Vaccines Induce Homeostatic Immunity, Generating Several Secondary Benefits

Abstract

The optimal immune response eliminates invading pathogens, restoring immune equilibrium without inflicting undue harm to the host. However, when a cascade of immunological reactions is triggered, the immune response can sometimes go into overdrive, potentially leading to harmful long-term effects or even death. The immune system is triggered mostly by infections, allergens, or medical interventions such as vaccination. This review examines how these immune triggers differ and why certain infections may dysregulate immune homeostasis, leading to inflammatory or allergic pathology and exacerbation of pre-existing conditions. However, many vaccines generate an optimal immune response and protect against the consequences of pathogen-induced immunological aggressiveness, and from a small number of unrelated pathogens and autoimmune diseases. Here, we propose an "immuno-wave" model describing a vaccine-induced "Goldilocks immunity", which leaves fine imprints of both pro-inflammatory and anti-inflammatory milieus, derived from both the innate and the adaptive arms of the immune system, in the body. The resulting balanced, 'quiet alert' state of the immune system may provide a jump-start in the defense against pathogens and any associated pathological inflammatory or allergic responses, allowing vaccines to go above and beyond their call of duty. In closing, we recommend formally investigating and reaping many of the secondary benefits of vaccines with appropriate clinical studies.

Keywords: adaptive immunity; cytokine storm; homeostasis; immuno-wave model; infections; innate immunity; para-specific effect; trained immunity; vaccine.

Figure 1

(A) Homeostasis of immunity by soluble mediators. Following stimulation, naïve CD4+ T cells mature into different subsets, secreting a variety of soluble cytokines. Effector cells, such as Th1 and Th17, secrete pro-inflammatory cytokines and interleukins, which in turn stimulate a cascade of inflammatory responses. However, effector cells, such as Th2 and Treg, generate anti-inflammatory cytokines, suppressing inflammatory responses. Peripheral Th1 effector cells produce IFN-γ, IL-2, and TNF-α, and predominantly intestine-bound Th17 effector cells secrete primarily IL-6, IL-17, IL-21, and IL-22 cytokines. Th2 effector cells produce IL-4, IL-5, and IL-10, while Treg cells, also known as suppressor T cells, produce IL-10, IL-35, and transforming growth factor–β (TGF-β) predominantly. The level of immune response is determined by the negative (solid red line) or positive (dashed black line) feedback exerted by these mediators. Secreted mediators contribute to immune homeostasis by helping to prevent polarization of the immune system, maintaining an overall balanced response. The abbreviations used are as follows: APC, antigen-presenting cell; CD, cluster of differentiation; IL, interleukin; IFN-γ, interferon gamma; TGF-β, transforming growth factor beta; Th, T helper cell; Tfh, follicular helper T cells; and Treg, regulatory T cells. (B) homeostasis of immunity by cell surface molecules. Through TCR, CD4+ T cells recognize peptide fragments of antigens displayed by MHC class II molecules on the surface of cells. In addition to this antigen-specific signal, CD4+ T cells require a co-stimulatory signal through the interaction of CD28 with CD80/86 molecules expressed on APC for their activation. CTLA-4 is a T-cell inhibitory molecule that serves to prevent immunological overreaction [30,31]. While the interaction of CD28 with CD80/CD86 (B7-1/7-2) on antigen-presenting cells promotes T-cell stimulation, the interaction of CTLA-4 with CD80/CD86 suppresses T cells and results in T-cell anergy or exhaustion. CTLA-4 is expressed at the basal level in conventional T cells and constitutively in Treg cells [32,33]. PD-1 is another ‘off-switch’ expressed in T cells. When PD-1 binds to ligands such as PD-L1 and PD-L2, which are expressed on antigen-presenting cells, lymphoid, non-lymphoid cells, and tumor cells, it elicits a signal promoting the apoptosis of antigen-specific T cells [34]. The abbreviations used are as follows: APC, antigen-presenting cell; CD, cluster of differentiation; CTLA, cytotoxic T-lymphocyte-associated protein; MHC, major histocompatibility complex; PD, programmed cell death protein; PD-L1 and PD-L2, PD Ligands 1 and 2; and TCR, T-cell receptor.

Figure 2

The figure shows the causes of cytokine storms. A cytokine storm is an umbrella term for life-threatening, systemic, inflammatory disorders resulting from elevated cytokine levels, occurring when immune homeostasis is disrupted, causing immune polarization. Polarization to either a type 1 or type 2 response can be caused by several factors, including genetic predisposition, tissue damage and repair, and direct activation and stimulation of immune cells. Microorganisms are the major cause of inflammatory disorders and immune dysregulation. Some infections cause extensive tissue damage and cell death by either direct lysis of cells or apoptosis, triggering the repair process, which becomes dysregulated, disrupting balance. Pathogens such as EBV, HIV, and SARS-CoV-2 can directly attack immune cells, causing over-activation and resulting in increased levels of cytokines. Mostly, the host’s immune system can regulate and prevent the accumulation of pro-inflammatory cytokines; however, an ineffective, over-active response can result in an uncontrolled cytokine storm. If left untreated, excessive levels of circulating cytokines can result in prolonged activation of signaling pathways, causing acute systemic effects such as organ failure and death. The following abbreviations are used: CD, cluster of differentiation; CTL, cytotoxic T cell; IL, interleukin; IFN-γ, interferon gamma; Th, T helper cell; Treg, regulatory T cells; and SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 3

The figure shows the specific and para-specific effects of vaccines. Vaccination often elicits a controlled immune response, containing a mix of pro-inflammatory and anti-inflammatory cytokines, thereby maintaining immune homeostasis. Beyond protecting against the target pathogen, vaccines also exhibit other immune benefits. Some vaccines may confer protection against closely related pathogens that share conserved antigenic epitopes. However, vaccines have also shown para-specific effects, which are non-specific or heterologous effects that protect or reduce host susceptibility to unrelated infectious and non-infectious diseases. Para-specific effect (PSE) of vaccines prevents or lowers the host’s susceptibility to secondary bacterial infections, sepsis, aggravation of pre-existing conditions, and non-infectious diseases, such as cancer and cardiovascular diseases, allergic asthma, as well as autoimmune diseases, such as type 1 diabetes.

Figure 4

The figure shows immuno-wave model describing spectrum of immune responses. The novel immuno-wave model displays the dynamic nature and various spectra of immune responses ranging from an equilibrium zone to a highly polarized zone of type 1 or type 2 immune responses. Type 1 and Type 2 response levels are represented by the color spectrum, with red being the strongest response and yellow the lowest. In the Goldilocks zone, the immuno-wave is bidirectional and not progressive enough to harm the host. Fluctuation to either end of the Goldilocks zone is minimal, or a shallow ‘seiche wave’, with type 1 and type 2 immunity counteracting one another, and does not result in severe adverse events. However, polarization to either type of immune response enters into unsafe immunity. Polarization can be caused by ‘seismic activity’, such as tissue injury, resulting in a tsunami-like wave. This unsafe immunity zone can cause allergies, autoimmune diseases, multi-organ failures, and death. In the immuno-wave model, vaccines elicit a seiche wave-like immunity, balancing type 1 and type 2 immune responses, resulting in a ‘quiet alert’ state of the immune system in the Goldilocks zone.