A Three-Dose Prophylactic Vaccine for Early-Childhood Food Allergy: A Falsifiable, WHO-Aligned Computational Framework with Extended Autoimmune-Disease Modeling and Global Sensitivity Analysis

Food allergy (FA) affects an estimated 4–10% of children and up to 8–10% of adults in industrialized countries, with growing recognition that non-IgE-mediated phenotypes add further, likely under-estimated, disease burden. No approved prophylactic vaccine currently exists. This manuscript presents a mechanistically detailed, preclinically motivated, and rigorously falsifiable conceptual framework for a three-dose prophylactic vaccine administered at 2, 4, and 12 months of age, aligned with the World Health Organization's Expanded Programme on Immunization (EPI) schedule and explicitly mapped onto the strategic priorities of the WHO Immunization Agenda 2030 (IA2030). The vaccine formulation incorporates hypoallergenic peptides from three principal allergens: peanut (Ara h 2), egg (ovomucoid, Gal d 1), and milk (αs1-casein), encapsulated in GE11-functionalized lipid nanoparticles (LNPs) and adjuvanted with Pam3Cys and monophosphoryl lipid A (MPLA) to promote regulatory T-cell (Treg)-mediated tolerance. Antigen release kinetics are formulated as a physiologically justified two-compartment (depot-release) pharmacokinetic process, calibrated to the days-to-weeks antigen-persistence window documented for sustained-release vaccine depots in draining lymph nodes, distinguishing local depot bioavailability at the injection site from the faster systemic clearance kinetics of circulating lipid nanoparticles. All ordinary differential equation (ODE) results, sensitivity analyses, and calibration outputs reported in this manuscript are generated by a single, fully reproducible, seeded computational pipeline (Appendix B). The core ODE system, tracking antigen-specific Treg, Th2, IgE, and IgG4 compartments, is extended to rheumatoid arthritis and type-1 diabetes to illustrate cross-disease generalizability of the tolerogenic-signal framework. A hierarchical sensitivity-analysis suite, comprising local elasticity analysis, one-at-a-time (OAT) sweeps, Morris elementary-effects screening (r = 80 trajectories), Sobol' variance-based global sensitivity analysis (Saltelli estimator, N = 280, with bootstrap standard errors), and an independent extended Fourier Amplitude Sensitivity Test (eFAST, Ns = 129), identifies the antigen-clearance rate γe, adjuvant efficacy κ, and Th2 decay rate δh as the dominant drivers of predicted IgE trajectories, with first- and total-order indices in broad qualitative agreement across the two independent global sensitivity analysis (GSA) methods. Forward Monte Carlo uncertainty propagation (N = 220) yields wide 95% prediction bands for the IgE trajectory at day 730 (median normalized Ie(730) = 0.0127, 95% CI [0.000102, 1.41]), reflecting the substantial parametric uncertainty inherent to a conceptual, not-yet-calibrated model and motivating the staged empirical validation roadmap proposed in Section 9. An approximate Bayesian computation (ABC) procedure calibrates the oral-to-intramuscular bridging parameter φ and adjuvant-efficacy parameter κ against the 70 to 80% relative-risk-reduction range reported by the LEAP and EAT trials, yielding posterior means φ = 0.764 ± 0.188 and κ = 0.649 ± 0.152. An explicit, code-verified falsifiability criterion is proposed and evaluated against the fitted posterior predictive distribution (posterior-predictive exceedance probability 0.004 against an illustrative normalized threshold), and a dedicated Scientific and Technical Risk Assessment section enumerates the critical assumptions whose failure would invalidate the framework. A probabilistic cost-effectiveness analysis (Monte Carlo, N = 20000) estimates a median incremental cost-effectiveness ratio of $293.8 per DALY averted (95% CI $122.2 to $958.1), within WHO-recommended cost-effectiveness thresholds for most low- and middle-income settings. This unfunded, hypothesis-generating conceptual work integrates immunology, systems biology, and translational science to advance equitable global prophylaxis, while transparently articulating epistemological boundaries and empirical refutability criteria.