Combinational PRR Agonists in Liposomal Adjuvant Enhances Immunogenicity and Protective Efficacy in a Tuberculosis Subunit Vaccine

Abstract

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-g, IL-2, TNF-a, 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 + T CM 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.

Landscape of T cell epitopes displays hot mutations of SARS‐CoV‐2 variant spikes evading cellular immunity

“…#551083) were used to detect cross‐T cell responses against different SARS‐CoV‐2 spike proteins among vaccinated mice. Each mouse in different groups was killed, and splenocytes were aseptically prepared as previously described 28 . Briefly, a 100 μL of 2.5 × 10 6 /mL splenocytes obtained from each mouse were added into each well of 96‐well plates in triplicate.…”

“…Each mouse in different groups was killed, and splenocytes were aseptically prepared as previously described. 28 Briefly, a 100 μL of 2.5 × 10 6 /mL splenocytes obtained from each mouse were added into each well of 96-well plates in triplicate. SARS-CoV-2 spike protein (2 μg/mL) from PS and VOCs (Alpha, Beta, Gamma, Delta, and Omicron BA.1; Sino Biological) were used to stimulate cells in each well for 16-24 h at 37°C with 5% CO 2 .…”

Deletion of BCG_2432c from the Bacillus Calmette‐Guérin vaccine enhances autophagy‐mediated immunity against tuberculosis

“…Specific pathogen‐free (SPF) female C57BL/6 mice (Beijing Vital River), 6–8 weeks old, were randomly divided into three groups (six mice in each group) and administered 10 6 Colony‐Forming Units (CFU) of different BCG vaccines (100 μl/dose s.c.) once and phosphate‐buffered saline (PBS) used as a negative control fed in an ABSL‐3 biosafety laboratory. To prepare antigen‐specific T cells, C57BL/6 mice were administered M. tuberculosis antigen Ag85B 21 (20 μg/dose) supplemented with the adjuvant DDA‐MPLA‐TDB (DMT) 22 twice at a 3‐week interval.…”

Gene Therapy Avenues for Chronic Obstructive Pulmonary Disease

“…requires nuclear transport of the contained genetic material; these shortcomings can be observed through endocytosis inhibitors and endosome trackers to visualize delivery sites 14 .…”