The antimicrobial-resistant (AMR) Klebsiella pneumoniae (Kp) poses an enormous threat to human health, with O2 serotypes accounting for up to 35-59% of infections. Although the O-polysaccharide (OPS) of the Kp O2 serotype can be used as an antigen target for vaccine preparation, its simple structure (only galactose repeats) makes it difficult to generate effective antibody responses and protection. Here, we prepared a novel Kp O2 OPS bioconjugate nanovaccine using protein glycan coupling technology (PGCT) and a SpyCatcher/SpyTag (SC/ST) orthogonal assembly system. The hepatitis B virus core antigen (HBc), which can assemble into nanoparticles, was used as a carrier to display OPS on its surface, allowing the bioconjugate to reach the nanoscale. The HBc-OPS exhibited attractive stability without aggregation or degradation for up to 10 months. A series of mouse experiments revealed the OPS-specific antibody activation ability of HBc-OPS and its protective effect against different infection doses. In particular, when coadministered with the AS03 adjuvant, all the mice were protected from higher doses of lethal attacks. Through in vitro and in vivo experiments, we found that the addition of AS03 further promoted the humoral immune response by stimulating increased levels of cytokines and T follicular helper (Tfh), germinal center B (GC B), and antigen-specific memory B cells. Moreover, we found that the use of AS03 as an adjuvant can provide a better protective effect than commonly used CpG-based adjuvants. Therefore, we have developed an attractive, stable, and effective bioconjugate nanovaccine against the Klebsiella pneumoniae O2 serotype. This bioconjugate nanovaccine design greatly potentiated the immunogenicity of polysaccharides, and the orthogonal modular assembly strategy reduced the technical difficulty of bioconjugate nanovaccine preparation, both of which could be applicable to the development of OPS conjugate vaccines for serotypes with low immunogenicity.
© 2025. The Author(s).

Although mRNA vaccines have the potential to be developed and deployed rapidly to combat infectious diseases, the ideal method of administration and boosting schedule strategy for generating optimal immunogenicity is an area of active research. We compared the immune responses resulting from different schedules for prime-boost and boosting either ipsilaterally or contralaterally in relation to the initial vaccine dose.
Influenza hemagglutinin (HA) was used as a model antigen for different vaccination regimens in mice using both mRNA lipid nanoparticles (mRNA-LNP) and AF03-adjuvanted recombinant protein (rHA-AF03) vaccines.
Increasing the prime-boost interval resulted in higher levels of serum anti-HA IgG and functional antibody hemagglutination inhibition (HAI) responses in mRNA-LNP-vaccinated animals, which correlated with an induction of germinal center (GC) B cells and follicular helper T (Tfh) cells in lymph nodes. In addition, longer prime-boost intervals resulted in higher levels of IL-2 and TNF-α producing CD4+ T cells two weeks after boosting. The number of Ig-secreting long-lived plasma cells increased with the length of prime-boost intervals. Contralateral boosting resulted in an increase in HAI titers and GC B cells compared to an ipsilateral boost. However, significantly higher numbers of GC B cells were induced in the draining lymph nodes following ipsilateral boosting than in the non-draining lymph nodes.
Overall, our data provides insights into the immune mechanisms of action of mRNA-LNP to develop the optimal vaccine regimen for mRNA vaccine platforms.

The tumour microenvironment is programmed by cancer cells and substantially influences anti-tumour immune responses1,2. Within the tumour microenvironment, CD8+ T cells undergo full effector differentiation and acquire cytotoxic anti-tumour functions in specialized niches3-7. Although interactions with type 1 conventional dendritic cells have been implicated in this process3-5,8-10, the underlying cellular players and molecular mechanisms remain incompletely understood. Here we show that inflammatory monocytes can adopt a pivotal role in intratumoral T cell stimulation. These cells express Cxcl9, Cxcl10 and Il15, but in contrast to type 1 conventional dendritic cells, which cross-present antigens, inflammatory monocytes obtain and present peptide-major histocompatibility complex class I complexes from tumour cells through 'cross-dressing'. Hyperactivation of MAPK signalling in cancer cells hampers this process by coordinately blunting the production of type I interferon (IFN-I) cytokines and inducing the secretion of prostaglandin E2 (PGE2), which impairs the inflammatory monocyte state and intratumoral T cell stimulation. Enhancing IFN-I cytokine production and blocking PGE2 secretion restores this process and re-sensitizes tumours to T cell-mediated immunity. Together, our work uncovers a central role of inflammatory monocytes in intratumoral T cell stimulation, elucidates how oncogenic signalling disrupts T cell responses through counter-regulation of PGE2 and IFN-I, and proposes rational combination therapies to enhance immunotherapies.
© 2024. The Author(s).

Abstract Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract disease in young children and older adults. We designed a codon optimized mRNA vaccine, mRNA-1345, that encodes the RSV F-glycoprotein stabilized in the prefusion (preF) conformation and with a deletion at the cytoplasmic tail. mRNA-1345 protein expression was higher in vitro versus previous mRNA-based RSV vaccine candidates evaluated clinically. In rodent models, mRNA-1345 induced a robust neutralizing and preF-biased antibody response, a T helper 1-biased cellular response, and demonstrated dose-dependent protection against RSV challenge with no evidence of enhanced respiratory disease. These findings underscored the potential of mRNA-1345 as an effective RSV vaccine and are substantiated by clinical data demonstrating efficacy of mRNA-1345 in older adults.

Loss of oral tolerance (LOT) to gluten, driven by dendritic cell (DC) priming of gluten-specific T helper 1 (Th1) cell immune responses, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. Whether certain commensals can moderate virus-mediated LOT remains elusive. Here, using a mouse model of virus-mediated LOT, we discovered that the gut-colonizing protist Tritrichomonas (T.) arnold promotes oral tolerance and protects against reovirus- and murine norovirus-mediated LOT, independent of the microbiota. Protection was not attributable to antiviral host responses or T. arnold-mediated innate type 2 immunity. Mechanistically, T. arnold directly restrained the proinflammatory program in dietary antigen-presenting DCs, subsequently limiting Th1 and promoting regulatory T cell responses. Finally, analysis of fecal microbiomes showed that T. arnold-related Parabasalid strains are underrepresented in human CeD patients. Altogether, these findings will motivate further exploration of oral-tolerance-promoting protists in CeD and other immune-mediated food sensitivities.
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