Vaccine Adjuvants Recapitulate the Early Innate Response to Live Vaccination: Implications for Therapeutic Cancer Vaccine Design

Abstract Background/Objectives: Therapeutic cancer vaccines rarely produce tumour regression despite generating measurable immune responses, and adjuvants are commonly selected on the strength of the early innate response they induce. Whether that response differs among clinically used adjuvants, and how it compares with the response to a vaccine that reliably confers durable immunity, has not been established under a single controlled comparison. Methods: We reanalysed public transcriptomic data from six randomised human vaccine studies and one controlled mouse experiment, one of which sequenced six sorted leukocyte populations separately. Twenty-three predefined immune gene sets were scored as within-sample percentile ranks. Every comparison used one design: participant-paired change from the dose-appropriate baseline, compared against a matched control arm, with Benjamini-Hochberg correction applied uniformly within each immunogen-versus-control family (3,633 evaluable comparisons in 17 families). One study (CRC305A-C) sampled daily and contained a placebo arm together with adjuvanted, unadjuvanted and live attenuated vaccines, permitting all classes to be compared against a common reference within one trial. Cell-lineage identity markers were used to separate changes in cell composition from changes in transcription. Results: AS01B, AS01E, AS03 and MF59 each produced a large type I interferon response 24 hours after vaccination, reaching 9.6, 8.6, 7.5 and 3.2 percentile points above their matched controls. AS01E and AS03 were indistinguishable from one another and AS01B differed from AS01E in one of twelve pairwise innate comparisons, while AS01B separated from AS03 in five, on early interferon and on inflammasome and pyroptosis gene sets, though not at the primary window. AS04 and aluminium salt produced no detectable response in any of 161 and 230 comparisons respectively, AS04 spanning -1.6 to +1.6 percentile points. In the trial containing all classes, yellow fever 17D sustained a significant interferon response from day 2 through day 7, peaking at 8.3 percentile points, and had resolved by day 14 when the same participants were sampled again, whereas MF59 spiked at day 1 and was gone by day 3; AS01 and AS03 remained detectable at day 3 and had resolved by day 7. Peak amplitude did not distinguish the classes: AS01B reached a higher peak (9.6) than yellow fever (8.3). Dendritic cell activation and MHC class I presentation rose with the interferon response in every responding arm and survived adjustment for cell composition, whereas the accompanying fall in cytotoxic and natural killer gene sets tracked T cell lineage abundance and lost 60 to 68 percent of its association after that adjustment. In sorted leukocyte populations the interferon response was present in all six lineages and survived false discovery correction in five of them (q = 0.007 to 0.039; natural killer cells marginal at q = 0.055), while the cytotoxic gene set within sorted T cells did not change (q = 0.96), confirming by cell sorting that the whole-blood decrease is compositional. Across 874 comparisons at day 7 or later no innate adjuvant effect persisted; the only surviving adjuvant signal was a germinal centre and plasmablast response at day 7 in the AS03 arms of two independent trials, and only yellow fever produced one at day 14. Conclusions: Clinically used adjuvants initiate an innate and antigen-presenting cell response equal in amplitude to that of a live attenuated vaccine, but sustain it for one to three days rather than the seven days over which the live comparator held its response before resolving, and no innate adjuvant effect persists beyond day 3. The limitation is duration rather than magnitude. This offers a specific and testable explanation for why therapeutic cancer vaccines generate measurable immunogenicity without tumour control, and argues that adjuvant development should target the persistence of innate stimulation rather than its peak intensity.