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AAV microdystrophin gene replacement therapy for Duchenne muscular dystrophy: progress and prospects.
Duchenne muscular dystrophy (DMD) is caused by pathogenic sequence variants occurring in the DMD gene which lead to the loss of the dystrophin protein, a molecular 'shock absorber' that protects muscle from contraction-induced injury. The large size of the dystrophin open reading frame precludes delivery of the full-length protein using a single adeno-associated virus (AAV) vector, which led to the development of internally-deleted dystrophin minigenes encoding partially-functional dystrophin. Indeed, five such microdystrophin therapies have been assessed in various clinical programmes. In 2023, Elevidys (Sarepta Therapeutics) received accelerated approval based on levels of dystrophin as a surrogate biomarker. In 2024, it received full approval despite unclear efficacy (i.e. not meeting primary or secondary outcomes in a phase 3 trial). Additionally, in 2025, two DMD individuals treated with Elevidys died after acute liver failure. A separate microdystrophin therapy, PF-06939926 (Pfizer) was discontinued for both efficacy and safety reasons (including the deaths of two clinical trial participants). Solid Biosciences, Genethon, REGENXBIO, and Insmed continue to develop microdystrophin therapies differing in transgene structure, promoter sequences, and AAV serotype. Here we describe recent progress in AAV-microdystrophin therapeutics development, and discuss the challenges facing such approaches, including pre-existing anti-capsid immunity, anti-transgene immunity, the unknown functionality of microdystrophin transgenes, transduction of muscle stem cells, and long-term transgene persistence.
Bivalent prefusion F vaccination in pregnancy and respiratory syncytial virus hospitalisation in infants in the UK: results of a multicentre, test-negative, case-control study.
BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in infants younger than 6 months globally. A maternal bivalent RSV prefusion F (RSVpreF) vaccine was introduced to the UK in late summer in 2024 (August 12 in Scotland and September 1 in England), with all pregnant women at 28 weeks or more of gestation eligible for vaccination. We aimed to understand RSVpreF vaccine effectiveness in a real-world setting. METHODS: We conducted a multicentre, test-negative, case-control study to analyse the vaccine effectiveness of maternal RSVpreF vaccination against the primary outcome of hospitalisation (ie, admission to hospital) for RSV-associated ALRI in infants. Patient and public involvement from a group of parents informed the study protocol design. Included patients were infants with ALRI born after Aug 12, 2024 (Scotland), and Sept 1, 2024 (England), and therefore had mothers eligible for maternal vaccination, who were admitted to 30 hospital sites across the UK from Sept 30, 2024, to Jan 20, 2025, and tested for RSV. Infants were followed up until hospital discharge or death as an inpatient. Primary vaccine effectiveness of maternal RSVpreF vaccination against RSV-associated hospitalisation was calculated with the use of a conditional logistic regression adjusted by site, calendar month of hospital attendance for the infant, age, preterm birth, and sex. FINDINGS: We included 537 mother-infant pairs, in whom there were 391 RSV-positive infant cases (median age 1·63 months [IQR 0·94-2·26]) and 146 RSV-negative infant controls (1·41 months [0·77-2·03]). Of 537 recruited infants, 297 (55%) were male and 240 (45%) were female. Ethnicity data were available for 533 mothers, of whom 434 (81%) self-identified as White. The mothers of 73 (19%) RSV-positive cases and 60 (41%) RSV-negative controls had received RSVpreF vaccine before delivery. The adjusted effectiveness of maternal RSVpreF vaccination for preventing infant hospitalisation was 58% (95% CI 28-75) for infants whose mothers were vaccinated at any time before delivery and 72% (48-85) for infants whose mothers were vaccinated more than 14 days before delivery (39 [11%] of 357 RSV-positive cases vs 43 [33%] of 129 RSV-negative controls). INTERPRETATION: In the real-world setting of the first season of vaccine implementation in England and Scotland, maternal RSVpreF vaccination was effective and equivalent to trial settings in reducing the risk of hospitalisation in infants with RSV-associated ALRI. FUNDING: National Institute for Health and Care Research, The Wellcome Trust, and Imperial College London.
Plasmodium falciparum Subtilisin-like Domain-Containing Protein (PfSDP), a Cross-Stage Antigen, Elicits Short-Lived Antibody Response Following Natural Infection with Plasmodium falciparum
With the increasing detection of artemisinin resistance to front-line antimalarials in Africa and notwithstanding the planned roll-out of RTS’S and R21 in Africa, the search for new vaccines with high efficacy remains an imperative. Towards this endeavour, we performed in silico screening to identify Plasmodium falciparum gametocyte stage genes that could be targets of protection or diagnosis. Through the analysis we identified a gene, Pf3D7_1105800, coding for a Plasmodium falciparum subtilisin-like domain-containing protein (PfSDP) and thus dubbed the gene Pfsdp. Genetic diversity assessment revealed the Pfsdp gene to be relatively conserved across continents with signs of directional selection. Using RT qPCR and Western blots, we observed that Pfsdp is expressed in all developmental stages of the parasite both at the transcript and protein level. Immunofluorescence assays found PfSDP protein co-localizing with PfMSP-1 and partially with Pfs48/45 at the asexual and sexual stages, respectively. Further, we demonstrated that anti-PfSDP peptide-specific antibodies inhibited erythrocyte invasion by 20–60% in a dose-dependent manner, suggesting that PfSDP protein might play a role in merozoite invasion. We also discovered that PfSDP protein is immunogenic in children from different endemic areas with antibody levels increasing from acute infection to day 7 post-treatment, followed by a gradual decay. The limited effect of antibodies on erythrocyte invasion could imply that it might be more involved in other processes in the development of the parasite.
Genotypic, functional, and phenotypic characterization in CTNNB1 neurodevelopmental syndrome.
CTNNB1 neurodevelopmental syndrome is a rare disorder caused by de novo heterozygous variants in the CTNNB1 gene encoding β-catenin. This study aims to characterize genetic variants in individuals with CTNNB1 neurodevelopmental syndrome, systematically assess the spectrum of clinical phenotypes using standardized measures and explore potential genotype-phenotype correlations. In this cross-sectional cohort study, individuals diagnosed with CTNNB1 neurodevelopmental syndrome underwent structured interviews using standardized scales to evaluate motor skills, speech, communication, feeding abilities, visual function, neurodevelopment, and psychopathology. Genetic variants were analyzed, and in a subset of cases, the impact of β-catenin variants on the Wnt/β-catenin signaling pathway was assessed. Across the 127 included participants (mean age: 70 months; range: 7-242 months) from 20 countries, we identified 88 different variants of the CTNNB1 gene, 87 of which were predicted to lead to loss of CTNNB1 function. Functional assays demonstrated reduced Wnt signaling activity, including 11 variants that also exhibited a dominant-negative effect. One missense variant demonstrated a gain-of-function effect. Dominant-negative variants were not clearly associated with a distinct phenotype, however, those with missense variants presented a milder phenotype, including earlier achievement of independent walking, fewer motor impairments, better conceptual and social skills, improved communication, and fewer feeding difficulties. This study describes genetic, functional, and phenotypic characteristics in individuals with CTNNB1 neurodevelopmental syndrome. Further investigation into the genotypic and phenotypic characteristics of this syndrome and their interrelationships is essential to deepen our understanding of the disorder and inform the development of targeted therapies.
Intravenous BCG vaccination in non-human primates induces superior serum antibody titers with enhanced avidity and opsonizing capacity compared to the intradermal route.
A new and more effective tuberculosis (TB) vaccine is urgently needed, but development is hampered by the lack of validated immune correlates of protection. Bacillus Calmette Guérin (BCG) vaccination by the aerosol (AE) and intravenous (IV) routes has been shown to confer superior levels of protection from challenge with Mycobacterium tuberculosis (M.tb) in non-human primates (NHP) compared with standard intradermal (ID) administration. This finding offers a valuable opportunity to investigate which aspects of immunity are associated with improved control of M.tb and may represent biomarkers or correlates of protection. As TB vaccine research to date has focused largely on cellular immunity, we aimed to better characterize the poorly-understood serum antibody response to BCG administered by different routes of vaccination in NHP. We demonstrate superior M.tb-specific IgG, IgA, and IgM titers in serum following IV BCG vaccination compared to the ID or AE routes. We also observe improved capacity of IgG induced by IV BCG to opsonize the surface of mycobacteria, and report for the first time that M.tb-specific IgG from IV BCG vaccinated animals is of higher avidity compared with IgG from ID or AE BCG vaccinated animals. Notably, we identified a significant correlation between IgG avidity and measures of protection from aerosol M.tb challenge. Our findings highlight a potential role for antibodies as markers and/or mediators of the superior vaccine-induced protection IV BCG confers against TB and suggest that quality, as well as quantity, of antibodies should be considered when developing and evaluating TB vaccine candidates.
Salmonella Typhi gut invasion drives hypoxic immune subsets associated with disease outcomes.
Salmonella Typhi (S. Typhi), the causative agent of typhoid disease, remains a major public health concern. Owing to the human-restricted nature of S. Typhi, studies of typhoid pathogenesis in animal models are limited to a murine non-typhoidal pathogen. More recently, human challenge models have been conducted, providing insight into immune correlates of infection outcomes, which are still incompletely understood. Here, we performed an integrated single-cell analysis of immune responses from the human S. Typhi challenge model and mouse model of typhoid disease, to associate biological mechanism with human infection outcome. Most prominent, we revealed immune subsets with a hypoxia-related signature in the blood of individuals who developed disease in the human challenge model. This signature was also evident in the mouse model in activated macrophages infiltrating into the Peyer's patches, but not during infection with a mutant strain impaired for gut invasion. We further identified hypoxia-related signature as a general immune correlate of disease outcome in other infection-and inflammatory-related diseases. Collectively, we identified a hypoxia-associated immune signature that correlates with disease outcomes in humans. Using a mouse model, we demonstrated that this signature is driven by bacterial invasion to the Peyer's patches, implicating a causal role in the pathogenesis of typhoid fever.
Understanding the interaction of upper respiratory tract infection with respiratory syncytial virus and Streptococcus pneumoniae using a human challenge model: a multicenter, randomized controlled study protocol.
BACKGROUND: Streptococcus pneumoniae (pneumococcus) and respiratory syncytial virus (RSV) are major causes of respiratory infections globally. Viral and bacterial co-infections are commonly observed in respiratory infections and there is evidence that these pathogens interact synergistically to evade host responses and lead to more severe disease. Notably, RSV seasonal outbreaks are associated with increased hospitalization and a subsequent peak in invasive pneumococcal disease cases, particularly in pediatric populations. Here, we summarize a protocol for a controlled human infection model aiming to evaluate pathogen interaction dynamics and immune responses in a combined pneumococcus and RSV model. The primary objective is to determine whether primary RSV challenge increases the risk of secondary pneumococcal colonization. METHODS: This is an open-label, multi-center, randomized controlled human co-infection study, inclusive of a pilot phase. Individuals will be randomized to primary inoculation with either pneumococcus (serotype 6B) or RSV (subtype RSV-A) intra-nasally on day 0 followed by a reciprocal challenge on day 7. During pilot phase A up to 10 participants will be monitored in an in-patient facility for 7-10 days following RSV-A challenge. If there are no safety concerns, we will then progress to an outpatient phase where participants will self-isolate at home. Clinical samples to be taken from participants include nasal swabs and washes for pathogen detection; and nasal cells, nasal lining fluid, and blood samples to examine mucosal and systemic immune responses. DISCUSSION: This work will lead to important scientific knowledge on the interaction and dynamics between pneumococcus and RSV. This knowledge could help inform pneumococcal and RSV vaccination strategies, particularly for groups at risk of developing severe pneumococcal and RSV disease. TRIAL REGISTRATION: The study is registered on ISRCTN (The UKs Clinical Study Registry). DOI https://doi.org/10.1186/ISRCTN12036902.
Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade.
The relationship between genetic variation and CD8+ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.
Nipah virus vaccines evaluated in pigs as a 'One Health' approach to protect public health.
Nipah virus (NiV) causes a severe neurological disease in humans. The first NiV outbreak, in Malaysia, involved pig-to-human transmission, that resulted in significant economic losses to the local pig industry. Despite the risk NiV poses to pig-dense regions, no licensed vaccines exist. This study therefore assessed three NiV vaccine candidates in pigs: (1) adjuvanted soluble NiV (s)G protein, (2) adjuvanted pre-fusion stabilised NiV (mcs)F protein, and (3) adenoviral vectored NiV G (ChAdOx1 NiV G). NiV sG induced the strongest neutralising antibody response, NiV mcsF induced antibodies best able to neutralise cell-cell fusion, whereas ChAdOx1 NiV G elicited CD8+ T-cell responses. Despite differences in immunogenicity, prime-boost immunisation with all candidates conferred a high degree of protection against NiV infection. Follow-up studies demonstrated longevity of immune responses and broadly comparable immune responses in Bangladeshi pigs under field conditions. These studies provide a platform for developing a NiV vaccine for pigs.
MetE: a promising protective antigen for tuberculosis vaccine development
IntroductionTuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains a significant global health concern. The existing vaccine, Bacillus Calmette-Guérin (BCG), provides inconsistent protection, highlighting the pressing need for a more effective vaccine. We aimed to identify novel MTB antigens and assess their protective efficacy as TB vaccine candidates.MethodsUsing immunopeptidomics, we identified 64 and 80 unique mycobacterial antigens derived from BCG and MTB, respectively. We prioritised antigens based on HLA allele coverage through an immunoinformatics approach.ResultsThe candidates, hisD, metE, and mmpL12, delivered as DNA vaccines, were evaluated for efficacy in mice using the ex vivo Mycobacterial Growth Inhibition Assay (MGIA) and metE was identified as a promising candidate. In vivo murine MTB challenge experiments confirmed the protective efficacy conferred by metE when formulated as recombinant protein with AS01™ or AddaS03™ adjuvants, compared to the naïve group. The immunogenic profiles of metE formulated in the two different adjuvants differed, with metE-AS01™ inducing antigen-specific IFN-γ, TNF-α, IL-2, IL-17, IgG1 and IgG2a-c, while metE-AddaS03™ induced TNF-α, IL-2, IL-17, IL-4, IgM, IgG1, IgG2b.ConclusionOur findings highlight metE as a promising protective antigen for future TB vaccine development.