Neutralization of BA.4-BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 With Bivalent Vaccine

The n e w e ng l a n d j o u r na l of m e dic i n e
C or r e sp ondence
Neutralization of BA.4–BA.5, BA.4.6, BA.2.75.2,

BQ.1.1, and XBB.1 with Bivalent Vaccine
To the Editor: Since its emergence in Novem- All the participants provided written informed
ber 2021, the B.1.1.529 (omicron) variant of se- consent.
vere acute respiratory syndrome coronavirus 2 Serum samples were obtained on the day of
(SARS-CoV-2) has continued to evolve into sub- the fourth dose and 1 month after the fourth
lineages.1 To mitigate the omicron pandemic, in dose was administered. Viral nucleocapsid anti-
late August and early September 2022, the Food body testing and a reverse-transcriptase–poly-
and Drug Administration and the European Med- merase-chain-reaction assay to detect SARS-CoV-2
icines Agency authorized emergency use of the infection were performed in all the participants.
BNT162b2 bivalent vaccine (Pfizer–BioNTech) that A subgroup of participants from both vaccine
targets both the omicron BA.4–BA.5 spike (BA.4 groups, with an equal distribution of partici-
and BA.5 encode an identical spike protein) and pants with or without evidence of infection at
the ancestral wild-type (D614G) spike of SARS- baseline (according to serum samples obtained
CoV-2. The vaccine was subsequently authorized on the day of the fourth dose), was selected for
for use in many countries worldwide. the neutralization analysis. This study was not a
New omicron sublineages, including those single randomized trial; therefore, unmeasured
that have descended from BA.2 and BA.4–BA.5, variables could have differed between the two
have emerged. These sublineages include BA.4.6, groups.
BA.2.75.2, BQ.1.1, and XBB.1. Although early The complete spike gene from omicron BA.4–
epidemiologic data suggest these new sublineages BA.5, BA.4.6, BA.2.75.2, BQ.1.1, or XBB.1 was
have not led to increased disease severity, they engineered into the backbone of the reporter
have accumulated additional spike mutations that USA-WA1/2020 SARS-CoV-2 (a strain isolated in
could further evade vaccine-elicited antibody neu- January 2020) with the use of a live-virus focus
tralization, infection-elicited antibody neutraliza- reduction neutralization mNeonGreen (mNG)
tion, or both.2-4 Here, we compare the neutraliza- test.6 The resulting wild-type (WT) spike, BA.4–
tion activity against these omicron sublineages in BA.5 spike, BA.4.6 spike, BA.2.75.2 spike, BQ.1.1
persons who had received three doses of BNT162b2 spike, and XBB.1 spike mNG USA-WA1/2020 vi-
vaccine and then received a fourth dose of either ruses were used to measure titers on a 50%
the original BNT162b2 vaccine or the bivalent fluorescence-basedt focus reduction neutraliza-
BA.4–BA.5 booster. tion test (FRNT50) (the reciprocal dilution of se-
Participants were older than 55 years of age rum that neutralizes 50% of the input virus).
and had received three 30-μg doses of BNT162b2 Tables S2 through S4 in the Supplementary Ap-
vaccine and either a fourth monovalent booster pendix (available at NEJM.org) summarize the
dose of BNT162b2 vaccine (30 μg) approximate- data from serum samples and their values as
ly 6.6 months after the third dose (in the measured with fluorescence-based FRNT50.
C4591031 clinical trial5) or the bivalent vaccine Among all the participants, the fourth dose
(15 μg of messenger RNA [mRNA] directed of monovalent BNT162b2 vaccine induced a geo-
against the ancestral strain of SARS-CoV-2 and metric mean factor increase (i.e., an increase from
15 μg of mRNA directed against BA.4–BA.5) ap- the day of the fourth dose to 1 month after the
proximately 11 months after the third dose (in fourth dose) in titers of 3.0 against WT; 2.9
the C4591044 clinical trial; ClinicalTrials.gov against BA.4–BA.5; 2.3 against BA.4.6; 2.1 against
number, NCT05472038). The protocols are avail- BA.2.75.2; 1.8 against BQ.1.1; and 1.5 against
able with the full text of this letter at NEJM.org. XBB.1; the bivalent vaccine induced neutralizing
n engl j med nejm.org 1

The New England Journal of Medicine
Downloaded from nejm.org by MIRNA LILIANA CARMONA GARCIA on February 1, 2023. For personal use only. No other uses without permission.
Copyright © 2023 Massachusetts Medical Society. All rights reserved.
Bivalent vaccine Monovalent vaccine
A Participants without SARS-CoV-2 Infection before Dose 4

USA-WA1/2020 BA.4–BA.5 Spike BA.4.6 Spike BA.2.75.2 Spike BQ.1.1 Spike XBB.1 Spike
GMFI Ratio: 2.3× 8.8× 8.9× 4.2× 8.4× 3.6×
GMFI: 9.9× 4.4× 26.4× 3.0× 22.2× 2.5× 8.4× 2.0× 12.6× 1.5× 4.7× 1.3×
GMT: 226 2237 304 1325 20 518 30 89 24 524 36 92 14 117 18 37 11 143 17 25 12 55 13 17

40,960
20,480
10,240
5,120
2,560
1,280
FRNT50
640
320
160
80
40
20
10
r e4
r e4
r e4
rD 4
r e4
rD 4
r e4
rD 4
r e4
rD 4
r e4
rD e4
4
se
se
e
e
se
e
e
se
e
e
se
e
e
se
e
af Dos
af Dos
Be Dos
af os
af os
os
af os
af os
os
af os
af os
os
af os
af os
os
af os
af os
os
Be Do
Be Do
Be Do
Be Do
Be Do
Be Do
D
D
M ore
M re
M ore
M ore
M ore
M ore
M ore
M ore
M ore
M ore
M ore
M ore
te
te
te
te
te
te
te
te
te
te
te
te
fo
f
f
Be
Be
Be
Be
Be
o
o
1
1
B Participants with SARS-CoV-2 Infection before Dose 4
USA-WA1/2020 BA.4–BA.5 Spike BA.4.6 Spike BA.2.75.2 Spike BQ.1.1 Spike XBB.1 Spike
GMFI Ratio: 1.8× 2.4× 2.7× 2.5× 2.7× 2.7×
GMFI: 3.5× 2.0× 6.7× 2.8× 5.6× 2.1× 5.3× 2.1× 6.0× 2.2× 4.9× 1.8×
GMT: 1377 4847 2516 5120 207 1377 226 629 282 1564 283 587 62 326 126 264 74 444 60 132 27 131 55 98
40,960
20,480
10,240
5,120
2,560
1,280
FRNT50
640
320
160
80
40
20
10
r e4
r e4
r e4
rD 4
r e4
rD 4
r e4
rD 4
r e4
rD 4
r e4
rD e4
4
se
se
e
e
se
e
e
se
e
e
se
e
e
se
e
af Dos
af Dos
Be Dos
af os
af os
os
af os
af os
os
af os
af os
os
af os
af os
os
af os
af os
os
Be Do
Be Do
Be Do
Be Do
Be Do
Be Do
D
D
M ore
M re
M ore
M ore
M ore
M ore
M ore
M ore
M ore
M ore
M ore
M ore
te
te
te
te
te
te
te
te
te
te
te
te
fo
f
f
Be
Be
Be
Be
Be
o
o
1
geometric mean factor increases of 5.8, 13.0, BQ.1.1; and 1.3 against XBB.1; the bivalent vac-
11.1, 6.7, 8.7, and 4.8, respectively (Fig. S1). In cine induced neutralizing geometric mean factor
the participants without previous SARS-CoV-2 increases of 9.9, 26.4, 22.2, 8.4, 12.6, and 4.7,
infection, the monovalent BNT162b2 vaccine in- respectively (Fig. 1A). In the participants with
duced neutralizing geometric mean factor increas- previous SARS-CoV-2 infection, the monovalent
es of 4.4 against WT; 3.0 against BA.4–BA.5; 2.5 BNT162b2 vaccine induced neutralizing geomet-
against BA.4.6; 2.0 against BA.2.75.2; 1.5 against ric mean factor increases of 2.0 against WT;
2 n engl j med nejm.org

Correspondence
Figure 1 (facing page). Neutralizing Responses with

sublineage, the difference between the original
Bivalent BA.4–BA.5 Vaccine or Monovalent BNT162b2 and bivalent neutralizing geometric mean factor
Booster Vaccine. increase was greater in the serum samples ob-
Shown is the neutralizing activity against the USA- tained from participants without previous infec-
WA1/2020 strain of severe acute respiratory syndrome tion than in those obtained from participants with
coronavirus 2 (SARS-CoV-2) and the omicron sublin‑ previous infection.
eages BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and
XBB.1 in all participants who did not have evidence of
Among all omicron sublineages, BA.2.75.2,
SARS-CoV-2 infection before the fourth dose of vac‑ BQ.1.1, and XBB.1 had the lowest vaccine-elicited
cine (Panel A) and in those who had evidence of neutralization; however, neutralizing titers after
SARS-CoV-2 infection before the fourth dose of vac‑ a bivalent booster were several times as high as
cine (Panel B). The heights of the bars and the num‑ those after the original BNT162b2 vaccine. These
bers immediately above the bars indicate the geomet‑
ric mean titers (GMTs) of neutralizing antibodies. The
data suggest that the bivalent vaccine is more
I bars indicate 95% confidence intervals. The results immunogenic than the original vaccine, with
of the fluorescence-based focus reduction neutraliza‑ greater breadth of responses against circulating
tion test (FRNT50 [the reciprocal dilution of serum that omicron sublineages. These findings support the
neutralizes 50% of the input virus]) against USA- use of the current bivalent vaccine and underscore
WA1/2020, BA.4–BA.5 spike, BA.4.6 spike, BA.2.75.2
spike, BQ.1.1 spike, and XBB.1 spike are shown. Each
the importance of monitoring real-world effec-
circle in the figure represents an individual partici‑ tiveness.
pant. The geometric mean factor increases (GMFI
[the increase in neutralizing titers in serum samples
Jing Zou, Ph.D.
from the day of the fourth dose to 1 month after the Chaitanya Kurhade, Ph.D.
fourth dose]) and GMFI ratios between GMFIs of biva‑ University of Texas Medical Branch
lent vaccine and GMFIs of monovalent vaccine are Galveston, TX
shown. In both panels, the lower boundaries of the Sohil Patel, M.D.
two-sided 95% confidence intervals for the GMFI of
bivalent or monovalent booster against USA-WA1/2020,
Nicholas Kitchin, M.D.
BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 are Pfizer
all greater than 1. Hurley, United Kingdom
Kristin Tompkins, B.Sc.

Mark Cutler, Ph.D.
David Cooper, Ph.D.
2.8 against BA.4–BA.5; 2.1 against BA.4.6; 2.1
Qi Yang, Ph.D.
against BA.2.75.2; 2.2 against BQ.1.1; and 1.8
Hui Cai, Ph.D.
against XBB.1; the bivalent vaccine induced neu-
Pfizer Vaccine Research and Development
tralizing geometric mean factor increases of 3.5, Pearl River, NY
6.7, 5.6, 5.3, 6.0, and 4.9, respectively (Fig. 1B).
Alexander Muik, Ph.D.
Despite different intervals from dose 3 to dose 4,
BioNTech
the neutralizing titers before the fourth dose were Mainz, Germany
similar in the monovalent-vaccine group and the
Ying Zhang, Ph.D.
bivalent-vaccine group in all the participants, re-
Dung‑Yang Lee, Ph.D.
gardless of history of SARS-CoV-2 infection.
Our results support three conclusions. First, Pearl River, NY
the bivalent BA.4–BA.5 vaccine consistently elic-
Ugur Şahin, M.D.
ited higher neutralizing responses against BA.5-
BioNTech
derived sublineages (BA.4.6, BQ.1.1, and XBB.1) Mainz, Germany
and the BA.2-derived sublineage (BA.2.75.2) than
Annaliesa S. Anderson, Ph.D.
the original BNT162b2 vaccine when adminis-
William C. Gruber, M.D.
tered as a fourth booster dose, regardless of the
participants’ history of SARS-CoV-2 infection. Pearl River, NY
Second, after the fourth dose, higher neutralizing
Xuping Xie, Ph.D.
titers developed in participants with a history of
University of Texas Medical Branch
SARS-CoV-2 infection than in those without a Galveston, TX
history of infection. Third, for each tested omicron xuxie@utmb.edu
n engl j med nejm.org 3

Kena A. Swanson, Ph.D. 2. Kurhade C, Zou J, Xia H, et al. Neutralization of omicron

Pfizer Vaccine Research and Development sublineages and deltacron SARS-CoV-2 by three doses of
Pearl River, NY BNT162b2 vaccine or BA.1 infection. Emerg Microbes Infect
kena.swanson@pfizer.com 2022;11:1828-32.
3. Liu Z, VanBlargan LA, Bloyet LM, et al. Identification of
Pei‑Yong Shi, Ph.D. SARS-CoV-2 spike mutations that attenuate monoclonal and
University of Texas Medical Branch serum antibody neutralization. Cell Host Microbe 2021;29(3):
Galveston, TX 477-488.e4.
peshi@utmb.edu 4. Davis-Gardner ME, Lai L, Wali B, et al. mRNA bivalent
booster enhances neutralization against BA.2.75.2 and BQ.1.1.
Drs. Zou and Kurhade contributed equally to this letter. November 1, 2022 (https://www.biorxiv.org/content/10.1101/
Supported by BioNTech and Pfizer. 2022.10.31.514636v1). preprint.
Disclosure forms provided by the authors are available with 5. Winokur P, Gayed J, Fitz-Patrick D, et al. Bivalent omicron
the full text of this letter at NEJM.org. BA.1–adapted BNT162b2 booster in adults older than 55 years.
New Engl J Med 2023;388:214-27.
This letter was published on January 25, 2023, at NEJM.org. 6. Muruato AE, Fontes-Garfias CR, Ren P, et al. A high-
throughput neutralizing antibody assay for COVID-19 diagnosis
1. Cele S, Jackson L, Khoury DS, et al. Omicron extensively but and vaccine evaluation. Nat Commun 2020;11:4059.
incompletely escapes Pfizer BNT162b2 neutralization. Nature DOI: 10.1056/NEJMc2214916
2022;602:654-6. Correspondence Copyright © 2023 Massachusetts Medical Society.
4 n engl j med nejm.org


Neutralization of BA.4-BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 With Bivalent Vaccine

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Neutralization of BA.4-BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 With Bivalent Vaccine

Uploaded by

Copyright:

Available Formats

The n e w e ng l a n d j o u r na l of m e dic i n e