This study included two cohorts. The first cohort received an anti-SARS-CoV-2 primary immunization and two monovalent boosts, with the final monovalent boost administered 1–6 months after the second dose (n = 101, Supplementary Figure 1). The second cohort received an anti-SARS-CoV-2 primary immunization, two booster immunizations, and a bivalent booster (both ancestral and BA.4/5 mRNA) 1 to 6 months after the third vaccination. (n = 42). . The nAb titer against the ancestral strain (WA1) in patients who received the bivalent booster was 2.05 times higher than the neutralizing titer in patients who received the monovalent booster (GMT 830 vs. 404, Supplementary Figure 2). nAbs against BA.1 and BA.5 after monovalent or divalent boosters had lower titers compared to WA1, with a reduction in neutralizing power of 7.1- to 8.2-fold for BA.1 and 8.9-fold for BA.5. ~12.4 times (Supplementary Figure 2). Neutralizing antibodies against the newly circulating Omicron variants BQ.1.1 and XBB.1.5 were low or undetectable (detection levels ranged between 707 for BQ.1.1 and 512 for XBB.1.5).
Detection of anti-nucleocapsid (NC)-binding antibodies (900 AU/ml as cutoff) was used as evidence of recent SARS-CoV-2 exposure 12 . In the monovalent boost group, 45.5% of monovalent boost patients were anti-NC+ (n = 46 of 101 participants) (Supplementary Figure 3). We then compared neutralizing titers and antibody binding titers between individuals with low/undetectable anti-NC antibodies and those recently exposed to SARS-CoV-2 (NC binding antibody titers above the cutoff). (defined by value). In the monovalent boost group, neutralizing titers against WA1 in patients recently exposed to SARS-CoV-2 were 11-fold higher compared to unexposed patients (geometric mean titer (GMT) 1379 vs. 125; P<0.0001). Neutralizing titers against Omicron mutants BA.1 (GMT 134 vs. 28, P < 0.0001), BA.5 (GMT 95 vs. 24, P < 0.0001), BQ.1.1 (GMT 38 vs. 20.5, P < 0.0001), XBB.1.5 (GMT 30 vs. <20, P < 0.0001) was higher in SARS-CoV-2 exposed patients compared to unexposed patients (Figure 1A). Next, we assessed the temporal distribution of sampling between the monovalent boost groups. In Figure 1B, antibody titers against WA1 show that most samples (69% and 59% for unexposed and exposed patients, respectively) were collected less than 50 days post-immunization. However, a higher proportion of responders to multiple mutations was observed in samples taken from exposed patients compared to unexposed patients (Figure 1C).
Figure 1: Live virus neutralizing antibody titers against WA1, BA.1, BA.5, BQ.1.1, and XBB.1.5 after monovalent or bivalent mRNA booster vaccination in MM patients.
Comparison of responses of samples taken from MM patients after monovalent booster immunization. Black line, patients with no evidence of natural exposure to SARS-CoV-2. Red line, patient naturally exposed to SARS-CoV-2 due to positive anti-nucleocapsid binding antibodies. The dark black and dark red lines represent the geometric mean titer (GMT). Focal Reduction Neutralization Test (FRNT50 (reverse dilution of serum to neutralize 50% of input virus)) of neutralizing antibodies against the WA1 strain and each Omicron subvariant Geometric mean titer (GMT) is shown at the top of the panel . GMT values for black unexposed patients, GMT values for red patients exposed to SARS-CoV-2 infection. B Time course of FRNT titers against WA1 in patients who received monovalent immunization and were not exposed (gray symbols) or exposed (red symbols) to SARS-CoV-2. C Proportion of responders to each variant tested among unexposed (gray bars) or exposed (red bars) to SARS-CoV-2 who received a monovalent booster. D Comparison of responses of samples taken from MM patients after bivalent booster immunization. Black line, patients with no evidence of natural exposure to SARS-CoV-2. Red line, patient naturally exposed to SARS-CoV-2 due to positive anti-nucleocapsid binding antibodies. The dark black and dark red lines represent the GMT of neutralizing antibodies against the tested viruses. The GMT of neutralizing antibodies is shown at the top of the panel, with GMT values for unexposed patients in black and GMT values for patients exposed to SARS-CoV-2 infection in red. E Time course of FRNT titers against WA1 in patients who received bivalent immunization and were not (gray symbols) or exposed (red symbols) to SARS-CoV-2. F Proportion of responders to each variant tested among unexposed (gray bars) or exposed (red bars) to SARS-CoV-2 who received a bivalent booster.
Consistent with the high community transmission and breakthrough infections caused by Omicron variants, we found that 73.8% of bivalent boosted patients were anti-NC+ (n = 31 of 42 participants) (Supplementary Figure 3). In the bivalent boost group, patients recently exposed to SARS-CoV-2 had moderately elevated (1.3-fold) neutralizing titers against WA1 compared to unexposed patients (GMT 894 vs. 676, P = 0.1722). Neutralizing antibody levels against Omicron mutants BA.1 (GMT 139 vs. 42, P = 0.0438), BA.5 (GMT 87 vs. 32, P = 0.0615), and BQ.1.1 (GMT 43 vs. 42, P = 0.0615) There was a tendency to increase. .22, P = 0.0991), and XBB.1.5 in SARS-CoV-2 exposed patients compared with unexposed patients (GMT 33.5 vs. <20, P = 0.0936) (Figure 1D). The temporal distribution of sampling between the bivalent booster groups (Figure 1E) shows that most samples (91% and 87% for unexposed and exposed patients, respectively) were collected at 50 days or more after immunization. I showed it. There was a higher proportion of responders to multiple mutations in samples taken from exposed patients compared to unexposed patients (Figure 1F).
IgG binding titers were then measured using the Spike-specific electrochemiluminescence assay. Almost all samples in the two cohorts tested positive for the SARS-CoV-2 spike IgG binding test (97% ). We tested a panel of pleomicron and omicron spike variants and found that avidity titers were significantly higher in SARS-CoV-2 exposed patients who received a monovalent boost compared to unexposed patients. (P<0.0001 for all mutants tested, Mann-Whitney test; Figure 2A). In contrast, no statistically significant differences were observed in the bivalent vaccination group (by Mann-Whitney test: WT, P = 0.3079, B.1.1.7, P = 0.3963, B.1.351, P = 0.2567, B.1.617) .2, P = 0.2815, BA.1, P = 0.1547, BA.2, P = 0.2333, BA.2.12.1, P = 0.1309, .1, P = 0.2448, BF.7, P = 0.1633, XBB.1.5, P = 0.2115, BQ.1, P = 0.5663. ). Spike proteins from early variants (B.1.1.7, B.1.351, and B) in all data points tested using serum samples taken from patients who received a boost with a monovalent or bivalent vaccine. No differences were observed between binding IgG titers. .1.617.2) and IgG titers binding to the spike protein of the ancestral SARS-CoV-2 strain (Supplementary Figure 4). However, in patients who have not been exposed to SARS-CoV-2 and those who have been exposed, there is a difference between IgG antibody responses to the spike protein of the ancestral SARS-CoV-2 strain and IgG responses to most Omicron variants. Differences were observed in (Supplementary Figure 4). .
Figure 2: SARS-CoV-2 spike-binding IgG antibody titers in MM patients who received monovalent or bivalent boosters.
Antibody responses were measured by electrochemiluminescence using the MesoScale Discovery (MSD) platform. Comparison of responses of samples taken from MM patients after monovalent booster immunization. Black line, patients with no evidence of natural exposure to SARS-CoV-2. Red line, patient naturally exposed to SARS-CoV-2 with confirmation of anti-nucleocapsid binding antibody positivity (titer >900 AU/ml). The dark black and dark red lines represent the geometric mean titer (GMT). B Comparison of responses of samples taken from MM patients after bivalent booster immunization. Black line, patients with no evidence of natural exposure to SARS-CoV-2. Red line, patient with natural exposure to SARS-CoV-2 by confirmation of anti-nucleocapsid binding antibody positivity (titer >900 AU/ml). The dark black and dark red lines represent the geometric mean titer (GMT). Pre-pandemic plasma samples from healthy individuals were used to establish detection cut-off levels for SARS-CoV-2 Spike-specific IgG antibody titers.
We then analyzed the clinical correlation of neutralizing antibodies against WA1 and modern XBB.1.5 variants as described 10,13 (Supplementary Tables 1 and 2). Anti-BCMA therapy was correlated with decreased induction of nAbs against WA1 in patients who received a monovalent boost (P = 0.007, Supplementary Table 1). nAbs against XBB-1 were low in all subsets and were not influenced by these variables (Supplementary Table 2). Anti-CD38 therapy was correlated with decreased induction of nAbs against WA1 in both cohorts of patients who received monovalent and bivalent boosters (P=0.044 and P=0.048, Supplementary Table 1).
All enrolled subjects attended the Myeloma Clinic at Emory University and were selected without selection bias. Therefore, samples were collected at different time intervals after immunization, with the monovalent group receiving three immunizations and the bivalent group receiving four immunizations. This study showed that bivalent vaccination induced significantly higher nAb titers against the ancestral strain in unexposed individuals, but not against circulating Omicron mutants (XBB .1) were very low or undetectable. Hybrid immunization allowed higher induction of broadly reactive nAbs. However, there was no correlation between spike-binding antibodies and neutralization of circulating variants, suggesting that vaccination induced antibodies that were not neutralizing. The failure to induce antibodies against neutralizing epitopes suggests that improving the efficacy of bivalent boosters in MM patients requires vaccination regimens that use repeated boosters or different vaccine platforms. I am.
We show that a single monovalent booster vaccine is associated with increased nAbs against the ancestral strain and the B.1.617.2 variant, but not the Omicron variant, in MM patients. Reported10. Immune imprinting resulting from previous infection or SARS-CoV-2 vaccination has been suggested to negatively impact booster vaccine immunogenicity 14 . Consistent with this, we observed preferential boosting of nAbs against the ancestral WA1 strain after boosting. Booster immunizations improved the extent and longevity of antibody responses, especially in hybrid-immunized patients. These results may be related to further proliferation of class-switched memory B cells after monovalent booster of MM10. Similar to monovalent vaccines 10 and consistent with reported data 15,16, patients who previously harbored anti-CD38 antibodies also had a poor response to bivalent vaccines, suggesting that these treatments may / May be associated with adverse effects on plasma cells and follicular helper cells 10. 15. The need for multiple vaccines in MM patients is not unique to SARS-CoV-2, as the MM17 randomized trial also showed that multiple vaccines improve seroprotection after influenza vaccination. There is a possibility that there is no. Overall, our data show that despite bivalent boosters, most MM patients lack detectable nAbs against Omicron variants circulating in early 2023 at the time of sample collection. are. In contrast, we found that in healthy volunteers, bivalent boosters improved neutralization against BQ.1.1 and XBB18, but not against the more recent Omicron variants EG.5.1, HK.3, HV.1, reported that JN.1 evades antibodies induced by bivalent booster immunization. . The detection of spike-binding IgG antibodies against several Omicron variants suggests that immune imprinting may influence the induction of broadly neutralizing antibodies, whereas the reduction of nAbs after vaccination in MM , suggesting that this is not due to a lack of antibody production ability. High-risk cohorts of MM patients, such as those who have previously received CD38- or BCMA-targeted therapy, may be at particularly high risk of ongoing reinfection with these viruses, and may require further treatment, such as additional boosters or new vaccine platforms. New approaches may need to be considered.
