Neutralization against BA.2.75.2, BQ.1.1, and XBB from mRNA Bivalent Booster | NEJM - nejm.org

• Related Articles

To the Editor:

The emergence of the highly divergent B.1.1.529 (omicron) variant of terrible acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to concerns astir the efficacy of vaccines based connected the ancestral spike and to the support successful the United States of bivalent vaccines for coronavirus illness 2019 (Covid-19) that see the ancestral spike and the omicron BA.5 spike proteins.^1-3 Since the support and organisation of these vaccines, further subvariants containing cardinal mutations that further heighten the quality of the microorganism to flight from vaccine-elicited antibodies and regulatory-approved monoclonal antibodies person been identified.⁴ Of peculiar interest is the R346T mutation, which has arisen successful aggregate omicron subvariants, including BA.2.75.2, BQ.1.1, and XBB (Fig. S1 successful the Supplementary Appendix, disposable with the afloat substance of this missive astatine NEJM.org). We tested serum samples obtained from participants who had received either 1 oregon 2 monovalent boosters oregon the bivalent booster to find the neutralization ratio of the booster vaccines against wild-type (WA1/2020) microorganism and superior isolates of omicron subvariants BA.1, BA.5, BA.2.75.2, BQ.1.1, and XBB utilizing an successful vitro, live-virus absorption simplification neutralization trial (FRNT). All the participants provided written informed consent.

We utilized the FRNT successful a VeroE6/TMPRSS2 compartment line¹ to comparison the neutralizing enactment successful serum samples obtained from participants successful 3 cohorts: the archetypal cohort comprised 12 participants 7 to 28 days aft 1 monovalent booster; the second, 11 participants 6 to 57 days aft a 2nd monovalent booster; and the third, 12 participants 16 to 42 days aft a bivalent booster. The differences successful neutralizing antibody responses among these 3 cohorts were quantitated by comparing the FRNT₅₀ (the reciprocal dilution of serum that neutralizes 50% of the input virus) geometric mean titers (GMTs) of neutralizing antibodies against the omicron subvariants with that against the ancestral SARS-CoV-2 WA1/2020 strain. Serum samples successful which the GMT fell beneath the bounds of detection (1:20) were fixed an arbitrary FRNT₅₀ worth of 10.

Figure 1. Figure 1. Neutralizing Responses against the WA1/2020 Strain and Omicron Subvariants.

Shown is the neutralization enactment against the WA1/2020 strain of terrible acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the omicron subvariants BA.1, BA.5, BA.2.75.2, BQ.1.1, and XBB successful 12 participants who received 1 monovalent booster (Panel A), successful 11 participants who received 2 monovalent boosters (Panel B), and successful 12 participants who received the updated bivalent booster (Panel C). The absorption simplification neutralization trial (FRNT₅₀ [the reciprocal dilution of serum that neutralizes 50% of the input virus]) geometric mean titer (GMT) of neutralizing antibodies against the WA1/2020 strain and each omicron subvariant is shown astatine the apical of each panel, on with the ratio of the neutralization GMT against the WA1/2020 strain to that against each omicron subvariant. The connecting lines betwixt the variants correspond matched serum samples. The horizontal dotted lines correspond the bounds of detection of the assay (FRNT₅₀ GMT 20). The reddish lines successful Panels B and C bespeak the participants who reported erstwhile SARS-CoV-2 infection, and the dashed enactment successful Panel C indicates 1 subordinate who received 2 monovalent boosters earlier the bivalent booster. The colored bars correspond the FRNT₅₀ GMT among the participants successful the cohort, and the 𝙸 bars bespeak 95% assurance intervals, which were not adjusted for multiplicity and whitethorn not beryllium utilized for proposal testing. LOD denotes bounds of detection, and NA not applicable.

In each 3 cohorts, neutralization enactment was little against each omicron subvariants than against the WA1/2020 strain; neutralizing enactment was lowest against the XBB subvariant (Figure 1 and Fig. S2). In the cohort that received 1 monovalent booster, the FRNT₅₀ GMTs were 857 against WA1/2020, 60 against BA.1, 50 against BA.5, 23 against BA.2.75.2, 19 against BQ.1.1, and beneath the bounds of detection against XBB. In the cohort that received 2 monovalent boosters, the FRNT₅₀ GMTs were 2352 against WA1/2020, 408 against BA.1, 250 against BA.5, 98 against BA.2.75.2, 73 against BQ.1.1, and 37 against XBB. The results successful some of these cohorts correspond with neutralization titers against BA.1 and BA.5 that were 5 to 9 times arsenic debased arsenic that against WA1/2020 and neutralization titers against BA.2.75.2, BQ.1.1, and XBB that were 23 to 63 times arsenic debased arsenic that against WA1/2020.

In the cohort that received the BA.5-containing bivalent booster, the neutralizing enactment against each the omicron subvariants arsenic compared with that against WA1/2020 was amended than successful the different 2 cohorts (Figure 1C). The FRNT₅₀ GMTs were 2481 against WA1/2020, 618 against BA.1, 576 against BA.5, 201 against BA.2.75.2, 112 against BQ.1.1, and 96 against XBB. The results successful this cohort correspond with neutralization titers against BA.1 and BA.5 that were 4 times arsenic debased arsenic that against WA1/2020 and neutralization titers against BA.2.75.2, BQ.1.1, and XBB that were 12 to 26 times arsenic debased arsenic that against WA1/2020.

Persons who received either 1 oregon 2 monovalent Covid-19 vaccine boosters had overmuch little neutralization enactment against omicron subvariants (especially against BA.2.75.2, BQ.1.1, and XBB, which incorporate the predicted flight mutation R346T) than that against the WA1/2020 strain. Persons who received the BA.5-containing bivalent booster had amended neutralizing enactment against each omicron subvariants (especially against BA.2.75.2, BQ.1.1, and XBB) than those who received either 1 oregon 2 monovalent boosters, adjacent though the neutralization GMT against WA1/2020 was akin successful the cohort that received the 2 monovalent boosters and the cohort that received the bivalent booster. These responses are accordant with caller observations successful persons with breakthrough omicron corruption showing broadened neutralizing enactment against omicron subvariants.⁵ Limitations of this survey see the tiny cohort size, differences successful property among the cohorts, the chartless effect of erstwhile vulnerability to SARS-CoV-2, and examination of the vaccines astatine a azygous clip point. These serologic information amusement an wide neutralization payment with bivalent booster immunizations.

Meredith E. Davis-Gardner, Ph.D.
Lilin Lai, M.D.
Bushra Wali, Ph.D.
Hady Samaha, M.D.
Emory University School of Medicine, Atlanta, GA

Daniel Solis, B.S.
Stanford University School of Medicine, Stanford, CA

Matthew Lee, M.S.
Andrea Porter-Morrison, B.S.
Ian T. Hentenaar, M.S.
Emory University School of Medicine, Atlanta, GA

Fumiko Yamamoto, Ph.D.
Stanford University School of Medicine, Stanford, CA

Sucheta Godbole, M.S.
National Institute of Allergy and Infectious Diseases, Bethesda, MD

Yuan Liu, Ph.D.
Emory University School of Medicine, Atlanta, GA

Daniel C. Douek, M.D., Ph.D.
National Institute of Allergy and Infectious Diseases, Bethesda, MD

Frances Eun-Hyung Lee, M.D.
Nadine Rouphael, M.D.
Alberto Moreno, M.D.
Emory University School of Medicine, Atlanta, GA

Benjamin A. Pinsky, M.D., Ph.D.
Stanford University School of Medicine, Stanford, CA

Mehul S. Suthar, Ph.D.
Emory University School of Medicine, Atlanta, GA
[email protected]

This missive was published connected December 21, 2022, astatine NEJM.org.

Supplementary Material