Multimodal vaccination targeting the receptor binding domains of <i>Clostridioides difficile</i> toxins A and B with an attenuated <i>Salmonella</i> Typhimurium vector (YS1646) protects mice from lethal challenge
Bibliographic record
Abstract
ABSTRACT Developing a vaccine against Clostridioides difficile is a key strategy to protect the elderly. Two candidate vaccines using a traditional approach of intramuscular (IM) delivery of recombinant antigens targeting C. difficile toxins A (TcdA) and B (TcdB) failed to meet their primary endpoints in large phase 3 trials. To elicit a mucosal response against C. difficile , we repurposed an attenuated strain of Salmonella Typhimurium (YS1646) to deliver the receptor binding domains (rbd) of TcdA and TcdB to the gut-associated lymphoid tissues, to elicit a mucosal response against C. difficile . In this study, YS1646 candidates with either rbdA or rbdB expression cassettes integrated into the bacterial chromosome at the att Tn 7 site were generated and used in a short-course multimodal vaccination strategy that combined oral delivery of the YS1646 candidate(s) on days 0, 2, and 4 and IM delivery of recombinant antigen(s) on day 0. Five weeks after vaccination, mice had high serum IgG titers and increased intestinal antigen-specific IgA titers. Multimodal vaccination increased the IgG avidity compared to the IM-only control. In the mesenteric lymph nodes, we observed increased IL-5 secretion and increased IgA + plasma cells. Oral vaccination skewed the IgG response toward IgG2c dominance (vs IgG1 dominance in the IM-only group). Both oral alone and multimodal vaccination against TcdA protected mice from lethal C. difficile challenge (100% survival vs 30% in controls). Given the established safety profile of YS1646, we hope to move this vaccine candidate forward into a phase I clinical trial. IMPORTANCE Clostridioides difficile remains a major public health threat, and new approaches are needed to develop an effective vaccine. To date, the industry has focused on intramuscular vaccination targeting the C. difficile toxins. Multiple disappointing results in phase III trials have largely confirmed that this may not be the best strategy. As C. difficile is a pathogen that remains in the intestine, we believe that targeting mucosal immune responses in the gut will be a more successful strategy. We have repurposed a highly attenuated Salmonella Typhimurium (YS1646), originally pursued as a cancer therapeutic, as a vaccine vector. Using a multimodal vaccination strategy (both recombinant protein delivered intramuscularly and YS1646 expressing antigen delivered orally), we elicited both systemic and local immune responses. Oral vaccination alone completely protected mice from lethal challenge. Given the established safety profile of YS1646, we hope to move these vaccine candidates forward into a phase I clinical trial.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".