Recent advances on biodegradable polymeric carrier-based mucosal immunization: an overview

Figures & data

Table 1. Comparison of parenteral and mucosal administration of vaccine.

	Parenteral	Nasal (mucosa)	Oral (mucosa)
Vaccine administration	Medically trained personnel required for injection	Self-administration and easy	Easy and self-administration
Risks	Infection (HIV, hepatitis B)	Inaccurate dose	Inaccurate dose
Immune response	Potent systemic immune response and T-cell response	To generate systemic (humoral andcellular) as well as mucosal immune response	Systemic and mucosal antibody responses can induce tolerance
Formulation	Mostly with alum	Need for mucosal adjuvant	Required potent mucosal adjuvant
Onset of action	Slow onset of action	Rapid onset of action	Slow onset of action
Clinical use	Broad	Restricted number of clinical trials	Restricted clinical trials of subunit but largely utilized for attenuated vaccines
Safety	No large trouble with sub-unit vaccines, but serious side effect with killed or attenuated vaccines	Largely unknown but safest route	Considered to be the safest route of vaccine delivery
Required antigen dose	Low	Low, generally required in μg andefficient transfer across nasal epithelium	Higher dose because of hostile GIT environment

Modified from Ref. [32].

Figure 1. Mechanism of immune response followed after mucosal immunization.

Figure 2. Schematic representation of pathways eliciting a local mucosal response and a systemic response through NALT and nasal mucosa. APCs: antigen-presenting cells (macrophages, dendritic cells); M: microfold epithelial cell; NALT: nasal-associated lymphoid tissue; PCLN: posterior cervical lymph nodes; SCLN: superior cervical lymph node.

Table 2. Classification of mucoadhesive polymers.

Based on origin	Synthetic mucoadhesive polymer: cellulose derivatives, poly(acrylic acid) polymers, poly(hydroxyethyl methylacrylate), poly(ethyleneoxide), poly(vinyl pyrrolidine), poly(vinyl alcohol) Natural mucoadhesive polymer: Tragacanth, sodium alginate, karaya gum. Guar gum, xanthangum, soluble starch, gelatin, pectin, chitosan
Based on nature	Hydophilic polymer: Polymer with this category are soluble in water examples – poloxamer, hydroxypropyl methyl cellulose, methyl cellulose, poly(vinyl alcohol), poly(vinyl pyrrolidine), have also been used mucoadhesive property
Polysaccharides	Numerous polysaccharides and its derivatives like chitosan, methyl cellulose, hyaluronic acid, hydroxypropyl methyl cellulose, gellan gum, carrageenan, xanthan gum, sodium carboxy methyl cellulose, have found application in ocular mucoadhesive delivery system
Hydrogels	Hydrogels can be characterized as three-dimensionally cross-linked polymer chains which can hold water inside its permeable structure. The water holding limit of the hydrogels is principally because of the presence of hydrophilic functional group like hydroxyl, amino and carboxyl groups
Novel mucoadhesive polymers	In novel mucoadhesive polymer cases, existing mucoadhesive polymers have been modified, while in others, new materials are developed. Examples – lectins, thiolated polymers, alginate-polyethylene glycolacrylate (alginate-PEGAc), poloxomer, pluronics
Others novel mucoadhesive polymers	The incorporation of ethyl hexyl acrylate into a copolymer with acrylic acid in order to produce a more hydrophobic and plasticized system was considered [34]. Glyceryl monooleate/water fluid crystalline phases have additionally been observed to be mucoadhesive utilizing a scope of mucosal surfaces, in spite of the fact that the system will vary to some degree from that of other mucoadhesive [35]

Figure 3. Schematic representation of targeting potential of surface-modified over non-modified nanocarriers [19].

Table 3. List of patent on biodegradable/mucoadhesive polymers used for vaccine delivery.

S. no	Inventor name	Delivery System	Title of patent	Patent name	Year	Ref.
1.	Makin J., Catherine B.,Andrew D.	Chitosan	Influenza vaccine composition with chitosan adjuvant	US6534065	2003	[89]
2.	Guidice, GD., Baudner B.	Chitosan	Mucosal vaccines with chitosan adjuvant and meningococcal antigens	US20060051378	2006	[90]
3.	Del G., Giuseppe C., Baudner B.	Chitosan	Mucosal vaccines with chitosan adjuvant and/or meningococcal antigens	EP1506008	2005	[91]
4.	Illum L., Chatfield SN.	Chitosan	Vaccine compositions including chitosan for intranasal administration and use thereof	US7323183	2008	[92]
5.	Kjems J., Howard K., Alan B., Flemming A., Morten Ã.	Chitosan	Dehydrated chitosan nanoparticles	WO09006905	2009	[93]
6.	Alonso FJ., Janes K. Csaba N.	Chitosan and PEG	Particles of chitosan and polyethylene glycol as a system for the administration of biologically active molecules	US2008095810	2008	[94]
7.	Fernandez	Chitosan	Nanoparticles of chitosan and polyethylene glycol as a system for the administration of biologically active molecules	US20080095810	2008	[95]
8.	Guidice GD., Baudner B.	Chitosan	Mucosal vaccines with chitosan adjuvant and meningococcal antigens	US20060051378	2006	[96]
9.	Del and Barbara	Chitosan	Mucosal vaccines with chitosan adjuvant and meningococcal antigens	US20060051378	2006	[97]
10.	Del G., Giuseppe C., Baudner B.	Chitosan	Mucosal vaccines with chitosan adjuvant and/or meningococcal antigens	EP1506008	2005	[98]
11.	Rao KK.	SLN	Polymerized solid lipid nanoparticles for oral or mucosal delivery of therapeutic proteins and peptides	US20080311214	2008	[99]
12.	Jeong S., Young K., Ick, Chan, Park, Joo A.	Alginate	Vaccine compositions using antigens encapsulated within alginate microspheres for oral administration and preparation proceed thereof	WO01000233	2001	[100]
13.	Mohapatra and Lee	Thiol-modified polymer	Controlled and sustained gene transfer mediated by thiol-modified polymers	WO2007086923	2007	[101]
14.	Blizzard CD., Rashba-Step J., Scott TL, et al.	Pollulan	Sustained release microspheres	EP1837018 B1	2010	[102]
15.	Giuseppe Del Guidice, Barbara Baudner	Chitosan adjuvant and meningococcal antigens	Mucosal vaccines with chitosan adjuvant and meningococcal antigen	US8926992B2	2015	[103]
16.	Billy M. Hargis	Chitosan	Novel mucosal adjuvants and delivery system	WO2014070709A1	2014	[104]
17	Billy M. Hargis	Chitosan adjuvant	Novel mucosal adjuvant and delivery system	US20170143823A1	2017	[105]
17.	Hilgers L.	Polyanionic polymer	Polyanionic polymers as adjuvants for mucosal immunization	US2003021793	2003	[106]
18.	King M.	Dextran	Use of charged dextran as a mucoactive agent and methods and pharmaceutical	US20040224922	2004	[107]
19.	Wang D., Erlanger, Bernard F., Kabat, Elvin A.	Dextran	Methods relating to immunogenic dextran–protein conjugates	US6287568	2001	[108]
20.	Singh and O’Hagan	PLGA	Use of bioadhesives and adjuvants for the mucosal delivery of antigens	US2005281843	2005	[109]
21.	O'Hagan D.	PLGA	Immunogenic compositions containing microparticles comprising adsorbed toxoid and polysaccharide-containing antigens	US20050118275	2005	[110]
22.	O’Hagan D., Singh M., Klinman DM.	PLGA	Immunogenic compositions containing anthrax antigen, biodegradable polymer microparticles, and polynucleotide-containing immunological adjuvant	US20080317784	2008	[111]
23.	Gerber JD.	Carbopol	Adjuvant composition for mucosal and injection delivered vaccines	US20046676958	2004	[112]
24.	McCluskie MJ.	Carbopol	Methods and products for inducing mucosal immunity	EP1733735	2006	[113]
25	Baker JR., Bielinska A., Myc A	Carbopol	Nanoemulsion vaccine	US20080181949	2008	[114]
26.	Chang, RC., Kivirikko KI., Neff TB, et al.	Gelatin	Recombinant gelatin in vaccines	EP2011874	2009	[115]
27.	Lawter JR., Biegajski JE.	Gelatin	Mucoadhesive tetracycline formulations	US20090098203	2009	[48]
28.	Elisseeff J.	Polyphosphazenes and polyanhydrides	Biological adhesive	US20100003329	2010	[116]
29.	Berkland, Shi	Polyphosphazenes and polyanhydrides	Nanoclusters for delivery of therapeutics	US7651770	2010	[117]
30.	O’Hagan D., Singh M., Klinman DM.	PLGA and PLA	Immunogenic compositions containing anthrax antigen, biodegradable polymer microparticles and polynucleotide containing immunological adjuvant	US20080317784	2008	[118]
31	Ghayur T., Morgan-lappe SE, Reilly EB., et al.	PLGA and PLA	Dual variable domain immunoglobulin and use thereof	US20100076178	2010	[119]
32	O’Hagan D., Van Nest G., Ott GS., et al.	PLGA and PLA	Use of microparticles with adsorbed antigen to stimulate immune responses	US20100021548	2010	[120]
33.	Baker Jr JR., Bielinska, AU., Mank NJ., et al.	PEG	Immunogenic composition comprising nano-emulsion and hepatitis B virus immunogen and method of using the same	US9415006 B2	2016	[121]
34	Orlowski M.	Poly(alkyl cyanoacrylate)	Coated expandable system	US20100076542	2010	[122]

Table 4. List of patent on ligands decorated system for vaccine delivery.

S. No.	Inventor name	Delivery system	Title of patent	Patent name	Year	Ref.
1.	Parmely, Michael J., Medhekar	Lectin	Therapeutic alkaline protease compositions and use in facilitating the transport of agents across the gastrointestinal mucosal lining	US20090068174	2009	[123]
2.	O’Hagan, Derek; Lavelle, Edward C.	Lectin	Plant lectins as mucosal adjuvants	US20050169938	2005	[124]
3.	Newell, Martha Karen, Newell, Evan, Villobos-Menvey, Elizabeth	MAbs	Compositions of UCP inhibitors, Fas antibody, a fatty acid metabolism inhibitor and/or a glucose metabolism inhibitor	US7510710	2009	[125]
4.	Sorio, Claudio	MAbs	Antibody and method for identification of dendritic cells	US20090131346	2009	[126]
5.	Sims, John E., O’Neal, Larry F.	MAbs	Methods for treating disease with an IL-1R antibody	US20090022733	2009	[127]
6.	Readett, David Robert John,Jungnelius, Jarl Ulf Birger, Gomez-Navarro, Jesus, Hanson, Douglas, Krieg, Arthur M.	MAbs	Anti-Ctla-4 antibody and Cpg-motif-containing synthetic oligodeoxynucleotide combination therapy for cancer treatment	US20090117132	2009	[128]
7.	Wu C., Ghayur T. et al., 2012	MAbs	Dual variable domain immunoglobulin and use thereof	US8258268B2	2012	[129]
8.	Allan, Christian B.	MAbs	Stabilized high concentration Anti-integrin alphavbeta3 antibody formulations	US20090053238	2009	[130]
9.	Fox, Barbara S	MAbs	Antibody therapy for modulating function of intestinal receptors	WO09020748	2009	[131]
10.	Gillies, Stephen D., Lan, Yan, Holden, Sylvia	MAbs	Enhancement of antibody–cytokine fusion protein-mediated immune responses by combined treatment with immunocytokine uptake enhancing agents	US7517526	2009	[132]
11.	Gelfand, Jeffrey A.	MAbs	Engineered antibody-stress protein fusions	US20090068184	2009	[133]

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