Intranasal and oral vaccination with protein-based antigens: advantages, challenges and formulation strategies

Abstract

pathogens initiate their infections at the human mucosal surface. Therefore, mucosal vaccination, especially through oral or intranasal administration routes, is highly desired for infectious diseases. Meanwhile, protein-based antigens provide a safer alternative to the whole pathogen or DNA based ones in vaccine development. However, the unique biopharmaceutical hurdles that intranasally or orally delivered protein vaccines need to overcome before they reach the sites of targeting, the relatively low immunogenicity, as well as the low stability of the protein antigens, require thoughtful and fine-tuned mucosal vaccine formulations, including the selection of immunostimulants, the identification of the suitable vaccine delivery system, and the determination of the exact composition and manufacturing conditions. This review aims to provide an up-to-date survey of the protein antigen-based vaccine formulation development, including the usage of immunostimulants and the optimization of vaccine delivery systems for intranasal and oral administrations.

Keywords

mucosal vaccine / protein antigen / adjuvant / immunostimulant / vaccine delivery system

References

[1] Abusugra I, Morein B (1999) Iscom is an efficient mucosal delivery system for Mycoplasma mycoides subsp. mycoides (MmmSC) antigens inducing high mucosal and systemic antibody responses. FEMS Immunol Med Microbiol23: 5-12

[2] Ali R, Kumar S, Naqvi RA, Sheikh IA, Rao DN (2013) Multiple antigen peptide consisting of B- and T-cell epitopes of F1 antigen of Y. pestis showed enhanced humoral and mucosal immune response in different strains of mice. Int Immunopharmacol15: 97-105

[3] Almeida AJ, Alpar HO (1996) Nasal delivery of vaccines. J Drug Target3: 455-467

[4] Alpar HO, Eyles JE, Williamson ED, Somavarapu S (2001) Intranasal vaccination against plague, tetanus and diphtheria. Adv Drug Deliv Rev51: 173-201

[5] Bachmann MF, Jennings GT (2010) Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nat Rev Immunol10: 787-796

[6] Bal SM, Slutter B, Verheul R, Bouwstra JA, Jiskoot W (2012) Adjuvanted, antigen loaded N-trimethyl chitosan nanoparticles for nasal and intradermal vaccination: adjuvant- and site-dependent immunogenicity in mice. Eur J Pharm Sci45: 475-481

[7] Ball JM, Hardy ME, Atmar RL, Conner ME, Estes MK (1998) Oral immunization with recombinant Norwalk virus-like particles induces a systemic and mucosal immune response in mice. J Virol72: 1345-1353

[8] Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature392: 245-252

[9] Barhate G, Gautam M, Gairola S, Jadhav S, Pokharkar V (2013) Quillaja saponaria extract as mucosal adjuvant with chitosan functionalized gold nanoparticles for mucosal vaccine delivery: stability and immunoefficiency studies. Int J Pharm441: 636-642

[10] Baudner BC, O’Hagan DT (2010) Bioadhesive delivery systems for mucosal vaccine delivery. J Drug Target18: 752-770

[11] Belyakov IM, Moss B, Strober W, Berzofsky JA (1999) Mucosal vaccination overcomes the barrier to recombinant vaccinia immunization caused by preexisting poxvirus immunity. Proc Natl Acad Sci USA96: 4512-4517

[12] Borges O, Tavares J, de Sousa A, Borchard G, Junginger HE, Cordeiro-da-Silva A (2007) Evaluation of the immune response following a short oral vaccination schedule with hepatitis B antigen encapsulated into alginate-coated chitosan nanoparticles. Eur J Pharm Sci32: 278-290

[13] Borges O, Cordeiro-da-Silva A, Tavares J, Santarem N, de Sousa A, Borchard G, Junginger HE (2008) Immune response by nasal delivery of hepatitis B surface antigen and codelivery of a CpG ODN in alginate coated chitosan nanoparticles. Eur J Pharm Biopharm69: 405-416

[14] Boyaka PN, Marinaro M, Jackson RJ, Menon S, Kiyono H, Jirillo E, McGhee JR (1999) IL-12 is an effective adjuvant for induction of mucosal immunity. J Immunol162: 122-128

[15] Brandhonneur N, Loizel C, Chevanne F, Wakeley P, Jestin A, Le Potier MF, Le Corre P (2009) Mucosal or systemic administration of rE2 glycoprotein antigen loaded PLGA microspheres. Int J Pharm373: 16-23

[16] Brunner R, Jensen-Jarolim E, Pali-Scholl I (2010) The ABC of clinical and experimental adjuvants–a brief overview. Immunol Lett128: 29-35

[17] Buffa V, Klein K, Fischetti L, Shattock RJ (2012) Evaluation of TLR agonists as potential mucosal adjuvants for HIV gp140 and tetanus toxoid in mice. Plos One7: e50529

[18] Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B, Hyodo M, Hayakawa Y, Vance RE (2011) STING is a direct innate immune sensor of cyclic di-GMP. Nature478: 515-518

[19] Caley IJ, Betts MR, Irlbeck DM, Davis NL, Swanstrom R, Frelinger JA, Johnston RE (1997) Humoral, mucosal, and cellular immunity in response to a human immunodeficiency virus type 1 immunogen expressed by a Venezuelan equine encephalitis virus vaccine vector. J Virol71: 3031-3038

[20] Carcaboso AM, Hernandez RM, Igartua M, Gascon AR, Rosas JE, Patarroyo ME, Pedraz JL (2003) Immune response after oral administration of the encapsulated malaria synthetic peptide SPf66. Int J Pharm260: 273-282

[21] Challacombe SJ, Rahman D, Jeffery H, Davis SS, O’Hagan DT (1992) Enhanced secretory IgA and systemic IgG antibody responses after oral immunization with biodegradable microparticles containing antigen. Immunology76: 164-168

[22] Chen YS, Hung YC, Lin WH, Huang GS (2010) Assessment of gold nanoparticles as a size-dependent vaccine carrier for enhancing the antibody response against synthetic foot-and-mouth disease virus peptide. Nanotechnology21: 195101

[23] Chen J, Li Z, Huang H, Yang Y, Ding Q, Mai J, Guo W, Xu Y (2011) Improved antigen cross-presentation by polyethyleneiminebased nanoparticles. Int J Nanomed6: 77-84

[24] Clark MA, Blair H, Liang L, Brey RN, Brayden D, Hirst BH (2001) Targeting polymerised liposome vaccine carriers to intestinal M cells. Vaccine20: 208-217

[25] Cortesi R, Ravani L, Rinaldi F, Marconi P, Drechsler M, Manservigi M, Argnani R, Menegatti E, Esposito E, Manservigi R (2013) Intranasal immunization in mice with non-ionic surfactants vesicles containing HSV immunogens: a preliminary study as possible vaccine against genital herpes. Int J Pharm440: 229-237

[26] Courtney AN, Nehete PN, Nehete BR, Thapa P, Zhou DP, Sastry KJ (2009) Alpha-galactosylceramide is an effective mucosal adjuvant for repeated intranasal or oral delivery of HIV peptide antigens. Vaccine27: 3335-3341

[27] Cox E, Verdonck F, Vanrompay D, Goddeeris B (2006) Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa. Vet Res37: 511-539

[28] Cruz LJ, Tacken PJ, Rueda F, Domingo JC, Albericio F, Figdor CG (2012) Targeting nanoparticles to dendritic cells for immunotherapy. Methods Enzymol509: 143-163

[29] Dawidczyk CM, Kim C, Park JH, Russell LM, Lee KH, Pomper MG, Searson PC (2014) State-of-the-art in design rules for drug delivery platforms: lessons learned from FDA-approved nanomedicines. J Control Release187: 133-144

[30] De Filette M, Fiers W, Martens W, Birkett A, Ramne A, Lowenadler B, Lycke N, Jou WM, Saelens X (2006) Improved design and intranasal delivery of an M2e-based human influenza A vaccine. Vaccine24: 6597-6601

[31] De Gregorio E, Rappuoli R (2014) From empiricism to rational design: a personal perspective of the evolution of vaccine development. Nat Rev Immunol14: 505-514

[32] Degim IT, Celebi N (2007) Controlled delivery of peptides and proteins. Curr Pharm Des13: 99-117

[33] Demento SL, Siefert AL, Bandyopadhyay A, Sharp FA, Fahmy TM (2011) Pathogen-associated molecular patterns on biomaterials: a paradigm for engineering new vaccines. Trends Biotechnol29: 294-306

[34] Deschuyteneer M, Elouahabi A, Plainchamp D, Plisnier M, Soete D, Corazza Y, Lockman L, Giannini S, Deschamps M (2010) Molecular and structural characterization of the L1 virus-like particles that are used as vaccine antigens in Cervarix (TM), the AS04-adjuvanted HPV-16 and-18 cervical cancer vaccine. Hum Vaccines6: 407-419

[35] Devriendt B, De Geest BG, Goddeeris BM, Cox E (2012) Crossing the barrier: targeting epithelial receptors for enhanced oral vaccine delivery. J Control Release160: 431-439

[36] Dormitzer PR, Grandi G, Rappuoli R (2012) Structural vaccinology starts to deliver. Nat Rev Microbiol10: 807-813

[37] Du L, Zhao G, He Y, Guo Y, Zheng BJ, Jiang S, Zhou Y (2007) Receptor-binding domain of SARS-CoV spike protein induces long-term protective immunity in an animal model. Vaccine25: 2832-2838

[38] Du L, Kou Z, Ma C, Tao X, Wang L, Zhao G, Chen Y, Yu F, Tseng CT, Zhou Y (2013a) A truncated receptor-binding domain of MERS-CoV spike protein potently inhibits MERS-CoV infection and induces strong neutralizing antibody responses: implication for developing therapeutics and vaccines. PloS One8: e81587

[39] Du L, Zhao G, Kou Z, Ma C, Sun S, Poon VK, Lu L, Wang L, Debnath AK, Zheng BJ (2013b) Identification of a receptorbinding domain in the S protein of the novel human coronavirus Middle East respiratory syndrome coronavirus as an essential target for vaccine development. J Virol87: 9939-9942

[40] Eastcott JW, Holmberg CJ, Dewhirst FE, Esch TR, Smith DJ, Taubman MA (2001) Oligonucleotide containing CpG motifs enhances immune response to mucosally or systemically administered tetanus toxoid. Vaccine19: 1636-1642

[41] Ebensen T, Schulze K, Riese P, Morr M, Guzman CA (2007) The bacterial second messenger cdiGMP exhibits promising activity as a mucosal adjuvant. Clin Vaccine Immunol14: 952-958

[42] Ebensen T, Libanova R, Schulze K, Yevsa T, Morr M, Guzman CA (2011) Bis-(3’,5’)-cyclic dimeric adenosine monophosphate: strong Th1/Th2/Th17 promoting mucosal adjuvant. Vaccine29: 5210-5220

[43] Elamanchili P, Lutsiak CM, Hamdy S, Diwan M, Samuel J (2007) “Pathogen-mimicking” nanoparticles for vaccine delivery to dendritic cells. J Immunother30: 378-395

[44] Ellis JA, West KH, Waldner C, Rhodes C (2005) Efficacy of a saponin-adjuvanted inactivated respiratory syncytial virus vaccine in calves. Can Vet J46: 155-162

[45] Eyles JE, Sharp GJ, Williamson ED, Spiers ID, Alpar HO (1998) Intra nasal administration of poly-lactic acid microsphere co-encapsulated Yersinia pestis subunits confers protection from pneumonic plague in the mouse. Vaccine16: 698-707

[46] Eyles JE, Williamson ED, Spiers ID, Stagg AJ, Jones SM, Alpar HO (2000) Generation of protective immune responses to plague by mucosal administration of microsphere coencapsulated recombinant subunits. J Control Release63: 191-200

[47] Florindo HF, Pandit S, Lacerda L, Goncalves LMD, Alpar HO, Almeida AJ (2009) The enhancement of the immune response against S. equi antigens through the intranasal administration of poly-epsiloncaprolactone-based nanoparticles. Biomaterials30: 879-891

[48] Fujita Y, Taguchi H (2011) Current status of multiple antigenpresenting peptide vaccine systems: application of organic and inorganic nanoparticles. Chem Cent J5: 48

[49] Garcia A, De Sanctis JB (2014) An overview of adjuvant formulations and delivery systems. APMIS122: 257-267

[50] Garcia-Fuentes M, Alonso MJ (2012) Chitosan-based drug nanocarriers: where do we stand? J Control Release161: 496-504

[51] Garinot M, Fievez V, Pourcelle V, Stoffelbach F, des Rieux A, Plapied L, Theate I, Freichels H, Jerome C, Marchand-Brynaert J (2007) PEGylated PLGA-based nanoparticles targeting M cells for oral vaccination. J Control Release120: 195-204

[52] Gherardi MM, Esteban M (2005) Recombinant poxviruses as mucosal vaccine vectors. J Gen Virol86: 2925-2936

[53] Gosselin EJ, Bitsaktsis C, Li Y, Iglesias BV (2009) Fc receptortargeted mucosal vaccination as a novel strategy for the generation of enhanced immunity against mucosal and nonmucosal pathogens. Arch Immunol Ther Exp (Warsz)57: 311-323

[54] Graham RL, Donaldson EF, Baric RS (2013) A decade after SARS: strategies for controlling emerging coronaviruses. Nat Rev Microbiol11: 836-848

[55] Grgacic EV, Anderson DA (2006) Virus-like particles: passport to immune recognition. Methods40: 60-65

[56] Guerrero RA, Ball JM, Krater SS, Pacheco SE, Clements JD, Estes MK (2001) Recombinant Norwalk virus-like particles administered intranasally to mice induce systemic and mucosal (fecal and vaginal) immune responses. J Virol75: 9713-9722

[57] Gupta PN, Khatri K, Goyal AK, Mishra N, Vyas SP (2007) M-cell targeted biodegradable PLGA nanoparticles for oral immunization against hepatitis B. J Drug Target15: 701-713

[58] Hamdy S, Haddadi A, Hung RW, Lavasanifar A (2011) Targeting dendritic cells with nano-particulate PLGA cancer vaccine formulations. Adv Drug Deliv Rev63: 943-955

[59] Hiroi T, Goto H, Someya K, Yanagita M, Honda M, Yamanaka N, Kiyono H (2001) HIV mucosal vaccine: nasal immunization with rBCG-V3J1 induces a long term V3J1 peptide-specific neutralizing immunity in Th1- and Th2-deficient conditions. J Immunol167: 5862-5867

[60] Holmgren J, Czerkinsky C (2005) Mucosal immunity and vaccines. Nat Med11: S45-53

[61] Hu KF, Elvander M, Merza M, Akerblom L, Brandenburg A, Morein B (1998) The immunostimulating complex (ISCOM) is an efficient mucosal delivery system for respiratory syncytial virus (RSV) envelope antigens inducing high local and systemic antibody responses. Clin Exp Immunol113: 235-243

[62] Hu KF, Lovgren-Bengtsson K, Morein B (2001) Immunostimulating complexes (ISCOMs) for nasal vaccination. Adv Drug Deliv Rev51: 149-159

[63] Huang X, Lu B, Yu W, Fang Q, Liu L, Zhuang K, Shen T, Wang H, Tian P, Zhang L (2009) A novel replication-competent vaccinia vector MVTT is superior to MVA for inducing high levels of neutralizing antibody via mucosal vaccination. PLoS One4: e4180

[64] Ibanez LI, Roose K, De Filette M, Schotsaert M, De Sloovere J, Roels S, Pollard C, Schepens B, Grooten J, Fiers W (2013) M2e-displaying virus-like particles with associated RNA promote T helper 1 type adaptive immunity against influenza A. PLoS One8: e59081

[65] Ichinohe T, Watanabe I, Ito S, Fujii H, Moriyama M, Tamura S, Takahashi H, Sawa H, Chiba J, Kurata T (2005) Synthetic double-stranded RNA poly(I:C) combined with mucosal vaccine protects against influenza virus infection. J Virol79: 2910-2919

[66] Ichinohe T, Watanabe I, Tao E, Ito S, Kawaguchi A, Tamura S, Takahashi H, Sawa H, Moriyama M, Chiba J (2006) Protection against influenza virus infection by intranasal vaccine with surf clam microparticles (SMP) as an adjuvant. J Med Virol78: 954-963

[67] Igartua M, Hernandez RM, Esquisabel A, Gascon AR, Calvo MB, Pedraz JL (1998) Enhanced immune response after subcutaneous and oral immunization with biodegradable PLGA microspheres. J Control Release56: 63-73

[68] Illum L, Jabbal-Gill I, Hinchcliffe M, Fisher AN, Davis SS (2001) Chitosan as a novel nasal delivery system for vaccines. Adv Drug Deliver Rev51: 81-96

[69] Ishii M, Kojima N (2010) Mucosal adjuvant activity of oligomannosecoated liposomes for nasal immunization. Glycoconj J27: 115-123

[70] Ishikawa H, Ma Z, Barber GN (2009) STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature461: 788-792

[71] Jaganathan KS, Vyas SP (2006) Strong systemic and mucosal immune responses to surface-modified PLGA microspheres containing recombinant hepatitis B antigen administered intranasally. Vaccine24: 4201-4211

[72] Jaganathan KS, Rao YU, Singh P, Prabakaran D, Gupta S, Jain A, Vyas SP (2005) Development of a single dose tetanus toxoid formulation based on polymeric microspheres: a comparative study of poly(d, l-lactic-co-glycolic acid) versus chitosan microspheres. Int J Pharm294: 23-32

[73] Jain AK, Goyal AK, Mishra N, Vaidya B, Mangal S, Vyas SP (2010) PEG-PLA-PEG block copolymeric nanoparticles for oral immunization against hepatitis B. Int J Pharm387: 253-262

[74] Jain S, Harde H, Indulkar A, Agrawal AK (2014) Improved stability and immunological potential of tetanus toxoid containing surface engineered bilosomes following oral administration. Nanomedicine10: 431-440

[75] Jariyapong P, Xing L, van Houten NE, Li TC, Weerachatyanukul W, Hsieh B, Moscoso CG, Chen CC, Niikura M, Cheng RH (2013) Chimeric hepatitis E virus-like particle as a carrier for oraldelivery. Vaccine31: 417-424

[76] Jiang T, Singh B, Li HS, Kim YK, Kang SK, Nah JW, Choi YJ, Cho CS (2014) Targeted oral delivery of BmpB vaccine using porous PLGA microparticles coated with M cell homing peptide-coupled chitosan. Biomaterials35: 2365-2373

[77] Kanekiyo M, Wei CJ, Yassine HM, McTamney PM, Boyington JC, Whittle JRR, Rao SS, Kong WP, Wang LS, Nabel GJ (2013) Selfassembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies. Nature499: 102-106

[78] Kang SM, Guo L, Yao Q, Skountzou I, Compans RW (2004) Intranasal immunization with inactivated influenza virus enhances immune responses to coadministered simian-human immunodeficiency virus-like particle antigens. J Virol78: 9624-9632

[79] Kanzler H, Barrat FJ, Hessel EM, Coffman RL (2007) Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med13: 552-559

[80] Kavanagh OV, Earley B, Murray M, Foster CJ, Adair BM (2003) Antigen-specific IgA and IgG responses in calves inoculated intranasally with ovalbumin encapsulated in poly(dl-lactide-coglycolide) microspheres. Vaccine21: 4472-4480

[81] Kavanagh OV, Adair BM, Welsh MD, Earley B (2013) Local and systemic immune responses in mice to intranasal delivery of peptides representing bovine respiratory syncytial virus epitopes encapsulated in poly (DL-lactide-co-glycolide) microparticles. Res Vet Sci94: 809-812

[82] Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science278: 1626-1629

[83] Kayamuro H, Yoshioka Y, Abe Y, Katayama K, Yoshida T, Yamashita K, Yoshikawa T, Hiroi T, Itoh N, Kawai Y (2009) TNF superfamily member, TL1A, is a potential mucosal vaccine adjuvant. Biochem Biophys Res Commun384: 296-300

[84] Kayamuro H, Yoshioka Y, Abe Y, Arita S, Katayama K, Nomura T, Yoshikawa T, Kubota-Koketsu R, Ikuta K, Okamoto S (2010) Interleukin-1 family cytokines as mucosal vaccine adjuvants for induction of protective immunity against influenza virus. J Virol84: 12703-12712

[85] Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, Cilley GE, Shen F, Eaton SM, Gaffen SL, Swain SL (2007) IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol8: 369-377

[86] Khader SA, Gaffen SL, Kolls JK (2009) Th17 cells at the crossroads of innate and adaptive immunity against infectious diseases at the mucosa. Mucosal Immunol2: 403-411

[87] Kim SH, Lee KY, Kim J, Park SM, Park BK, Jang YS (2006) Identification of a peptide enhancing mucosal and systemic immune responses against EGFP after oral administration in mice. Mol Cells21: 244-250

[88] Kim SH, Seo KW, Kim J, Lee KY, Jang YS (2010) The M celltargeting ligand promotes antigen delivery and induces antigenspecific immune responses in mucosal vaccination. J Immunol185: 5787-5795

[89] Klinman DM, Currie D, Gursel I, Verthelyi D (2004) Use of CpG oligodeoxynucleotides as immune adjuvants. Immunol Rev199: 201-216

[90] Klippstein R, Pozo D (2010) Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies. Nanomedicine6: 523-529

[91] Kobayashi T, Fukushima K, Sannan T, Saito N, Takiguchi Y, Sato Y, Hasegawa H, Ishikawa K (2013) Evaluation of the effectiveness and safety of chitosan derivatives as adjuvants for intranasal vaccines. Viral Immunol26: 133-142

[92] Kong IG, Sato A, Yuki Y, Nochi T, Takahashi H, Sawada S, Mejima M, Kurokawa S, Okada K, Sato S (2013) Nanogel-based PspA intranasal vaccine prevents invasive disease and nasal colonization by Streptococcus pneumoniae. Infect Immun81: 1625-1634

[93] Koping-Hoggard M, Sanchez A, Alonso MJ (2005) Nanoparticles as carriers for nasal vaccine delivery. Expert Rev Vaccines4: 185-196

[94] Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature374: 546-549

[95] Krugman S (1982) The newly licensed hepatitis B vaccine. Characteristics and indications for use. JAMA247: 2012-2015

[96] Lamphear BJ, Jilka JM, Kesl L, Welter M, Howard JA, Streatfield SJ (2004) A corn-based delivery system for animal vaccines: an oral transmissible gastroenteritis virus vaccine boosts lactogenic immunity in swine. Vaccine22: 2420-2424

[97] Lawson LB, Norton EB, Clements JD (2011) Defending the mucosa: adjuvant and carrier formulations for mucosal immunity. Curr Opin Immunol23: 414-420

[98] Lema D, Garcia A, De Sanctis JB (2014) HIV vaccines: a brief overview. Scand J Immunol80: 1-11

[99] Lemesre JL, Holzmuller P, Goncalves RB, Bourdoiseau G, Hugnet C, Cavaleyra M, Papierok G (2007) Long-lasting protection against canine visceral leishmaniasis using the LiESAp-MDP vaccine in endemic areas of France: double-blind randomised efficacy field trial. Vaccine25: 4223-4234

[100] Lewis DJ, Huo Z, Barnett S, Kromann I, Giemza R, Galiza E, Woodrow M, Thierry-Carstensen B, Andersen P, Novicki D (2009) Transient facial nerve paralysis (Bell’s palsy) following intranasal delivery of a genetically detoxified mutant of Escherichia coli heat labile toxin. PLoS One4: e6999

[101] Lewis JS, Zaveri TD, Crooks CP 2nd, Keselowsky BG (2012) Microparticle surface modifications targeting dendritic cells for non-activating applications. Biomaterials33: 7221-7232

[102] Li T, Takeda N, Miyamura T (2001) Oral administration of hepatitis E virus-like particles induces a systemic and mucosal immune response in mice. Vaccine19: 3476-3484

[103] Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC (2003) Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature426: 450-454

[104] Li K, Chen D, Zhao X, Hu H, Yang C, Pang D (2011a) Preparation and investigation of Ulex europaeus agglutinin I-conjugated liposomes as potential oral vaccine carriers. Arch Pharm Res34: 1899-1907

[105] Li K, Zhao X, Xu S, Pang D, Yang C, Chen D (2011b) Application of Ulex europaeus agglutinin I-modified liposomes for oral vaccine: Ex Vivo bioadhesion and in Vivo immunity. Chem Pharm Bull (Tokyo)59: 618-623

[106] Libanova R, Ebensen T, Schulze K, Bruhn D, Norder M, Yevsa T, Morr M, Guzman CA (2010) The member of the cyclic dinucleotide family bis-(3′,5′)-cyclic dimeric inosine monophosphate exerts potent activity as mucosal adjuvant (vol 28, pg 2249, 2010). Vaccine28: 3625-3625

[107] Liu X, Chen DW, Xie LP, Zhang RQ (2003) Oral colon-specific drug delivery for bee venom peptide: development of a coated calcium alginate gel beads-entrapped liposome. J Control Release93: 293-300

[108] Liu L, Wei Q, Alvarez X, Wang H, Du Y, Zhu H, Jiang H, Zhou J, Lam P, Zhang L (2011) Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques. J Virol85: 4025-4030

[109] Lu G, Hu Y, Wang Q, Qi J, Gao F, Li Y, Zhang Y, Zhang W, Yuan Y, Bao J (2013) Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26. Nature500: 227-231

[110] Lycke N (2012) Recent progress in mucosal vaccine development: potential and limitations. Nat Rev Immunol12: 592-605

[111] Ma C, Li Y, Wang L, Zhao G, Tao X, Tseng CT, Zhou Y, Du L, Jiang S (2014a) Intranasal vaccination with recombinant receptor-binding domain of MERS-CoV spike protein induces much stronger local mucosal immune responses than subcutaneous immunization: Implication for designing novel mucosal MERS vaccines. Vaccine32: 2100-2108

[112] Ma T, Wang L, Yang T, Ma G, Wang S (2014b) M-cell targeted polymeric lipid nanoparticles containing a toll-like receptor agonist to boost oral immunity. Int J Pharm473: 296-303

[113] Maisonneuve C, Bertholet S, Philpott DJ, De Gregorio E (2014) Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci USA111: 12294-12299

[114] Malik B, Goyal AK, Markandeywar TS, Rath G, Zakir F, Vyas SP (2012) Microfold-cell targeted surface engineered polymeric nanoparticles for oral immunization. J Drug Target20: 76-84

[115] Maloy KJ, Donachie AM, O’Hagan DT, Mowat AM (1994) Induction of mucosal and systemic immune responses by immunization with ovalbumin entrapped in poly(lactide-co-glycolide) microparticles. Immunology81: 661-667

[116] Mann JFS, Scales HE, Shakir E, Alexander J, Carter KC, Mullen AB, Ferro VA (2006) Oral delivery of tetanus toxoid using vesicles containing bile salts (bilosomes) induces significant systemic and mucosal immunity. Methods38: 90-95

[117] Mann JF, Shakir E, Carter KC, Mullen AB, Alexander J, Ferro VA (2009) Lipid vesicle size of an oral influenza vaccine delivery vehicle influences the Th1/Th2 bias in the immune response and protection against infection. Vaccine27: 3643-3649

[118] Mann JF, Stieh D, Klein K, de Stegmann DS, Cranage MP, Shattock RJ, McKay PF (2012) Transferrin conjugation confers mucosal molecular targeting to a model HIV-1 trimeric gp140 vaccine antigen. J Control Release158: 240-249

[119] Mansoor F, Earley B, Cassidy JP, Markey B, Foster C, Doherty S, Welsh MD (2014) Intranasal delivery of nanoparticles encapsulating BPI3V proteins induces an early humoral immune response in mice. Res Vet Sci96: 551-557

[120] Marasini N, Skwarczynski M, Toth I (2014) Oral delivery of nanoparticle- based vaccines. Expert Rev Vaccines13: 1361-1376

[121] Marciani DJ (2003) Vaccine adjuvants: role and mechanisms of action in vaccine immunogenicity. Drug Discov Today8: 934-943

[122] Marrack P, McKee AS, Munks MW (2009) Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol9: 287-293

[123] Mason HS, Ball JM, Shi JJ, Jiang X, Estes MK, Arntzen CJ (1996) Expression of Norwalk virus capsid protein in transgenic tobacco and potato and its oral immunogenicity in mice. Proc Natl Acad Sci USA93: 5335-5340

[124] Mata-Haro V, Cekic C, Martin M, Chilton PM, Casella CR, Mitchell TC (2007) The vaccine adjuvant monophosphoryl lipid A as a TRIF-biased agonist of TLR4. Science316: 1628-1632

[125] Mathew S, Lendlein A, Wischke C (2014) Characterization of protein-adjuvant coencapsulation in microparticles for vaccine delivery. Eur J Pharm Biopharm87: 403-407

[126] Matsuo K, Koizumi H, Akashi M, Nakagawa S, Fujita T, Yamamoto A, Okada N (2011) Intranasal immunization with poly(gammaglutamic acid) nanoparticles entrapping antigenic proteins can induce potent tumor immunity. J Control Release152: 310-316

[127] McAleer WJ, Buynak EB, Maigetter RZ, Wampler DE, Miller WJ, Hilleman MR (1984) Human hepatitis B vaccine from recombinant yeast. Nature307: 178-180

[128] McCluskie MJ, Davis HL (1998) Cutting edge: CpG DNA is a potent enhancer of systemic and mucosal immune responses against hepatitis B surface antigen with intranasal administration to mice. J Immunol161: 4463-4466

[129] McCluskie MJ, Weeratna RD, Krieg AM, Davis HL (2000) CpG DNA is an effective oral adjuvant to protein antigens in mice. Vaccine19: 950-957

[130] McDermott MR, Heritage PL, Bartzoka V, Brook MA (1998) Polymergrafted starch microparticles for oral and nasal immunization. Immunol Cell Biol76: 256-262

[131] Meng S, Liu Z, Xu L, Li L, Mei S, Bao L, Deng W, Li L, Lei R, Xie L (2011) Intranasal immunization with recombinant HA and mast cell activator C48/80 elicits protective immunity against 2009 pandemic H1N1 influenza in mice. PLoS One6: e19863

[132] Minato S, Iwanaga K, Kakemi M, Yamashita S, Oku N (2003) Application of polyethyleneglycol (PEG)-modified liposomes for oral vaccine: effect of lipid dose on systemic and mucosal immunity. J Control Release89: 189-197

[133] Mirchamsy H, Manhouri H, Hamedi M, Ahourai P, Fateh G, Hamzeloo Z (1996) Stimulating role of toxoids-laden liposomes in oral immunization against diphtheria and tetanus infections. Biologicals24: 343-350

[134] Morein B, Sundquist B, Hoglund S, Dalsgaard K, Osterhaus A (1984) Iscom, a novel structure for antigenic presentation of membrane proteins from enveloped viruses. Nature308: 457-460

[135] Morris CB, Cheng E, Thanawastien A, Cardenas-Freytag L, Clements JD (2000) Effectiveness of intranasal immunization with HIV-gp160 and an HIV-1 env CTL epitope peptide (E7) in combination with the mucosal adjuvant LT(R192G). Vaccine18: 1944-1951

[136] Moschos SA, Bramwell VW, Somavarapu S, Alpar HO (2004) Adjuvant synergy: the effects of nasal coadministration of adjuvants. Immunol Cell Biol82: 628-637

[137] Mould JA, Drury JE, Frings SM, Kaupp UB, Pekosz A, Lamb RA, Pinto LH (2000) Permeation and activation of the M2 ion channel of influenza A virus. J Biol Chem275: 31038-31050

[138] Mowat AM, Smith RE, Donachie AM, Furrie E, Grdic D, Lycke N (1999) Oral vaccination with immune stimulating complexes. Immunol Lett65: 133-140

[139] Mummert ME (2005) Immunologic roles of hyaluronan. Immunol Res31: 189-206

[140] Mutsch M, Zhou W, Rhodes P, Bopp M, Chen RT, Linder T, Spyr C, Steffen R (2004) Use of the inactivated intranasal influenza vaccine and the risk of Bell’s palsy in Switzerland. N Engl J Med350: 896-903

[141] Muzzarelli RA (2010) Chitins and chitosans as immunoadjuvants and non-allergenic drug carriers. Mar Drugs8: 292-312

[142] Nagase S, Doyama R, Yagi K, Kondoh M (2013) Recent advances in claudin-targeting technology. Biol Pharm Bull36: 708-714

[143] Neirynck S, Deroo T, Saelens X, Vanlandschoot P, Jou WM, Fiers W (1999) A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med5: 1157-1163

[144] Neutra MR, Kozlowski PA (2006) Mucosal vaccines: the promise and the challenge. Nat Rev Immunol6: 148-158

[145] Neutra MR, Frey A, Kraehenbuhl JP (1996) Epithelial M cells: gateways for mucosal infection and immunization. Cell86: 345-348

[146] Niikura K, Matsunaga T, Suzuki T, Kobayashi S, Yamaguchi H, Orba Y, Kawaguchi A, Hasegawa H, Kajino K, Ninomiya T (2013) Gold nanoparticles as a vaccine platform: influence of size and shape on immunological responses in vitro and in vivo. ACS Nano7: 3926-3938

[147] Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol8: 34-47

[148] Nochi T, Yuki Y, Takahashi H, Sawada S, Mejima M, Kohda T, Harada N, Kong IG, Sato A, Kataoka N (2010) Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. Nat Mater9: 572-578

[149] Noh YW, Hong JH, Shim SM, Park HS, Bae HH, Ryu EK, Hwang JH, Lee CH, Cho SH, Sung MH (2013) Polymer nanomicelles for efficient mucus delivery and antigen-specific high mucosal immunity. Angew Chem Int Ed Engl52: 7684-7689

[150] Oliveira CR, Rezende CM, Silva MR, Pego AP, Borges O, Goes AM (2012) A new strategy based on SmRho protein loaded chitosan nanoparticles as a candidate oral vaccine against schistosomiasis. PLoS Negl Trop Dis6: e1894

[151] Olszewska W, Steward MW (2001) Nasal delivery of epitope based vaccines. Adv Drug Deliv Rev51: 161-171

[152] Pandey RS, Dixit VK (2010) Evaluation of ISCOM vaccines for mucosal immunization against hepatitis B. J Drug Target18: 282-291

[153] Park CG (2014) Vaccine strategies utilizing C-type lectin receptors on dendritic cells in vivo. Clin Exp Vaccine Res3: 149-154

[154] Park YM, Lee SJ, Kim YS, Lee MH, Cha GS, Jung ID, Kang TH, Han HD (2013) Nanoparticle-based vaccine delivery for cancer immunotherapy. Immune Netw13: 177-183

[155] Pashine A, Valiante NM, Ulmer JB (2005) Targeting the innate immune response with improved vaccine adjuvants. Nat Med11: S63-68

[156] Patel GB, Chen W (2010) Archaeal lipid mucosal vaccine adjuvant and delivery system. Expert Rev Vaccines9: 431-440

[157] Patel GB, Zhou HY, Ponce A, Chen WX (2007) Mucosal and systemic immune responses by intranasal immunization using archaeal lipid-adjuvanted vaccines. Vaccine25: 8622-8636

[158] Patel GB, Ponce A, Zhou H, Chen W (2008) Safety of intranasally administered archaeal lipid mucosal vaccine adjuvant and delivery (AMVAD) vaccine in mice. Int J Toxicol27: 329-339

[159] Pedersen GK, Ebensen T, Gjeraker IH, Svindland S, Bredholt G, Guzman CA, Cox RJ (2011) Evaluation of the sublingual route for administration of influenza H5N1 virosomes in combination with the bacterial second messenger c-di-GMP. PLoS One6: e26973

[160] Petersson P, Hedenskog M, Alves D, Brytting M, Schroder U, Linde A, Lundkvist A (2010) The Eurocine (R) L3 adjuvants with subunit influenza antigens induce protective immunity in mice after intranasal vaccination. Vaccine28: 6491-6497

[161] Pogrebnyak N, Golovkin M, Andrianov V, Spitsin S, Smirnov Y, Egolf R, Koprowski H (2005) Severe acute respiratory syndrome (SARS) S protein production in plants: development of recombinant vaccine. Proc Natl Acad Sci USA102: 9062-9067

[162] Porporatto C, Bianco ID, Correa SG (2005) Local and systemic activity of the polysaccharide chitosan at lymphoid tissues after oral administration. J Leukoc Biol78: 62-69

[163] Prevec L, Schneider M, Rosenthal KL, Belbeck LW, Derbyshire JB, Graham FL (1989) Use of human adenovirus-based vectors for antigen expression in animals. J Gen Virol70: 429-434

[164] Pun PB, Bhat AA, Mohan T, Kulkarni S, Paranjape R, Rao DN (2009) Intranasal administration of peptide antigens of HIV with mucosal adjuvant CpG ODN coentrapped in microparticles enhances the mucosal and systemic immune responses. Int Immunopharmacol9: 468-477

[165] Qian ZM, Li H, Sun H, Ho K (2002) Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol Rev54: 561-587

[166] Rappuoli R, Aderem A (2011) A 2020 vision for vaccines against HIV, tuberculosis and malaria. Nature473: 463-469

[167] Rebelatto MC, Guimond P, Bowersock TL, HogenEsch H (2001) Induction of systemic and mucosal immune response in cattle by intranasal administration of pig serum albumin in alginate microparticles. Vet Immunol Immunopathol83: 93-105

[168] Reed SG, Bertholet S, Coler RN, Friede M (2009) New horizons in adjuvants for vaccine development. Trends Immunol30: 23-32

[169] Reineke JJ, Cho DY, Dingle YT, Morello AP 3rd, Jacob J, Thanos CG, Mathiowitz E (2013) Unique insights into the intestinal absorption, transit, and subsequent biodistribution of polymer-derived microspheres. Proc Natl Acad Sci USA110: 13803-13808

[170] Renegar KB, Small PA Jr, Boykins LG, Wright PF (2004) Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract. J Immunol173: 1978-1986

[171] Rivera-Hernandez T, Hartas J, Wu Y, Chuan YP, Lua LH, Good M, Batzloff MR, Middelberg AP (2013) Self-adjuvanting modular virus-like particles for mucosal vaccination against group A streptococcus (GAS). Vaccine31: 1950-1955

[172] Rose MA, Zielen S, Baumann U (2012) Mucosal immunity and nasal influenza vaccination. Expert Rev Vaccines11: 595-607

[173] Rydell N, Sjoholm I (2004) Oral vaccination against diphtheria using polyacryl starch microparticles as adjuvant. Vaccine22: 1265-1274

[174] Rydell N, Sjoholm I (2005) Mucosal vaccination against diphtheria using starch microparticles as adjuvant for cross-reacting material (CRM197) of diphtheria toxin. Vaccine23: 2775-2783

[175] Rydell N, Stertman L, Sjoholm I (2005) Starch microparticles as vaccine adjuvant. Expert Opin Drug Deliv2: 807-828

[176] Sahdev P, Ochyl LJ, Moon JJ (2014) Biomaterials for nanoparticle vaccine delivery systems. Pharm Res31: 2563-2582

[177] Sajadi Tabassi SA, Tafaghodi M, Jaafari MR (2008) Induction of high antitoxin titers against tetanus toxoid in rabbits by intranasal immunization with dextran microspheres. Int J Pharm360: 12-17

[178] Sanchez MV, Ebensen T, Schulze K, Cargnelutti D, Blazejewska P, Scodeller EA, Guzman CA (2014) Intranasal delivery of influenza rNP adjuvanted with c-di-AMP induces strong humoral and cellular immune responses and provides protection against virus challenge. PLoS One9: e104824

[179] Sanders MT, Brown LE, Deliyannis G, Pearse MJ (2005) ISCOMbased vaccines: the second decade. Immunol Cell Biol83: 119-128

[180] Santi L, Batchelor L, Huang Z, Hjelm B, Kilbourne J, Arntzen CJ, Chen Q, Mason HS (2008) An efficient plant viral expression system generating orally immunogenic Norwalk virus-like particles. Vaccine26: 1846-1854

[181] Saraf S, Mishra D, Asthana A, Jain R, Singh S, Jain NK (2006) Lipid microparticles for mucosal immunization against hepatitis B. Vaccine24: 45-56

[182] Sarti F, Perera G, Hintzen F, Kotti K, Karageorgiou V, Kammona O, Kiparissides C, Bernkop-Schnurch A (2011) In vivo evidence of oral vaccination with PLGA nanoparticles containing the immunostimulant monophosphoryl lipid A. Biomaterials32: 4052-4057

[183] Sayin B, Somavarapu S, Li XW, Sesardic D, Senel S, Alpar OH (2009) TMC-MCC (N-trimethyl chitosan-mono-N-carboxymethyl chitosan) nanocomplexes for mucosal delivery of vaccines. Eur J Pharm Sci38: 362-369

[184] Scheerlinck JP, Greenwood DL (2008) Virus-sized vaccine delivery systems. Drug Discov Today13: 882-887

[185] Scolnick EM, McLean AA, West DJ, McAleer WJ, Miller WJ, Buynak EB (1984) Clinical evaluation in healthy adults of a hepatitis B vaccine made by recombinant DNA. JAMA251: 2812-2815

[186] Seder RA, Hill AV (2000) Vaccines against intracellular infections requiring cellular immunity. Nature406: 793-798

[187] Senchi K, Matsunaga S, Hasegawa H, Kimura H, Ryo A (2013) Development of oligomannose-coated liposome-based nasal vaccine against human parainfluenza virus type 3. Front Microbiol4: 346

[188] Shank-Retzlaff M, Wang F, Morley T, Anderson C, Hamm M, Brown M, Rowland K, Pancari G, Zorman J, Lowe R (2005) Correlation between mouse potency and in vitro relative potency for human papillomavirus Type 16 virus-like particles and gardasil (R) vaccine samples. Hum Vaccines1: 191-197

[189] Sharma S, Mukkur TK, Benson HA, Chen Y (2009) Pharmaceutical aspects of intranasal delivery of vaccines using particulate systems. J Pharm Sci98: 812-843

[190] Shaw N, Ouyang SY, Liu ZJ (2013) Binding of bacterial secondary messenger molecule c di-GMP is a STING operation. Protein Cell4: 117-129

[191] Sheppard NC, Brinckmann SA, Gartlan KH, Puthia M, Svanborg C, Krashias G, Eisenbarth SC, Flavell RA, Sattentau QJ, Wegmann F (2014) Polyethyleneimine is a potent systemic adjuvant for glycoprotein antigens. Int Immunol26: 531-538

[192] Shibata Y, Honda I, Justice JP, Van Scott MR, Nakamura RM, Myrvik QN (2001) Th1 adjuvant N-acetyl-D-glucosamine polymer upregulates Th1 immunity but down-regulates Th2 immunity against a mycobacterial protein (MPB-59) in interleukin-10-knockout and wild-type mice. Infect Immun69: 6123-6130

[193] Shukla A, Khatri K, Gupta PN, Goyal AK, Mehta A, Vyas SP (2008) Oral immunization against hepatitis B using bile salt stabilized vesicles (bilosomes). J Pharm Pharm Sci11: 58-66

[194] Shukla A, Katare OP, Singh B, Vyas SP (2010) M-cell targeted delivery of recombinant hepatitis B surface antigen using cholera toxin B subunit conjugated bilosomes. Int J Pharm385: 47-52

[195] Shukla A, Singh B, Katare OP (2011) Significant systemic and mucosal immune response induced on oral delivery of diphtheria toxoid using nano-bilosomes. Br J Pharmacol164: 820-827

[196] Singh M, O’Hagan D (1998) The preparation and characterization of polymeric antigen delivery systems for oral administration. Adv Drug Deliv Rev34: 285-304

[197] Singh M, Briones M, O’Hagan DT (2001) A novel bioadhesive intranasal delivery system for inactivated influenza vaccines. J Control Release70: 267-276

[198] Singh J, Pandit S, Bramwell VW, Alpar HO (2006) Diphtheria toxoid loaded poly-(epsilon-caprolactone) nanoparticles as mucosal vaccine delivery systems. Methods38: 96-105

[199] Skene CD, Sutton P (2006) Saponin-adjuvanted particulate vaccines for clinical use. Methods40: 53-59

[200] Skountzou I, Quan FS, Gangadhara S, Ye L, Vzorov A, Selvaraj P, Jacob J, Compans RW, Kang SM (2007) Incorporation of glycosylphosphatidylinositol-anchored granulocyte- macrophage colony-stimulating factor or CD40 ligand enhances immunogenicity of chimeric simian immunodeficiency virus-like particles. J Virol81: 1083-1094

[201] Smith DM, Simon JK, Baker JR Jr (2013) Applications of nanotechnology for immunology. Nat Rev Immunol13: 592-605

[202] Sneh-Edri H, Likhtenshtein D, Stepensky D (2011) Intracellular targeting of PLGA nanoparticles encapsulating antigenic peptide to the endoplasmic reticulum of dendritic cells and its effect on antigen cross-presentation in vitro. Mol Pharm8: 1266-1275

[203] Somavarapu S, Pandit S, Gradassi G, Bandera M, Ravichandran E, Alpar OH (2005) Effect of vitamin E TPGS on immune response to nasally delivered diphtheria toxoid loaded poly(caprolactone) microparticles. Int J Pharm298: 344-347

[204] Specht EA, Mayfield SP (2014) Algae-based oral recombinant vaccines. Front Microbiol5: 60

[205] Staats HF, Fielhauer JR, Thompson AL, Tripp AA, Sobel AE, Maddaloni M, Abraham SN, Pascual DW (2011) Mucosal targeting of a BoNT/A subunit vaccine adjuvanted with a mast cell activator enhances induction of BoNT/A neutralizing antibodies in rabbits. PLoS One6: e16532

[206] Stephenson I, Zambon MC, Rudin A, Colegate A, Podda A, Bugarini R, Del Giudice G, Minutello A, Bonnington S, Holmgren J (2006) Phase I evaluation of intranasal trivalent inactivated influenza vaccine with nontoxigenic Escherichia coli enterotoxin and novel biovector as mucosal adjuvants, using adult volunteers. J Virol80: 4962-4970

[207] Sui ZW, Chen QJ, Fang F, Zheng M, Chen Z (2010) Cross-protection against influenza virus infection by intranasal administration of M1-based vaccine with chitosan as an adjuvant. Vaccine28: 7690-7698

[208] Sun HX, Xie Y, Ye YP (2009a) Advances in saponin-based adjuvants. Vaccine27: 1787-1796

[209] Sun HX, Xie Y, Ye YP (2009b) ISCOMs and ISCOMATRIX. Vaccine27: 4388-4401

[210] Svindland SC, Pedersen GK, Pathirana RD, Bredholt G, Nostbakken JK, Jul-Larsen A, Guzman CA, Montomoli E, Lapini G, Piccirella S (2013) A study of Chitosan and c-di-GMP as mucosal adjuvants for intranasal influenza H5N1 vaccine. Influenza Other Respir Viruses7: 1181-1193

[211] Tafaghodi M, Rastegar S (2010) Preparation and in vivo study of dry powder microspheres for nasal immunization. J Drug Target18: 235-242

[212] Takahashi H (2003) Antigen presentation in vaccine development. Comp Immunol Microbiol Infect Dis26: 309-328

[213] Tam JP (1988) Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci USA85: 5409-5413

[214] Tamura S, Kurata T (2004) Defense mechanisms against influenza virus infection in the respiratory tract mucosa. Jpn J Infect Dis57: 236-247

[215] Tao W, Ziemer KS, Gill HS (2014) Gold nanoparticle-M2e conjugate coformulated with CpG induces protective immunity against influenza A virus. Nanomedicine (Lond)9: 237-251

[216] Thomas C, Gupta V, Ahsan F (2009) Influence of surface charge of PLGA particles of recombinant hepatitis B surface antigen in enhancing systemic and mucosal immune responses. Int J Pharm379: 41-50

[217] Tiwari S, Agrawal GP, Vyas SP (2010) Molecular basis of the mucosal immune system: from fundamental concepts to advances in liposome-based vaccines. Nanomedicine (Lond)5: 1617-1640

[218] Tiwari B, Agarwal A, Kharya AK, Lariya N, Saraogi G, Agrawal H, Agrawal GP (2011a) Immunoglobulin immobilized liposomal constructs for transmucosal vaccination through nasal route. J Liposome Res21: 181-193

[219] Tiwari S, Verma SK, Agrawal GP, Vyas SP (2011b) Viral protein complexed liposomes for intranasal delivery of hepatitis B surface antigen. Int J Pharm413: 211-219

[220] Tobio M, Gref R, Sanchez A, Langer R, Alonso MJ (1998) Stealth PLA-PEG nanoparticles as protein carriers for nasal administration. Pharm Res15: 270-275

[221] Torchilin VP (2005) Recent advances with liposomes as pharmaceutical carriers. Nat Rev Drug Discov4: 145-160

[222] Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol13: 251-276

[223] Tripathi V, Chitralekha KT, Bakshi AR, Tomar D, Deshmukh RA, Baig MA, Rao DN (2006) Inducing systemic and mucosal immune responses to B-T construct of F1 antigen of Yersinia pestis in microsphere delivery. Vaccine24: 3279-3289

[224] Trumpfheller C, Caskey M, Nchinda G, Longhi MP, Mizenina O, Huang Y, Schlesinger SJ, Colonna M, Steinman RM (2008) The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci USA105: 2574-2579

[225] Turner TM, Jones LP, Tompkins SM, Tripp RA (2013) A novel influenza virus hemagglutinin-respiratory syncytial virus (RSV) fusion protein subunit vaccine against influenza and RSV. J Virol87: 10792-10804

[226] Ulery BD, Kumar D, Ramer-Tait AE, Metzger DW, Wannemuehler MJ, Narasimhan B (2011) Design of a protective single-dose intranasal nanoparticle-based vaccine platform for respiratory infectious diseases. PLoS One6: e17642

[227] van der Lubben IM, Verhoef JC, Borchard G, Junginger HE (2001) Chitosan for mucosal vaccination. Adv Drug Deliv Rev52: 139-144

[228] van Ginkel FW, Jackson RJ, Yuki Y, McGhee JR (2000) Cutting edge: The mucosal adjuvant cholera toxin redirects vaccine proteins into olfactory tissues. J Immunol165: 4778-4782

[229] van Riet E, Ainai A, Suzuki T, Kersten G, Hasegawa H (2014) Combatting infectious diseases; nanotechnology as a platform for rational vaccine design. Adv Drug Deliv Rev74: 28-34

[230] Velasquez LS, Shira S, Berta AN, Kilbourne J, Medi BM, Tizard I, Ni Y, Arntzen CJ, Herbst-Kralovetz MM (2011) Intranasal delivery of Norwalk virus-like particles formulated in an in situ gelling, dry powder vaccine. Vaccine29: 5221-5231

[231] Vicente S, Peleteiro M, Diaz-Freitas B, Sanchez A, Gonzalez-Fernandez A, Alonso MJ (2013) Co-delivery of viral proteins and a TLR7 agonist from polysaccharide nanocapsules: a needle-free vaccination strategy. J Control Release172: 773-781

[232] Vila A, Sanchez A, Evora C, Soriano I, Vila Jato JL, Alonso MJ (2004) PEG-PLA nanoparticles as carriers for nasal vaccine delivery. J Aerosol Med17: 174-185

[233] Vila A, Sanchez A, Evora C, Soriano I, McCallion O, Alonso MJ (2005) PLA-PEG particles as nasal protein carriers: the influence of the particle size. Int J Pharm292: 43-52

[234] Wang X, Meng D (2014) Innate endogenous adjuvants prime to desirable immune responses via mucosal routes, Protein Cell, 1-15

[235] Wang L, Cheng C, Ko SY, Kong WP, Kanekiyo M, Einfeld D, Schwartz RM, King CR, Gall JG, Nabel GJ (2009) Delivery of human immunodeficiency virus vaccine vectors to the intestine induces enhanced mucosal cellular immunity. J Virol83: 7166-7175

[236] Wegmann F, Gartlan KH, Harandi AM, Brinckmann SA, Coccia M, Hillson WR, Kok WL, Cole S, Ho LP, Lambe T (2012) Polyethyleneimine is a potent mucosal adjuvant for viral glycoprotein antigens. Nat Biotechnol30: 883-888

[237] Wikingsson LD, Sjoholm I (2002) Polyacryl starch microparticles as adjuvant in oral immunisation, inducing mucosal and systemic immune responses in mice. Vaccine20: 3355-3363

[238] Williamson ED, Oyston PC (2013) Protecting against plague: towards a next-generation vaccine. Clin Exp Immunol172: 1-8

[239] Wong SK, Li W, Moore MJ, Choe H, Farzan M (2004) A 193-amino acid fragment of the SARS coronavirus S protein efficiently binds angiotensin-converting enzyme 2. J Biol Chem279: 3197-3201

[240] Wu T, Li SW, Zhang J, Ng MH, Xia NS, Zhao Q (2012) Hepatitis E vaccine development: a 14 year odyssey. Hum Vaccin Immunother8: 823-827

[241] Yoo MK, Kang SK, Choi JH, Park IK, Na HS, Lee HC, Kim EB, Lee NK, Nah JW, Choi YJ (2010) Targeted delivery of chitosan nanoparticles to Peyer’s patch using M cell-homing peptide selected by phage display technique. Biomaterials31: 7738-7747

[242] Yoshikawa T, Suzuki Y, Nomoto A, Sata T, Kurata T, Tamura S (2002) Antibody responses and protection against influenza virus infection in different congenic strains of mice immunized intranasally with adjuvant-combined A/Beijing/262/95 (H1N1) virus hemagglutinin or neuraminidase. <?Pub Caret?>Vaccine21: 60-66

[243] Zhang P, Yang QB, Marciani DJ, Martin M, Clements JD, Michalek SM, Katz J (2003) Effectiveness of the quillaja saponin semisynthetic analog GPI-0100 in potentiating mucosal and systemic responses to recombinant HagB from Porphyromonas gingivalis. Vaccine21: 4459-4471

[244] Zhang N, Jiang S, Du L (2014) Current advancements and potential strategies in the development of MERS-CoV vaccines. Expert Rev Vaccines13: 761-774

[245] Zhao Q, Li S, Yu H, Xia N, Modis Y (2013) Virus-like particle-based human vaccines: quality assessment based on structural and functional properties. Trends Biotechnol31: 654-663

[246] Zhao L, Seth A, Wibowo N, Zhao CX, Mitter N, Yu C, Middelberg AP (2014) Nanoparticle vaccines. Vaccine32: 327-337

[247] Zhu Q, Talton J, Zhang G, Cunningham T, Wang Z, Waters RC, Kirk J, Eppler B, Klinman DM, Sui Y (2012) Large intestinetargeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection. Nat Med18: 1291-1296

RIGHTS & PERMISSIONS

2014 This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.