West Nile virus vaccine candidates attenuated by dinucleotide enrichment are immunogenic and protective against lethal infection
Bibliographic record
Abstract
West Nile virus (WNV) poses a global public health threat. This study demonstrates that the WNV RNA tolerates CpG and UpA dinucleotide enrichment in different genomic regions resulting in attenuation of CpG- and CpG/UpA-enriched variants. Attenuation was zinc finger antiviral protein 1 (ZAP)-dependent, and ZAP knockout (ZAP-KO) cells were used to generate high-titer stocks. Ten enriched variants, with permuted control and wild-type (WT) viruses, were screened in immunocompetent mice upon intraperitoneal injection. In contrast to lethal WNV-WT and permuted viruses, the E-MAX variant, with the RNA region encoding envelope (E) protein enriched both with CpG and UpA, caused no mortality. E-MAX was immunogenic and protective against lethal challenge. Stability of enriched dinucleotides was confirmed upon serial passaging in ZAP-WT and ZAP-KO cells, with only minor (17-21%) reversion at a single site in ZAP-WT condition. E-MAX upregulated interferon (IFN) signaling genes in human cells, suggesting that the combination of CpG/UpA-mediated attenuation, and concurrent activation of IFN responses potentially driven by CpG/UpA enrichment, may contribute to E-MAX immunogenicity. Evaluation using footpad injection in mice showed E-MAX had a promising safety and immunogenicity profile, although brain infection was occasionally detected. Then, we developed the E-MAX+ FR variant by combining CpG/UpA enrichment with two amino acid substitutions in functional domains of the E protein. This strategy eliminated neuroinvasion while maintaining immunogenicity and protection. Altogether, CpG/UpA dinucleotide enrichment in the genomic E region in combination with amino acid substitutions in the E protein yields a promising platform for vaccine development against WNV and potentially other flaviviruses.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".