Mucosal delivery of tuberculosis vaccines: a review of current approaches and challenges

Figures & data

Figure 1. Respiratory mucosal responses following M.tb infection or mucosal vaccination. DC = dendritic cells, EC = epithelial cells, sIgA = secreroty IgA, Brm = resident memory B cells, Trm = resident memory T cells, M.tb= Mycobacterium tuberculosis, iBALT = inducible bronchus-associated lymphoid tissue. Created with Biorender.com.

Table 1. Mucosal adjuvants in human clinical trials. Vaccine clinical trials registered on clinicaltrials.gov were searched for compounds categorized as adjuvants and delivered to mucosal surfaces.

Compound	Antigen	Phase	Results	Investigators	Ref	Trial Id
Type 1 IFN	Influenza, 2006–2007 trivalent inactivated vaccine	1	No effect	NIAID, Baylor College of Medicine	[113]	NCT00436046
E.coli LT	Influenza, virosome/subunit	n/a vaccine used in Switzerland in 2000–2001	Effective, but strong association with Bell’s Palsy	Berna Biotech	[114]
polyICLC (Hiltonol)	Respiratory viral infections, including influeza	1		NIAID		NCT00646152
polyI:polyC12U (Ampligen)	Influenza, FluMist	I/II Canceled due to withdrawal of FluMist in 2016	Specific SIgA titers >4x over baseline. Well tolerated	Hemispherx Biopharma Inc.	[115]	NCT01591473
Oleic acid, mono-olein (Endocine™)	Influenza A/California/07/2009 H1N1	I		Eurocine Vaccines Ab		NCT02998996
Oleic acid, mono-olein (Endocine™)	HIV Vacc-4x p24 consensus peptides	I	Safe, antigenic dose-dependent immune responses	Eurocine Vaccines Ab	[116]	NCT01473810
Cholera toxin B subunit	None					NCT00820144
Aluminum hydroxide	Streptococcus pneumoniae GEN-004	I	Non-significant reduction in carriage rate	Genocea Biosciences		NCT02116998
Rintatolimod	FluMist	I/II	Well tolerated. 92% of vaccinees produced specific sIgA.	Hemispherx Biopharma Inc.		NCT01591473 (terminated as nasal flu spray not CDC recommended 2016–2017)
Proteasome (N. meningitides OMP)	Trivalent Influenza HA			ID Biomedical, Quebec	[117]	NCT02522754^1

Table 2. Experimental mucosal prophylactic vaccines for TB. Vaccines tested in multiple animal models or human clinical trial(s) are listed along with selected other studies.

Vaccine	Mouse	Guinea Pig	Cow	NHP	Human Clinical Trials
Viral Vectored Vaccines
MVA85A(University of Oxford)	Intranasal boost enhances BCG protection [121]			Aerosol boost immunogenic [141]	NCT01954563 [95] NCT01497769 [94] NCT02532036 – terminated poor recruitment
Ad5Ag85A(McMaster University)	Intranasal boost enhances BCG protection [122]	Intranasal boost to BCG improved survival of vaccinated animals compared to control BCG [123]	Endobronchial instillation. Similar immunogenicity to intradermal [124]		NCT02337270 – recruiting since Jan 2015
ChAOx1.85A(University of Oxford)	Intranasal boost with MVA85A enhances BCG protection [106]				Aerosol Phase I clinical trial in Lausanne (BASEC ID: 2017–02308) ^97
ChAdOx1.PPE15 (University of Oxford)	Intranasal boost enhances BCG protection [109]	Intranasal BCG boost improves CFU counts in spleen (S.Clark, pers. Comm, manuscript in preparation)
AdCh68.85A(McMaster University)	Intranasal boost enhances BCG protection [108]
Subunit vaccines
Nano-FP1 (Ag85B-Acr-ESAT6-HbHA adsorbed carnauba wax nanoparticles): polyIC	Intranasal boost enhances BCG protection [131]	Endobronchial BCG boost reduces disease (M. Rottenberg pers. Comm)
Spore-FP1 (Ag85B-Acr-ESAT6-HbHA adsorbed onto Bacillus subtilis spores): polyIC	Intranasal Bacterial burden in lungs reduced after homologous i.n. vaccination or BCG boost [46]	Endobronchial vaccination reduces disease (S. Clark pers. Comm. Manuscript in preparation)		Aerosol boost immunogenic (A. White pers. Comm)
H56:CAF01	Intranasal boosting immunogenic but protection not superior to systemic [56]
Whole cell vaccines
BCG	Intranasal BCG [125] Intranasal BCG + CT [62]	Aerogenic [79]	Aerosol [126]	Aerosol [127] (immunogenicity only)	NCT02709278 – status unclear NCT03912207 – recruiting April 2019
MtbΔSigH	Intranasal Establishes infection with reduced lethality to wild-type [128]			Aerosol vaccination protective (superior to BCG) [17]
TBvac85 (M. shottsii/Mtb Ag85B)		Intranasal protection equivalent to intradermal BCG [129]
Salmonella/Ag85B-ESAT6	Oral prime immunogenic [130]	Oral prime systemic boost regime equivalent to BCG [130]

Figure 2. Respiratory system in man and vaccine deposition following aerosol delivery (created with BioRender.com).

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