Explore the Pathogenesis and Drug Development of SARS-CoV-2 (III)
- 2 Antibody drugs
In clinical trials, the recovery period plasma (CP) of COVID-19 patients can significantly improve lung disease in severe patients, relieve acute respiratory distress syndrome, increase lymphocyte count in the blood, reduce C-reactive protein, and reduce viral load. There are no obvious adverse reactions. CP therapy is well tolerated, suggesting the application prospect of SARS-CoV-2 neutralizing monoclonal antibody in the treatment of COVID-19 patients, especially severe patients. At present, many companies have launched the SARS-CoV-2 monoclonal antibody development plan. Vir Biotechnology uses the patient-derived monoclonal antibody technology Humabs BioMed to isolate the S protein monoclonal antibody from the recovered patient, which has been screened in the pseudo-protein system. Two high-efficiency SARS-CoV-2 monoclonal antibodies were developed. AbCellera Biologics also cooperated with DARPA and NIH, using a single B-cell antibody discovery platform (Pandemic Prevention Platform) to isolate S protein antibodies from patients. Regeneron Pharmaceuticals and BARDA cooperated using its mouse expression human antibody platform (VelcoImmune) to isolate S protein monoclonal antibodies. VIB and Tegen University used the S protein in the pre-fusion conformation to immunize camels to obtain SARS-CoV and SARS-CoV containing only heavy chains -2 conserved epitope antibody product of S protein VHH. Ligand Phamaceuticals used the engineered chicken platform (OminiChiken) combined with the method of selecting specific B cells to isolate S protein antibodies. ImmunoPrecos also announced the development of SARS-CoV-2 antibodies against viral antigens and human viral receptor ACE2. At present, many teams have isolated neutralizing antibodies from COVID-19 patients.
In addition, the existing SARS-CoV-specific human monoclonal antibody CR3022 can effectively bind to SARS-CoV-2 RBD, as a potential neutralizing antibody for the prevention and treatment of SARS-CoV-2. It is worth noting that in the neutralization experiment of MERS coronavirus RBD monoclonal antibody, the antibody/Fc-receptor complex can functionally mimic the virus entry mediated by the virus receptor, and it is possible that RBD-specific neutralizing monoclonal antibody may trigger antibody-dependent increase effect (ADE). When designing the SARS-CoV-2 monoclonal antibody, it is possible to reduce the possibility of triggering ADE by not stimulating the conformational changes of the S protein. Although humanized SARS-CoV-2 virus neutralizing antibodies may play a role in the clinical treatment of COVID-19, the production of vaccines can fundamentally prevent and control the spread of SARS-CoV-2.
3 Preparation of virus vaccine
Because SARS-CoV-2 has a high transmission capacity, a long incubation period, and has the characteristics of transmission capacity in the asymptomatic period, it is very likely to become a seasonal virus, so vaccine development is particularly important. Vaccination allows the body to produce an immune response to form an immune memory, which can prevent SARS-CoV-2 infection. However, which type of immune response the vaccine should stimulate, the time limit for the existence of antibodies after immunization, and the safety of the vaccine require more detailed evaluation. This also includes the selection of target antigens, immune pathways, relevant immune protection, selection of animal models, scalability of experiments, selection of production facilities, overview of target products, outbreak prediction and target populations.
SARS-CoV-2 vaccine development plan is based on mRNA, DNA, adenovirus vector, recombinant protein, and inactivated or attenuated virus. Among them, the mRNA vaccine mRNA-1273, led by Moderna, has entered phase II clinical trials. At the same time, the recombinant COVID-19 vaccine (adenovirus vector) developed by Cansino Biologics and the Chinese Academy of Military Sciences has also entered the phase III clinical trial stage.
Nucleic acid vaccine: Inovio Pharmaceuticals is developing a DNA vaccine (INO-4800) for SARS-CoV-2 and has entered the clinical stage. Moderna Therapeutics, Curevac, Pfizer and BioNTech are all developing RNA vaccines.
Based on the viral infection mechanism that the spike protein is combined with the ACE2 receptor, spike protein (S) is a popular choice for virus subunit vaccines, and many companies have also developed related vaccines, such as the cooperation between Clover Biopharmaceuticals and GSK for S-trimer vaccine, and immunogenic virus-like nanoparticles based on recombinant expression of S protein developed by Novavax. Clover Biopharmaceuticals uses its patented technology Trimer-Tag to develop a subunit vaccine composed of trimeric SARS-CoV-2 S protein. An attenuated or inactivated complete virus vaccine is a classic strategy for virus vaccination. Codagenix announced in February that it had used the nCoV genome to map multiple candidate vaccine genes for COVID-19. Zydus Cadila also announced in February that it had targeted COVID-19. For live attenuated vaccines, Beijing Kexing is researching candidate vaccines for formalin inactivation and alum adjuvant. Johnson & Johnson and Janssen's AdVac cooperated with their PER. C6 cell line technology to produce adenovirus vectors.
At present, there are at least six candidate vaccines, including live viruses, recombinant protein subunits and nucleic acids, which may eventually be used as vaccines to prevent COVID-19. However, these vaccines need to undergo phase I clinical trials related to safety and immunogenicity, followed by phase II and phase III clinical trials to improve safety and effectiveness.
Reference
[1] VICTOR MC, DOREEN M, DANIELA N, et al. Hosts and sources of endemic human coronaviruses [J]． Adv Virus Res, 2018, 100: 163-188.
[2] World Health Organization. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003[J]. (2003-09-26)
[3] World Health Organization. Middle East respiratory syndrome coronavirus (MERS-CoV) 2019 [J]． (2019-08-21)
[4] QUN L, XU Hua G, PENG W, et al. Early transmission dynamics in Wuhan, China, of novel coronavirus-infected pneumonia [J]. New England Journal of Medicine, 2020, 382: 1199-1207.
[5] ROTHE C, SCHUNK M, SOTHMANN P, et al. Transmission of 2019-nCoV infection from an asymptomatic contact in Germany ［J］． New England Journal of Medicine, 2020, 382: 970-971.
[6] VAN RM, MAYO M, FAUQUET C, et al. Virus nomenclature: consensus versus chaos [J]. Arch Virol, 2000, 145: 2227-2232.
[7] SCHOEMAN D, FIELDING B C. Coronavirus envelope protein: current knowledge[J]． Virol J, 2019, 16: 69.
[8] LU R J, XIANG Z, JUAN L, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding [J]． Lancet, 2020.
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