Harnessing the non-specific immunogenic effects of available vaccines to combat COVID-19

Figures & data

Table 1. Clinical trials on BCG vaccine usage for prevention of COVID-19, Available from: https://clinicaltrials.gov/at 2020 September 1

NCT Number	Title	Recruiting	Interventions	Outcome Measures	Age	Phase	Enrollment	Study Type	Study Designs	Start Date	Completion Date	Locations
NCT04328441	Reducing Health Care Workers Absenteeism in Covid-19 Pandemic Through BCG Vaccine	Yes	BCG Vaccine | Placebo	Health Care Workers absenteeism/the cumulative incidence of documented COVID-19/Hospital Admission due to documented COVID-19 and any reason, self-reported acute respiratory symptoms or fever/death due to documented COVID-19/ICU Admission due to documented COVID-19 and any reason/the cumulative incidence of self-reported fever/self-reported acute respiratory symptoms/death for any reason/the number of days of unplanned absenteeism, because of documented COVID-19, because of imposed quarantine as a result of exposure to COVID-19, because of imposed quarantine as a result of having acute respiratory symptoms/fever or documented COVID-19, because of self-reported acute respiratory symptoms/the number of days of self-reported fever [>38 deg C]/the number of days of self-reported acute respiratory symptoms/the cumulative incidence and magnitude of plasma-serum antibodies [IgA,M,G] and SARS-CoV-2-specific antibodies at 12 weeks after vaccination and at the end of the study period	18<	3	1500	Interventional	Allocation: Randomized | Intervention Model: Parallel Assignment | Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) | Primary Purpose: Prevention	Mar-20	Dec-20	Netherlands
NCT04362124	Performance Evaluation of BCG Vaccination in Healthcare Personnel to Reduce the Severity of SARS-COV-2 Infection	Not yet	BCG Vaccine | Placebo	Incidence of COVID-19 cases confirmed or probable in the study population/Incidence of severe or critical infection in COVID-19 cases, Lethality of the infection in both groups, Assess the safety (frequency, seriousness, and severity of adverse events) of BCG vaccination, Prevalence of SARS-Cov-2 infection	18–65	3	1000	Interventional	Allocation: Randomized | Intervention Model: Parallel Assignment | Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) | Primary Purpose: Supportive Care	Apr-20	Nov-21	Colombia
NCT04379336	BCG Vaccination for Healthcare Workers in COVID-19 Pandemic	Yes	BCG Vaccine | Placebo	Incidence of HCWs hospitalized due to COVID-19 per arm | Incidence of SARS-CoV-2 infection per arm | Incidence of upper respiratory tract infections per arm | Days of unplanned absenteeism due to COVID-19 or any reason per arm | Incidence of hospitalization for any reason per arm | Incidence of ICU admission per arm | Incidence of death per arm | Prevalence of latent TB infection | Incidence of active TB per arm | Compare the effect of latent TB on morbidity and mortality due to COVID-19 per arm | Incidence of treatment related adverse events	18<	3	500	Interventional	Allocation: Randomized | Intervention Model: Parallel Assignment | Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) | Primary Purpose: Prevention	May-20	Apr-21	South Africa
NCT04350931	Application of BCG Vaccine for Immune-prophylaxis Among Egyptian Healthcare Workers During the Pandemic of COVID-19	Not yet	BCG Vaccine | Placebo	incidence of confirmed COVID-19 | Effectiveness of BCG vaccine	18<	3	900	Interventional	Allocation: Randomized | Intervention Model: Parallel Assignment | Masking: Single (Participant) | Primary Purpose: Prevention	Apr-20	Dec-20	Egypt
NCT04417335	Reducing COVID-19 Related Hospital Admission in Elderly by BCG Vaccination	Active	BCG Vaccine | Placebo	SARS-CoV-2 related hospital admission | the duration of hospital admission due to documented COVID-19 | the cumulative incidence of documented SARS-CoV-2 infection, self-reported acute respiratory symptoms or fever, death due to documented SARS-CoV-2 infection, hospital admission for any reason, ICU Admission due to documented SARS-CoV-2 infection	60<	4	2014	Interventional	Allocation: Randomized | Intervention Model: Parallel Assignment | Masking: Single (Participant) | Primary Purpose: Prevention	Apr-20	May-21	Netherlands
NCT04347876	Outcome of COVID-19 Cases Based on Tuberculin Test: Can Previous BCG Alter the Prognosis?	Yes	Diagnostic Test: Tuberculin test	Pneumonia severity index | Need for ICU admission | COVID −19 test conversion | Mortality	12–80		100	Observational	Observational Model: Case-Control | Time Perspective: Prospective	Apr-20	Jun-20	Egypt
NCT04475302	BCG Vaccine in Reducing Morbidity and Mortality in Elderly Individuals in COVID-19 Hotspots	Yes	BCG Vaccine | Placebo	Mortality due to COVID-19 disease | Hospital admission and ICU admission due to Covid-19, Severity of Covid-19 (mild, moderate or severe), Hospital admission due to other respiratory febrile illness, immunological outcomes in the sub study	60–80	3	2175	Interventional	Allocation: Non-Randomized | Intervention Model: Single Group Assignment | Masking: None (Open Label) | Primary Purpose: Prevention	Jul-20	May-21	India
NCT04461379	Prevention, Efficacy and Safety of BCG Vaccine in COVID-19 Among Healthcare Workers	Not yet	BCG Vaccine | Placebo	Demonstrate COVID- 19 disease incidence, cumulative hospitalization, specific Antibodies against SARS-CoV-2 at 3 and 6 months among Health care workers | Hospitalization, Oxygen supplementation in severe disease COVID-19 | Need for intubation or noninvasive ventilation for the patient. | Critical care admission with SARS-CoV2 | Mortality associated to progressive pulmonary disease | safety of the vaccine by measuring the incidence rates of local and systemic adverse effects that occur after one month its application. | Incidence of COVID-19 complications | Mean days of hospitalization and days in ICU by COIVD-19 | Cost associated with in-hospital medical care | Scores of the Clinical Prediction Rules associated with mortality using Sequential Organ Failure Assessment (SOFA score) | Scores of the Clinical Prediction Rules associated with mortality using Acute Physiology and Chronic Health disease Classification System (APACHE) | Alteration profile in laboratory studies | Registration of chronic medications | Need for vasopressors	18<	3	908	Interventional	Allocation: Randomized | Intervention Model: Parallel Assignment | Masking: Triple (Participant, Care Provider, Outcomes Assessor) | Primary Purpose: Prevention	Jul-20	Jan-21	Mexico

Quadruple masking: P = Participant, C = Care Provider, I = Investigator, O = Outcomes Assessor

Figure 1. The schematic representation of immune responses against SARS-CoV-2. a. Optimal innate and adaptive immunity responses: The virus binds to ACE2 to infect cells. The engagement of pattern recognition receptors (PRRs) results in the production of interferons I and other proinflammatory mediators, which induces dendritic cells (DCs) to process antigens and present them to naïve circulating T cells, leading to T cell activation. The activated T cells migrate to the site of infection and secrete effector cytokines, such as IFN-γ. The APCs also induce B cells leading to optimal NAb production. b. Early and sub-optimal NAb activity results in antibody-dependent enhancement, leading macrophages to be exploited for virus replication. This process also causes elevated cytokine production and subsequent immunopathological overreactions

APC: Antigen Presenting Cell, NAb: Neutralizing Antibody

Table 2. The impact of BCG, influenza vaccine, and interferon (IFN)-I on the immune system compared with the dysregulation of immunity as a result of COVID-19 or aging

	BCG vaccine	Influenza vaccines	IFN-I	Aging	COVID-19
PRRs	Engaging TLR2, TLR4, TLR8, and C-type lectin receptors,^Citation40 NOD-like receptors, RIG-I^Citation41	Engaging TLR7,^Citation42 LAIV: increasing expression of RIG-I and TLR-3^Citation43	Enhancing TLR responsiveness in macrophages^Citation44	Decline in TLR expression and function^Citation45
Proinflammatory mediators	*Inducing the production of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-6^Citation46	*Increasing the production of TNF-α and IL-6 and downregulation of IL-1b, IFN-γ, and IL-10 after stimulation of PBMCs with LPS, M. tuberculosis, C. albicans, and S. aureus.^Citation47 TIV/MF59: significant increase in IL-5 and IL-6, IFN-γ, IL-2, Th2 responses,^Citation48 AS03: STAT1 and MX1 upregulation^Citation49	Cytokines/chemokine regulation such as IL-15 and IFN-γ^Citation50	Increase in proinflammatory cytokines such as TNF, IL-1, and IL-6^Citation51,Citation52	Elevated levels of IL1β, IFN-γ, IP10, MCP1, IL4, and IL10 at disease late stages, higher concentrations of GCSF, IP10, MCP1, MIP1A, and TNFα in ICU patients versus non-ICU patients,^Citation27 elevated levels of IL-6, which is associated with cytokine storm^Citation32
IFNs [production and duration]	*Increasing IFN-γ production,^Citation53 inducing a negative regulator of JAK/STAT signaling pathway, SOCS1^Citation54	TIV: early induction of type-I and -III IFNs,^Citation55 LAIV: increased expression of IFN-related genes [mostly IFN-I] in three days, including STAT1, STAT2, TLR7, IRF3, and IRF7, slighter changes by unadjuvanted TIV,^Citation56 TIV and LAIV induce overexpression of IFN-related genes^Citation55		Significant impairment of antiviral IFN responses, reduction in the magnitude of the inducible responses, lowering IFN-I production in DCs^Citation39	Antagonizing the IFN-mediated immune responses by several strategies^Citation21,Citation27
Neutrophils	*Increasing TNF-α, IL-6, and IL-12 production in lymph nodes^Citation41	MF59: inducing CCL3 and CXCL8 chemoattractants,^Citation49 AS03: inducing neutrophil chemoattractants^Citation49	Effect on recruitment by suppression of CXCL1 and CXCL2 production^Citation57	Impairment of phagocytic and chemotactic abilities^Citation45	Elevated levels of neutrophils^Citation58
NK cells	*Inducing the production of IFN-γ,^Citation59 *inducing trained immunity in NK cells^Citation46	*TIV: increased NK cell activity until 30 days, with a peak at day six,^Citation60 possibly due to increased IFN-α production,^Citation61 *enhancing the functionality of NK cells^Citation62	Enhanced function and survival of NK cells,^Citation23 effects on NK cell recruitment by induction of CCL3, CCL4, and CCL5^Citation57	Decline in the functional capacity of NK cells^Citation45	Reduced total number of NK cells^Citation58
DCs	BCG sensing leads to DC maturation and migration, consequent co-stimulatory molecules expression, and pro-inflammatory mediators production^Citation41	MF59: activation of DCs^Citation49	Potent induction of DC maturation and migration,^Citation24 enhanced expression of MHC and co-stimulatory molecules resulting in increasing their ability to induce T cells^Citation57	Reduction of phagocytosis, pinocytosis, migratory capacity, and Ag presentation,^Citation45 dysregulation of inflammatory cytokine production, such as lower IFN-I production^Citation39
Macrophages	*Inducing GM-CSF production,^Citation40 *inducing trained immunity in macrophages, and shifting to an M1-like phenotype^Citation46	MF59: activation of macrophages^Citation49	Effects on cytokine production and antibody-dependent cytotoxicity,^Citation50 upregulation of IL-10 and PDL1 and down-regulation of IFN-γ receptor expression^Citation57	Reduction of TLR expression and pro-inflammatory cytokines production, accumulation of alternatively activated [M2-like] macrophages^Citation45	Macrophage infection, which subsequently leads to viral spread and excessive inflammation^Citation19
T cells	*Inducing nonspecific lymphocyte responses through both cross-reactivity and bystander activation,^Citation11,Citation13 *enhancing the responsiveness of Th1 and Th17 corresponding cytokine induction^Citation46	*Mounting heterologous cellular immune responses against 2009 A[H1N1] pandemic influenza virus by 2007/2008 TIV/MF59,^Citation63 AS03: Inducing the upregulation of CD4 T cell responses,^Citation64 MF59: shifting toward Th2 responses^Citation49	Direct activation of CD4+ and CD8 + T cells, enhancing ability of CD4 + T cells to help B cells,^Citation23 Th1 induction dependent on exposure to IL-12, IFN-I, and IFN-γ^Citation25	Reduction in the number of naïve T cells and elevation in senescent or exhausted T cells, shift toward a Th2-like phenotype^Citation45	Significant T cell lymphopenia,^Citation28,Citation65 elevated exhaustion of T cells and reduced functionality,^Citation29 increased in the mortality rate of patients with more serum Th2 cytokines [17]
B cells	*Enhancing the Ab-mediated responses to nonspecific pathogen or vaccine^Citation11,Citation13	*Mounting heterologous humoral immune responses against nonspecific influenza strains.^Citation63	Promoting B cells activation and antibody responses in the early stages of infection^Citation23	Decrease in the ability of B cells to mount an optimal Ab response^Citation45

* represents relatedness to nonspecific effects.

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