Elsevier

Experimental Gerontology

Volume 54, June 2014, Pages 21-26
Experimental Gerontology

Review
Mucosal adjuvants for vaccines to control upper respiratory infections in the elderly

https://doi.org/10.1016/j.exger.2014.01.006Get rights and content

Highlights

  • Pathogen-specific SIgA Abs are the central players for mucosal Immunity in aging.

  • A nasal DC-targeting, double adjuvant system overcomes mucosal immunosenescence.

  • A double adjuvant system induces a more balanced Th1- and Th2-type cytokine response.

Abstract

Influenza virus and Streptococcus pneumoniae are two major pathogens that lead to significant morbidity and mortality in the elderly. Since both pathogens enter the host via the mucosa, especially the upper respiratory tract (URT), it is essential to elicit pathogen-specific secretory IgA (SIgA) antibody (Ab) responses at mucosal surfaces for defense of the elderly. However, as aging occurs, alterations in the mucosal immune system of older individuals result in a failure to induce SIgA Abs for protection from these infections. To overcome mucosal immunosenescence, we have developed a mucosal dendritic cell targeting, novel double adjuvant system which we show to be an attractive and effective immunological modulator. This system induces a more balanced Th1- and Th2-type cytokine response which supports both mucosal SIgA and systemic IgG1 and IgG2a Ab responses. Thus, adaptation of this adjuvant system to nasal vaccines for influenza virus and S. pneumoniae could successfully provide protection by supporting pathogen-specific SIgA Ab responses in the URT in the mouse model of aging. In summary, a double adjuvant system is considered to be an attractive and potentially important strategy for the future development of mucosal vaccines for the elderly.

Introduction

Vaccines that provide protection of the mucous membranes in addition to the systemic tissues are an ideal strategy for preventing infectious diseases, most of which are initiated by the invasion of pathogens through the mucosa. In this regard, the development of effective mucosal vaccines requires a complete understanding of the intricacies within the mucosal immune system itself. The mucosae can be divided anatomically and functionally into organized lymphoid tissues where initial induction of immunity occurs and more diffuse sites where actual effector immune responses take place (Fujihashi and Kiyono, 2009, Fujihashi et al., 2013, Kiyono et al., 2008). Both nasopharyngeal- and gut-associated lymphoid tissues (NALT and GALT) serve as major inductive sites for mucosal immunity in the upper respiratory (UR) and gastrointestinal (GI) tracts. NALT and GALT are covered by a lymphoepithelium containing microfold (M) cells which are most proficient in the uptake of luminal antigens (Ags) (Fujihashi et al., 2013, Kiyono et al., 2008). The subepithelium is especially enriched in Ag-presenting cells (APCs) including dendritic cell (DC) subsets. Underneath this APC enriched subepithelium lies two distinct areas, a B cell zone with germinal centers enriched in surface IgA+ B cells and a separate but adjacent T cell area with both naïve and memory CD4+ and CD8+ T cell phenotypes (Fujihashi et al., 2013, Kiyono et al., 2008). Thus, the GALT and NALT contain all of the necessary immunocompetent cells for the initiation of Ag-specific T and B cell responses.

Secretory IgA (SIgA) is the primary antibody (Ab) involved in protecting mucosal surfaces and is locally produced by plasma cells in mucosal effector sites such as the lamina propria of the GI, UR and reproductive tracts, originally induced in the distant organized inductive sites (e.g., GALT and NALT) (Fujihashi et al., 2013, Kiyono et al., 2008). For the formation of SIgA, Ag-specific IgA Abs produced by cellular cooperation between IgA+ B cells and helper T (Th) cells interact with polymeric Ig receptor (pIgR) expressed by epithelial cells. Similarly, mucosal cytotoxic T cells are initiated at mucosal inductive tissues and exhibit their actual function at effector sites (Fujihashi et al., 2013, Kiyono et al., 2008). In this regard, the majority of T and B cells in mucosal effector tissues are activated and express a memory phenotype (Fujihashi et al., 2013, Kiyono et al., 2008).

It has been shown that Ag-specific SIgA Abs play a central role in the induction of mucosal immunity to infectious diseases (Fujihashi et al., 2013, Kiyono et al., 2008). However, protective mucosal immunity is dramatically affected in aging and thus, the GI tract in the elderly is deficient in SIgA Ab synthesis and is particularly susceptible to infectious diseases (Powers, 1992, Schmucker et al., 1996). In this regard, it has been shown that Ag-specific mucosal IgA Ab responses were significantly altered in aged experimental animals including non-human primates (Enioutina et al., 2000, Schmucker et al., 1988, Taylor et al., 1992, Thoreux et al., 2000). Further, it has been shown that age-associated immune dysregulation occurs in mucosal immune compartments as early as 12–14 months of age in mice (Fujihashi and Kiyono, 2009, Koga et al., 2000). Thus, both Ag-specific Ab and cytokine responses, induced by oral ovalbumin (OVA) and native cholera toxin (nCT) as mucosal adjuvant were markedly reduced in one-year-old mice, and were essentially the same as those seen in fully aged two-year-old mice (Fujihashi and Kiyono, 2009, Koga et al., 2000). Since it has been shown that NALT shares common immunological and functional features with Peyer's patches (PPs), a major component GALT, one could assume that NALT would follow a similar immunosenescence process as seen in GALT. However, the duration of immunosenescence in NALT markedly differs from that seen in GALT (Fujihashi and Kiyono, 2009, Hagiwara et al., 2003). Furthermore, it has been shown that the longevity, organogenesis and cell trafficking of these two inductive tissues are distinctly regulated (Kunisawa et al., 2008). In this regard, in contrast to oral immunization, nasal immunization effectively induced Ag-specific mucosal and systemic immune responses in one-year old mice (Fujihashi and Kiyono, 2009, Hagiwara et al., 2003, Koga et al., 2000). More importantly, one-year old mice given nasal tetanus toxoid (TT) vaccine and nCT as adjuvant were protected from tetanus toxin challenge (Hagiwara et al., 2003). These results suggest that a distinct immune aging process exists between the two sites; this occurs earlier in GALT (than in NALT) accounting for differences in Ag-specific mucosal SIgA and parenteral IgG Ab responses (Fujihashi and Kiyono, 2009).

It is well established that respiratory influenza viral and Streptoccocus pneumoniae bacterial infections are sharply increased in the elderly and are often fatal (Fujihashi and Kiyono, 2009). To this end, a cellular and molecular understanding of the impaired mucosal immune response to these pathogens and the development of a novel way to enhance specific immunity in the elderly would be clinically relevant and important. Lamina propria plasma cells secrete polymeric (largely dimeric) IgA (pIgA) Abs which are taken up by a pIgA/pIgM receptor (pIgR) for transport across epithelial cells with ultimate release into the lumen as SIgA Abs. Pathogen-specific SIgA Abs in the nasal mucosa and URT block invasion of and/or reduce growth of pathogenic viruses and bacteria (Fig. 1). This can result in the inhibition of disease development, less severe clinical damage and early recovery even when these pathogens partially invade the host. In this regard, one should strongly consider developing a new generation of mucosal adjuvants that could overcome immunosenescence of mucosal immunity and induce universal pathogen-specific SIgA Ab responses in the UR tract. In this brief review, we will focus on several nasal vaccination strategies and a two component adjuvant system that may have the potential to correct altered mucosal immune responses in aging and provide protection from infectious pathogens such as influenza virus and S. pneumoniae in the UR tract.

Section snippets

Roles for SIgA in upper respiratory tract infections

It is well accepted that specific Abs with neutralizing activity play a major role in protection from influenza virus infections. Furthermore, pathogen-specific SIgA Abs are a key player as a first line of defense against infectious diseases (Fujihashi et al., 2013, Kiyono et al., 2008). Although it has been shown that some protection can be provided by influenza-specific systemic IgG without mucosal SIgA Ab responses (Harriman et al., 1999), influenza-specific SIgA Ab responses are thought to

Correction of mucosal aging by use of a double adjuvant strategy

It has been shown that nasal immunization may provide a better means to induce protective immunity in aging when compared with oral vaccine delivery (Hagiwara et al., 2003). However, when completely aged (two-year old) mice were nasally immunized with OVA plus the most potent mucosal adjuvant nCT, significantly lower levels of OVA-specific SIgA Ab responses were noted in all external secretions (NWs, saliva and fecal extracts) than those seen in identically immunized, young adult or one-year

Potential influenza vaccines for the elderly

Influenza virus infection remains a serious respiratory disease since the virus often escapes from pre-existing host immunity by altering the antigenic properties of its surface hemagglutinin (HA). In addition, new types of viruses including highly pathogenic avian influenza (HPAI; H5N1) as well as swine influenza (H1N1) viruses cause disease in humans (Beigel and Bray, 2008, Dawood et al., 2009, Wright et al., 2007). Therefore, effective vaccine development is essential for the prevention of

A pneumococcal mucosal vaccine for the elderly

Pneumococcal infection is a major disease affecting the URT and subsequently causes severe illness, resulting in over 40,000 deaths in the United States each year (Murray and Lopez, 1997). Most notably, severe illness and mortality caused by pneumococci have sharply increased in the elderly (Janssens and Krause, 2004). Infections with pneumococci are thought to always be preceded by nasal colonization (Gray et al., 1980). As a result, optimal protection against pneumococci is thought to require

Future applications for these double adjuvant and mucosal delivery systems for the induction of protective immunity in aging

The elderly have already experienced viral and bacterial pathogens and thus possess pathogen-specific Abs, whose titers are both too low and too clonally restricted to effectively combat reinfection. It would be of great benefit to the aged population if one could use an innate adjuvant system alone, without Ag, in order to enhance mucosal immunity against past respiratory infections. Thus, it will be interesting to investigate whether nasal delivery of the innate molecules pFL and CpG ODN

Conflict of interest

The authors have no conflicts of interests.

Acknowledgments

This work is supported by the National Institutes of Health (NIH) grants AG025873 as well as by the Japan Society of the Promotion of Science (JSPS) program entitled “Young Researcher Overseas Visits Program for Vitalizing Brain Circulation”, Global Center of Excellence (GCOE) Program “Center of Education and Research for the Advanced Genome-based Medicine — for Personalized Medicine, the Control of Worldwide Infectious Diseases” — “MEXT” Japan.

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