**6. Vaccination against influenza: the prospect of using adjuvants**

The flu is widespread around the world and causes seasonal epidemics, which result in the death of hundreds of thousands of people each year [56]. Complications leading to morbidity and mortality following infection are predominantly observed in high-risk groups: children of early age, people with chronic diseases and pregnant women [57]. According to WHO, globally annual epidemics result in 3,000,000–5,000,000 cases of severe disease and approximately 250,000–500,000 deaths [58].

The vaccination is the most effective tools for preventing of influenza and, as a consequence, reducing the number and severity of post-infectious complications. Inactivated influenza vaccines received the most widely used, due to its high efficiency and low reactogenicity. But, at the same time, inactivated influenza vaccines, including seasonal trivalent vaccines, used for the annual prevention of influenza in the autumn-winter period, are not without some limitations. These vaccines are not enough (effective) immunogenic in vaccinating a number of population groups - small children, pregnant women, the elderly, people with various chronic diseases that are considered to be influenza risk groups. Also, inactivated influenza vaccines are not sufficiently protected against antigenically different strains (drift and heterologous) of the influenza virus that are not contained in the vaccine. In addition, the capacity of all manufacturers may not be sufficient to provide mass vaccine prevention around the world, especially in the event of a pandemic [59–61].

To increase the immunogenicity of inactivated influenza vaccines, adjuvants (immunoadjuvants) have been proposed. With the use of adjuvants, it is possible to increase the immunogenicity of influenza vaccines against a set of antigenically different strains. Adjuvants in the influenza vaccine can also provide efficacy in the immunization of various population groups, including at-risk groups. In addition, a significant increase in the immunogenicity of the vaccine due to the adjuvant will allow the transition to simple (single) immunization regimens, as well as reduce the dose of the antigen (hemagglutinin). This is especially important for pre-pandemic vaccines, because with the same production capacity, more vaccines will be obtained - and as a result, more people are immunized [59, 61].

The action of most adjuvants is based on the prolongation of the AG action, which is provided by the creation of a "depot" of the AG, which slows its absorption. Due to the sorption of AG on certain carriers, the antigen is held in places necessary for exposure of the antigen to antigen presenting cells and lymphocytes. Such an effect occurs when using aluminum alum, immunostimulating complexes, an oil microemulsion [62].

The effect of deposition is also achieved through the use of liposomes [63]. Adjuvants that primarily affect the phagocytic link of the immune system include polyelectrolytes, including PO. Structural association of the AG and polymer-immunostimulant enhances the migration of phagocytes, the functional activity of macrophages in tissues and increases their processing activity [64].

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 injections of the vaccine [63].

(CTL, B lymphocytes) immunity, which provide antiviral effect and induce body's own

The flu is widespread around the world and causes seasonal epidemics, which result in the death of hundreds of thousands of people each year [56]. Complications leading to morbidity and mortality following infection are predominantly observed in high-risk groups: children of early age, people with chronic diseases and pregnant women [57]. According to WHO, globally annual epidemics result in 3,000,000–5,000,000 cases of severe disease and approxi-

The vaccination is the most effective tools for preventing of influenza and, as a consequence, reducing the number and severity of post-infectious complications. Inactivated influenza vaccines received the most widely used, due to its high efficiency and low reactogenicity. But, at the same time, inactivated influenza vaccines, including seasonal trivalent vaccines, used for the annual prevention of influenza in the autumn-winter period, are not without some limitations. These vaccines are not enough (effective) immunogenic in vaccinating a number of population groups - small children, pregnant women, the elderly, people with various chronic diseases that are considered to be influenza risk groups. Also, inactivated influenza vaccines are not sufficiently protected against antigenically different strains (drift and heterologous) of the influenza virus that are not contained in the vaccine. In addition, the capacity of all manufacturers may not be sufficient to provide mass vaccine prevention around the

To increase the immunogenicity of inactivated influenza vaccines, adjuvants (immunoadjuvants) have been proposed. With the use of adjuvants, it is possible to increase the immunogenicity of influenza vaccines against a set of antigenically different strains. Adjuvants in the influenza vaccine can also provide efficacy in the immunization of various population groups, including at-risk groups. In addition, a significant increase in the immunogenicity of the vaccine due to the adjuvant will allow the transition to simple (single) immunization regimens, as well as reduce the dose of the antigen (hemagglutinin). This is especially important for pre-pandemic vaccines, because with the same production capacity, more vaccines will be

The action of most adjuvants is based on the prolongation of the AG action, which is provided by the creation of a "depot" of the AG, which slows its absorption. Due to the sorption of AG on certain carriers, the antigen is held in places necessary for exposure of the antigen to antigen presenting cells and lymphocytes. Such an effect occurs when using aluminum alum,

The effect of deposition is also achieved through the use of liposomes [63]. Adjuvants that primarily affect the phagocytic link of the immune system include polyelectrolytes, including PO. Structural association of the AG and polymer-immunostimulant enhances the migration of phagocytes, the functional activity of macrophages in tissues and increases

**6. Vaccination against influenza: the prospect of using adjuvants**

defense mechanisms against microbial infection.

world, especially in the event of a pandemic [59–61].

obtained - and as a result, more people are immunized [59, 61].

immunostimulating complexes, an oil microemulsion [62].

their processing activity [64].

mately 250,000–500,000 deaths [58].

100 Influenza - Therapeutics and Challenges

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

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 experience [66, 67].

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].

Protective immunity induced by SF-10 (synthetic human pulmonary surfactant with a carboxy vinyl polymer as a viscosity improver) against lethal influenza virus infection was partially and predominantly suppressed after depletion of CD8+ and CD4+ T cells (induced by intraperitoneal injection of the corresponding antibodies), respectively, suggesting that CD4+ T cells predominantly and CD8+ T cells partially contribute to the protective immunity in the advanced stage of influenza virus infection [71]. These results suggest that adjuvants can promote effective antigen delivery to antigen presenting cells, activates CD8+ T cells via cross-presentation, and induces cell-mediated immune responses against antigen.

V Vaccine

AB Antibody

RNA Ribonucleic acid

HA hemagglutinin

Foxp3 Forkhead box рЗ

LPS lipopolysaccarides

DNA deoxyribonucleic acid

APC antigen-presenting cell

Svetlana Anatolyevna Skhodova1

University", Ulyanovsk, Russia

Novokuznetsk, Russia

Alexander Petrovich Cherdantsev3

IL interleukin

AG antigen

**Author details**

Moscow, Russia

PBMC peripheral blood mononuclear cell

MHC Major histocompatibility complex

TGF-β transforming growth factor beta

PRRs pathogen-recognize receptors

CVID common variable immunodeficiency

Mikhail Petrovich Kostinov1,2\*, Nelli Kimovna Akhmatova1

\*Address all correspondence to: vaccinums@gmail.com

1 I. Mechnikov Research Institute of Vaccines and Sera, Moscow, Russia

, Vera Nikolaevna Stolpnikova1

2 Federal State-Funded Educational Institution of Higher Education "First Moscow State Medical University named after I.M. Sechenov" of Ministry of Healthcare of Russia,

3 Federal State-Funded Educational Institution of Higher Education "Ulyanovsk State

4 Novokuznetsk State Institute of Advanced Medical Education, the Branch of Federal State-Funded Educational Institution of Additional Professional Education "Russian Medical Academy of Continuous Professional Education" of the Ministry of Healthcare of Russia,

and Anna Egorovna Vlasenko4

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

, Ekaterina Alexandrovna Khromova<sup>1</sup>

http://dx.doi.org/10.5772/intechopen.77006

103

,

,

nTreg natural thymus-derived regulatory cells

Influenza infection elicits high-affinity IgA in the respiratory tract and virus-specific IgG, which correlates with protection. Long-lived influenza-specific T cells have also been shown to ameliorate disease [72]. Activation of the parameters of innate immunity is critical for the recognition of infection, as well as for the effectiveness of vaccination, which allows not only eliminating pathogens and cells with altered antigenic properties, but also having a significant effect on the formation of adaptive immunity [73].

Development of a universal influenza vaccine currently seems to be quite workable and promising task. Such universal vaccines are expected to contain both antibody production stimulants and inductors of cellular immune response with effectors of innate and adaptive immunity being involved. Adjuvants may play an important part, their functions being aimed both at enhancing immune response to an antigen and at regulating that response [74]. Thus, due to the emergence of a new type of vaccine (adjuvant), in assessing the immunological efficacy is important not only humoral but also cellular immune response.
