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.

Key words： 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