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Jungersen, G.

Publications and source records attributed to Jungersen, G..

2 recordsLinked to original sources

Effects of different immunomodulating liposome-based adjuvants and injection sites on immunogenicity in pigs

Vaccine adjuvants are able to boost immune responses and steer immunity towards a desired direction. Liposome-based cationic adjuvant formulations (CAFs) are effective in inducing cell-mediated immune responses in mice, non-human primates and humans. In the translation from mouse to humans, pigs could play an important role. In this study, we thus used commercial pigs housed under field conditions to investigate the effects of four different CAFs incorporating distinct immunomodulators: C-type lectin receptor ligands trehalose-6,6-dibehenate and monomycolyl glycerol, toll-like receptor ligand Poly(I:C) or retinoic acid. The vaccines were formulated with a recombinant Chlamydia model protein antigen and administered via distinct injection routes. All adjuvants significantly increased antigen-specific IgA and IgG in serum, compared to non-adjuvanted antigen. Administering the vaccines through intramuscular and intraperitoneal routes induced significantly higher antigen-specific IgA and IgG serum antibodies, than the perirectal route. Although the immunizations triggered cell-mediated immunity, no significant differences between the adjuvants or injection sites were detected by intracellular flow cytometry or cytokine-release assays. Genes depicting T cell subtypes were monitored by qPCR, which revealed minor differences only. Our findings suggest that the adjuvant-specific signature of the tested adjuvant immunomodulation does not translate well from mice to pigs. This study provides new insights into immune responses to CAFs in the pig model, and highlights that adjuvant studies should be ideally carried out in the intended species of interest.

immunology↗

In vivo antigen expression regulates CD4 T cell differentiation and vaccine efficacy against Mycobacterium tuberculosis infection

New vaccines are urgently needed against Mycobacterium tuberculosis (Mtb), which kills more than 1.4 million people each year. CD4 T cell differentiation is a key determinant of protective immunity against Mtb, but it is not fully understood how host-pathogen interactions shape individual antigen-specific T cell populations and their protective capacity. Here, we investigated the immunodominant Mtb antigen, MPT70, which is upregulated in response to IFN-{gamma} or nutrient/oxygen deprivation of in vitro infected macrophages. Using a murine aerosol infection model, we compared the in vivo expression kinetics of MPT70 to a constitutively expressed antigen, ESAT-6, and analysed their corresponding CD4 T cell phenotype and vaccine-protection. For wild-type Mtb, we found that in vivo expression of MPT70 was delayed compared to ESAT-6. This delayed expression was associated with induction of less differentiated MPT70-specific CD4 T cells but, compared to ESAT-6, also reduced protection after vaccination. In contrast, infection with an MPT70-overexpressing Mtb strain promoted highly differentiated KLRG1+CX3CR1+ CD4 T cells with limited lung-homing capacity. Importantly, this differentiated phenotype could be prevented by vaccination and, against the overexpressing strain, vaccination with MPT70 conferred similar protection as ESAT-6. Together our data indicate that high in vivo antigen expression drives T cells towards terminal differentiation and that targeted vaccination with adjuvanted protein can counteract this phenomenon by maintaining T cells in a protective less-differentiated state. These observations shed new light on host-pathogen interactions and provide guidance on how future Mtb vaccines can be designed to tip the immune-balance in favor of the host. ImportanceTuberculosis, caused by Mtb, constitutes a global health crisis of massive proportions and the impact of the current COVID-19 pandemic is expected to cause a rise in tuberculosis-related deaths. Improved vaccines are therefore needed more than ever, but a lack of knowledge on protective immunity hampers their development. The present study shows that constitutively expressed antigens with high availability drive highly differentiated CD4 T cells with diminished protective capacity, which could be a survival strategy by Mtb to evade T cell immunity against key antigens. We demonstrate that immunisation with such antigens can counteract this phenomenon by maintaining antigen-specific T cells in a state of low differentiation. Future vaccine strategies should therefore explore combinations of multiple highly expressed antigens and we suggest that T cell differentiation could be used as a readily measurable parameter to identify these in both preclinical and clinical studies.

immunology↗