key: cord-0841882-hbc2bzx1 authors: Hossein-khannazer, Nikoo; Shokoohian, Bahare; Shpichka, Anastasia; Aghdaei, Hamid Asadzadeh; Timashev, Peter; Vosough, Massoud title: An update to “novel therapeutic approaches for treatment of COVID-19” date: 2021-01-03 journal: J Mol Med (Berl) DOI: 10.1007/s00109-020-02027-1 sha: 7b118028ace6e7c75fcf2920fce1df146deac1f6 doc_id: 841882 cord_uid: hbc2bzx1 nan & mRNA-1273 (Moderna TX, Inc.) is an mRNA vaccine that is composed of synthetic mRNA expressing the prefusion-stabilized SARS-CoV-2 spike trimer (mRNA-1273) [5, 6] . The efficacy and immunogenicity of Moderna vaccine investigated in a phase III clinical trial (NCT04470427). Moderna has announced its primary efficacy analysis (95%) and recently applied to the FDA (USA) for emergency use authorization. & ChAdOx1 nCOV-19 is another vaccine under evaluation in phase II/III clinical trials. This vaccine has been developed by Oxford University and produced due to the technology in which an adeno-viral vector encodes SARS-CoV-2 S protein (NCT04400838) [7] . The pre-clinical investigations showed that ChAdOx1 nCOV-19 was immunogenic in vaccinated mice and rhesus macaques and triggered robust humoral and cell-mediated responses [8] . Its safety and immunogenicity were evaluated in a phase II/III trial in a prime-boost regimen in young and old adults. In 14 days after receiving the boost dose, > 99% of participants had neutralizing antibodies [9] . & BNT162b2 is a COVID-19 RNA vaccine candidate that has been announced by BioNTech/Pfizer. This vaccine encodes the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Data from a phase III clinical trial showed vaccine efficiency over 95% [12, 13] . & CoronaVac is inactivated SARS-CoV-2 manufactured by Sinovac Life Sciences (Beijing, China). Its safety, tolerability, and immunogenicity have been approved in healthy adults aged 18-59 years in a phase I/II clinical trial [14] ; and now it is under investigation in a phase III clinical trial (NCT04582344). & Gam-COVID-Vac (Sputnik V) is a combined vector vaccine that consists of recombinant adenovirus type 26 (rAd26) and type 5 (rAd5) vectors. They carry the spike glycoprotein gene. Gam-COVID-Vac has been developed by Gamaleya National Research Center for Epidemiology and Microbiology (Moscow, Russia) [15] . Its safety and immunogenicity was approved in two formulations in a phase I/II clinical trial [15] . And now, the safety and efficiency of this vaccine is under assessment in a phase III clinical trial (NCT04530396). & Using Ad5 vector to carry the spike glycoprotein gene, CanSino Biologics Inc. (China) has developed a recombinant novel coronavirus vaccine which safety and efficiency has been being evaluated in a phase III clinical trial (NCT04526990). The progress in vaccine development is critically discussed in the following recently published reviews in detail [10, 11] . In our recently published paper entitled "Novel therapeutic approaches for treatment of COVID-19," we grouped novel therapies into passive immunotherapy, cell-based therapies (including immune cell and non-immune cell therapies), monoclonal antibodies, and anti-viral drugs. Searching terms "COVID-19" and "treatment" using https://clinicaltrials.gov/ resulted in more than 2200 clinical trials (October 29, 2020). Among these clinical trials, over 200 studies were related to cell-based therapies. They included mesenchymal stromal cell (MSC) therapies and adoptive T cell and natural killer (NK) cell therapies. Other studies applied monoclonal antibodies and nano-medicine to treat COVID-19 patients ( & Due to the immunomodulatory effects of MSCs [16, 17] , clinical trials using MSCs from various sources including the umbilical cord, adipose tissue, and bone marrow have been registered for the treatment of acute respiratory distress syndrome (ARDS) caused by COVID-19 (NCT04341610, NCT04366063). Primary results showed that this strategy was safe and effective. The MSC therapy improved lung function, downregulated inflammatory cytokines, increased anti-inflammatory ones, and decreased mortality rate [18] [19] [20] . MSCs exert their antiinflammatory properties through direct cell-cell contact, paracrine effects, and their extracellular vesicles such as exosomes [21, 22] . It seems that application of MSCs and their exosomes could be a promising approach for the management of respiratory complications in COVID-19. & Some studies reported lymphopenia and functional exhaustion due to the over-activation of the immune system during infection [23] . COVID-19 specific T and T CD8+ cells play an important role in the virus clearance by producing inflammatory cytokines and their cytotoxicity effects [24] . Moreover, virus-specific memory T cells were isolated from the serum of the recovered patients [25] [26] [27] . Based on this evidence, recent clinical trials designed and used the adoptive T cells in severe COVID-19 patients. Using this treatment protocol, HLA-matched T cells from fully recovered patients were transfused into newly infected individuals. This approach may help patients who are at the risk of requiring mechanical ventilation (NCT04457726, NCT04401410, and NCT04406064). & In addition, another clinical trial used COVID-19-specific T cell-derived exosomes (CSTC-Exo) for the treatment of early infected patients in order to boost the IFN-γ production. Compared to the cells, CSTC-Exo does not need HLA-matching, and their administration route is an aerosol inhalation (NCT04389385). If it meets the endpoints, it could be a suitable alternative as an off-the-shelf product. & Since regulatory T cells (Treg) are known as major antiinflammatory T cell subsets, Treg cell therapy may be a novel regenerative and anti-inflammatory treatment strategy for COVID-19. Infusion of cord blood-derived Treg cells (CK0802) may improve the ARDS symptoms in these patients (NCT04468971). RAPA-501-ALLO is a hybrid Treg/Th2 off-the-shelf reprogrammed Treg cell product produced by the healthy donors. RAPA-501-ALLO could have a dual advantage by modulating Th1 and Th17 subpopulations and inhibiting the massive production of inflammatory cytokines, as well as regenerating the damaged alveolar tissues [28] . This product may be a useful therapeutic option for the treatment of severe COVID-19 (NCT04482699). II/III I/II I/II I II II II II I I/II I I II II I -I/II I/II I II I I/II I I II II II I/II I I/II I I I/II I II I II II I/II I II I/II I/II I/II I/II II I/II II I III II I I II I II I II I/II I/ II II I I/II IV -II -I -I/II I/II I II II III I/II I II II/III III I II/III I II II I II -III II IV I II II/III II I II II II/III II II II -III II II II III III II II II II II III III III II II II III III III -II I --II II -III -II/III Nivolumab PD-1 Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab/anakinra Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Tocilizumab Anakinra These cells simultaneously target ACE2 (the main receptor for SARS-CoV-2) [29] and NKG2D on the infected cells and removed them. Therefore, they could inhibit the SARS-CoV-2 infection through ACE2 blockade. & It has been shown that monoclonal antibodies could be a promising treatment approach for COVID-19. Monoclonal antibodies against inflammatory cytokines such as anti-IL-1 receptor, IL-6 antagonist, anti-TNF-α, Fig. 1 Overview of molecular-and cellular-based treatments anti-GM-CSF, anti-IFN-γ, and C5a inhibitor have been studied in different clinical trials. Over 60 clinical trials have been registered to evaluate the treatment efficiency of Tocilizumab and Olokizumab (anti-IL-6 mAbs) [30] [31] [32] [33] . The published studies showed that Tocilizumab (anti-IL-6 mAb) could improve the outcomes in COVID-19 patients and inhibit a cytokine storm [34] . Anakinra (IL-1ra) [35, 36] also showed beneficial effects for the treatment of COVID-19 patients and could decrease the mechanical ventilation need. Moreover, REGN-COV2 has been developed and consists of two neutralizing antibodies (REGN10987 + REGN10933) targeting SARS-CoV-2 spike protein [37, 38] . & Using nano-medicine including aerosol inhalations of therapeutic agents attracts lots of attention. Recent studies have investigated the efficiency and safety of the MSCderived exosome (NCT04491240, NCT04276987) and interferon beta inhalation (NCT04385095). Now, most of the mentioned studies are ongoing. The growing number of clinical trials in this field could provide more validated designs and higher quality data. In this context, the increase in international collaborations to provide larger number of patients will be helpful to obtain more definite results [39] . Identifying the exact mechanisms of the COVID-19 immunopathogenesis will ensure the development of more effective therapies. The trinity of COVID-19: Immunity, inflammation and intervention COVID-19: Molecular diagnostics overview Comparative analysis of therapeutic approaches to treat COVID-19 Outbreak of chronic renal failure: Will this be a delayed heritage of COVID-19? Novel therapeutic approaches for treatment of COVID-19 SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults The early landscape of coronavirus disease 2019 vaccine development in the UK and rest of the world ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): A single-blind, randomised, controlled, phase 2/3 trial SARS-CoV-2 immunity: Review and applications to phase 3 vaccine candidates Krammer F (2020) SARS-CoV-2 vaccines in development RNAbased COVID-19 vaccine BNT162b2 selected for a pivotal efficacy study A systematic review of SARS-CoV-2 vaccine candidates Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: A randomised, double-blind, placebo-controlled, phase 1/2 clinical trial Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous primeboost COVID-19 vaccine in two formulations: two open, nonrandomised phase 1/2 studies from Russia Study of the immunomodulatory effects of osteogenic differentiated human dental pulp stem cells Investigating the route of administration and efficacy of adipose tissuederived mesenchymal stem cells and conditioned medium in type 1 diabetic mice Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of shortterm treatment efficacy and side effects Therapeutic modalities and novel approaches in regenerative medicine for COVID-19 Mesenchymal stem cells: Current clinical progress in ARDS and COVID-19 Mesenchymal stem cell therapy for COVID-19: Present or future Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications Immuno-epidemiology and pathophysiology of coronavirus disease 2019 (COVID-19) T cell responses in patients with COVID-19 Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with COVID-19 pneumonia SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls A review of mesenchymal stem cell therapy for severe SARS-CoV-2 infection ACE polymorphisms and COVID-19-related mortality in Europe Tocilizumab treatment in COVID-19: A single center experience The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality Effective treatment of severe COVID-19 patients with tocilizumab Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence Sars-Cov-2 interference in HEME production: Is it the time for an early predictive biomarker? Use of anakinra to prevent mechanical ventilation in severe COVID-19: A case series High dose subcutaneous Anakinra to treat acute respiratory distress syndrome secondary to cytokine storm syndrome among severely ill COVID-19 patients REGN-COV2 antibodies prevent and treat SARSCoV-2 infection in rhesus macaques and hamsters A cocktail of antibodies for COVID-19 therapy Ongoing clinical trials for the management of the COVID-19 pandemic Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations