Contribution of Nanotechnologies to Vaccine Development and Drug Delivery against Respiratory Viruses

Table 1

Nanoparticle-based vaccines against respiratory viruses.

Material	Size (nm)	Virus	Antigen/epitope	Adjuvant	Vaccine trial phase	Administration route	Benefits	References (year)
Liposomes
DLPC liposomes	30–100	Influenza (H1N1)	M2, HA, and NP; highly conserved peptides	MPL and trehalose 6,6-dimycolate	In vivo; Mice	Intranasal	(i) Protection against diverse influenza strains; (ii) Highly specific T-cell responses that sharply limit viral replication following infection	[143] (2010)
Lipid nanoparticles (LPN)	43–54	Influenza (H1N1); (H3N2)	Hemagglutinin (split vaccine)	CpG-ODN (TLR 9 agonist)	In vivo; Mice	Subcutaneous	(i) Improve adjuvant effects in vivo with greater production of cytokines and costimulatory molecules CD80 and CD86 on DCs; (ii) Improved T-cell responses and protection over heterologous and heterosubtypic strain	[144] (2019)
	—	SARS-CoV-2	mRNA encoding full-length, prefusion stabilized spike protein	—	Licensed	Intramuscular (deltoid)	Safety, efficacy	[73, 145] (2021); Moderna
	—	SARS-CoV-2	Full spike mRNA	—	Licensed	Intramuscular (deltoid)	Safety, efficacy	[73, 145] (2021) BioNTech SE and Pfizer
	—	SARS-CoV-2	Spike mRNA	—	Phase 2b/3	Intramuscular	Safety, efficacy	[73, 145] (2021); CureVac
Polymeric nanoparticles
PLGA	225.4	Bovine parainfluenza 3 virus (BPI3V)	BPI3V proteins	—	In vivo; Calves	Intranasal	Greater mucosal IgA responses	[146] (2015)
	200–300	Swine influenza virus (H1N2)	Inactivated virus H1N2 antigen	—	In vivo; Pigs	Intranasal	Reduce the clinical disease and induce cross-protective cell-mediated immune response in a pig model	[147] (2017)
γ-PGAa	100–200	Influenza (H1N1)	Hemagglutinin	—	In vivo; Mice	Subcutaneous/intranasal	Sufficient cross-protective immune responses against influenza virus infection in mice; Effective cross-protection with minimal side effects	[148] (2009)
PGA-PLL	150–600	RSV	G protein; CX3C motif	—	In vivo; Mice	Subcutaneous	Induce blocking antibodies that prevent the interaction of the RSV G protein with the fractalkine receptor (CX3CR1) and protect mice against RSV replication and disease pathogenesis	[149] (2015)
Chitosan	140	Influenza (H1N1)	H1N1 antigen	—	In vivo; Mice	Intranasal	(i) Stimulate macrophages to produce IL-1β and IL-6; (ii) Stimulate spleen lymphocytes to produce IL-2 and IFN-γ	[150] (2015)
	220–500	All influenza viruses	HA2 and NP	Trimethyl chitosan TMC np	In vitro	—	(i) Systemic adaptive immunity; (ii) Conserved proteins delivered in an adjuvanted nanoparticle system	[151] (2020)
	300–350	Influenza (H1N1)	HA-split	—	In vivo; Mice	Intranasal	(i) Vaccine innocuousness; (ii) Effective and safe delivery vehicle/adjuvant for the influenza vaccine	[152] (2014)
	571.7	Swine influenza virus (H1N2)	Killed swine influenza antigen	—	In vivo; Pigs	Intranasal	(i) In CNP-KAg vaccinated pigs challenged with heterologous virus, reduced severity of macroscopic and microscopic influenza-associated pulmonary lesions were observed; (ii) Chitosan SwIAV nanovaccine delivered by IN route elicited strong cross-reactive mucosal IgA and cellular immune responses in the respiratory tract that resulted in a reduced nasal viral shedding and lung virus titers in pigs	[153] (2018)
	200–250	Influenza (H1N1)	M2e	Heat shock protein 70c	In vivo; Mice	Intranasal	(i) Induce a long lasting M2e-specific humoral and cellular immune responses; (ii) Provide full protection against a 90% lethal dose (LD90) of the influenza virus A/PR/8/34 (H1N1).	[154] (2018)
HPMA/NIPAM	12–25	RSV	F protein	TLR-7/8 agonist	In vivo; Mice	Subcutaneous	The improved pharmacokinetic profile by particulate polymer-TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T-cell immunity; (i) Optimizing adjuvant design to elicit broad-based antibody and T-cell responses with protein antigens; (ii) Protective immunity	[155, 156]; (2018, 2015)
Polyanhydride	200–800	RSV	F and G glycoproteins	—	In vivo; Calves	Intranasal	Enhanced interactions with antigen-presenting cells that are necessary in the initiation of efficacious immune responses; BRSV-F/G nanovaccine is highly immunogenic, and with optimization, has the potential to significantly reduce the disease burden associated with RSV infection in both humans and animals	[157, 158]
Self-assembling proteins and peptide-based nanoparticles
N nucleocapsid protein of RSV	15	RSV	RSV phosphoprotein	R192G detoxified E. coli enterotoxin LT	In vivo; Mice	Intranasal	Efficient and safe intranasal vaccine against RSV	[159] (2008)
	15	RSV	FsII	Montanide™ Gel 01	In vivo; Mice	Intranasal	N-specific cellular immunity and F-specific antibodies for protection	[160] (2016)
	15	Influenza (H1N1)	M2e	Montanide™ Gel 01	In vivo; Mice	Intranasal	Nucleoprotein nanoring is a potent carrier for mucosal delivery of vaccine antigens	[161] (2013)
Ferritin	12.5	Influenza (H1N1)	M2e	—	In vivo; Mice	Intranasal	High immunogenicity, cross-protection, and convenient administration, as well as being economical and suitable for large-scale production	[162] (2018)
Q11	—	Influenza (H1N1)	Acid polymerase	—	In vivo; Mice	Intranasal	Immunogenic, noninflammatory, and promote more lung-resident memory CD8+ T cells compared to subcutaneous immunization	[163] (2018)
Self-assembling proteins	55	RSV	F protein (prefusion)	Squalene-oil-in-water	In vivo; Mice	Subcutaneous	In mice and nonhuman primates, the full-valency nanoparticle immunogen displaying 20 DS-Cav1 trimers induced neutralizing antibody responses ∼10-fold higher than trimeric DS-Cav1	[164] (2019)
Protein recombinant nanoparticle; ResVax	—	RSV	F protein	Aluminum phosphate	Phase III	Humans	First RSV vaccine to show Phase 3 efficacy; Favorable safety and tolerability data	[165] (2020)-; Failed to hit its primary endpoint
Self-assembling proteins		Influenza (H1N1, H3N2)	HA, M2e	—	In vivo; Mice	Intramuscular	Controlled release; Protective potency	[166] (2018)
Inorganic nanoparticles
Gold	12	Influenza	M2e	CpG	In vivo; Mice	Intranasal	Generate robust anti-M2e serum IgG antibodies in mice	[167] (2017)
Gold nanorods		RSV	F protein	—	In vitro	—	A potent method for immunizing against viruses such as RSV with surface glycoproteins that are targets for the human immune response	[168] (2013)-
Ferritin	—	RSV	F protein	AF03	In vivo; Mice	Intramuscular	This pre-F vaccine increased the generation of NAbs targeting the desired pre-F conformation, an attribute that facilitates the development of an effective RSV vaccine	[169] (2020)-
Others
VLP	—	SARS-CoV-2	Full-length, prefusion spike protein	Saponin-based Matrix-M™	Phase 3	Intramuscular	Safety	[73, 145, 170]; (2021); Novavax
	80–120	Influenza (H1N1)	Hemagglutinin	—	In vivo; Mice	Intranasal	Intranasal immunization with VLPs containing HA induced high serum and mucosal antibody titers and neutralizing activity against PR8 and A/WSN/33 (H1N1) viruses; A promising strategy for the development of a safe and effective vaccine	[171] (2007)
	80–120	Influenza (H1N1, H3N2, and H5N1)	M2e	—	In vivo; Mice	Intranasal	Cross-protection by inducing humoral and cellular immune responses	[172] (2018)
	—	Influenza (H3N2)	HA	Matrix-M1	Phase 1/2a	In vivo; ferret	Broadly protective immunity and improved vaccine efficacy	[173] (2020)
	80–120	RSV	F protein and G glycoprotein of RSV and M1 protein of Influenza	—	In vivo; Mice	Intranasal	Enhanced protection against live RSV challenges; Significant decreases in lung viral replication and obvious attenuation of histopathological changes associated with viral infections	[174] (2017)
	—	RSV	RSV-F	Aluminum phosphate	Phase 3	Humans	(i) Tolerated without dose-related increases in adverse events; (ii) A 7- to 19-fold increase in the anti-F IgG and a 7- to 24-fold increase in the antigenic site II binding and palivizumab competitive antibodies	[175] 2013; Not effective in a large phase 3 trial
	80–120	MERS-CoV	MERS spike protein (S)	Alum	In vivo; Mice	Intramuscular	High-titer antibodies in mice	[176] (2014)
	80–120	MERS-CoV	Recombinant MERS-CoV S	Matrix-M1	In vivo; Mice	Intramuscular	High-titer anti-S neutralizing antibody and protected mice from MERS-CoV infection in vivo	[177] (2017)
	80–120	MERS-CoV	MERS-CoV VLPs; With protein S, E, and M	Alum	Rhesus macaques	Intramuscular	Excellent immunogenicity in rhesus macaques	[178] (2016)
ISCOMb	40	Influenza (H1N1)	Hemagglutinin	ISCOMATRIX	In vivo; Sheep/mice	Intranasal	(i) Induce serum haemagglutination inhibition (HAI) titres in mice far superior to those obtained with nonadjuvanted vaccine delivered subcutaneously; (ii) Induce mucosal IgA responses in the lung, nasal passages, and large intestine, together with high levels of serum IgA; (iii) Improved protection	[179, 180]; (2008, 2003)
Virosomes	150	Influenza A	Virus envelope proteins	Virosomes	Licensed	Intramuscular	Good immunogenicity in both healthy and immunocompromised elderly, adults, and children.	[181] (2009)

Abbreviations: DLPC—dilauroylphosphatidylcholine; MPL—monophosphoryl lipid A; CpG-ODN—unmethylated cytosine-guanine dinucleotide oligodeoxynucleotides; PGA—gamma-polyglutamic acid; PGA-PLL—poly(γ-glutamic acid)-poly(L-lysine); HA—hemagglutinin; NA—neuraminidase; IL—interleukin; HPMA—N-(2-hydroxypropyl)methacrylamide; NIPAM—poly(N-isopropylacrylamide); TLR—Toll-like receptor; ISCOM—immune stimulating complexes; SwIAV—swine influenza A virus; TMC np—trimethyl chitosan nanoparticle.