Table 1.

Platform manufacturing technologies for modularization.

Mechanism of Modularization	Advantages and Challenges	Platform	Disease	References
VLP – Molecular insertion	Simple molecular cloning Co-production of platform and module Reproducible module display Identification of insertion site Determination of suitable linkers Limitations on module size Steric hindrance with large modules	Bacteriophage AP205	Influenza (M2)	[84]
		Cucumber Mosaic Virus	Alzheimer’s disease (Amyloid β)	[85]
			Newcastle disease virus	[86]
		Hepatitis B Core	Malaria (Circumsporozite)	[28]
			Dengue virus type 2 (Envelope domain III)	[87]
			Influenza (M2e)	[88]
			Tuberculosis (CFP-10)	[89]
		Human Papillomavirus L1 Capsid	Human respiratory syncytial virus	[27]
		Murine Polyomavirus	Influenza (M2e)	[32]
			Group A Streptococcus (J8)	[31]
			Rotavirus (VP8*)	[38]
		Tobacco mosaic virus	Poliovirus (type 3)	[90]
			Foot-and-mouth disease	[91]
VLP – Conjugation	Conjugation of large modules without affecting VLP assembly Range of conjugation chemistries Quantification of conjugation efficiency Removal of unconjugated material Location of module dependent upon method of conjugation Harsh conditions alter epitope structure	Bacteriophage AP250	Malaria (Circumsporozite)	[34]
			Malaria (Pfs25 / VAR2CSA), Tuberculosis (Ag58A)	[59]
			Malaria (Pfs25 / CIDR)	[58]
		Bacteriophage Qβ	Influenza (Hemagglutinin)	[92]
		Hepatitis B Core	Influenza A (M2e)	[93]
		Rabbit Haemorrhagic Disease Virus	Human papillomavirus type 16 (E6)	[94]
Liposome – Encapsulated	Module protected from proteases Longer circulation time Low encapsulation efficiency	Cationic liposome	Leishmania	[61],[65]
			Hepatitis E	[62]
			Duck Tembusu virus	[70]
Liposome – Surface conjugation	Modularization possible on pre-formed liposomes Range of conjugation chemistries Harsh conditions alter epitope structure Determination of suitable linkers Removal of unconjugated material	Cationic liposome	Human papillomavirus type 16 (E7)	[75]
		DMPC-DMPG-cholesterol-MPLa	Human immunodeficiency virus type 1 (gp41)	[95]
		Metallochelating liposome	Candida albicans (Heat shock protein 90)	[66]
		Neutral liposome	Group A Streptococcus	[76]
		Oleoyl liposome	Hepatitis C virus	[96]
Liposome – Adsorbed	Minimal preparation Lacks control of module orientation or display	Cationic liposome	Tuberculosis (Ag85B-ESAT-6)	[97]
		Cationic and neutral liposomes	Influenza (Hemagglutinin)	[98]

^aDMPC, 1,2-dimyristoyl-sn-glycero-3-phosphocholine; DMPG, 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol; MPL, monophosphoryl lipid A.