**5. Conclusion**

nTreg is implemented both through cytokine secretion, such as TGF-β and IL-10, and through

Innate immune mechanisms are key to protection against pathogens, since they ensure prompt inflammatory reactions including detection of highly conservative structures, which are common to many microorganisms, through special receptors of broad specificity. These

Having recognized a specific pattern, PRRs initiate a series of signal cascades, which make the first line of defense against microorganisms. Besides, these signals initiate maturation of dendritic cells, which prepare the second line of immune response to the infection, known as acquired immunity. Thus, TLRs contribute to the regulation of innate and acquired immunity. Currently known are 11 types of TLRs in humans and 13 types in mice [37, 38]. Four of them (TLR3, TLR7, TLR8, and TLR9) recognize virus RNA and DNA. TLRs have an established role in physiological regulation of pro-inflammatory cytokine production, which are required for immune response to infections caused by bacteria, fungi, and viruses [39]. Inflammation is known to be directly associated primarily with neutrophils, which express almost all identified TLRs, as it has been shown recently. This explains the importance of TLRs in neutrophil activity regulation: LPS-induced TLR4 activation induces the production of pro-inflammatory cytokines and chemokines (IL-1β, IL8, and TNFα); TLR2, TLR4, and TLR9 stimulation is accompanied by respiratory burst and changed expression of adhesion molecules [40, 41].

The study of the effect influenza vaccine has on TLR-positive cell (granulocyte) expression

Patients with initially different anti-influenza AT titers *in vitro* showed statistically significant differences in TLR3, TLR8, and TLR9-expressing cell counts, depending on the type of influ-

All the influenza vaccines studied, caused a statistically significant (p < 0.05) increase in TLR2-, TLR6-, TLR8-, and TLR9-positive granulocyte counts in PBMC culture, compared to

*Subunit vaccine* showed statistically significant (p < 0.001) stimulating effect on the expression of TLR4-positive granulocytes, compared to control group and split vaccine. TLR4 is known

*Split vaccine* provided better increase in TLR3- (p = 0.008) and TLR9- (p = 0.001) positive cell counts, compared to subunit vaccine. Both vaccines had similar effect on TLR8+ granulocyte proliferation. TLR3 is an important receptor in recognition of viral double-stranded RNA generated during replication [43]. TLR3 expression by CD4+ и CD8+ lymphocytes is known to be accompanied by their activation, which allows them to get directly involved in various

Dendritic cell activation has been reported to occur predominantly with TLR2, TLR3, TLR4, TLR7, and TLR9. TLRs are effective contributors to APC activation, not only because they induce pro-inflammatory cytokine production, but also because they enhance expression of various co-stimulating molecules required for effective antibody recognition [45, 46]. Moreover, TLRs control dendritic cell maturation and antigen-presenting function [47].

contact interaction with the effector T lymphocytes and antigen-presenting cells [31, 32].

are signal PRRs, and TLRs are the most important of them [33–36].

gave the following results.

98 Influenza - Therapeutics and Challenges

non-stimulated cells.

types of immune response [44].

enza vaccine added to leukocyte culture.

to be an important regulator of neutrophil survival [40–42].

Thus, the studies have shown that influenza vaccines activate cellular immunity effectors as well as induce humoral immune response. PO-containing adjuvanted vaccine showed the strongest capability of inducing the cellular response, among the three vaccines studied.

Influenza vaccines *in vitro* induced an increase in the number of the innate and acquired immunity effectors: NK cells, NKT cells, В lymphocytes, cells with early activation marker, Т lymphocytes with late activation marker, and regulatory Т cells.

Despite the fact that influenza vaccines must activate endosomal receptors, they cause nonspecific activation of the surface TLRs. This might be due to the influence exerted by antigen complexes contained in influenza vaccines of various types and due to the presence of an adjuvant in one of the vaccines studied. These vaccines activate TLR signaling cascade and, thus, can probably stimulate key effectors of the innate (DC, NK, and NKT cells) and adaptive (CTL, B lymphocytes) immunity, which provide antiviral effect and induce body's own defense mechanisms against microbial infection.

The action of adjuvants depends on the initial immune status of the organism preceding the vaccination. Adjuvants accelerate development and increase the level of immune response, increase the duration of its retention. Long rise and a slow decrease in the intensity of postvaccination immunity is characteristic of adjuvanted vaccines. At the same time, a reliable immune response is achieved with the help of small doses of AG and a small number of

The Impact of Adjuvanted and Non-Adjuvanted Influenza Vaccines on the Innate and Adaptive…

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PO possesses expressed immune modulating effects acting first of all on the innate immunity factors such as monocytic-macrophagal system cells, neutrophils and NK-cells and inducing their activation under initially reduced functions. Flow cytochemistry data showed that PO does interact with three lymphocyte subclasses, predominantly binds with monocytes and neutrophils and to a lesser extent with lymphocytes, enhancing intracellular H2O2 production. Hydrogen peroxide being the secondary messenger activates the transcriptional NF-kB factor that is the participant of the cytokines synthesis regulation. The enhancement of the pro-inflammatory cytokines IL-1β, IL6, TNF-α synthesis takes place. Activation by PO cells of monocytic-macrophagal cluster and natural killers promotes mobilization of both cellular and humoral immunity. Finally, all immunity starts up for adequate response development

Besides its own clinical application as independent drug, Polyoxidonium is used as immunoadjuvant in new generation vaccines and is a compound in subunit adjuvanted Grippol family vaccines since 1997 when first Grippol® vaccine was registered in Russian market. Due to Polyoxidonium, all Grippol family vaccines contain 3-times lower antigen content in one immunizing dose - 5 mcg per strain, in comparison to 15 mcg per strain in other subunit and split influenza vaccines. This provides Grippol family vaccines with higher safety profile. Today Grippol vaccines are approved and especially recommended for vaccination of cohorts that previously were considered to be not vaccinated (patients with allergic conditions, subjects with chromic somatic diseases, individuals with different immune deficiencies), and children from 6 months of age, and pregnant women. These recommendations were made based on relevant clinical trials results followed by many years practical mass vaccine application

Annual vaccination with the "yearly adapted vaccine" is an effective means of prevention and control of influenza in immunocompetent individuals, even in those with a known poor antibody response. In addition to the development of protective antibodies after vaccination, the induction of cell-mediated immunity is considered to be of critical importance [68]. Recent researches concerning the response to influenza vaccination in patients with CVID and unclassified antibody deficiency have shown that while the humoral immune response was strongly impaired, a T cell response against the vaccine was detected in most patients [69]. Seasonal vaccines primarily work through the induction of neutralizing antibodies against the principal surface antigen HA. This important role of HA-specific antibodies explains why previous pandemics have emerged when new HAs have appeared in circulating human viruses. It has long been recognized that influenza virus-specific CD4(+) T cells are important in protection from infection through direct effector mechanisms or by providing help to B cells and CD8(+) T cells. However, the seasonal influenza vaccine is poor at inducing CD4(+) T cell responses and needs to be combined with an adjuvant facilitating this response [70].

injections of the vaccine [63].

experience [66, 67].

similarly to that as it occurs in natural way [65].
