Combinational PRR Agonists in Liposomal Adjuvant Enhances Immunogenicity and Protective Efficacy in a Tuberculosis Subunit Vaccine.
Bacillus Calmette-Guerin (BCG) is the only licensed vaccine to prevent children from tuberculosis (TB), whereas it cannot provide effective protection for adults. Our previous work showed a novel vaccine candidate, liposomal adjuvant DMT emulsified with a multistage antigen CMFO, could protect mice against primary progressive TB, latency, and reactivation. To develop a more effective vaccine against adult TB, we aimed to further understand the role of pattern recognition receptor (PRR) agonists monophosphoryl lipid A (MPLA) and trehalose-6,6'-dibehenate (TDB) of the liposomal adjuvant DMT in the CMFO subunit vaccine-induced protection. Using C57BL/6 mouse models, the current study prepared different dimethyldioctadecylammonium (DDA)-based liposomal adjuvants with MPLA, TDB, or both (DMT), and then compared the immunogenicity and the protective efficacy among different liposomal adjuvanted CMFO subunit vaccines. Our study demonstrated that CMFO/DMT provided stronger and longer-lasting protective efficacy than the CMFO emulsified with adjuvants DDA or DDA/TDB. In addition, DDA/MPLA adjuvanted CMFO conferred a comparable protection in the lung as CMFO/DMT did. Higher levels of IFN-γ, IL-2, TNF-α, and IL-17A secreted by splenocytes were related with a more powerful and durable protection induced by CMFO/DMT through a putative synergistic effect of both MPLA and TDB via binding to TLR4 and Mincle. IL-2+ CD4+ T cells, especially IL-2+ CD4+ TCM cells, in the lung after infection were significantly associated with the vaccine-induced protection, whereas stronger IL-10 response and lower IL-2+ CD4+ T cells also contributed to the inferior protection of the DDA/TDB adjuvanted CMFO subunit vaccine. Given their crucial roles in vaccine-induced protection, combinational different PRR agonists in adjuvant formulation represent a promising strategy for the development of next-generation TB vaccine.
['Hao|Ling|L|', 'Wu|Yaqi|Y|', 'Zhang|Yandi|Y|', 'Zhou|Zijie|Z|', 'Lei|Qing|Q|', 'Ullah|Nadeem|N|', 'Banga Ndzouboukou|Jo-Lewis|JL|', 'Lin|Xiaosong|X|', 'Fan|Xionglin|X|']
D000276:Adjuvants, Immunologic D000818:Animals D015496:CD4-Positive T-Lymphocytes D016207:Cytokines D004195:Disease Models, Animal D004339:Drug Compounding D005260:Female D006017:Glycolipids D054884:Host-Pathogen Interactions D000071497:Immunogenicity, Vaccine D008050:Lipid A D008081:Liposomes D008168:Lung D008810:Mice, Inbred C57BL D009169:Mycobacterium tuberculosis D000644:Quaternary Ammonium Compounds D051192:Receptors, Pattern Recognition D013997:Time Factors D032581:Tuberculosis Vaccines D014397:Tuberculosis, Pulmonary D014611:Vaccination D022223:Vaccines, Subunit D014774:Virulence
adjuvant tuberculosis subunit vaccine Bacillus Calmette-Guerin monophosphoryl lipid A pattern-recognition receptor agonist primary infection trehalose-6,6’-dibehenate