MedCheck in English No 27

Supplementary appendix
Sept. 15, 2023
MedCheck Editorial team

Change of Omicron XBB sublineage：reached 50％ in March 2023
https://www.bousai.metro.tokyo.lg.jp/_res/projects/default_project/_page_/001/027/736/20230413_05.pdf

Data disclosed by Tokyo Prefecture
Changes in genome analysis results (monthly)

Changes in genome analysis results (weekly)

XBB Total

XBB Total

4 5 6 7 8 9 10 11 12 1 2 32022 2023

0
2/14
-2/20

3/7
-3/13

3/21
-3/27

Changes in genome analysis results
98.0%

Up/
Down

XBB Total

EG.5
31.3%
≧/≦1.0％≧/≦0.5％https://www.mhlw.go.jp/content/001091819.pdf

Proportion

Sublineages
Japan Institute of
Infectious Diseases

Weeks

COVID-19 Data Explorer - Our World in Data
https://ourworldindata.org/explorers/coronavirus-data-explorer?facet=none&country=JPN~GBR~USA&Interval=7-day+rolling+average&Relative+to+Population=true&Color+by+test+positivity=false&Metric=Variants

Omicron XBB
sublineage
Total

2023/6/5

UK

98%

英国
US

Japan

98%

XBB 9%+ XBB.1.5 48%+ XBB.1.16 29%= 86%

JapanXBBsubvariantn

1.2 417
XBB. 1.9 330
2.3 147
EG.5.1 323
Total
1311

％
31.8
25.2
11.2
24.6
100.0

XBB
Total*
92.8*: XBB Total includes %for EG.5.1 subvariant
but excludes CH.1.1

FranceUK
US
Japan
Germany①Original vax 4 doses

Even bivalent vax only produce
antibody against original strain,
but not against variants③ Original vax 2～４dose＋bivalent+infection hiostory②Original vax
2～４dose＋bivalent

9) Kurhade C, Zou J, Xia H et al https://pubmed.ncbi.nlm.nih.gov/36473500/
Low neutralization of SARS-CoV-2 Omicron
BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster.
Nat Med. 2023 Feb;29(2):344-347. doi: 10.1038/s41591-022-02162-x. PMID: 36473500

Abstract
The newly emerged severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) Omicron sublineages, including
the BA.2-derived BA.2.75.2 and the BA.5-derived BQ.1.1
and XBB.1, have accumulated additional spike mutations
that may affect vaccine effectiveness. Here we reportneutralizing activities of three human serum panels
collected from individuals 23–94 days after dose 4 of aparental mRNA vaccine; 14–32 days after a BA.5 bivalent
booster from individuals with 2–4 previous doses ofparental mRNA vaccine; or 14–32 days after a BA.5 bivalent
booster from individuals with previous SARS-CoV-2
infection and 2–4 doses of parental mRNA vaccine. The
results showed that a BA.5 bivalent booster elicited a highneutralizing titer against BA.4/5 measured at 14–32 days
after boost; however, the BA.5 bivalent booster did not
produce robust neutralization against the newly emerged
BA.2.75.2, BQ.1.1 or XBB.1. Previous infection substantiallyenhanced the magnitude and breadth of BA.5 bivalent
booster-elicited neutralization. Our data support a vaccine
update strategy that future boosters should match newly
emerged circulating SARS-CoV-2 variants.

Comparison of following 3 groups:①Original vaccine (vax) 4 doses②Original vax 2～４dose＋bivalent③ Original vax 2～４dose＋bivalent+history of SARS-CoV-2 infection
・BA.5 bivalent vax didn’t produce
antibody against BQ.1.1 or XBB.1.
・The more (the newer) mutated,
the less production of antibody.
・person with history of infection
produced more antibody than neverinfected.

Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants.
Highlights••BQ.1, BQ.1.1, XBB, and XBB.1 are the most resistant SARS-CoV-2 variants to date••Serum neutralization was markedly reduced, including with the bivalent booster••All clinical monoclonal antibodies were rendered inactive against these variants••The ACE2 affinity of these variants were similar to their parental strains
10) Wang Q, Iketani S, Li Z et al. https://pubmed.ncbi.nlm.nih.gov/36580913/
Alarming antibody evasion properties of rising SARS-CoV-2 BQ andXBB subvariants. Cell. 2023 Jan 19;186(2):279-286.e8.
doi: 10.1016/j.cell.2022.12.018. Epub 2022 Dec 14. PMID: 36580913

Substantial Neutralization Escape by SARSCoV-2 Omicron Variants BQ.1.1 and XBB.1
11) Miller J et al NEJM 2023 Feb 16;388(7):662-664. https://pubmed.ncbi.nlm.nih.gov/36652339/
doi: 10.1056/NEJMc2214314. Epub 2023 Jan 18.PMID: 36652339

Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBB12) Imai M et al. Efficacy of Antiviral Agents against Omicron Subvariants
BQ.1.1 and XBB https://pubmed.ncbi.nlm.nih.gov/36476720/
NEJM 2023 Jan 5;388(1):89-91. doi: 10.1056/NEJMc2214302.

1.

2.

3.

Note: scale of x-axis is very different
3.Nirmatrelvir
1.Remdesivir
2.Molnupiravir

Above is the enlarged scale for the x-axis of
1.remdesivir and 2.molnupiravir as described
the same scale as that of 3.Nirmatrelvir.

Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBBnirmatrelvir

If the scale ofX-axis (concentration)
for the 3 agentswere the same,
only nirmatrelvir
is effective.

Remdesivir

Molnupiravir12) Imai M et al. NEJM 2023 Jan 5;388(1):89-91. doi: 10.1056/NEJMc2214302. https://pubmed.ncbi.nlm.nih.gov/36476720/

16) Butler CC, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk ofadverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2022 Dec 22. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/36566761/

Background: The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinatedpatients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care
reduced hospital admissions and deaths associated with COVID-19 in this population.
Methods: PANORAMIC was a UK-based, national, multicentre, open-label, multigroup, prospective, platform adaptive randomised controlled trial. Eligible
participants were aged 50 years or older-or aged 18 years or older with relevant comorbidities-and had been unwell with confirmed COVID-19 for 5 days or fewer
in the community. Participants were randomly assigned (1:1) to receive 800 mg molnupiravir twice daily for 5 days plus usual care or usual care only. A secure,web-based system (Spinnaker) was used for randomisation, which was stratified by age (<50 years vs ≥50 years) and vaccination status (yes vs no). COVID-19
outcomes were tracked via a self-completed online daily diary for 28 days after randomisation. The primary outcome was all-cause hospitalisation or death within
28 days of randomisation, which was analysed using Bayesian models in all eligible participants who were randomly assigned. This trial is registered with ISRCTN,
number 30448031.
Findings: Between Dec 8, 2021, and April 27, 2022, 26 411 participants were randomly assigned, 12 821 to molnupiravir plus usual care, 12 962 to usual care alone,and 628 to other treatment groups (which will be reported separately). 12 529 participants from the molnupiravir plus usual care group, and 12 525 from the usual
care group were included in the primary analysis population. The mean age of the population was 56·6 years (SD 12·6), and 24 290 (94%) of 25 708 participants
had had at least three doses of a SARS-CoV-2 vaccine. Hospitalisations or deaths were recorded in 105 (1%) of 12 529 participants in the molnupiravir plus usual
care group versus 98 (1%) of 12 525 in the usual care group (adjusted odds ratio 1·06 [95% Bayesian credible interval 0·81-1·41]; probability of superiority 0·33).
There was no evidence of treatment interaction between subgroups. Serious adverse events were recorded for 50 (0·4%) of 12 774 participants in the molnupiravir
plus usual care group and for 45 (0·3%) of 12 934 in the usual care group. None of these events were judged to be related to molnupiravir.
Interpretation: Molnupiravir did not reduce the frequency of COVID-19-associated hospitalisations or death among high-risk vaccinated adults in the community.
Funding: UK National Institute for Health and Care Research.

19) Shah MM, Joyce B, Plumb ID et al. https://pubmed.ncbi.nlm.nih.gov/36454693/

MMWR Morb Mortal Wkly Rep. 2022 Dec 2;71(48):1531-1537. doi: 10.15585/mmwr.mm7148e2.PMID: 36454693

19) Shah MM et al. MMWR Morb Mortal Wkly Rep. 2022:;71(48):1531-1537. https://pubmed.ncbi.nlm.nih.gov/36454693/
To examine the real-world benefit of Paxlovid in adults aged ≥18 years in the United States, a large electronic health record(EHR) data set (Cosmos†) was analyzed to assess the association between receiving a prescription for Paxlovid and hospitalization
with a COVID-19 diagnosis in the ensuing 30 days. A Cox proportional hazards model was used to estimate this association,
adjusted for demographic characteristics, geographic location, vaccination, previous infection, and number of underlying healthconditions. Among 699,848 adults aged ≥18 years eligible for Paxlovid during April-August 2022, 28.4% received a Paxlovid
prescription within 5 days of COVID-19 diagnosis. Being prescribed Paxlovid was associated with a lower hospitalization
rate among the overall study population (adjusted hazard ratio [aHR] = 0.49), among those who had received ≥3 mRNA COVID19 vaccines (aHR = 0.50), and across age groups (18-49 years: aHR = 0.59; 50-64 years: aHR = 0.40; and ≥65 years: aHR = 0.53).
Paxlovid should be prescribed to eligible adults to reduce the risk of COVID-19-associated hospitalization.

19) Shah MM et al. MMWR Morb Mortal Wkly Rep. 2022;71(48):1531-1537. https://pubmed.ncbi.nlm.nih.gov/36454693/

Not effective20) Dryden-Peterson S et al. https://pubmed.ncbi.nlm.nih.gov/36508742/
2023;176(1):77-84. doi: 10.7326/M22-2141.
Primary outcome: a composite of hospitalization
within 14 days or death within 28 days diagnosis
No nirmatrelvir

Nirmatrelvir

Hospitalisation
within 14 days
RR: 0.60[0.44-0.81]

Death within 28 days
RR: 0.29[0.12-0.71]

Design and methods: Population-based cohort study,
2022 /1/1~7/17 (under epidemic of Omicron variant).
Patients: 44,551 nonhospitalized adults (90.3% with
≥3 vaccine doses) aged 50 years or older with
COVID-19 and no contraindications for Nir/Rit.
Results: 12 541 (28.1%) were prescribed Nir/Rit and
32 010 (71.9%) not. Patients with Nir/Rit were more
likely to be older, have more comorbidities, and be
vaccinated. The outcome (hosp/death) occurred in
69 (0.55%) on Nir/Rit and 310 (0.97%) not(adjusted risk ratio, 0.56 [95% CI, 0.42 to 0.75]).
Recipients on Nir/Rit had lower risk for
hospitalization (adjusted RR=0.60 [CI: 0.44 to 0.81])
anddeath (adjusted RR=0.29 [CI: 0.12 to 0.71]).
Conclusion: The overall risk for hospitalization ordeath was already low (1%) after an outpatient
diagnosis of COVID-19, but nirmatrelvir plus ritonavir
reduced this risk further.

Killingley B et al. Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults.
Nat Med. 2022 May;28(5):1031-1041. doi: 10.1038/s41591-022-01780-9. Epub 2022 Mar 31.PMID: 35361992

https://pubmed.ncbi.nlm.nih.gov/35361992/

Abstract
Since its emergence in 2019, severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) has caused
hundreds of millions of cases and continues to circulate
globally. To establish a novel SARS-CoV-2 humanchallenge model that enables controlled investigation ofpathogenesis, correlates of protection and efficacy
testing of forthcoming interventions, 36 volunteers
aged 18-29 years without evidence of previous infection
or vaccination were inoculated with 10 TCID50 of awild-type virus (SARS-CoV-2/human/GBR/484861/
2020) intranasally in an open-label, non-randomized
study (ClinicalTrials.gov identifier
NCT04865237 ;funder, UK Vaccine Taskforce).
After inoculation, participants were housed in a highcontainment quarantine unit, with 24-hour close
medical monitoring and full access to higher-level
clinical care. The study's primary objective was to
identify an inoculum dose that induced well-tolerated
infection in more than 50% of participants, withsecondary objectives to assess virus and symptom
kinetics during infection. All pre-specified primary andsecondary objectives were met.
Two participants were excluded from the perprotocol analysis owing to seroconversion between
screening and inoculation, identified post hoc. Eighteen(~53%) participants became infected, with viral load
(VL) rising steeply and peaking at ~5 days after
inoculation.

Virus was first detected in the throat but rose tosignificantly higher levels in the nose, peaking at ~8.87
log10 copies per milliliter (median, 95% confidence
interval (8.41, 9.53)). Viable virus was recoverable fromthe nose up to ~10 days after inoculation, on average.
There were no serious adverse events. Mild-to-moderate
symptoms were reported by 16 (89%) infectedparticipants, beginning 2-4 days after inoculation,
whereas two (11%) participants remained asymptomatic(no reportable symptoms). Anosmia or dysosmia
developed more slowly in 15 (83%) participants. No
quantitative correlation was noted between VL andsymptoms, with high VLs present even in asymptomatic
infection.
All infected individuals developed serum spike-specific
IgG and neutralizing antibodies. Results from lateral flow
tests were strongly associated with viable virus, andmodeling showed that twice-weekly rapid antigen tests
could diagnose infection before 70-80% of viable virus
had been generated.
Thus, with detailed characterization and safety analysisof this first SARS-CoV-2 human challenge study inyoung adults, viral kinetics over the course of primary
infection with SARS-CoV-2 were established, with
implications for public health recommendations andstrategies to affect SARS-CoV-2 transmission. Futurestudies will identify the immune factors associated withprotection in those participants who did not develop
infection or symptoms and define the effect of prior
immunity and viral variation on clinical outcome.

Safety, tolerability and viral kinetics during SARS-CoV-2 human challenge in young adults.
Killingley B et al. doi: 10.1038/s41591-022-01780-9.
Precise viral titre measurement revealed:
https://pubmed.ncbi.nlm.nih.gov/35361992/
Remdesivir did not reduce viral load.
peak

AUC

AUC (nose)

Nasal viral load
(AUC):
No difference

Throat: no difference:(AUC & peak)Time of peak viral load:
NS: not significant(although slightly delayedwhen treated with remdesivir)

RCT showed hospitalization reduction without
showing viral load reduction. Why this occur?
• There is an RCT [a] which showed that remdesivir prevented hospitalization for
mild COVID-19. However, there was no difference in viral load in this RCT.
Therefore, the finding that remdesivir reduced the incidence of severe disease(hospitalization) is unrelated to the reduction of viral load. The apparent effect may
be due to the apparent reduction in symptom severity caused byimmunosuppression by remdesivir which is similar to favipiravir or fluorouracil [b,c].
These mechanisms are similar to those of Tamiflu, which suppresses the immune
system and apparently alleviates clinical symptoms through its inhibitory effect on
hosts’ endogenous neuraminidase [d].
a) Gottlieb RL et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients NEJM 2022; 386(4):305-15b) Med Check editorial team. Favipiravir (trade name: Avigan Tablet): Most probably no efficacy on COVID-19, and harmful.
MedCheck in English 2020: 6 (18): 46-50.
c) Med Check editorial team. Remdesivir (trade name: Veklury): Most likely ineffective for COVID-19. MedCheck in English 2020:
6 (18): 39-45.
d) Hama R. The mechanisms of delayed-onset type adverse reactions to oseltamivir Infect Dis (Lond). 2016 Sep;48(9):651-60.
doi: 10.1080/23744235.2016.1189592. Epub 2016 Jun 2

Gottlieb RL et al. NEJM 2022; 386(4):305-15
https://pubmed.ncbi.nlm.nih.gov/34937145/

DOI: 10.1056/NEJMoa2116846* Baseline stratification factors wereresidence in a skilled nursing facility (yes orno), age (<60 years or ≥60 years), andcountry (UnitedStates or outside the United States). Covid19 denotes coronavirus disease 2019, andNC not calculated.
adolescents, none had a Covid-19–related
hospitalization or death from any cause by
day 28.

Change of viral load on d7: NS

underwent randomization, received at least
one infusion of remdesivir or placebo, andmet eligibility criteria
as defined in protocol amendment 2 orlater.
§ The analysis was conducted post hoc.
¶ The value is the least-squares mean.
⁇‖ On the FLU-PRO (Influenza PatientReported Outcome) Plus questionnaire,
which was adapted for patients with Covid19, alleviation of
Covid-19 symptoms was defined as mild or
absent symptoms.
** The value is the rate ratio.