Biology subjects

Mortensen, R.

Publications and source records attributed to Mortensen, R..

5 recordsLinked to original sources

bioRxiv2026

Subunit vaccination enhances protection conferred by prior Mycobacterium tuberculosis exposure

Mycobacterium tuberculosis (Mtb) remains the leading cause of death from a single infectious agent. Although BCG protects against disseminated tuberculosis in infants, it has failed to curb transmission among adults. Animal models are used to prioritize vaccines entering clinical trials, but current models use Mtb-naive mice, limiting their relevance to humans in endemic settings, the primary targets of vaccine trials. Here we used a mouse model of Mtb exposure, CoMtb, where a cervical lymph node Mtb infection protects against aerosol challenge, consistent with historical observations in humans that prior Mtb exposure reduces disease risk. When we compared the impact of CoMtb on vaccine efficacy, BCG failed to provide added protection over CoMtb, while protein subunit vaccination further reduced lung burdens. This protection was associated with decreased KLRG1+ vascular CD4+ T cells and enhanced polyfunctional lung CD4+ T cells before and after aerosol challenge. Our findings were corroborated in an analysis of vaccinated humans stratified by QuantiFERON-TB status, which revealed a similar enrichment of polyfunctional CD4+ T cells in Mtb-exposed individuals. These data support the use of CoMtb to test vaccine efficacy in Mtb-exposed individuals and highlight the potential of subunit vaccines in endemic regions.

immunology↗

bioRxiv2023

A novel adjuvant formulation induces robust Th1/Th17 memory and mucosal recall responses in Non-Human Primates

After clean drinking water, vaccination is the most impactful global health intervention. However, development of new vaccines against difficult-to-target diseases is hampered by the lack of diverse adjuvants for human use. Of particular interest, none of the currently available adjuvants induce Th17 cells. Here, we develop and test an improved liposomal adjuvant, termed CAF(R)10b, that incorporates a TLR-9 agonist. In a head-to-head study in non-human primates (NHPs), immunization with antigen adjuvanted with CAF(R)10b induced significantly increased antibody and cellular immune responses compared to previous CAF(R) adjuvants, already in clinical trials. This was not seen in the mouse model, demonstrating that adjuvant effects can be highly species specific. Importantly, intramuscular immunization of NHPs with CAF(R)10b induced robust Th17 responses that were observed in circulation half a year after vaccination. Furthermore, subsequent instillation of unadjuvanted antigen into the skin and lungs of these memory animals led to significant recall responses including transient local lung inflammation observed by Positron Emission Tomography-Computed Tomography (PET-CT), elevated antibody titers, and expanded systemic and local Th1 and Th17 responses, including >20% antigen-specific T cells in the bronchoalveolar lavage. Overall, CAF(R)10b demonstrated an adjuvant able to drive true memory antibody, Th1 and Th17 vaccine-responses across rodent and primate species, supporting its translational potential.

immunology↗

bioRxiv2021

A novel Mycobacterium tuberculosis-specific subunit vaccine provides synergistic immunity upon co-administration with Bacillus Calmette-Guerin

Tuberculosis (TB) remains a global health crisis. Following encouraging clinical results of subunit vaccination and revaccination with Bacillus Calmette-Guerin (BCG), it has been suggested to combine BCG and subunit vaccines for increased efficacy. Current subunit vaccines are almost exclusively designed as BCG boosters. The goal of this study was to design a subunit vaccine that does not share antigens with BCG and explore the advantages of a BCG+subunit vaccine co-administration strategy, where the two vaccines do not cross-react. Eight protective antigens were selected to create a Mycobacterium tuberculosis (Mtb)-specific subunit vaccine, named H107. Whereas subunit vaccines with BCG-shared antigens displayed cross-reactivity to BCG in vivo in both mice and humans, H107 showed no cross-reactivity and did not inhibit BCG colonization in mice. Encouragingly, co-administering H107 with BCG (BCG+H107) led to increased adaptive immune responses against both H107 and BCG leading to improved BCG-mediated immunity. In contrast to subunit vaccines with BCG-shared antigens, boosting BCG with H107 led to substantial expansion of clonal diversity in the T cell repertoire, and BCG+H107 co-administration conferred significantly increased Th17 responses and less differentiated CD4 T cells. CD4 T cells induced by BCG+H107 maintained functional superiority after Mtb infection, and BCG+H107 provided significantly increased long-term protection compared to both BCG and H107 alone, as well as, BCG co-administered with a subunit vaccine composed of antigens shared with BCG. Overall, we identify several advantages of combining an Mtb-specific subunit vaccine with BCG and introduce H107 as a BCG-complementing vaccine with distinctive value for co-administration with BCG.

immunology↗

bioRxiv2021

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↗

bioRxiv2019

Novel patterns of complex structural variation revealed across thousands of cancer genome graphs

Cancer genomes often harbor hundreds of somatic DNA rearrangement junctions, many of which cannot be easily classified into simple (e.g. deletion, translocation) or complex (e.g. chromothripsis, chromoplexy) structural variant classes. Applying a novel genome graph computational paradigm to analyze the topology of junction copy number (JCN) across 2,833 tumor whole genome sequences (WGS), we introduce three complex rearrangement phenomena: pyrgo, rigma, and tyfonas. Pyrgo are "towers" of low-JCN duplications associated with early replicating regions and superenhancers, and are enriched in breast and ovarian cancers. Rigma comprise "chasms" of low-JCN deletions at late-replicating fragile sites in esophageal and other gastrointestinal (GI) adenocarcinomas. Tyfonas are "typhoons" of high-JCN junctions and fold back inversions that are enriched in acral but not cutaneous melanoma and associated with a previously uncharacterized mutational process of non-APOBEC kataegis. Clustering of tumors according to genome graph-derived features identifies subgroups associated with DNA repair defects and poor prognosis.

genomics↗