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Development of adenoviral vector-based mucosal vaccine against influenza

Journal of Molecular Medicine volume 89, pages 331–341 (2011)Cite this article

Abstract

The recent pandemic threat of the influenza virus makes the increased safety and efficiency of vaccination against the pathogen a most important issue. It has been well established that for maximum protective effect, the vaccination should mimic natural infection. Therefore, recent efforts to develop a new influenza vaccine have focused on intranasal immunization strategies. Intranasal immunization is capable of inducing secretory IgA and serum IgG responses to provide a double defense against mucosal pathogens. On the other hand, it is desirable that a live pathogen is not present in the vaccine. In addition, for optimal induction of the immune responses via the nasal route, efficient and safe mucosal adjuvants are also required. This is possible to attain using an adenoviral vector for vaccine development. Adenoviral vectors are capable of delivering and protecting the antigen encoding sequence. They also possess a natural mechanism for penetrating into the nasal mucous membrane and are capable of activating the innate immune response. This review describes the basic prerequisites for the involvement of recombinant adenoviruses for mucosal (nasal) vaccine development against the influenza virus.

Introduction

The influenza virus (IFV) replicates in epithelial cells (ECs) of upper respiratory tract (URT) mucosa and causes acute respiratory infection. Worldwide, seasonal influenza epidemics result in about three to five million cases of severe illness, and about 250,000 to 500,000 deaths. Pandemic strains of IFV cause more human deaths than seasonal flu in due to absence of protective immunity against newly emerging IFV variants. The most effective way to reduce morbidity and mortality from influenza infection is vaccination [1]. According to WHO program of influenza vaccines development the new vaccine must be safe, effective in preventing disease and death, especially in high risk groups, and should induce long-lasting and broad spectrum of immune responses. These features depend on two primary characteristics of vaccine: composition (chemical, biochemical, and type of vaccine) and route of administration.

Historically established parenteral administration of influenza vaccines lead to predominant formation of systemic humoral IgG immune response. However, several studies have shown that the induction of immune response in the mucous membrane is one of the main vaccine features greatly affecting on immunization efficacy [2]. Immunization through mucous membranes could induce both cell-mediated and humoral immune response generating not only IgG, but also sIgA (secretory IgA), which effectively prevent penetration of pathogen inside the cells and its dissemination throughout the human body. Another advantage of mucosal vaccines is the absence of the needlestick injury.

The most promising method of mucosal vaccination is the nasal route, because mucous membranes of the URT are characterized by a low concentration of enzymes (including proteases) in comparison with other routes of vaccine administration [3] and a high availability of immune reactive sites. [4]. However, mucous membranes of the URT exhibit low epithelium permeability [5]. Therefore, during intranasal administration, free antigens such as proteins and peptides fail to induce an immune response [6]. Different strategies have been developed for delivering vaccine antigens through respiratory epithelium (usage of liposomes, genetic vectors) [7–11]. Among them, the special place occupies usage of viral vectors. They efficiently deliver gene of interest (encoding protective antigen) using effective receptor-mediated mechanism of host cell penetration; provide the expression of vaccine antigens during no less than 2 weeks that is essential for formation of protective immune response and can activate innate immunity by itself that is crucial for induction of adaptive immune response against delivered antigen. Adenoviral vectors (AdVs) are one of the most perspective types of viral-based vectors according their additional positive properties. Most of these vectors have the same routes of infection as influenza virus (penetration into URT mucosal epithelium). Adenoviral vectors infect both divided and non-divided cells; have high transduction efficiency; lack integration into the host genome and other properties. Also, these vectors are safe and was confirmed in more than 150 clinical trials [12]. This review describes the basic underlying conditions for development of mucosal (nasal) vaccines against the IFV using recombinant adenoviruses (rAds).

Respiratory immune system implication in influenza vaccine development

The structure of the nasal mucosal immune system

The mucosa-associated lymphoid tissue (MALT) locates diffusely in various sites of the body in close proximity to mucosal epithelium (nasal, bronchial, gastrointestinal, etc.). MALT is populated by T, B lymphocytes, plasmacytes, macrophages, and DCs, and being a nearest lymphoid tissue to the portals of infection makes significant contribution in immune system formation.

One of the MALT subtypes is nasal-associated lymphoid tissue (NALT), which is located mainly in lymphoid tissue ring in the pharynx and fauces (Waldeyer's tonsillar ring). Membranous cells (M cells) located in mucosal epithelium capture pathogen microorganisms and/or separate antigens and deliver them to dendritic (DCs) and B cells via transcytosis. DCs or B cells present processed antigens to immature T cells in NALT. Additionally, DCs may capture antigens and migrate via draining lymph to regional lymph nodes where they become active antigen-presenting cells and stimulate T and B cells. T and B cells from inductive region of NALT and regional lymphatic nodes migrate via efferent lymph vessels by preferential homing mechanisms to the effector mucosal sites in lamina propria (subepithelial layers of mucosa tissue). In these effector areas, differentiated cytotoxic T lymphocytes (CTLs) execute their protective function by infected cells elimination, whereas B cells differentiate to plasma cells (PCs) producing secretory antibodies [13]. These antibodies secreting by PCs is the major component of acquired mucosal immunity. They include sIgA and, in a less degree, the secretory immunoglobulin M (sIgM), as well as both plasma and local IgG.

At present time, it is considered that sIgA expression is a key mechanism which serves not only for inhibition of infection process in the immunized individuals but also prevents viral dissemination from infected persons [14].

The mechanisms of the immune response development against an influenza virus infection

Induction of immune response against IFV starts from viral components recognition by innate immune system (Table 1). One of the first receptors which recognize viral infection is pattern-recognition receptors (PRRs) [15]. IFV which genome is presented by segmented single stranded RNA (ssRNA) is recognized by TLR3, TLR7, TLR8, and RIG-1 receptors. [16–21]. Interaction of these receptors with their ligands initiate number of intracellular signal transduction cascades, leading to activation of major proinflammatory transcription factor NF-kB and several interferon regulatory factors (IRFs), resulting in induction of innate immune response. As result of TLRs-mediated IRFs activation various cell types (DCs, monocytes/macrophages, fibroblasts) are able to express type 1 IFNs [22]. Their antiviral action is mediated by protein kinase A (PKA)-mediated blockage of protein synthesis and by viral RNA degradation by RNAase1. Other humoral components of innate immunity which contribute substantial impact in inhibition of IFV infection are complement system (C5), surfactant proteins A and D and scavenger-receptor gp340.

Table 1 Comparative analysis of the immune response development upon vaccination with adenoviral vectors and live attenuated vaccine against influenza virus
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Another important role in inhibition of influenza infection plays cellular components of innate immunity. The lung infiltrate produced during influenza infection contains mainly neutrophils, NK-cells, and macrophages. Neutrophils appearing in lung infiltrate about 18 h after infection are able to adhere to influenza virus-infected cells and to phagocytose influenza virions [23–25]. Also, they exhibit antiviral activity by secretion of immune mediators such as myeloperoxidase [26], defensins [27], reactive oxygen and/or nitrogen species [25, 28], producing IFNα or antiviral cytokines such as TNFα. Lung macrophages are capable to engulf both viral particles, virus-infected cells [29] and secrete proinflammatory cytokines: TNFα, IL-1β, IL-6, and IFNα/β [30], and chemokines MIP-1α, MCP-1, RANTES, and IP-10 [31], which inhibit virus reproduction and stimulate migration of immune cells into infection site. NK cells appear in lung infiltrate in 48 h after infection [32, 33]. NK cells recognize IFV-infected cells (with exposed on the cell surface hemagglutinin) using NKp46 [34] and NKp44 [35] receptors [36]. Activated NK cells realize their direct cytotoxic functions secreting granzymes and perforins as well as producing IFNγ, which inhibit viral replication [37].

The activation of all above-mentioned reactions of innate immunity is necessary to retard the progression of viral infection until formation of adaptive immune response.

An adaptive response development occurs in the peripheral lymph nodes and lymphoid tissues associated with the mucosal surfaces [38]. The important role in intricate cooperation among innate and adaptive immunity play DCs. These cells phagocyte viral particles and present viral antigens in association with MHC class I and II molecules to T cells. Cytokine microenvironment developing during IFV infection (IFNγ, IFNα/β, IL-12, and TNFα) polarizes DCs for priming immature Th0 into Th1, Th2, and Th3 types. Differentiated T helpers stimulate the development of CTLs and PCs which are secreting IgG and IgA (Table 1) [39]. Thus, Th cells secrete IL-2 which is important for CTLs generation. Th1 cytokine IFN-γ is important for switching of B cells to IgG2a- and IgG3-producing PCs. The Th2 cytokine IL-4 is essential for normal IgG1 and IgE isotype switching. For switching of B cells to IgA-producing PCs, three types of Th are essential. Th3 (TGF-b1) regulates the switching to IgA isotype, Th2 (IL-4) stimulates proliferation of IgA+ B cells, and Th1 (IFN-γ) enhances expression of pIgR [40].

Activated B and T lymphocytes formed in response to influenza infection migrate into mucosal epithelium and execute their effector functions in a direct proximity to the viral infection site. The migration of activated lymphocytes is mediated by expression of specific homing receptor, α4β7 integrin on their surface. Using this receptor, lymphocytes penetrate through endothelium into the mucosal tissue interacting with adhesion molecule MAdCAM-1 (Fig. 1) [41, 42].

Fig. 1
figure 1

The NALT immune system. Antigen uptake by M cells occurs in NALT and results in the initial induction of the immune response. The viral infection of cells directly stimulates the production of cytokines (interferons). This is accompanied by the inhibition of both viral replication and cell proliferation, as well as the augmentation of the natural killer (NK) cell's ability to lyse virally infected cells. Macrophages and dendritic cells absorb the antigens and “present” them to T helper cells. T helpers provide a stimulating signal to B lymphocytes (B) and activate T killer (TK) cells. B lymphocytes produce antibodies and “memory cells.” Antigen-sensitized, precursor sIgA+ B cells, CD4+ Th cells, and CD8+ CTLs depart via efferent lymphatics and migrate to the bloodstream. They extravasate from the blood using the α4β7 integrin, which binds to MAdCAM on lamina propria vessels, where terminal differentiation, synthesis, and transport of sIgA occur. Effector sites for mucosal immune responses include the lymphoid cells in the lamina propria

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SIgA represents the major antibody isotype produced at the mucosa. It consists of two IgA (dimeric IgA (dIgA)). dIgA binds to polymeric Ig receptor (pIgR) at the basolateral membrane of mucosal epithelium. Complexes of dIga with pIgR are endocytosed and transported to the mucosal lumen, where secretory component (ectodomain of the pIgR) are cleaved, leading to local SIgA production [43]. It is considered that sIgA antibodies secreted by PCs are able to migrate by transcytosis from the effector NALT regions to the tracheal and bronchial mucosal surfaces and prevent cell infection both on mucosal surfaces and inside the infected ECs, preventing virus replication and release from infected cells. Additionally, sIgA is considered to play a major role in the development of protective immunity against different IFV subtypes (cross-protective immunity). The accurate mechanism of the cross-reactive effects of sIgA is still unknown [44].

The second class of antibodies essential for protection from pneumonia caused by influenza infection is IgG. This type of antibodies passively diffuses to alveolar and bronchoalveolar mucosal surface from peripheral blood or from effector sites of NALT. The other part (cell-mediated) of adaptive immune response against influenza is realized by CTLs and Th1 cells. CTLs appear in NALT by days 7–10 after infection and eliminate virus-infected cells by direct cytotoxicity. Additionally, CTLs as Th1 cells inhibit viral replication by the IFNγ secretion (Table 1) [45, 46].

Modern influenza vaccines and major requirements for new vaccine development

Current seasonal influenza vaccines include material from two strains of influenza A and one of influenza B. Today, inactivated IFV (whole, split, or subunit) or live attenuated IFV are used as the vaccine. They stimulate production of virus-neutralizing Abs, most of them recognize hemagglutinin (HA), which is the major surface glycoprotein of IFV. High efficacy, safety, and low cost are main requirements for influenza vaccines. Inactivated parenteral influenza vaccines are safe enough (can be used with immunodeficient patients, children 6 months to 18 years of age, adults ages 50 and up) but has several major disadvantages:

  1. (1)

    In the case of parenteral administration of influenza vaccine, only 18–31.8% of the recipients exhibited sIgA secretion, which is likely responsible for formation cross-protective immunity against IFV [47].

  2. (2)

    Parenteral vaccines require recurrent administration (revaccination), which increase cost of preventive measures.

The above-mentioned disadvantages stimulate the development of new effective non-injectional vaccine types.

At the present time, live cold-adapted reassortant influenza vaccine based on the attenuated IFV strain has been developed for intranasal vaccination [11]. This vaccine was effective for the mass vaccination of healthy people. It has been shown that this vaccine induce robust immune response against influenza consisting of humoral (sIgA formation on mucosa surface of URT, and IgG in blood serum) and T cell-mediated response.

However, attenuated vaccines are not recommended for aged people, children under 3 years of age, and immunodeficient patients on account of their residual virulence and viral ability to undergo to genetic reversion into a pathogenic virus.

Therefore, in order to increase vaccine safety, a lot of efforts have been made to create inactivated mucosal influenza vaccines. However, such vaccines exhibited low immunogenicity, which is likely a result of the inability of an inactivated IFV or its capsid components to effectively penetrate into submucosal layer and induce strong immune response against influenza. This problem has been solved by the virosomal vaccine development (based on an inactivated IFV), NasalFlu (Bern, Biotech, Switzerland), with Escherichia coli thermolabile enterotoxin as adjuvant. Such vaccine effectively penetrates of the mucosa due to its liposomal component and activate strong immune response (including sIgA secretion in URT), whereas heat-labile E. coli toxin enhance cell-mediated immune response against IFV. This vaccine has been licensed and recommended for clinical practice. Unfortunately, usage of this vaccine was not safe enough; in some cases, vaccination with NasalFlu led to facial paralysis [48].

Despite the failure, attempts to create live pathogen-free vaccines are continuing. One of perspective approaches is development of vaccines based on viral vectors. Such vaccines are safe enough (viral vectors cannot replicate in human organism), effectively stimulate innate immunity (serve as adjuvants), and stimulate development of strong immunity against expressing transgene (provide prolonged antigen expression in native form).

Adenovirus-based mucosal vaccines

Immune response to adenoviral vector-based mucosal vaccines

AdVs have a lot of features (Table 2) which allow to use them for effective delivery of foreign genes into eukaryotic cells. It has been shown that AdVs bearing genes encoding protective antigens of pathogen induce strong immune response against corresponding pathogen [49]. This phenomenon served as a prerequisite for AdV-based vaccine development against various pathogens [49–53]. In due to the ability of adenoviruses to effectively penetrate human organism through mucosal epithelium, this vector type are extensively used for creation of new generations of needle-free mucosal vaccines [54]. It allows to deliver genes into different cell types (ECs, DCs, macrophages, etc.) and express corresponding proteins in close proximity of inductive sites of MALT regions.

Table 2 Major properties of recombinant adenoviruses
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Although exact mechanism of protective immune response induction after immunization with AdV-based mucosal vaccine was not clearly defined, there are several studies that allow us to suggest that cascade of immune reactions after AdVs penetration is similar to influenza but has some differences (Table 1) [55–57]. TLR9 and RIG-1 recognize double-stranded adenoviral genomic DNA, stimulating phagocytosis and antigen presentation of immune cells [58, 59].

DCs expressing target antigen due to transduction by Ad-vector or DCs which phagocyted target antigen present processed antigen to immature CD8+ or CD4+ cells consequently. As a result of antigen presentation, CD8+ becomes mature CTL, whereas CD4+ polarizes to Th1, Th2, and Th3 cells which create appropriate conditions (by secretion of specific cytokines) for formation of PCs producing IgG and sIgA antibodies [57, 60, 61].

It is worth to note that the development of an adaptive immune response to Ad-based vaccine is predominantly oriented on the expression of transgenic product and, in a much lesser extent, on the expression of the vector itself [60]. It is due to preferential AdV-mediated expression of transgene, whereas almost no expression of adenoviral-specific genes occurs. The expression time of antigen of interest during adenoviral infection (4–5 weeks) resembles character of antigen expression occurring during real virus infection. Thereby, AdV-based vaccines imitate respiratory infections (including influenza) in human organism, and as result, induce an efficient immune response without usage of adjuvant (Table 1) [60].

Adenovirus-based vaccine development

The efficacy of nasal vaccines based on AdVs has been proven in series of works focused on development of vaccines against various IFV serotypes (including the avian IFV H5N1) [62, 63]. It was shown that vaccines based on AdVs are able to effectively induce both humoral and cell-mediated immunity against corresponding IFV strain [62–65]. Study results made by Hoelscher and co-workers have shown that intranasal immunization with Ad5-H5HA induces both humoral and cell-mediated immunity against H5HA [64]. Moreover, even single-dose nasal immunization led to induction of protective immunity against influenza [62–65].

At present time, phase I clinical trials of nasal vaccine based on RCA-free Ad5 vector against IFV H5N1 successfully finished in the United States. This study showed that the rAd bearing IFV hemagglutinin (HA) gene was safe for human, possessed high immunogenicity to this pathogen, and could be further used as a vaccine [66], whereas another trials initiated in 2008 are still continuing [67]. Phase II clinical trials using two different nasal influenza vaccines based on Ad5 vectors are expected to be completed within 5 years [68].

The existence of preformed humoral immunity against adenovirus in human populations is one of the potential limitations of the use of adenoviruses as vaccine [69]. For example, more than 50% of the adult human population has the high titer of neutralizing antibodies against Ad5 [70–73]. Different strategies were suggested and applied to circumvent Ad (Ad5) pre-existing immunity [69]: covalent modification of capsid proteins and Ad incapsulation [74–77], serotype switching [78, 79], and usage of helper-dependent Ad vectors [80]. Interestingly enough, intranasal route of AdV-based vaccine administration may help to solve this problem too [66, 81, 82]. For example, the data obtained by Croyle and co-workers have shown that single intranasal immunization with rAd5-based vaccine against Zaire Ebola led to 100% protection in both naive mice and those with pre-existing immunity [81].

Adenovirus-based vaccines induce heterosubtypic immunity against influenza

It was believed for a long time that heterosubtypic immunity can be provided by subtype cross-reactive CTLs that recognize conserved epitopes of IFV internal proteins such as nucleoprotein and matrix protein. A lot of studies reported about it. Some of them are devoted to adenovirus-based vaccines [62, 83, 84]. Humoral immunity, B cells, and antibodies also contribute to heterosubtypic protection against IFV [85–88]. Recent studies showed that monoclonal antibody (including virus-neutralizing) that reacts with a variety of IFV subtypes recognizes a common epitope of HA [85–88]. Additionally, it was shown that different genetic vaccines (including AdV-based) bearing hemagglutinin gene are capable to induce cross-protective immunity between IFV subtypes containing the same hemagglutinins but expressing various neuraminidases. One study showed that AdV-based vaccine bearing hemagglutinin gene are capable to induce cross-protective immunity between subtypes containing different hemagglutinins (H5 and H7) [89].

Formation of heterosubtypic humoral immunity probably associated with existence of conservative epitope in the structure of hemagglutinin [89–91]. Recent data showed that various IFV subtypes could be divided into four clades according to the similarity not only of HA nucleotides sequences, but also of conservative epitope localized in the stem domain of hemagglutinin, some of which recognized with virus-neutralizing antibodies (Fig. 2a) [92–95]. The percent homology between conserved epitopes of IFV subtypes from different clades is 70–90%, but 90–100% between conserved epitopes of different subtypes within one clade [94].

Fig. 2
figure 2

Heterosubtypical immunity to the influenza virus development followed intranasal vaccination by recombinant adenovirus. a Division of influenza subtypes by clades. b The scheme of nasal immunization for a mouse with recombinant adenovirus Ad-HA5-2. Ad-HA5-2virus was constructed using Ad-Easy method and manual as described previously. Infection units were determined by plaque assay in 293 cells. The mice were divided into ten groups (ten animals in each) and were intranasally immunized twice by recombinant adenoviruses Ad5-HA5-2 and Ad5-null at a dose of 108 PFU/mouse with an interval of 21 days. On day 21 after the second immunization, the mice were stupefied by ether and injected by either a lethal dose (50LD50) of influenza virus A/Mallard/Pensylvania/10218/84 H5N2 strain, adequately virulent for mice, or a lethal dose (10LD50) of influenza viruses A/Black duck/New Jersey/1580/78 (H2N3), A/CCCP/90/77 (H1N1), and A/Aichi/2/68 (H3N2). c Survival graph of mice immunized with Ad5-HA5-2 after the influenza viruses of various clades infection. Survival was estimated 16 days after infection

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Therefore, we suggested that an AdV-based vaccination could induce secretion of antibodies against conservative epitopes of external influenza antigens. AdV-based vaccination could provide cross-protective immunity against IFVs within one clade (viruses within one branch of phylogenetic tree of influenza A virus hemagglutinins). To examine this hypothesis, we have constructed recombinant Ad-HA5-2 based on Ad5 bearing influenza hemagglutinin A/Mallard/Pensylvania/10218/84 (H5N2) (GenBank: AF512940.1). Ad-HA5-2 virus was constructed using Ad-Easy method as described previously [96]. Mice had been intranasally immunized with this rAd, and after, different groups of mice have been infected with three IFV strains belonging to one clade (A/Mallard/Pensylvania/10218/84 (H5N2), A/USSR/90/77 (H1N1) and A/Black duck/New Jersey/1580/78 (H2N3) and with one IFV strain from another clade (A/Aichi/2/68 (H3N2)). We have shown that immunization with rAd lead to 100% protection against A/Mallard/Pensylvania/10218/84 (H5N2), A/USSR/90/77 (H1N1), and 70% protection against A/Black duck/New Jersey/1580/78 (H2N3) viruses. However, there was no protection against A/Aichi/2/68 (H3N2) virus (Fig. 2b, c).

Thus, according to these results, immunization with rAd bearing in genome expressing cassette with hemagglutinin gene of IFV A/Mallard/Pensylvania/10218/84 (H5N2), induce immune response and protect immunized mice from lethal dose of IFVs within H5 clade, but not protect from H3 IFV which belongs to another clade. One of the probable approaches to achieve protection against H3 influenza infection is usage of rAd with HA gene from H3, H4, or H14 virus types (H3-clade). [96]

Obtained data may be explained by presence or absence of homological epitopes in HA structure of IFVs from different clades. According to study obtained by Throsby and colleagues [92], H5 and H1 virus HAs have a common conservative epitope, whereas amino acids sequence of H3 virus HAs in site of H5 and H1 conservative epitope differ. An analysis of the amino acid sequences of IFV hemagglutinins in strains A/USSR/90/77 (H1N1), A/Mallard/Pennsylvania/10218/84 (H5N2), and A/Aichi/2/68 (H3N2), which were all used in this study, showed that the described hemagglutinin epitopes are highly homologous in H1 and H5 subtypes. This epitope is, however, significantly different in strain A/Aichi/2/68 (H3N2), which does not belong to the first clade of IFVs.

Another way to stimulate heterosubtypic immune response against IFV consists in utilization of more conservative antigens than hemagglutinin,—nucleoprotein (NP), M2 protein. As was shown, mice immunized with rAds, expressing NP and M2 of influenza virus H1N1 had 95–100% protection against infection of H5N1 [62, 97].

In spite of ability of Ad-based vaccines to induce heterosubtypic immunity, this vaccine type is needed to be studied further. We may suppose that construction of panel of AdVs bearing IFV hemagglutinin gene from four various clades allow to create vaccine which could provide protection against most part of epidemic variants of the IFV.

Conclusions

A lot of pathogens are mucosally transmitted, but influenza undoubtedly has the greatest epidemiological impact. Today, safe and effective vaccine that could induce long-lasting and heterosubtypic immune responses still have not been developed. Influenza infection is a predominantly mucosal-acquired disease. It is well known that for maximum protective effect, vaccination should mimic natural infection. On the other hand, it is desirable that a live pathogen shouldn't be present in a vaccine. Immunization through mucosal route is capable to induce sIgA and serum IgG responses to provide a double defense against mucosal pathogens. These facts highlight the importance of mucosal immunity in influenza infection and the necessity to develop vaccines and/or immunization strategies to induce local mucosal immune responses against this pathogen.

For a long time, intranasal drug delivery has been used for administration of various drugs. The advantages of intranasal delivery are follows: it is needle-free, noninvasive, and essentially painless, does not require sterile preparation, and it can be self-administered. However, there are several disadvantages of intranasal delivery: low permeability for polar and high molecular weight drugs, mucociliary clearance of foreign molecules and irritation of nasal mucosa that results in coughing and sneezing with the accidental expulsion of the part of vaccine dose. Data summarized in this review indicates that AdVs, primarily Ad5, can be used as a nasal vaccine against the IFV. The major advantage of AdVs is their natural tropism to mucosal surfaces, which makes them an ideal tool for mucosal vaccination. It has been also suggested that numerous DCs in the nasal mucosa could be also targeted by these vaccines [98]. Mice infected with a lethal dose of IFV after intranasal immunization with AdV-based vaccine were absolutely protected. Our data shows that rAd5 carrying hemagglutinin gene of IFV H5N2 (clade H1) do not protect against H3N2 virus (clade H3). Regarding to these findings, we suggested that vaccine based on four rAds, bearing genes of antigens from each of four clades or multivalent rAd could be effective and induce broad heterosubtypic humoral immune response against different IFV strains.

The data obtained from animal studies has suggested that intranasal vaccination with AdVs is also effective for protection against the measles virus and Mycobacterium tuberculosis infections [99–101]. These pathogens have similar to influenza airway-mucosal route of infection. We believe that these encouraging results of adenoviral vaccine studies will soon promote their further evaluation in clinical trials.

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  1. Laboratory of Molecular Biotechnology, Gamaleya Research Institute of Epidemiology and Microbiology, ul. Gamaleya 18, Moscow, 123098, Russia

    Irina L. Tutykhina, Denis Y. Logunov, Dmitriy N. Shcherbinin, Maxim M. Shmarov, Amir I. Tukhvatulin, Boris S. Naroditsky & Alexander L. Gintsburg

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  1. Irina L. Tutykhina
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  2. Denis Y. Logunov
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  3. Dmitriy N. Shcherbinin
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Tutykhina, I.L., Logunov, D.Y., Shcherbinin, D.N. et al. Development of adenoviral vector-based mucosal vaccine against influenza. J Mol Med 89, 331–341 (2011). https://doi.org/10.1007/s00109-010-0696-0

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Keywords

  • Nasal vaccines
  • Influenza virus
  • Adenoviral vector