A multivalent subunit vaccine augments pre-existing immunity to protect against T3SS-positive Pseudomonas aeruginosa but reveals immunological interference against ExlA-positive strains

An adenovirus-based multiantigen vaccine protects against tuberculosis by coordinating adaptive immunity and curbing immunosuppressive mechanisms

ABSTRACT Given that tuberculosis (TB) remains the leading cause of death from a single infectious agent, and that vaccination is the most effective control strategy, we systematically compared several vaccine construction strategies using a chimpanzee adenovirus vector platform. This led to the identification of a multi-antigen vaccine candidate, Ad-8CPR2, as the most immunogenic construct. This candidate incorporates M. tuberculosis Ag85B, RpiB, and Rv2628 fused with the autophagy-inducing peptide C5 and Pan DR-binding epitope (PADRE) peptide. The C5 peptide in Ad-8CPR2 vaccine enhanced the autophagic activity of antigen-presenting cells, thereby enhancing antigen presentation via the MHCI pathway and eliciting broad, multidimensional T-cell responses. Notably, Ad-8CPR2 promoted the enrichment of tissue-resident memory T cells in the lungs, establishing local mucosal immunity that may restrict M. tuberculosis dissemination, while also generating antibodies capable of preventing M. tuberculosis infection. Furthermore, Ad-8CPR2 limited the accumulation of myeloid-derived suppressor cells and alleviated T-cell exhaustion, thereby preserving adaptive immune function during chronic infection. Ultimately, we identified Th1 and Th17 responses, alongside functionally relevant antibodies, as key correlates of vaccine-induced protection. IMPORTANCE Current efforts in developing novel tuberculosis vaccines are to enhance the protective efficacy of vaccine candidates, with research primarily centered on rational vaccine design strategies for the generation of multivalent antigen constructs. In this context, we propose an approach involving the selection of M. tuberculosis antigenic proteins with strong immunogenicity and functional properties, which are then fused with peptide segments capable of augmenting antigen-specific immune responses. Delivery of these constructs via viral vector platforms induces robust and durable adaptive immunity. Such a strategy may further improve vaccine-mediated protection and could provide a theoretical foundation for developing next-generation tuberculosis vaccine candidates. Current efforts in developing novel tuberculosis vaccines are to enhance the protective efficacy of vaccine candidates, with research primarily centered on rational vaccine design strategies for the generation of multivalent antigen constructs. In this context, we propose an approach involving the selection of M. tuberculosis antigenic proteins with strong immunogenicity and functional properties, which are then fused with peptide segments capable of augmenting antigen-specific immune responses. Delivery of these constructs via viral vector platforms induces robust and durable adaptive immunity. Such a strategy may further improve vaccine-mediated protection and could provide a theoretical foundation for developing next-generation tuberculosis vaccine candidates.

ESAT-6-derived lipopeptide-based mucosal vaccine elicits distinct humoral immune responses concomitant with a reduction in mycobacterium infection.

Respiratory mycobacterial infections remain a major global health threat, yet current vaccine strategies, which focus primarily on cell-mediated immunity, have met with limited success. We previously demonstrated that a vaccine composed of five lipopeptides (LPs) encoding immunodominant ESAT-6 epitopes elicits protective cellular immune responses against Mycobacterium tuberculosis infection. In this study, we enhanced the ESAT-LPs vaccine with a novel mucosal immune modulator, heat-killed Caulobacter crescentus (HKCC), and examined both cellular and humoral immunity in a mouse model (BALB/c) of M. avium (Mav) infection. Our findings revealed that incorporating HKCC significantly increased cellular responses and mucosal IgA and systemic IgG titers in pre- and post-exposure models, respectively. These elevated antibody levels correlated with reduced mycobacterial burden in the lungs, spleens, and livers and with improved lung pathology. Notably, serum samples from vaccinated mice markedly reduced the intracellular Mav burden and activated antimicrobial mechanisms in an ex vivo bone marrow-derived macrophage infection model. Heat-inactivated serum samples also reduced intracellular Mav burden, suggesting a complement-independent intracellular bactericidal function of the tested serum samples. Collectively, the ESAT-LPs-HKCC mucosal vaccine induces a robust, distinct humoral response and a remarkable reduction in bacterial load in both prophylactic and therapeutic settings, offering a promising new strategy for combating mycobacterial infections.

Tc17-driven antibody-independent mucosal immunity is critical for protection against extracellular bacterial pneumonia

Induction of Robust Immunity Against Hepatitis C Virus Using Rationally Adjuvanted Microneedle Patches Integrating A Secreted Form of E1E2 Heterodimer 2259568

The preclinical development of a novel HCV vaccine candidate engineered by formulating a novel native-like secreted E1E2 immunogen and a well-established combinatorial adjuvant of QS-21 + 3D-(6-acyl) PHAD into unique microneedle patches (MNPs).

TLR2/TLR7 Conjugated Adjuvant Enhances Anti-Nucleoprotein Immunity and Provides Protection Against Lethal H1N1 Influenza Infection 2253752

Influenza A virus (IAV) poses a significant public health threat due to its high mutation rate. Antigenic drift (slight changes in the outer coat proteins) leads to seasonal epidemics, while antigenic shift (new hemagglutinin (HA) or neuraminidase (NA) antigens) can produce novel strains with pandemic potential. Limited population immunity to these new strains increases the risk of severe illness and mortality, underscoring the urgent need for a universal vaccine. To develop a universal influenza A virus (IAV) vaccine that induces robust B and T cell memory responses we take a two-layered approach. First, we utilize toll-like receptor (TLR) agonists as vaccine adjuvants and second, we add a conserved internal protein (nucleoprotein (NP)) to increase the breadth of the immune response and activate T cell responses to provide a second armament of protection. We show that a conjugated, dual TLR2/7 agonist CL413 and NP antigen can enhance both antibody and T cell responses after intramuscular (i.m.) injection and provide enhanced heterosubtypic immunity to lethal IAV infection compared to either agonist alone. In determining the utility of this approach across mouse strains we found that BALB/c mice generated a hyperinflammatory response to the initial i.m. vaccination with CL413 and antigen, with the TLR2 agonist being responsible for the higher side effects. In contrast, the i.m. injection of CL413 (or TLR agonist) in C57BL/6 strain showed no adverse outcomes. Interestingly, vaccination of BALB/c mice via the intranasal (i.n.) route did not induce visible side effects, yet provided complete protection against challenge. Together, these data indicate that conjugated adjuvants with conserved IAV proteins provide superior heterosubtypic protection compared to antigen alone, or antigen with singular agonists. Investigating the protective mechanisms of this combination strategy, brings us closer to developing a universal vaccine against both seasonal and pandemic IAV strains. Biomedical Research Scholars Program, Trudeau Institute Vaccines and Immunotherapy (VAC)

Synergistic effect of AddaS03 and poly I:C adjuvants on antibody titers and Th1-biased T cell responses following RBD vaccination in BALB/c mice.

Combining AddaS03 and Poly I:C adjuvants is a potent strategy to modulate and enhance immune responses elicited by an RBD-based vaccine.