Thread by @BagaiDr

Persistent immune imprinting after XBB.1.5 COVID vac; XBB.1.5 booster elicits nAbs responses against current variants that dominate by recall of pre-existing mBcells previously induced by Wuhan-Hu-1 spike. biorxiv.org/content/10.110…

immune imprinting persists even after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 spike booster mRNA vacci

2 updated vaccine boosters. A bivalent Wuhan-Hu-1/BA.5 (or BA.1 for few countries) spike (S) mRNA booster vac was approved in August 2022, & monovalent XBB.1.5 S mRNA booster vac in September 2023; NAbs are correlate of protection against COVID19 & most plasma Neutrz activity is

directed to the S (RBD); Abs responses to Omicron variants dominated by pre-existing immunity resulting from prior exposure to Wuhan-Hu-1 spike, due to immune imprinting; inactivated Wuhan-Hu-1 viral vac,repeated Omicron infections overcome immune imprinting,

leading to elicitation Abs responses specific for these variants; similar outcome thro repeated admin of updated vac boosters in previously imprinted via multiple Wuhan-Hu-1 S exposure.
humoral immunity elicited upon receipt of XBB.1.5 S mRNA vac booster,

plasma from previously received multiple vac doses with or without known infection. Wuhan-Hu-1/D614G S, BQ.1.1 S, XBB.1.5 S or BA.2.86 S to potency & breadth of plasma nAbs vs plasma receipt of bivalent Wuhan-Hu-1/BA.5 vac booster.

Neutrz activity highest against Wuhan-Hu-1/G614 S with (GMTs) of 1,700 & 3,000 after recd XBB.1.5 S & Wuhan-Hu-1/BA.5 S bivalent vac boosters. GMTs against BQ.1.1, XBB.1.5, BA.2.86 S were 510, 540, 480 (XBB.1.5 S vac) or 420, 240, 320 (bivalent vac). updated vac booster gv nAb

Plasma neutralizing antibody titers after vaccination with the XBB.1.5 S mRNA booster (A) and after the bivalent Wuhan-Hu-1/BA.5 S mRNA booster (B).

Immune imprinting dominates immune response elicited upon XBB.1.5 S mRNA booster vac.
Panels A & B: plasma nAbs titers with Wuhan-Hu-1 S harboring D614G mutation, BQ.1.1 mutations, XBB.1.5 mutations, BA.2.86 mutations using plasma at 7 to 13d (mean: 9.7d)

after vac with XBB.1.5 S mRNA booster (A) or 22 to 51d (mean: 33d) after vac with bivalent Wuhan-Hu-1/BA.5 S mRNA booster. (GMTs) against each pseudovirus. Panels C and D show Ab binding titers (mean effective dilution 50%, ED50) against Wuhan-Hu-1 S (C) XBB.1.5 S

D) before/ after depletion of Abs recogn Wuhan-Hu-1 S, using XBB.1.5 S vac plasma. Panels E, F show nAb against, XBB.1.5 S (E) Wuhan-Hu-1 S (F) depleted & after depletion of Abs recogn Wuhan-Hu-1 S. Panel G: XBB.1.5 & Wuhan-Hu-1 RBD binding mBcells from XBB.1.5 S mRNA booster

XBB.1.5 S booster gv⬆️plasma neutrz activity against Wuhan-Hu-1/D614G S (vac-mismatch) relative to XBB.1.5 S (Vac-matched)-serological immune imprinting. depleted polyclonal plasma Abs recogn Wuhan-Hu-1 S trimer & binding titers against Wuhan-Hu-1 S & XBB.1.5 S ectodomain trimers

no Ab binding to Wuhan-Hu-1 S detected after depletion, depletion Abs targeting Wuhan-Hu-1 S entirely abrogated binding to XBB.1.5 S except for(binding titers⬇️10x); not detect nAbs against Wuhan-Hu-1/D614G S & XBB.1.5 S following depletion: absence of XBB.1.5 S-specif Abs

in plasma (were not cross-reactive with Wuhan-Hu-1 S). XBB.1.5 S vac⬆️ cross-reactive plasma Ab titers prev elicited by Wuhan-Hu-1 S exposure, which also binding to and Neutrz XBB.1.5 and other variants, instead of inducing Ab responses against XBB.1.5 S.

vast majority of XBB.1.5 RBD-binding mBcells also bound to the Wuhan-Hu-1 RBD, elicitation of mBcells is possible thro variant-specific mRNA booster, as is case for XBB.1.5, but difficult to induce due to preferential recall of pre-existing Wuhan-Hu-1 mBcells.

lack of detectable plasma Abs specific for XBB.1.5 S & scarcity of mBcells binding to XBB.1.5 RBD, but not Wuhan-Hu-1 RBD, that humoral immune responses elicited by XBB.1.5 S vac are dominated by recall of pre-existing mBcells previously induced by Wuhan-Hu-1 S vac

instead of inducing responses against this new variant. after Omicron BA.1, BA.2, BA.5 BTI & bivalent Wuhan-Hu-1/BA.5 & Wuhan-Hu-1/BA.1 S vac boosters. As SARS-CoV-2 S-specific mBcells continue to evolve &⬆️frequency several months post infection or vac.

long-term immunological impact of imprinting, updated XBB.1.5 S vaccine elicit nAbs against circulating variants & persistence of immune imprinting which to guide design of future vac boosters.