Here is a crazy Jev @typesafeai example that I’m betting nobody has thought about: I asked @Muse

Sep 19

Here is a crazy Jev @typesafeai example that I’m betting nobody has thought about: I asked @Muse from @Meta to use Jev to select the top 100 unanswered questions in immunology from 10,000 literature-grounded candidates. A few minutes later, it came back with some of the best immunology questions I had ever seen! (some examples below) Now I’m trying this with Codex Astra, bringing in the big guns and going all in with Jev for million decisions, why not 😅 I’ve already had Jev make tens of thousands of other decisions and have still only spent a few bucks. Insane efficiency! Muse + Jev top questions in immunology, this is good stuff: 1. What are the triggers that drive a primed bNAb precursor B cell through the convoluted, highly-mutated maturation pathway to a true broadly neutralizing antibody in vivo — i.e., what heterologous immunogen sequences and regimens are required beyond germline-targeting primes? Subfield: B cells & antibodies · Jev stage-A: 8.06/10 · stage-B: 7.54/10 Insights from HIV-1 vaccine and passive immunization efficacy trials (2024) Precise targeting of HIV broadly neutralizing antibody precursors in humans (2025) 2. After nearly a century of use, what is the actual mechanism of alum — the most widely used human vaccine adjuvant — and why is there still no consensus among the depot, NLRP3-inflammasome, membrane-lipid-binding, and uric-acid models? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.60/10 · stage-B: 7.45/10 Aluminium adjuvants in vaccines - A way to modulate the immune response (2021) Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells (2008) 3. Why do broadly neutralizing antibodies against HIV-1 take years to develop in only a small fraction of infected individuals, and what host B-cell repertoire and viral co-evolution dynamics determine who becomes an 'elite neutralizer'? Subfield: B cells & antibodies · Jev stage-A: 7.34/10 · stage-B: 7.39/10 Insights from HIV-1 vaccine and passive immunization efficacy trials (2024) 4. What are the human immune correlates of protection against tuberculosis disease, given that M72/AS01E showed ~50-54% efficacy against progression to pulmonary TB without any identified correlate? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 8.01/10 · stage-B: 7.38/10 Key recent advances in TB vaccine development and understanding of protective immune responses against Mycobacterium tuberculosis (2020) M72/AS01E tuberculosis vaccine candidate consensus-generating consultation on the development pathway (2023) 5. What molecular and niche signals determine whether a plasma cell becomes long-lived (decades, e.g., tetanus/measles) versus short-lived (months, e.g., pertussis/COVID mRNA), and can vaccines be designed to favor the long-lived fate? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.69/10 · stage-B: 7.31/10 Mechanisms that determine plasma cell lifespan and the duration of humoral immunity (2020) Germinal centre-driven maturation of B cell response to mRNA vaccination (2022) 6. By what mechanisms do primary infections (measles, influenza, HIV, malaria, pertussis) transiently 'stun' or permanently deplete host immunity to unrelated secondary pathogens, and can this be predicted or reversed? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.67/10 · stage-B: 7.28/10 Infections that cause secondary immune deficiency (2020) 7. Which immune correlates of protection are truly mechanistic (causal) versus merely statistical, and how often do vaccines protect through pathways their measured correlate does not capture? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.56/10 · stage-B: 7.25/10 Immune Biomarkers, Profiles, and Responses: A Vaccine Ontology Perspective (2026) A correlate of protection for SARS-CoV-2 vaccines is urgently needed (2021) 8. What immune mechanisms control the HIV reservoir in elite controllers who have weak HIV-specific CD8+ T cell responses, given that known HLA-associated CD8 effects explain less than 25% of viral-load variability? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.67/10 · stage-B: 7.24/10 Viral reservoirs in elite controllers of HIV-1 infection: Implications for HIV cure strategies (2020) CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21 (2011) 9. What are the immune correlates of protection for the malaria vaccines RTS,S and R21, and which antibody Fc-mediated effector functions (opsonic phagocytosis, NK cytotoxicity) actually mediate protection in children? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 8.00/10 · stage-B: 7.21/10 WHO technical consultation on immune correlates of protection for malaria — June 2024 meeting report (2024) RTS,S, the first malaria vaccine - what mediates protection and how long does immunity last? (2026) 10. How can the ~80% of IEI genetic tests that return variants of uncertain significance (VUS) be functionally validated at scale so they become clinically actionable? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.64/10 · stage-B: 7.20/10 Finding patterns in genetic uncertainty: Clues for inborn errors of immunity (2025) Hidden cases of rare disease uncovered by rapid genetic testing method (2025) 11. What defines a high-quality neoantigen beyond MHC binding affinity, and why do most computationally predicted neoantigens fail to be immunogenic in patients? Subfield: Tumor immunology, transplantation & systems · Jev stage-A: 7.88/10 · stage-B: 7.19/10 Neoantigen dissimilarity to the self-proteome predicts immunogenicity and response to immune checkpoint blockade (2019) 12. What fraction of suspected inborn errors of immunity (IEI) that remain unsolved after exome sequencing is explained by non-coding, structural, splicing, or oligogenic variation, and how should diagnostics capture it? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.42/10 · stage-B: 7.19/10 A multidisciplinary RNA-guided approach to complement genomic analysis of unsolved patients with an inborn error of immunity (2026) 13. Can sequential germline-targeting immunization reliably shepherd rare VRC01-class bnAb precursor B cells through the long, improbable somatic-hypermutation pathways needed to produce true broadly neutralizing antibodies in humans? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.68/10 · stage-B: 7.15/10 HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen (2016) Germline-targeting vaccine elicits HIV broadly neutralizing antibodies in nonhuman primates (2026) 14. What is the molecular decision point that routes an innate stimulus toward trained immunity versus tolerance, when both outcomes use the same epigenetic and metabolic machinery — and how does ligand dose or concentration flip the switch? Subfield: Innate immunity · Jev stage-A: 7.27/10 · stage-B: 7.15/10 Probiotics and Trained Immunity (2021) 15. Which of the many proposed Treg suppression mechanisms — IL-2 consumption, CTLA-4/B7 trans-endocytosis, IL-10/TGF-beta/IL-35, adenosine, granzyme killing, rapid Ca2+/NFAT/NF-kB signal suppression — actually operates in vivo, in which tissue, and against which target cell? Subfield: Tolerance, autoimmunity & allergy · Jev stage-A: 7.67/10 · stage-B: 7.14/10 Foxp3+ T Regulatory Cells: Still Many Unanswered Questions—A Perspective After 20 Years of Study (2018) Molecular Mechanisms of Treg-Mediated T Cell Suppression (2012) 16. How can HIV Env immunogen design overcome the glycan shield and trimer metastability to engage naive bnAb precursors, given that the conserved epitopes evolution has made poorly immunogenic are the ones vaccines must target? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.87/10 · stage-B: 7.13/10 Test of a new 'germline-targeting' HIV vaccine prepares to launch (2022) HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen (2016) 17. What determines the widely different lifespans of TRM across tissues (e.g., long-lived TGF-beta-restrained skin TRM versus short-lived liver and lung TRM), and can longevity be extended for durable vaccines? Subfield: Antigen presentation & T cell biology · Jev stage-A: 7.66/10 · stage-B: 7.12/10 Intricacies of tissue memory T cells could be the future of immunotherapies and vaccines (2021) Tissue-resident memory T cells (2013) 18. To what extent do effective two-dimensional (membrane) BCR affinity, force-dependent bond stability (slip-bond vs catch-bond behavior), and epitope geometry — rather than solution affinity measured by SPR/BLI — determine GC B cell competitive fitness in vivo? Subfield: B cells & antibodies · Jev stage-A: 7.31/10 · stage-B: 7.12/10 Deconstructing the germinal center, one cell at a time (2017) 19. What sustains lifelong allergen-specific IgE memory given that IgE plasma cells are mostly short-lived and IgE+ memory B cells are vanishingly rare — continuous renewal from type 2 IgG memory B cells (MBC2s), or bone-marrow long-lived IgE plasma cells? Subfield: Tolerance, autoimmunity & allergy · Jev stage-A: 7.27/10 · stage-B: 7.10/10 Chronic allergen exposure drives accumulation of long-lived IgE plasma cells in the bone marrow, giving rise to serological memory (2020) Reservoirs of allergic memory (2023) Type 2 IgG Memory B Cells and Long‐Lived IgE Plasma Cells in the Persistence of Allergy (2026) 20. Do long-lived IgE plasma cells in human bone marrow and chronically inflamed tissues make a clinically meaningful contribution to persistent allergic sensitization, and can they be selectively depleted without erasing protective IgG/IgA memory? Subfield: Tolerance, autoimmunity & allergy · Jev stage-A: 7.22/10 · stage-B: 7.10/10 Long-Lived plasma cells: mysterious sentinels and persistent IgE producers? (2026) Type 2 IgG Memory B Cells and Long‐Lived IgE Plasma Cells in the Persistence of Allergy (2026) 21. Why does BCG reliably protect infants against disseminated TB yet show highly variable, often negligible, efficacy against adult pulmonary TB? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.68/10 · stage-B: 7.08/10 Key recent advances in TB vaccine development and understanding of protective immune responses against Mycobacterium tuberculosis (2020) New avenues in the age old battle against TB (2024) 22. What are the cognate microbial ligands for most NLRs (e.g., NLRP2, NLRP5, NLRP7, NLRC3, NLRX1), given that only a handful of NLR ligands have ever been identified? Subfield: Innate immunity · Jev stage-A: 7.63/10 · stage-B: 7.08/10 Unsolved Mysteries in NLR Biology (2013) 23. How is trained immunity epigenetically and metabolically encoded in long-lived hematopoietic progenitors, and why does its duration vary from weeks to years across stimuli? Subfield: Tumor immunology, transplantation & systems · Jev stage-A: 7.60/10 · stage-B: 7.08/10 Defining trained immunity and its role in health and disease (2020) The Role of Pattern Recognition Receptors in Epigenetic and Metabolic Reprogramming: Insights into Trained Immunity (2025) 24. What are safe, effective mucosal adjuvants for intranasal vaccines, and which innate signals are required to generate durable secretory IgA and lung-resident T cells without toxicity? Subfield: Vaccines, infection & immunodeficiency · Jev stage-A: 7.38/10 · stage-B: 7.07/10 Intranasal vaccines adjuvanted with Nexavant demonstrate robust protective efficacy by inducing both mucosal and systemic immunity in a murine model (2025) Comparative Evaluation of Mucosal Adjuvants for Intranasal Immunization with a Recombinant RSV Prefusion F Protein (2026) 25. How does Epstein-Barr virus trigger multiple sclerosis when ~95% of humans are infected yet only a tiny fraction develop MS — via molecular mimicry (e.g., EBNA1/GlialCAM), infected autoreactive B cells, or latent-lytic cycling driving relapses? Subfield: Tolerance, autoimmunity & allergy · Jev stage-A: 7.65/10 · stage-B: 7.06/10 Epstein-Barr virus and multiple sclerosis: moving from questions of association to questions of mechanism (2023) The case for targeting latent and lytic Epstein-Barr virus infection in multiple sclerosis (2025)

Original post

Sep 19