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Nasal vaccination: a non-invasive vaccine delivery method that holds great promise for the future
Advanced Drug Delivery Reviews 51 (2001) 1–3 www.elsevier.com / locate / drugdeliv
Preface
Nasal vaccination: a non-invasive vaccine delivery method that holds great promise for the future In recent years, there has been an increasing interest in the development of novel vaccine systems for prophylactic and therapeutic purposes. Formulation strategies and the use of so-called adjuvants that can affect the immune response in both quantitative and qualitative terms have attracted the interest of those more familiar with problems in drug delivery. Early efforts were focussed on injectable (parenteral vaccines) and the role of controlled release technologies with an emphasis (or overemphasis?) on biodegradable microspheres. Mucosal routes of immunization, as well as the skin, are attractive alternatives to parenteral immunization since, with the ‘right’ system, it is possible to stimulate both arms of the immune system and provide both humoral (antibody) and cell-mediated responses (cytotoxic lymphocytes) [1,2]. Moreover, it is now well recognised that the majority of invading pathogens enter the body via some form of mucosal surface. At first sight, oral vaccination would appear to be an attractive strategy but unfortunately it is difficult to obtain good immune responses in larger animal models and in humans. This may well be due to poor access of the antigen to antigen presenting cells, degradation of the antigen in the harsh environment of the gastrointestinal tract and dilution of the delivery system in the gut contents. Nasal administration offers an attractive alternative [2,3] since it is possible to use smaller doses and to deliver the formulation to the appropriate site (nose-associated lymphoid tissues — Waldeyer’s ring in humans). In addition, because of the properties of the common mucosal immune system, the nose can act as an inducer and effector site and good secretory immune responses can be obtained at distant mucosal sites such as the intestines, lung and vagina. Hence, nasal
vaccines can have an important role in the prophylaxis of upper respiratory infections as well as diseases involving other mucosal surfaces (Heliobacter pylori, sexually transmitted diseases). The advantages and disadvantages of the nose versus the lung as a site for vaccine delivery are presently under consideration [8] with a firm preference so far for the nasal route. Antigens for nasal delivery can take many different forms to include whole cells (virus, bacteria), surface proteins, synthetic peptides as well as DNA. As a consequence, there will be no one system that fits all applications. Instead, it is important to choose a system that addresses the clinical need and the nature of the antigen. Most antigens require some form of adjuvant that will increase the immune response or provide a degree of selectivity. A wide range of materials is now available to include liposomes, chitosan, microspheres, bacterial toxins. These various systems will be reviewed in this issue as well as alternative strategies such as cold adapted live attenuated viruses that have achieved success for influenza [4] and will, no doubt, be applied to other viruses (RSV) [5]. The safety, efficacy and effectiveness of cold-adapted influenza virus vaccines administered intranasally have been described recently by Mendelman et al. [6]. Studies in adults and children conducted by Aviron and NIH (10 443 subjects) have demonstrated good efficiency and the vaccine was generally safe and well tolerated with no vaccine-related serious adverse events. In understanding the potential role of nasal vaccines, it is important to choose appropriate animal models and to understand their limitations. Moreover, good responses obtained following nasal dosing could be due to contributive responses from other
0169-409X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved PII: S0169-409X( 01 )00176-4
2
Preface
sites, particularly the lung. Certainly in the mouse it is difficult to dose to the nasal cavity alone. This is illustrated well by the recent work of Nardelli-Haefliger et al. [7] who have used attenuated Salmonella typhimurium strains expressing the hepatitis B nucleocapsid as a vaccine system. They found that nasal administration of attenuated strains to mice was more efficient in inducing antibody response than oral vaccination but the nasal route gave more adverse effects. Interestingly, on reducing the dose they found that nasal vaccination was still efficient while oral vaccination was ineffective. The role of the lung would appear to be critical in determining the response when very few organisms are dosed. The great number of intraepithelial dendritic cells scattered throughout the large surface area of the lower airways could play an important role in addition to that of the NALT. Hence, it might be advantageous to target a recombinant S. typhimurium vaccine to both lung and NALT to induce high antibody responses at local and distant mucosal surfaces [7]. For some situations, the nose could provide a suitable route for priming and boosting (for example in children) while in other situations, the nasal route could be more appropriate for boosting. For example, Yoshizawa et al. [9] examined the feasibility of using Gag-expression DNA as a potential candidate for an HIV vaccine using a mouse model. They injected DNA into mice i.m. and then boosted intranasally with the p24 protein and cholera toxin. Their results indicated that i.m. DNA immunization induced memory cells and that i.m. DNA priming followed by nasal booster immunization could be a regimen applicable to a HIV vaccine. Despite the promise of nasal immunization, Hodge et al. [10] have cautioned that there is the potential for adverse immunopathogenic reactions. For example, they gave mice an intranasal vaccine based on an influenza virus combined with cholera toxin. Enhanced IgA responses were found in both the nasal passages and the lung. However, inflammatory reactions occurred in the lung that were characterised by mononuclear cell infiltration. Systemic immunization did not cause such adverse effects. In putting together this special issue, we invited contribution from those known to us in the field of mucosal immunology as well as in drug / vaccine
delivery. We were very pleased that almost everyone so invited agreed to provide a manuscript and all but a few delivered (some even on time)! The authors are all well-known authorities in their respective fields and it is pleasing to have attracted articles from academia as well as industry. This, no doubt, reflects the considerable and growing interest in the field from both sectors. Last, but not least, while putting the issue together, we were gratified that one intranasal vaccine for human use (Nasal flu ) had made it through the regulatory hurdles to the market and another (Flumist ) would seem to be close on its heels. More commercial nasal vaccine products will surely follow.
Lisbeth Illum (Theme Editor) West Pharmaceutical Sciences, Drug Delivery and Clinical Research Centre Ltd., Albert Einstein Centre, Nottingham Science and Technology Park, Nottingham NG7 2 TN, UK E-mail: lisbeth] illum@ westpharma.com Stanley S. Davis (Theme Editor) Institute of Pharmaceutical Sciences University of Nottingham, Boots Science Building, Science Road, University Park, Nottingham NG7 2 RD, UK E-mail: stanley.davis@ nottingham.ac.uk
References [1] C.D. Partidos, A.-S. Beignon, V. Semetey, J.-P. Briand, S. Muller, The bare skin and the nose as non-invasive routes for administering peptide vaccines, Vaccine 19 (2001) 2708– 2715. [2] L. de Haan, W.R. Verweij, M. Holtrop et al., Nasal or intramuscular immunization of mice with influenza subunit antigen and the B subunit of Escherichia coli heat-labile toxin induces IgA- or IgG-mediated protective mucosal immunity, Vaccine 19 (2001) 2898–2907. [3] Y. Byun, M. Ohmura, K. Fijihashi et al., Nasal immunization
Preface with E. coli verotoxin 1 (VT1)-B subunit and a nontoxic mutant of cholera toxin elicits serum neutralizing antibodies, Vaccine 19 (2001) 2061–2070. [4] J.P. Wong, M.A. Zabielski, F.L. Schmaltz et al., DNA vaccination against respiratory influenza virus infection, Vaccine 19 (2001) 2461–2467. [5] C. Andersson, P. Liljestrom, S. Stahl, U.F. Power, Protection against respiratory syncytial virus (RSV) elicited in by plasmid DNA immunisation encoding a secreted RSV G pre-derived antigen, FEMS Immunol. Med. Microbiol. 29 (2000) 247–253. [6] P.M. Mendelman, J. Cordova, I. Cho, Safety, efficacy and effectiveness of the influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) in healthy children and healthy adults, Vaccine 19 (2001) 2221–2226.
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[7] D. Nardelli-Haefliger, J. Benyacoub, R. Lemoine et al., Nasal vaccination with attenuated Salmonella typhimurium strains expressing the hepatitis B nucleocapsid: dose response analysis, Vaccine 19 (2001) 2854–2861. [8] J.M. Kyd, A.R. Foxwell, A.W. Cripps, Mucosal immunity in the lung and upper airway, Vaccine 19 (2001) 2527–2533. [9] I. Yoshizawa, Y. Soda, T. Mizuochi et al., Enhancement of mucosal immune response against HIV-1 Gag by DNA immunization, Vaccine 19 (2001) 2995–3003. [10] L.M. Hodge, M. Marinaro, H.P. Jones, J.R. McGhee, H. Kiyona, J. Simecka, Immunoglobulin A (IgA) responses and IgE-associated inflammation along the respiratory tract after mucosal but not systemic immunization, Infect. Immun. 69 (2001) 2328–2338.
Preface
Nasal vaccination: a non-invasive vaccine delivery method that holds great promise for the future In recent years, there has been an increasing interest in the development of novel vaccine systems for prophylactic and therapeutic purposes. Formulation strategies and the use of so-called adjuvants that can affect the immune response in both quantitative and qualitative terms have attracted the interest of those more familiar with problems in drug delivery. Early efforts were focussed on injectable (parenteral vaccines) and the role of controlled release technologies with an emphasis (or overemphasis?) on biodegradable microspheres. Mucosal routes of immunization, as well as the skin, are attractive alternatives to parenteral immunization since, with the ‘right’ system, it is possible to stimulate both arms of the immune system and provide both humoral (antibody) and cell-mediated responses (cytotoxic lymphocytes) [1,2]. Moreover, it is now well recognised that the majority of invading pathogens enter the body via some form of mucosal surface. At first sight, oral vaccination would appear to be an attractive strategy but unfortunately it is difficult to obtain good immune responses in larger animal models and in humans. This may well be due to poor access of the antigen to antigen presenting cells, degradation of the antigen in the harsh environment of the gastrointestinal tract and dilution of the delivery system in the gut contents. Nasal administration offers an attractive alternative [2,3] since it is possible to use smaller doses and to deliver the formulation to the appropriate site (nose-associated lymphoid tissues — Waldeyer’s ring in humans). In addition, because of the properties of the common mucosal immune system, the nose can act as an inducer and effector site and good secretory immune responses can be obtained at distant mucosal sites such as the intestines, lung and vagina. Hence, nasal
vaccines can have an important role in the prophylaxis of upper respiratory infections as well as diseases involving other mucosal surfaces (Heliobacter pylori, sexually transmitted diseases). The advantages and disadvantages of the nose versus the lung as a site for vaccine delivery are presently under consideration [8] with a firm preference so far for the nasal route. Antigens for nasal delivery can take many different forms to include whole cells (virus, bacteria), surface proteins, synthetic peptides as well as DNA. As a consequence, there will be no one system that fits all applications. Instead, it is important to choose a system that addresses the clinical need and the nature of the antigen. Most antigens require some form of adjuvant that will increase the immune response or provide a degree of selectivity. A wide range of materials is now available to include liposomes, chitosan, microspheres, bacterial toxins. These various systems will be reviewed in this issue as well as alternative strategies such as cold adapted live attenuated viruses that have achieved success for influenza [4] and will, no doubt, be applied to other viruses (RSV) [5]. The safety, efficacy and effectiveness of cold-adapted influenza virus vaccines administered intranasally have been described recently by Mendelman et al. [6]. Studies in adults and children conducted by Aviron and NIH (10 443 subjects) have demonstrated good efficiency and the vaccine was generally safe and well tolerated with no vaccine-related serious adverse events. In understanding the potential role of nasal vaccines, it is important to choose appropriate animal models and to understand their limitations. Moreover, good responses obtained following nasal dosing could be due to contributive responses from other
0169-409X / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved PII: S0169-409X( 01 )00176-4
2
Preface
sites, particularly the lung. Certainly in the mouse it is difficult to dose to the nasal cavity alone. This is illustrated well by the recent work of Nardelli-Haefliger et al. [7] who have used attenuated Salmonella typhimurium strains expressing the hepatitis B nucleocapsid as a vaccine system. They found that nasal administration of attenuated strains to mice was more efficient in inducing antibody response than oral vaccination but the nasal route gave more adverse effects. Interestingly, on reducing the dose they found that nasal vaccination was still efficient while oral vaccination was ineffective. The role of the lung would appear to be critical in determining the response when very few organisms are dosed. The great number of intraepithelial dendritic cells scattered throughout the large surface area of the lower airways could play an important role in addition to that of the NALT. Hence, it might be advantageous to target a recombinant S. typhimurium vaccine to both lung and NALT to induce high antibody responses at local and distant mucosal surfaces [7]. For some situations, the nose could provide a suitable route for priming and boosting (for example in children) while in other situations, the nasal route could be more appropriate for boosting. For example, Yoshizawa et al. [9] examined the feasibility of using Gag-expression DNA as a potential candidate for an HIV vaccine using a mouse model. They injected DNA into mice i.m. and then boosted intranasally with the p24 protein and cholera toxin. Their results indicated that i.m. DNA immunization induced memory cells and that i.m. DNA priming followed by nasal booster immunization could be a regimen applicable to a HIV vaccine. Despite the promise of nasal immunization, Hodge et al. [10] have cautioned that there is the potential for adverse immunopathogenic reactions. For example, they gave mice an intranasal vaccine based on an influenza virus combined with cholera toxin. Enhanced IgA responses were found in both the nasal passages and the lung. However, inflammatory reactions occurred in the lung that were characterised by mononuclear cell infiltration. Systemic immunization did not cause such adverse effects. In putting together this special issue, we invited contribution from those known to us in the field of mucosal immunology as well as in drug / vaccine
delivery. We were very pleased that almost everyone so invited agreed to provide a manuscript and all but a few delivered (some even on time)! The authors are all well-known authorities in their respective fields and it is pleasing to have attracted articles from academia as well as industry. This, no doubt, reflects the considerable and growing interest in the field from both sectors. Last, but not least, while putting the issue together, we were gratified that one intranasal vaccine for human use (Nasal flu ) had made it through the regulatory hurdles to the market and another (Flumist ) would seem to be close on its heels. More commercial nasal vaccine products will surely follow.
Lisbeth Illum (Theme Editor) West Pharmaceutical Sciences, Drug Delivery and Clinical Research Centre Ltd., Albert Einstein Centre, Nottingham Science and Technology Park, Nottingham NG7 2 TN, UK E-mail: lisbeth] illum@ westpharma.com Stanley S. Davis (Theme Editor) Institute of Pharmaceutical Sciences University of Nottingham, Boots Science Building, Science Road, University Park, Nottingham NG7 2 RD, UK E-mail: stanley.davis@ nottingham.ac.uk
References [1] C.D. Partidos, A.-S. Beignon, V. Semetey, J.-P. Briand, S. Muller, The bare skin and the nose as non-invasive routes for administering peptide vaccines, Vaccine 19 (2001) 2708– 2715. [2] L. de Haan, W.R. Verweij, M. Holtrop et al., Nasal or intramuscular immunization of mice with influenza subunit antigen and the B subunit of Escherichia coli heat-labile toxin induces IgA- or IgG-mediated protective mucosal immunity, Vaccine 19 (2001) 2898–2907. [3] Y. Byun, M. Ohmura, K. Fijihashi et al., Nasal immunization
Preface with E. coli verotoxin 1 (VT1)-B subunit and a nontoxic mutant of cholera toxin elicits serum neutralizing antibodies, Vaccine 19 (2001) 2061–2070. [4] J.P. Wong, M.A. Zabielski, F.L. Schmaltz et al., DNA vaccination against respiratory influenza virus infection, Vaccine 19 (2001) 2461–2467. [5] C. Andersson, P. Liljestrom, S. Stahl, U.F. Power, Protection against respiratory syncytial virus (RSV) elicited in by plasmid DNA immunisation encoding a secreted RSV G pre-derived antigen, FEMS Immunol. Med. Microbiol. 29 (2000) 247–253. [6] P.M. Mendelman, J. Cordova, I. Cho, Safety, efficacy and effectiveness of the influenza virus vaccine, trivalent, types A and B, live, cold-adapted (CAIV-T) in healthy children and healthy adults, Vaccine 19 (2001) 2221–2226.
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[7] D. Nardelli-Haefliger, J. Benyacoub, R. Lemoine et al., Nasal vaccination with attenuated Salmonella typhimurium strains expressing the hepatitis B nucleocapsid: dose response analysis, Vaccine 19 (2001) 2854–2861. [8] J.M. Kyd, A.R. Foxwell, A.W. Cripps, Mucosal immunity in the lung and upper airway, Vaccine 19 (2001) 2527–2533. [9] I. Yoshizawa, Y. Soda, T. Mizuochi et al., Enhancement of mucosal immune response against HIV-1 Gag by DNA immunization, Vaccine 19 (2001) 2995–3003. [10] L.M. Hodge, M. Marinaro, H.P. Jones, J.R. McGhee, H. Kiyona, J. Simecka, Immunoglobulin A (IgA) responses and IgE-associated inflammation along the respiratory tract after mucosal but not systemic immunization, Infect. Immun. 69 (2001) 2328–2338.