests that it is difficult to generate a broad spectrum of viral vectors in vivo against SARS-associated coronaviruses by common vaccination strategies or natural infection routes, a durable and strong protective immune response. Thus, the development of a broad-spectrum, long-acting and potent universal vaccine against SARS-associated virus is critical to combat the current epidemic of SARS-CoV-2 (including mutants of SARS-CoV-2) and SARS-associated virus that may occur in the future. Adjuvants are critical to enhancing the immunoprotection of protein subunit vaccines or inactivated vaccines. The most commonly used adjuvant at present is aluminium adjuvant. Recently, aluminum adjuvants have been used in clinical trials for various protein subunit vaccines. Although safe, aluminum adjuvants primarily enhance antibody humoral immune responses, which also play a critical role in combating viral infections. Therefore, the development of novel adjuvants, particularly small molecule immunopotentiators, to enhance the immunoprotection of subunit or inactivated vaccines against SARS-CoV-2, induce more types of immune responses, and prolong the persistence of immunity is a current leading-edge hotspot. Disclosure of Invention In recent years, STING agonists have been found to have potential for use as vaccine adjuvants. The inventors have previously used nano-encapsulated STING agonist cGAMP pulmonary biomimetic particles as an adjuvant for influenza vaccines. Vaccination with intranasal drops can produce a strong and broad spectrum of immune protection (Wang,J.et al.Pulmonary surfactant-biomimetic nanoparticles potentiate heterosubtypic influenza immunity.Science,2020). against influenza virus in mice, however cGAMP by intramuscular injection is inefficient. In the present disclosure, novel STING small molecule agonists are used as adjuvants for the protein subunit RBD-Fc vaccine against SARS-CoV-2. In animal models us