T h e n e w e ng l a n d j o u r na l o f m e dic i n e

C or r e sp ondence

Neutralization against BA.2.75.2, BQ.1.1,and XBB from mRNA Bivalent Booster
To the Editor: The emergence of the highly
divergent B.1.1.529 (omicron) variant of severe
acute respiratory syndrome coronavirus 2 (SARSCoV-2) led to concerns about the efficacy of vaccines based on the ancestral spike and to theapproval in the United States of bivalent vaccines
for coronavirus disease 2019 (Covid-19) that include the ancestral spike and the omicron BA.5
spike proteins.1-3 Since the approval and distribution of these vaccines, additional subvariants
containing key mutations that further enhance
the ability of the virus to escape from vaccineelicited antibodies and regulatory-approved monoclonal antibodies have been identified.4 Of particular concern is the R346T mutation, which
has arisen in multiple omicron subvariants, including BA.2.75.2, BQ.1.1, and XBB (Fig. S1 in
the Supplementary Appendix, available with thefull text of this letter at NEJM.org). We tested
serum samples obtained from participants who
had received either one or two monovalent
boosters or the bivalent booster to determine theneutralization efficiency of the booster vaccines
against wild-type (WA1/2020) virus and primaryisolates of omicron subvariants BA.1, BA.5,
BA.2.75.2, BQ.1.1, and XBB using an in vitro,
live-virus focus reduction neutralization test(FRNT). All the participants provided written
informed consent.
We used the FRNT in a VeroE6/TMPRSS2 cellline1 to compare the neutralizing activity in serum samples obtained from participants in threecohorts: the first cohort comprised 12 participants 7 to 28 days after one monovalent booster;
the second, 11 participants 6 to 57 days aftera second monovalent booster; and the third, 12participants 16 to 42 days after a bivalent booster. The differences in neutralizing antibody ren engl j med 388;2sponses among these three cohorts were quantitated by comparing the FRNT50 (the reciprocal
dilution of serum that neutralizes 50% of the
input virus) geometric mean titers (GMTs) ofneutralizing antibodies against the omicron subvariants with that against the ancestral SARSCoV-2 WA1/2020 strain. Serum samples in which
the GMT fell below the limit of detection (1:20)
were given an arbitrary FRNT50 value of 10.
In all three cohorts, neutralization activity
was lower against all omicron subvariants thanagainst the WA1/2020 strain; neutralizing activity was lowest against the XBB subvariant (Fig. 1and Fig. S2). In the cohort that received one
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 below the limit of detection against XBB.
In the cohort that received two 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 in both of these cohorts
correspond with neutralization titers against

this week’s letters
183

Neutralization against BA.2.75.2, BQ.1.1,
and XBB from mRNA Bivalent Booster

185

Physician-Delegated Unobserved Induction
with Buprenorphine in Pharmacies

186PCI for Ischemic Left Ventricular Dysfunction

189

Regimens for Drug-Resistant Tuberculosis

191

Spontaneous Intracerebral Hemorrhage

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T h e n e w e ng l a n d j o u r na l o f m e dic i n e

24.0 32.2 >63.6

5.8

37103
102

GMT: 2481 618

576

Ratio:

4.0

4.3 >12.3 >22.2 >25.8

59.4104201

112

96103102

XB
B

2.1.1

5.
.7

BQ

A1W

BA
2.1

XB
B

.1

25.

BQ

5.7

BA
21BA.

/20A1BA.

101

20.1.1
XBB

25.

BQ

15.7

BA
2BA.

BA.

/20A1W

Ratio:

73

101

20101

98

1102

250

104

FRNT50 GMT

103

C Bivalent Booster

GMT: 2352 408

BA.

19 Below
LOD>14.3 >17.1 >37.3 >45.1 NABA.

23

W

FRNT50 GMT

104

B Two Monovalent Boosters

50

20Ratio:60/20

GMT: 857

FRNT50 GMT

A One Monovalent Booster

Figure 1. Neutralizing Responses against the WA1/2020 Strain and Omicron Subvariants.
Shown is the neutralization activity against the WA1/2020 strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) andthe omicron subvariants BA.1, BA.5, BA.2.75.2, BQ.1.1, and XBB in 12 participants who received one monovalent booster (Panel A),
in 11 participants who received two monovalent boosters (Panel B), and in 12 participants who received the updated bivalent booster(Panel C). The focus reduction neutralization test (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 at the top of eachpanel, along with the ratio of the neutralization GMT against the WA1/2020 strain to that against each omicron subvariant. The connecting lines between the variants represent matched serum samples. The horizontal dotted lines represent the limit of detection of the assay (FRNT50 GMT 20). The red lines in Panels B and C indicate the participants who reported previous SARS-CoV-2 infection, and thedashed line in Panel C indicates one participant who received two monovalent boosters before the bivalent booster. The colored bars
represent the FRNT50 GMT among the participants in the cohort, and the I bars indicate 95% confidence intervals, which were not adjusted for multiplicity and may not be used for hypothesis testing. LOD denotes limit of detection, and NA not applicable.

BA.1 and BA.5 that were 5 to 9 times as low asthat against WA1/2020 and neutralization titers
against BA.2.75.2, BQ.1.1, and XBB that were 23to 63 times as low as that against WA1/2020.
In the cohort that received the BA.5-containing bivalent booster, the neutralizing activity
against all the omicron subvariants as comparedwith that against WA1/2020 was better than in
the other two cohorts (Fig. 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 in this cohort correspond with neutralization titers against BA.1 and BA.5 that were4 times as low as that against WA1/2020 andneutralization titers against BA.2.75.2, BQ.1.1,and XBB that were 12 to 26 times as low as thatagainst WA1/2020.
Persons who received either one or two monovalent Covid-19 vaccine boosters had much lower
neutralization activity against omicron subvariants (especially against BA.2.75.2, BQ.1.1, andXBB, which contain the predicted escape mutation R346T) than that against the WA1/2020
strain. Persons who received the BA.5-contain-n engl j med 388;2

ing bivalent booster had better neutralizing activity against all omicron subvariants (especiallyagainst BA.2.75.2, BQ.1.1, and XBB) than those
who received either one or two monovalent
boosters, even though the neutralization GMT
against WA1/2020 was similar in the cohort thatreceived the two monovalent boosters and thecohort that received the bivalent booster. These
responses are consistent with recent observations in persons with breakthrough omicron
infection showing broadened neutralizing activity against omicron subvariants.5 Limitations of
this study include the small cohort size, differences in age among the cohorts, the unknown
effect of previous exposure to SARS-CoV-2, andcomparison of the vaccines at a single time
point. These serologic data show an overall neutralization benefit 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

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Correspondence

Daniel Solis, B.S.

Mehul S. Suthar, Ph.D.

Stanford University School of Medicine
Stanford, CAEmory University School of Medicine
Atlanta, GA
mehul.s.suthar@emory.edu

Matthew Lee, M.S.
Andrea Porter-Morrison, B.S.
Ian T. Hentenaar, M.S.

Supported in part by grants from the National Institute ofAllergy and Infectious Diseases (NIAID) and the National Institutes of Health (NIH) (NIH P51OD011132, 3U19AI057266-17S1,
1U54CA260563, HHSN272201400004C, NIH/NIAID Centers ofExcellence for Influenza Research and Response [CEIRR] undercontract 75N93021C00017 [to Emory University]), an Emory
Executive Vice President for Health Affairs Synergy Fund award,
funding from the Pediatric Research Alliance Center for Childhood Infections and Vaccines and Children’s Healthcare ofAtlanta, COVID-Catalyst-I3 Funds from the Woodruff Health
Sciences Center and Emory School of Medicine, and a Woodruff
Health Sciences Center 2020 COVID-19 CURE Award.
Disclosure forms provided by the authors are available withthe full text of this letter at NEJM.org.

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

This letter was published on December 21, 2022, at NEJM.org.

Yuan Liu, Ph.D.

1. Edara VV, Manning KE, Ellis M, et al. mRNA-1273 andBNT162b2 mRNA vaccines have reduced neutralizing activity
against the SARS-CoV-2 omicron variant. Cell Rep Med 2022;​3:​100529.
2. Lyke KE, Atmar RL, Islas CD, et al. Rapid decline in vaccineboosted neutralizing antibodies against SARS-CoV-2 Omicronvariant. Cell Rep Med 2022;​3:​100679.
3. Chalkias S, Harper C, Vrbicky K, et al. A bivalent omicroncontaining booster vaccine against Covid-19. N Engl J Med 2022;​
387:​1279-91.
4. Sheward DJ, Kim C, Fischbach J, et al. Omicron sublineage
BA.2.75.2 exhibits extensive escape from neutralising antibodies. Lancet Infect Dis 2022;​22:​1538-40.
5. Linderman SL, Lai L, Bocangel Gamarra EL, et al. Neutralizing antibody responses in patients hospitalized with SARSCoV-2 Delta or Omicron infection. J Clin Invest 2022 October 18(Epub ahead of print).

Emory University School of Medicine
Atlanta, GADaniel 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

DOI: 10.1056/NEJMc2214293

Physician-Delegated Unobserved Induction
with Buprenorphine in Pharmacies
To the Editor: Inadequate access to buprenorphine impedes care in the current opioid crisis.
Pharmacists may be able to expand access tothis medication with the use of collaborativepractice agreements1,2 that allow prescribers todelegate evaluation and some treatment decisions to pharmacists. Rhode Island amended acollaborative practice agreement to incorporate
induction with buprenorphine, the first-line medication approved by the Food and Drug Administration for the treatment of opioid withdrawal
and opioid use disorder.
From February 2021 through April 2022, wen engl j med 388;2

conducted a feasibility pilot trial involving six
behavioral health pharmacies and 21 pharmacists who were trained to implement facilitatedunobserved (“take-home”) induction by the participant and to provide ongoing follow-up care atthe pharmacy (details of training are provided in
the Supplementary Appendix, available with thefull text of this letter at NEJM.org). This pilot
trial is a component of a phase 3 randomized
trial to evaluate pharmacy-based medication
treatment for addiction as compared with usual
care (ClinicalTrials.gov number, NCT04139213).
Patients with a history of opioid use disordernejm.org

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