|Ahead of print publication
Infectious disease immunotherapies – An update: Revisiting an age-old adage in times of COVID-19
Mahima Lall1, Suyash Singh1, Amar Atal2, Anuj Singhal3
1 Department of Microbiology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Medicine, Armed Forces Medical College, Pune, Maharashtra, India
3 Department of Internal Medicine, Army Hospital Research and Referral, New Delhi, India
|Date of Submission||31-Aug-2020|
|Date of Decision||02-Sep-2020|
|Date of Acceptance||27-Jan-2021|
|Date of Web Publication||27-May-2021|
Department of Internal Medicine, Army Hospital Research and Referral, New Delhi
Source of Support: None, Conflict of Interest: None
This review article tries to bring together the important active and passive immunotherapeutic modalities currently under consideration for COVID-19 disease. The basis of immunotherapy is based on use of naturally occurring agents or drugs to modify the body's immune response to certain antigens, the host immune system competent to successfully target and eliminate the infectious agent, without altering the normal physiology. Pubmed was screened for studies using key words; COVID-19, Convalescent plasma therapy, Immunotherapy, Clinical trials. We identified 537 studies through database searches. After reviewing the title and abstracts, we excluded 452 studies that were not relevant, leaving 85 studies for full-text evaluation. Of these, 53 studies fulfilling predefined inclusion/exclusion criteria were finally included. This study found that the common immunotherapies which were used in COVID-19 pandemic times were plasma therapy, T-reg based therapy, tocilizumab, hydroxychloroquine, dexamethasone, and baricitinib.
Keywords: Clinical trials, convalescent plasma therapy, COVID-19, immunotherapy
| Introduction|| |
There is no specific antiviral drug available against most viruses. Due to their ability to cause immune-mediated tissue destruction, treating viral infections becomes challenging. Viruses may cause latent infection or immune suppression as in case of the human immunodeficiency virus. The concept of passive immunotherapy came to light only after the discovery of the diphtheria toxin by von Behring and Kitasato. Toxin antiserum was administered to patients with diphtheria. Serum therapy was used for treating pneumococcal pneumonia, scarlet fever, and meningococcal meningitis. Passive immunotherapy was the only known lifesaving intervention available for many infections before the advent of antibiotics. With the development of antibiotics, the use of passive immunotherapy declined considerably. However, indiscriminate and inappropriate use of antibiotics led to the emergence of antimicrobial resistance in microbes rendering antibiotics ineffective and infections difficult to treat and eradicate.
The basis of immunotherapy is the use of naturally occurring agents, the host immune system competent to successfully target and eliminate the infectious agent, without altering the normal physiology. It thereby provides a possible modality to prevent or treat infectious diseases. In recent times, there has been a resurgence of interest in immunotherapy, both active and passive, for therapeutic and prophylactic use to treat infections. This is partly due to the great success of immunotherapy in oncology. Upregulation of immune checkpoint molecules present on immune cells such as the programmed death ligand-1 and cytotoxic T-lymphocyte-associated protein 4 is seen in acute infections. Immune checkpoint blockade has been used in cancer therapy, suggesting that these may be effective in preventing and treating infectious diseases. Prospects are being investigated for bacterial, viral, fungal, and parasitic diseases.
The recent global pandemic by the novel coronavirus (severe acute respiratory syndrome-coronavirus-2 [SARS-CoV-2]) has become a health concern across the world., Convalescent plasma therapy (CPT) has shown promise even when antiviral therapy did not show optimal benefit. This article will try to outline the various immunotherapeutic approaches used currently for COVID-19 disease.
| Methods|| |
Studies were searched using keywords such as COVID-19, Convalescent plasma therapy, Immunotherapy, and Clinical trials in PubMed. Mendeley Reference Manager was used for article extraction and removal of duplication. Independent screening of titles/abstracts was done using the predefined inclusion/exclusion criteria, and further evaluation was performed for possible inclusion.
We identified 155 studies through database searches. After reviewing the title and abstracts, we excluded studies that were not relevant, leaving 55 studies for full-text evaluation. Of these, studies fulfilling predefined inclusion/exclusion criteria were finally included in the current systematic review.
| Results|| |
The commonly used immunotherapies being tried and undergoing trials for SARS-CoV-2 are as follows:
Convalescent plasma therapy
Convalescent plasma therapy (CPT) has shown a role in the management of viral diseases including COVID-19. Its use during both the outbreaks of SARS and Middle East respiratory syndrome is documented. The most recent example is the use of CPT during the ongoing pandemic. The pathology of severe COVID-19 disease is marked by a cytokine storm. However, this is different from that seen in sepsis and bloodstream infections. In a study, administering CPT in the dosage of 200–2400 mL, with neutralizing antibody titers >1:640, showed a decline in the coronavirus viral load and better patient outcome as indicated by normalization of body temperature, resolution of lung pathology, improvement in acute respiratory distress syndrome, and eventually weaning off from the ventilator. Despite having limitations, the study has brought immunotherapy to the forefront, however, the findings are yet to be translated into clinical guidelines.
Blocking interleukin-6 signaling
A dysregulated host immune response secondary to effects of interleukin-6 (IL-6), a pro-inflammatory cytokine produced by T- and B-cells, monocytes, and fibroblasts, has been found in severely ill COVID-19 patients. It causes T-cell activation, induces immunoglobulin secretion, and initiates the hepatic acute-phase protein synthesis. The evidence of treating CS with drugs directed at IL-6, IL-1, and tumor necrosis factor-α (TNF-α) reduction has shown their possible immunotherapeutic use in COVID-19 disease. Anti-IL-6 has shown to be an effective chimeric antigen receptor T-cell therapy and may be tried in cytokine response release syndrome. A recombinant human IL-6 monoclonal antibody, tocilizumab (TCZ), has shown efficacy in COVID patients. Autopsy studies on patients who died of COVID-19 and histopathological examination of tissue sections from their lungs have shown evidence of extensive alveolar edema, proteinaceous exudate, and patchy inflammatory infiltration. Clinical studies have shown that IL-6 receptor antagonist TCZ in a dose of 8 mg/kg, by binding IL-6 receptors and preventing it from exerting its pro-inflammatory effects, is effective in treating COVID-19 patients with extensive bilateral lung lesions., However, it is suggested to have trials to further understand the clinical efficacy of TCZ and its late-onset infectious complications.
Blocking other cytokines
The severity of COVID-19 has also been associated with increased TNF-α, IL-1β, and inflammasome sensor NLR family pyrin domain-containing protein-3 (NLRP3). TNF-α-blocking antibodies have been recommended for hospitalized COVID-19 patients. Anakinra, the recombinant form of IL-1 receptor antagonist, is known to inhibit NLRP3 via blockade of the IL-1 receptor. In the French Ana-COVID prospective cohort study, it reduced the requirement for invasive mechanical ventilation and mortality.
Regulatory T-cell-based therapy
Dysfunction of the regulatory T-cells (Tregs) has been proposed to cause a dysregulated inflammatory response to the virus. Treg therapy may balance inflammation in the lungs. The Treg cell expresses a homing marker for the lung tissue and interrupts the virus-induced cytokine storm. In some initial studies, Treg cells have shown a decrease in the levels of IL-17 and IL-6 with consequent less alveolar damage.
The role of the glucocorticoid dexamethasone in salvaging patients on ventilator support has come from the initial preliminary Randomised Evaluation of COVID-19 Therapy (RECOVERY) trials. The trial declares overall mortality benefit in ventilated patients who received dexamethasone in a dose of 6 milligrams (mg) once a day for 10 days. Already used for autoimmune and inflammatory conditions, the initial success of steroids has rekindled interest for treating the inflammatory phase of COVID-19. Potent anti-inflammatory action and cytokine storm amelioration are mediated at many levels, involving direct action on both T- and B-lymphocytes, inhibition of immunoglobulin synthesis, and stimulation of lymphocyte apoptosis. It is additionally orchestrated by the induction of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) inhibitor and resultant inhibition of the action of NF-κB, a cytokine gene transcription regulator.
Hydroxychloroquine (HCQ), a drug used in malaria, rheumatoid arthritis, and autoimmune connective tissue disorders, is a prophylactic and therapeutic option in COVID-19. Its mechanism of action is believed to alter the terminal glycosylation of angiotensin-converting enzyme 2 (ACE2) receptor which is the binding site for the envelope spike glycoprotein of the SARS-COV-2. Suppression of T-lymphocyte response to mitogens, decreased leukocyte chemotaxis, interference with Toll-like receptors signaling, stabilization of lysosomal enzymes, inhibition of DNA and RNA synthesis, and the trapping of free radicals are proposed as its mechanisms of action. Thus, it is the only drug shown to have antiviral as well as anti-inflammatory properties. The present data and knowledge are not sufficient to use HCQ treatment on a mass scale and yield desired effects. Its role as a prophylactic to lessen the effects of infection cannot be conclusively ruled out.
Thymosin alpha (Tα1), a thymic peptide involved in regulating the immune system by enhancing the T-cell function, stimulates thymocyte differentiation and converts T-cells into active T-cells. Tα1 has shown to significantly reduce mortality in severe COVID-19 patients. Tα1 may boost immunity at an early stage of infection providing immune tolerance.
Ivermectin is an antihelminthic which inhibits the host importin α/β transporter proteins, thereby decreasing translocation of SARS-CoV nucleocapsid protein from cytoplasm to the nucleus, disrupting viral propagation and survival. Observational studies in Bangladesh listed encouraging results in a series of COVID-19 patients given a combination of doxycycline plus ivermectin.,,
JAK inhibitors may find a role in controlling the cytokine storm. ACE2 receptors which are the entry point for the SARS-COV-2 may allow invasion and entry into host cells through endocytosis. They are present on the alveolar epithelial cells, heart, kidney, and blood vessels. Adapter-associated protein kinase 1 (AP2-associated protein kinase 1 [AAK1]) regulates endocytosis, and AAK1 inhibitors can interrupt virus entry into cells, thus preventing their infection. Baricitinib, a JAK and AAK1 inhibitor, is a candidate for treatment of COVID-19. Plasma concentrations attained by a dose of 2–4 mg once a day are sufficient to inhibit the virus. However, the concern about JAK inhibitors is that they can inhibit other inflammatory cytokines including interferon-alpha (INF-α), which has an important role in virus clearance.
Colchicine, a drug used to treat gout, has been included in the RECOVERY trial. 2500 patients recruited to the RECOVERY trial will be randomly received colchicine at a dose of 1 mg followed by 500 micrograms every 12 h for a total of 10 days plus the standard care, and results will be compared with a control arm. The main outcome of mortality at 28 days, need for ventilation, and hospital stay shall be assessed.
The limitations of convalescent plasma include the difficulty in collection, variability of binding and neutralizing antibody titers, potential contamination with infectious agents, risk of transfusion reactions, and circulatory overload associated with administration. However, convalescent plasma research serves to inspire the development and use of monoclonal antibodies. It is possible to generate effective monoclonal antibodies by immunization of humanized mice. Modern methods allow the rapid identification of pathogen-specific B-cells and recovery of immunoglobulin heavy-chain and light-chain genes that can be expressed to produce monoclonal antibodies, usually immunoglobulin G.
The main target of SARS-CoV-2-neutralizing monoclonal antibodies is the receptor-binding domain (RBD) on the surface spike glycoprotein that mediates viral entry into host cells via interaction with the ACE2 receptor found on numerous cell types. Regeneron Pharmaceuticals REGN-COV2 is a combination of two monoclonal antibodies (REGN10933 (CASIRIVIMAB) and REGN10987 (IMDEVIMAB)) that bind noncompetitively to the RBD of the virus's spike protein. The fragment antigen-binding region of REGN10933 binds the RBD from the top, where it collides with ACE2, while REGN10987 only binds to the front or the lower left side of the RBD, away from REGN10933, and has little to no overlap with the ACE2 binding site. REGN-COV2 clinical trials began in June 2020, a month later it advanced into Phase 3, and is now under study in four late-stage clinical trials estimated to recruit at least a combined 11,074 participants: NCT04426695, NCT04425629, NCT04381936, and most recently, a Phase 3 trial NCT04452318. Eli Lilly has simultaneously developed SARS-CoV-2-neutralizing monoclonal antibody, LY-CoV555, and a combination of LY-CoV555 and LY-CoV016 antibodies. In a Phase 2 double-blind randomized controlled trial (RCT), a 72% decrease in hospitalization and emergency visits with LY-CoV555 and an 85.5% decrease using the combination were noted. Both pharmaceutical giants have applied for fast track authorization to the US Food and Drug Administration.
Utility of INF-β1a in managing SARS-CoV-2 is seen in many studies. SARS-CoV-2 with presence of premature stop codons in its ORF3b gene is a potent interferon antagonist. The SOLIDARITY trial by the WHO showed the benefit of IFNs. IFNs also boost the efficacy of antiviral drugs. IFN-β1a in addition to lopinavir/ritonavir was shown to be superior to lopinavir/ritonavir alone. Lopinavir/ritonavir in the RECOVERY trial did show benefit. Another trial ACTT-3 exploring the efficacy of IFN beta-1 a is underway. This will evaluate the combination of interferon beta1a and Remdesivir compared to Remdesivir alone.
| Discussion|| |
The studies in support of immunotherapies and not in support are tabulated in [Table 1] and [Table 2]. Joyner et al. in their study on CPT for COVID-19 reported the 7-day mortality as 8.7% in patients transfused within 3 days of diagnosis. A systematic review published on the use of CPT in COVID-19 was seen to reduce and eventually eliminate the virus, however, in critically ill patients, CPT was not able to reduce mortality. Serious adverse events reported by Joyner et al. in the first 4 h were <1%, and 1-week mortality rate was 14.9%. Yongran et al. in their retrospective study on the effect of CPT in COVID patients reported reduced viral load and shortened hospital stay.
|Table 1: Summary of studies and clinical trials supporting the use of immunotherapies in COVID-19|
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|Table 2: Summary of studies and clinical trials not supporting role of immunotherapy in COVID-19|
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Biran et al. in their observational study on the effects of TCZ noted decreased hospital-related mortality. Similar observations were noted with TCZ among groups on mechanical ventilatory support and high C-reactive protein (<15 mg/dL). Roche reported that Phase III COVACTA study of TCZ did not meet its primary endpoint of improved clinical status in hospitalized adult patients with COVID-associated pneumonia, although TCZ-treated patients had a shorter hospital stay compared with those given placebo. The subsequent data released by Roche of its Phase 3 RCT, evaluating minority patients with Actemra involving 389 patients, however, favored its use. The primary endpoint was met when patients with COVID-19-associated pneumonia who received TCZ plus standard of care were found 44% less likely to progress to mechanical ventilation or death compared to patients who received placebo plus standard of care. The cumulative proportion of patients who progressed to mechanical ventilation or death by day 28 was 12.2% in the TCZ arm versus 19.3% in the placebo arm.
A preliminary report by authors of the Recovery Collaborative Group on the use of dexamethasone in hospitalized COVID-19 patients reported a low 1-month mortality among those receiving invasive mechanical ventilation or oxygen but not among those who were not receiving any respiratory support. The pooled report from seven trials suggests an overall lower 28-day mortality. Cavalcanti et al. noted no significant improvement in clinical status at 15 days with treatment with HCQ alone nor HCQ with azithromycin compared with standard care modalities in patients with mild-to-moderate disease. Boulware et al. in their randomized trial of HCQ as postexposure prophylaxis to moderate- or high-risk exposure within 4 days of exposure did not prevent illness compatible with COVID-19. COVID-19 patients are at higher risk of thrombosis. Aspirin, an antiplatelet agent, will be investigated in the RECOVERY trial, and it may reduce the risk of blood clots in patients with COVID-19.
| Conclusion|| |
Immunotherapy is an efficacious therapeutic option for infectious diseases. It can be applied at all levels of disease management, from primary prevention, treatment, to secondary prevention. It has the potential to tackle even refractory infections and bridge the gap due to both pathogen and host factors such as drug-resistant organisms and immune suppression. Revisiting CPT during the COVID-19 pandemic highlights the promise this age-old therapeutic method holds.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]