key: cord-0699878-iw53d31f authors: Gunjegaonkar, Shivshankar Malkarjun; Shanmugarajan, Thukani Sathanantham; Arunsundar, Mohanasundaram; Arjun, Uppuluri Varuna Naga Venkata; Devi, Kadirrel; Wankhede, Sagar Baliram; Ravichandiran, Velayutham title: Harnessing immunotherapy to combat COVID-19: A modern snake oil or silver bullet? date: 2020-11-01 journal: Therapie DOI: 10.1016/j.therap.2020.10.004 sha: de7ea8cb67255949c448e926e210752318abb1b0 doc_id: 699878 cord_uid: iw53d31f Coronavirus disease 2019 (COVID-19), an infectious disease caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has emerged into a global health and economic menace. Amidst the COVID-19 turmoil, recent failures/uncertain outcomes in clinical trials involving the anti-malarial (hydroxychloroquine), anti-viral (remdesivir) or the combination of anti-malarial/antibiotic (hydroxychloroquine/azithromycin) regimens have predisposed the physicians to distrust these “highly-touted” drugs for COVID-19. In this milieu, immunotherapy might be a credible modality to target or modify specific/non-specific immune responses that interfere with the survival of intracellular pathogens. This scientific review throws light on the epidemiology of COVID-19, its pathogenesis and the current clinical scenario of immunotherapeutics including convalescent plasma (CP), type-1 interferons (IFN–I) and human monoclonal antibodies (mAbs) to combat COVID-19. The treatment outcomes underscore that immunotherapy might be a reliable tool to assuage COVID-19-associated immunopathology. However, specific patient pool studies are warranted to ascertain the precise (re)purposing of immunotherapeutics for COVID-19. J o u r n a l P r e -p r o o f 5 promotes the secretion and activation of granulocyte colony-stimulating factors (G-CSF), while IL-17 along with granulocyte-macrophage colony-stimulating factor (GM-CSF) triggers inflammation through Janus kinase 2 (JAK2) signaling [6] . Current clinical investigations showed significantly increased in blood levels with cytokines including TNF-α, interleukins (IL1-β, IL7, IL8, IL9, IL10), IFNγ, fibroblast growth factor (FGF2), G-CSF and GM-CSF. Some of the cases with severity showed enhanced levels of (IL-2, 7, 10) [1, 7] . In a cascade of eventspecific signaling, type I IFN via IFNAR activates the JAK-STAT1/2 (STAT; signal transducer and activator of transcription proteins) pathway and causes phosphorylation of STAT1 and STAT2 through kinases (JAK1 and TYK2) [8] . Further phosphorylated STAT1/2 associated and forms a complex with IRF9 and translocates to host nuclei. This complex initiate interferonstimulated genes (ISGs) under the influence of interferon stimulated response elements (ISRE) and suppresses viral replication and further infection in early stage [7, 9] . It is proposed that coronavirus infection enhances influx of neutrophils and monocytes-macrophages which lead to increased immunological responses in lung epithelial and causes respiratory congestion and showed delayed asymptomatic responses in individuals [10, 11] . It was also observed that the prevalence in children and young adults were less due to prominent efficient inbuilt immunity. These data strappingly indicate that innate immune response is a critical factor for disease effect. On extensive literature review, it is proposed that innate immunity plays a crucial role and inhibiting important cytokines, enhancing IFN and boosting immunity will be effective strategies in controlling the COVID-19 infection and its propagations [12, 13] . Hitherto, there is no FDA-approved disease modifying drug to treat COVID-19. Recent failures/uncertain outcomes in clinical trials involving the "highly touted" anti-malarial (hydroxychloroquine), anti-malarial plus antibiotic combination (hydroxychloroquine plus azithromycin) and anti-viral (remdesivir) drugs are creating distrust in the use of these drugs for COVID-19 [14] [15] [16] . These reports accentuate that there is a dire need for deployment of newer strategies like immunotherapy to combat COVID-19. Convalescent plasma Activation of humoral immunity is possible with administration of convalescent plasma (CP), collected from humans who have suffered from COVID-19 and got cured [17] . CP contains SARS-CoV-2 specific antibodies and able to provide short term immunization against infectious disease [17] . The circulating pathogens are rapidly neutralized and eradicated by administration of CP in initial course of infection [18, 19] . Recent 5 clinical investigation in human beings with administration of CP showed promising treatment option as CP reduced mortality rate in severe and clinically ill patients, eradication of SARS-CoV-2 RNA by increasing neutralizing antibody titers and improvement in clinical symptoms [20] . Shen C et. al. (2020) showed that CP has improved the clinical outcome in the five critically ill patients with uncontrolled COVID-19 and acute respiratory distress syndrome (ARDS) [21] (Table 1) . Following CP transfusion, an appreciable reduction in viral load, increased neutralizing antibodies and improvement in ARDS were observed. Three-out-of-five patients were discharged after 52-55 days and two were stable after 37 days of CP administration. Another clinical finding of 10 critical adult patients showed improvement in clinical symptoms and laboratory parameters, increased in neutralizing antibody, increase of oxyhemoglobin saturation and lymphocytes, decreased C-reactive protein and lung lesions in radiological examination [22] . Rojas et al. (2020) proposed that the ameliorative effect of CP against COVID-19 involves direct viral neutralization, regulation of immune-hyperactivity (in terms of cytokine burst, Th1/Th17 ratio, activation of complement system) and control of hyper coagulopathy [23] . Furthermore, the study advocated no significant adverse effects upon ABO-compatible convalescent plasma treatment [24] . In a phase 2 clinical trial in 86 severally ill adult patients, [27] . Hospital of Zhejiang University, China carried out a clinical investigation using convalescent plasma treatment in 19 patients (11 males and 8 females). Among them, 10 was severely ill and 9 were critically ill. The result indicated a progressive and marked improvement in clinical outcomes. Patients treated with convalescent plasma showed improved lymphocytopenia, an index of immunomodulation, as well as improved C-reactive protein and SaO2 indicating recovery from lung damage [28] . The first 2 cases tested COVID-19 positive were treated with convalescent plasma and investigated for clinical improvement at the National Institute of Hematology and Infectious Diseases, Hungary. Results indicated that convalescent plasma treatment improved oxygenation, decreased inflammatory markers, increased lymphocyte counts, and decreased IL-6 levels. Mechanical ventilator was removed from both patients after 2 weeks of treatment [29] (Table 1) . Families of natural proteins secreted by immune system cells (WBC's, NK cells, epithelial cells etc.) like interferons are another approach in the treatment of infectious diseases [30] . Several [32, 33] . Recent Chinese guidelines recommended IFNα in combination with antiviral drugs (ribavirin) for treatment of COVID-19 [34] . Interferon therapy with Chinese traditional medicines, antibacterial, antiviral, and corticosteroids was found to enhance the clinical outcome in 135 COVID-19 patients. The recruited population had a median age of 47 years, no significant gender differences with clinically ill to severely ill patients (cardiovascular diseases and malignancy). The study revealed remarkable improvement in patients and reported the death of one patient. The findings showed improved oxygen saturation, lymphocyte, CD4+ T, CD8+ T, B cell, and NK cell counts; also, CT scan advocated resolved GGOs inpatient after treatment with interferons [35] . An open randomized phase 2 trial carried out in Hong Kong involving triple combination therapy viz. interferon beta-1b, lopinavir-ritonavir, and ribavirin were provided to 86 patients, who were tested positive to COVID-19. The result showed that triple combination therapy significantly reduced the viral load, subsided symptoms completely and IL-6 levels within 4 days. In conclusion, it was stated that the therapy appreciably reduces virus shedding duration, shortens hospitalization of patients, alleviates cytokine response and resolves lung GGOs [36] . In another study, 158 randomized and 79 placebo-controlled patients were enrolled in the double-blind multicentre trial at ten hospitals in National Clinical Research Center for Respiratory Diseases, China. The patients received remdesivir and concomitant lopinavirritonavir regimen, interferons, and corticosteroids for the treatment of COVID-19. The findings depicted that remdesivir with interferon regimen significantly improved clinical symptoms, relieved fever, improved oxygen saturation, reduced respiration rate and also suppressed cough [37] . In an investigation conducted at the Ningbo Women and Children's Hospital, China, clinical outcome of INF-alpha along with concomitant use of lopinavir-ritonavir was assessed in 36 children with a mean age of 8.3 years. The study displayed improved clinical manifestations in terms of fever, cough, tachypnoea, congestion, sore throat, vomiting, and diarrhea. Serum level of the immune cells were significantly increased; CT scan showed resolved pulmonary GGOs as well as improved oxygen saturation [38] . A phase two multi-center randomized controlled trial carried out at Golestan University of Medical Sciences, Iran involved 105 critically ill COVID-19 patients, who were treated with a combination of interferon-beta, dexamethasone, and immunoglobulin. Main outcome of the trial showed improvement in clinical symptoms, SpO2 level was increased, further, the hospitalization of patients was shortened and the patient did not require mechanical ventilation [39] . In a study, COVID-19 positive multiple sclerosis patient was treated with interferon along with hydroxychloroquine, azithromycin, and enoxaparin sodium at Ankara City Hospital, Ankara, Turkey. This single patient study showed that the combined regimen successfully enables recovery from SARS-2 infection. The patient did not show any symptoms; also, normal respiration, normal levels of WBC, hemoglobin, CRP, platelet count, liver/kidney function parameters were observed [40] . A recent non-controlled trial investigation involved 20 COVID-19 positive patients, who were treated with subcutaneous administration of IFN-β-1a every alternate day along with conventional hydroxychloroquine, and lopinavir/ritonavir treatment. The primary outcomes achieved were subsided symptoms like fever, cough, chest pain, headache, diarrhea, and sore throat. The secondary outcomes were resolved GGOs, reduced ICU stay, and mortality rate [41] Administration of IFN-α2b alone or along with arbidol remarkably mitigated the viral load in the upper respiratory tract (Table 1 ) [42] . Immunopotentiation through active or passive immunization strategies have proven beneficial against a gamut of viral infections, as observed in our previous study and the reports of other research groups [43] [44] [45] . Specifically, passive immunization with antibodies is a well-known strategy in the treatment of infectious diseases. But, the specific monoclonal antibodies (mAbs) prevents viral replication; also, the viral burden was reduced by 10 2.4 -10 3.9 and associated interstitial pneumonitis was ameliorated [46] . A new monoclonal antibody tocilizumab (IL-6 receptor inhibitor) was used for the treatment of COVID-19 in Iceland in a patient with severe respiratory symptoms and fatigue ( Table 1 ). The study results showed improvement in clinical symptoms, oxygen saturation levels and minimum cytokine burst, and importantly the patient did not require endotracheal intubation [47] . Another clinical investigation of tocilizumab against COVID-19 in 20 patients at Anhui Provincial Hospital and Anhui Fuyang Second People's Hospital showed improvement in symptoms of patients as fever was returned to normal, oxygen demand was reduced in 75% patient. More than 90% of patients showed reduction in lung lesion in the CT scan report. Besides, reduced lymphocyte level and elevated C-reactive protein were also normalized in the tocilizumab-treated patients. The data showed that tocilizumab, along with routine therapy with antiviral and broad-spectrum antibiotics, improved clinical outcomes in severe COVID-19 patients without any adverse effect [48] . Another study involving fifteen patients (12 males and 3 females) with COVID-19 admitted at Zhongfaxincheng campus of Tongji Hospital in Wuhan, China for clinical investigation of tocilizumab treatment. Tocilizumab was administered with and without prednisolone treatment and evaluated for Creactive protein, IL-6 and clinical outcomes before and after treatment. Results showed that treatment with Tocilizumab attenuated "cytokine burst", reduced C-reactive protein and mitigated the inflammatory responses. Unfortunately, ill and critical patient death was occurred during the tocilizumab treatment and needs further investigation in large number of COVID-19 patients [49] . Leronlimab a product of CytoDyn Inc. was investigated in 10 COVID-19 patients with severe illness. Treatment with leronlimab showed rapid reduction in IL-6 levels, restoration of CD4/CD8 ratio, reduction in plasma viremia. This result underscores that treatment with leronlimab restores immunological deficiencies and resolves inflammatory responses [50] . The new ACE-MAB by Sorrento and Mabpharm is in pipeline and under clinical trial against treatment of COVID-19. ACE-MAB is a bi-specific fusion protein with two arms, one comprises human antibody targeting SARS-CoV-2 spike protein whereas another is a truncated ACE2 protein that binds to the spike protein epitope. This fusion selectively blocks the interaction between RBD and CD147, and attenuates inflammation and cytokine burst [51] . Gimsilumab, a product of Roivant Sciences and Mavrilimumab of Kiniksa Pharmaceuticals are granulocytemonocyte colony-stimulating factor inhibitors and could be effective in treating SARS-CoV-2 [52] [53] [54] . Siltuximab, an interleukin (IL)-6 receptor antagonist found clinical significance in COVID-19 patients [55] . CEL-SCI corporation's biotech product LEAPS (ligand antigen epitope presentation system), a cell modulation peptide and an immunomodulator administered via epitope delivery technology to activate cell-mediated T-cell immune response against infection and viral burden reduction [56] . Beyond Spring group has submitted a provisional U.S. patent application for BPI-002, a novel oral small molecule and a T-cell co-stimulator against COVID-19 [57] . mAbs including infliximab or adalimumab are anti-TNF antibodies with remarkable efficacy, broad spectrum of safety and wide availability [58] . A 60-year-old clinically ill patient with multiple myeloma working in Wuhan was admitted to the Hospital of USTC, Hefei, China and treated with tocilizumab along with moxifloxacin and arbidol. After following the treatment protocol significant progress was reported viz. improved oxygen saturation and breathing, chest tightness disappeared, decreased IL-6 level, normal lymphocyte count, and resolved groundglass opacities. The effect of tocilizumab was mediated through antagonizing the IL-6 receptor and avoiding cytokine storm. The patient found COVID-19 negative and was discharged from the hospital [57] . 100 COVID-19 positive, hyperinflammatory syndrome (HIS) patients were enrolled at Spedali Civili University Hospital in Brescia (Italy). An intravenous infusion of tocilizumab (8 mg/kg) was administered every 12 hours for 11 days. The reported outcomes were improvement in acute respiratory failure, resolved diffuse bilateral opacities, and attenuated symptoms of COVID-19. Unfortunately, 24% of patients died and 2 patients reported adverse effects of tocilizumab viz. septic shock and gastrointestinal perforation [58] . A case study of COVID-19 positive patients with sickle cell syndrome was successfully treated with tocilizumab. The research report showed progressive improvement in general condition, radiological examination, and SpO2 was observed as 97%. [59] . Another case study of COVID-19 positive patient with a history of kidney transplant was successfully treated with a combined regimen of tocilizumab and hydroxychloroquine. The clinical outcomes underscored that after treatment with tocilizumab, the fever was absent, with oxygen saturation of 95%, reduced respiration rate, and normalized WBC count. Radiological examination showed normal lungs and patient was discharged [60] The single-center study involved 15 COVID-19 positive patients (2 moderately ill, 6 seriously ill and 7 were critically ill) and treated with tocilizumab at Zhongfaxincheng campus of Tongji Hospital in Wuhan, China. The laboratory findings reported that CRP levels in all 15 patients were found normal after treatment with tocilizumab and methylprednisolone. Also, decreased inflammatory activity, and IL-6 level was noted; besides, 6 patients displayed improved/stabilized clinical symptoms. In 4 patients, disease aggravation was observed and the death of 5 patients was reported [61] . Another recent investigation involved 3 clinically ill patients, treated with tocilizumab in combination with the conventional regimen (lopinavir/ritonavir plus hydroxychloroquine) in an Italian Hospital. The clinical outcome in the first hypertensive patient, reported an absence of fever, improvement in the PaO2-to-Fio2 ratio, and CRP was found normal. In the second patient progressive results were obtained and reported as an improvement in the clinical condition, absence of fever, and rapid reduction in CRP. The third patient also showed similar results as an improved clinical condition, oxygen saturation, and resolved fever [49] . Two COVID-19 positive patients with acute hypertriglyceridemia were treated with tocilizumab along with lopinavir/ritonavir, ribavirin, hydroxychloroquine at Henry Ford Hospital, Michigan, USA. The investigational outcome reported that tocilizumab is a potential treatment option in patients with severe COVID-19 (Table 1 ) [62] . In addition to these interventions, IFN-k plus TFF2 with standard care [63] and type 1 IFN Nevertheless, future investigations are warranted to address the precise (re)purposing of immunotherapeutics for treating specific patient pool in the COVID-19 spectrum. The authors report no conflicts of interest. 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