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,40 NOD-like receptors, RIG-I41	Engaging TLR7,42 LAIV: increasing expression of RIG-I and TLR-343	Enhancing TLR responsiveness in macrophages44	Decline in TLR expression and function45
Proinflammatory mediators	*Inducing the production of pro-inflammatory cytokines such as TNFα, IL-1β, and IL-646	*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.47 TIV/MF59: significant increase in IL-5 and IL-6, IFN-γ, IL-2, Th2 responses,48 AS03: STAT1 and MX1 upregulation49	Cytokines/chemokine regulation such as IL-15 and IFN-γ50	Increase in proinflammatory cytokines such as TNF, IL-1, and IL-651,52	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,27 elevated levels of IL-6, which is associated with cytokine storm32
IFNs [production and duration]	*Increasing IFN-γ production,53 inducing a negative regulator of JAK/STAT signaling pathway, SOCS154	TIV: early induction of type-I and -III IFNs,55 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,56 TIV and LAIV induce overexpression of IFN-related genes55		Significant impairment of antiviral IFN responses, reduction in the magnitude of the inducible responses, lowering IFN-I production in DCs39	Antagonizing the IFN-mediated immune responses by several strategies21,27
Neutrophils	*Increasing TNF-α, IL-6, and IL-12 production in lymph nodes41	MF59: inducing CCL3 and CXCL8 chemoattractants,49 AS03: inducing neutrophil chemoattractants49	Effect on recruitment by suppression of CXCL1 and CXCL2 production57	Impairment of phagocytic and chemotactic abilities45	Elevated levels of neutrophils58
NK cells	*Inducing the production of IFN-γ,59 *inducing trained immunity in NK cells46	*TIV: increased NK cell activity until 30 days, with a peak at day six,60 possibly due to increased IFN-α production,61 *enhancing the functionality of NK cells62	Enhanced function and survival of NK cells,23 effects on NK cell recruitment by induction of CCL3, CCL4, and CCL557	Decline in the functional capacity of NK cells45	Reduced total number of NK cells58
DCs	BCG sensing leads to DC maturation and migration, consequent co-stimulatory molecules expression, and pro-inflammatory mediators production41	MF59: activation of DCs49	Potent induction of DC maturation and migration,24 enhanced expression of MHC and co-stimulatory molecules resulting in increasing their ability to induce T cells57	Reduction of phagocytosis, pinocytosis, migratory capacity, and Ag presentation,45 dysregulation of inflammatory cytokine production, such as lower IFN-I production39
Macrophages	*Inducing GM-CSF production,40 *inducing trained immunity in macrophages, and shifting to an M1-like phenotype46	MF59: activation of macrophages49	Effects on cytokine production and antibody-dependent cytotoxicity,50 upregulation of IL-10 and PDL1 and down-regulation of IFN-γ receptor expression57	Reduction of TLR expression and pro-inflammatory cytokines production, accumulation of alternatively activated [M2-like] macrophages45	Macrophage infection, which subsequently leads to viral spread and excessive inflammation19
T cells	*Inducing nonspecific lymphocyte responses through both cross-reactivity and bystander activation,11,13 *enhancing the responsiveness of Th1 and Th17 corresponding cytokine induction46	*Mounting heterologous cellular immune responses against 2009 A[H1N1] pandemic influenza virus by 2007/2008 TIV/MF59,63 AS03: Inducing the upregulation of CD4 T cell responses,64 MF59: shifting toward Th2 responses49	Direct activation of CD4+ and CD8 + T cells, enhancing ability of CD4 + T cells to help B cells,23 Th1 induction dependent on exposure to IL-12, IFN-I, and IFN-γ25	Reduction in the number of naïve T cells and elevation in senescent or exhausted T cells, shift toward a Th2-like phenotype45	Significant T cell lymphopenia,28,65 elevated exhaustion of T cells and reduced functionality,29 increased in the mortality rate of patients with more serum Th2 cytokines [17]
B cells	*Enhancing the Ab-mediated responses to nonspecific pathogen or vaccine11,13	*Mounting heterologous humoral immune responses against nonspecific influenza strains.63	Promoting B cells activation and antibody responses in the early stages of infection23	Decrease in the ability of B cells to mount an optimal Ab response45

* represents relatedness to nonspecific effects.