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June 2023〈Review Article〉

Global trends in novel coronavirus infection(COVID-19) and its treatment
̶ Analyses of the background ofivermectin clinical trials ̶Morimasa Yagisawa, Ph.D.1,3, Patrick J. Foster, M.D.2,
Hideaki Hanaki, Ph.D.1 and Satoshi Omura, Ph.D.1
1

Kitasato University Omura Satoshi Memorial Institute2
Keio University Faculty of Pharmacy
3
Louis Pasteur Center for Medical Research(Received for publication May 9, 2023)

The authors collected and analyzed information on the details of the outbreak andglobal spread (pandemic) of novel coronavirus (SARS-CoV-2) infection (COVID-19)
and clinical studies of ivermectin for the prevention and treatment of COVID-19. The
time period covered was until the third wave of the epidemic stabilized in February of2021, which was 15 months after the COVID-19 outbreak in Wuhan, Hubei, China.
Review articles were published, in Japanese and English, in this journal.
This review describes the results of data collection and analysis of the global
trends of COVID-19 from the fourth to the eighth wave in the ensuing two years andtwo months. The situations in the United States (most severely aﬀected), Europe andAsia (where diﬀerent trends were observed among countries), and India and Japan(where unique trends were observed), are also described. In particular, theemergence of variants, the most prominent feature of COVID-19 — including
subsequent transitions to various lineages, which strongly inﬂuence diﬀerences inthe virulence and infectivity of mutant and subtype strains — is analyzed anddescribed in detail.
As the COVID-19 epidemic progressed, both the infectiousness of COVID-19 andthe number of patients increased. However, the pathological course of clinicalpatients tended to become milder, and the disease prognosis less severe, as patientmanagement improved with the introduction of various therapeutic agents, including
rapid detection and increased frequency of testing. Although vaccination of the
population progressed rapidly, SARS-CoV-2 mutated just as rapidly, rendering thevaccines less eﬀective in both the prevention and spread of infection. In addition,
monoclonal antibody drugs targeting the spike proteins on the surface of SARS-June 2023

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57（ 45 ）CoV-2 became less eﬀective due to ongoing mutations involving the target receptors.
Novel therapeutic agents continue to be developed, and further improvements in
COVID-19 therapy are expected.
The COVID-19 pandemic is currently on a downward trend, and the United States
and Japan lifted their emergency pandemic response alerts in May of 2023. The
WHO declared the termination of the Public Health Emergency of International
Concern for COVID-19 on the 5th of May 2023. It is hoped that no new pandemic
waves will appear in the future.
This review provides the necessary background information for the next review by
the authors on the clinical trials of ivermectin, by analyzing the status of COVID-19
worldwide and the current status of therapeutic agents being used.

Introduction
The authors have collected and analyzed information on the course of events of the outbreakand global spread (pandemic) of novel coronavirus (SARS-CoV-2) infection (COVID-19) andclinical studies of ivermectin for the prevention and treatment of COVID-19 during the 15
months following the outbreak in Wuhan, Hubei Province, China. The time period covered was
up to the point that the third wave of the epidemic subsided in February of 2021. Reviews in both
Japanese and English were published in this journal1,2).
At that time of writing, the SARS-CoV-2 Alpha variant strain (systematic name: B.1.1.7),
ﬁrst detected in the United Kingdom in September of 2020, accounted for 97% of cases in thatcountry and had begun to spread worldwide, replacing the Iota (B.1.526) and Epsilon (B.1.427 /B.1.429) variants in the United States and the B.1.1.214 subtype strain prevalent in Japan3). On
the other hand, the diversity of COVID-19 virus strains began to become evident4), with the Beta
variant (B.1.351) accounting for 99% in South Africa, the Gamma variant (P.1) accounting for
70% in Brazil, and the Delta variant (B.1.617.2) appearing in India.
Also, by that time, the total number of COVID-19 cases and deaths had already reachedmore than 100 million and 2.2 million, respectively, in more than 220 countries/regions worldwide5). On the other hand, in the United States, where the situation was most severe, the numberof new cases, including deaths, was declining rapidly; there was optimism that the COVID-19
pandemic would subside with the cessation of the third wave recorded between October of 2020and February of 2021. Such optimism was supported by the widespread use of the COVID-19
vaccine, and the use of the antiviral drug remdesivir and the monoclonal antibody combination
drug casirivimab/imdevimab, which received an Emergency Use Authorization (EUA)6) from the
U.S. Food and Drug Administration (FDA), and the steroidal drug dexamethasone, which prevented patients with mild to moderate disease from becoming seriously ill. These also saved thelives of patients with severe disease. Some progress was therefore made in the management of

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patients with COVID-19.
However, contrary to expectations, the COVID-19 pandemic continued, and by the end of
May 2021, as described in detail in this review, three waves of epidemics were observed: an
Alpha variant7) that spread from the United Kingdom to all of Europe and raged in the UnitedStates, a Beta variant8) that spread from South Africa to Europe, Asia, and Oceania but did notreach the level of a large-scale epidemic, and a Gamma variant9) that caused a fairly large outbreak from Brazil to all of South and Central America.
In India, on the other hand, the epidemic was diﬀerent, with the ﬁrst wave of the epidemic
occurring over a nine-month period from early May 2020 to late January 2021, caused by mutant
strains (B.1.1.32, B.1.1.8, B.1.113, etc.)10) diﬀerent from those in other countries. This outbreakpeaked at 96,000 new cases per day on the 17th of September, but the subsequent transmission of
the third wave of the worldwide epidemic caused by the Alpha variant of British origin was notobserved. However, from around the 10th of March 2021, cases of infection with the Delta variant11) increased rapidly, reaching a peak of more than 410,000 new cases on the 6th of May, and amajor fourth wave of the epidemic was observed until the number of cases fell to less than 50,000
by the end of June. The epidemic strain in India (B.1.617.2) was named the Delta variant by theWorld Health Organization (WHO) on the 31st of May. The spread of the Delta variant from India
to the rest of the world was rapid, and the ﬁfth wave, which peaked on the 6th of August with approximately 820,000 cases in the United States and the United Kingdom, continued until midOctober 2021. In Japan, the ﬁfth wave of the epidemic was observed, this time with the Delta
variant, coinciding with the Tokyo Olympics and Paralympics.
The subsequent transition from the sixth wave caused by the Omicron variant (B.1.1.529)12),
which began in Zimbabwe/South Africa in mid-November of 2021, to the seventh and eighthwaves caused by various lineages of the Omicron variant is described in detail in the text of thisreview. These waves diﬀered from those caused by the Alpha- and the Delta-variants in that thepathological clinical course was mainly mild, but the infectious capacity was enhanced and theepidemic waves so large that the number of new infections worldwide exceeded 4 million perday.
On the 11th of March 2020, the WHO declared that COVID-19 had reached pandemic status,
but on the 14th of September 2022, two years and six months later, the WHO announced13) that
COVID-19 was on a declining trend and that the declaration was expected to be lifted in the near
future. However, the number of newly infected cases worldwide was approximately 500,000 per
day at the time the seventh wave was in the process of converging, and the situation thereafter remained ﬂat. This did not lead to the lifting of the pandemic declaration. In the winter of 2022–
2023, an eighth wave was caused by various lineages of the Omicron variant and it progressed simultaneously with a seasonal inﬂuenza epidemic — the global spread of infection had become
unpredictable. Additionally, children and susceptible adults were alerted to the possibility of seri-

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59（ 47 ）ous respiratory syncytial virus (RSV) infections. Therefore, the simultaneous outbreaks of threeviral respiratory infections were termed “tridemic” or “triple threats”. On the 27th of January2023, the WHO convened a COVID-19 Emergency Committee based on International HealthRegulations to discuss whether or not to declare the pandemic over. However, due to repeatedchanges in the causative viruses driving the pandemic and the high number of deaths, the committee concluded14) that it would take several more months of surveillance before oﬃcially declaring the pandemic over.
The COVID-19 epidemic has lasted more than three years, despite extensive and diligent efforts — such as antigen testing, vaccinations, antiviral drug therapies, as well as antibody and steroid therapies — being made to prevent the spread of infection and seek a cure. Furthermore,
post-COVID/long COVID (post-acute sequelae of COVID-19 or PASC) has been observed15) in
4.5% of patients infected with the Omicron variant. Although the Omicron variant is considered
to be less pathogenic, it, along with other variants, has resulted in pathological sequelae that havebecome a signiﬁcant and persistent social problem.
It is not necessary to describe the details of the COVID-19 pandemic in this review, since
there are specialized information sources such as the WHO16) and the database of Johns Hopkins
University17) in the United States. However, the changes in pathogenicity and infectivity of
SARS-CoV-2, the status of approval and usage of COVID-19 drugs, and the development of new
drugs are all important factors that exert a great inﬂuence on the background for the authorsʼ analysis of the “status of clinical trials of ivermectin against COVID-19” to be described in our subsequent review.

1. Global trends in COVID-19
The virus responsible for the November 2019 outbreak of COVID-19 in Wuhan, Hubei
Province, China, was identiﬁed to be two strains of SARS coronaviruses belonging to the genus
Beta-coronavirus of the family Coronaviridae — the same family as the previous outbreaks of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) —and was referred to as the Wuhan virus. The WHO prohibits the naming of infectious diseases
and pathogens with a personʼs or regional name, due to the potential for discrimination and prejudice. On the 7th of January 2020, the Wuhan virus (also called the Chinese Virus in the UnitedStates) was provisionally named the 2019 novel coronavirus (2019-nCoV). In response, the national authorities and the press in Japan began to refer to it as the “novel coronavirus”. Subsequently, the International Committee on Virus Classiﬁcation oﬃcially named the virus, Severe
Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)18) on the 11th of February that same
year. On that same day, the WHO also named19) SARS-CoV-2 infection as Coronavirus Disease2019 (COVID-19).

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SARS-CoV-2 is an enveloped virus, with a positive-sense, single-stranded RNA genome thesize of approximately 30,000 bases — which is extremely large for an RNA virus and easily mutable. Nomenclature for mutant strains has been proposed under eight global clades20） by the
Global Initiative on Sharing All Inﬂuenza Data (GISAID). It is an international organization thatprovides the complete genomic sequence of SARS-CoV-2 as shared information. It follows therules of global lineage assignment in accordance with PANGO (Phylogenic Assignment on
Named Global Outbreak lineages) nomenclature21) and was developed by a research group in the
United Kingdom. On the 31st of May 2021, the WHO published a simpliﬁed nomenclature22) thatlabels SARS-CoV-2 variants with letters of the Greek alphabet, and further proposed the additional labels “variants of interest (VOI)” and “variants of concern (VOC)”. The PANGO strain
names and GISAID branch group names are used in epidemiological and molecular biologicalstudies of mutant strains, and a list of names contrasting them with the WHO simpliﬁed labels23)
has been published.
1) COVID-19 epidemic waves caused by SARS-CoV-2 variants
The transition of the COVID-19 epidemic in the world from the ﬁrst to the eighth wave isshown in Fig. 1, using the Global Change Data Lab (GCDL) database24) of the United Kingdom,
and is based on the WHO COVID-19 dashboard16). For the number of new cases and deaths perday, the 7-day average ﬁgures are applied in order to provide a birdʼs-eye view of the 3-year and3-month endemic period.
The number of newly infected cases remained below 850,000 from the 12th of April 2020
(the peak of the ﬁrst wave) to the 21st of August 2021 (the peak of the ﬁfth wave). Then, in what
has been described as an infection explosion, the number rapidly rose to reach 3.44 million at theﬁrst peak of the sixth wave on the 25th of January 2022. After the peak, the number of cases rapidly declined, but began to rise again, reaching the second peak of the sixth wave at 1.81 million
on the 17th of March 2022. The number of cases dropped to 500,000 in early May, and the sixthwave appeared to subside. However, in early June, the number of cases began to rise again, andthe seventh wave struck. The number of infected cases in the seventh wave increased rapidly,reaching 1.1 million on the 23rd of July (the ﬁrst peak of this wave), but then also rapidly declined — reaching less than 450,000 on the 22nd of September. Thereafter, another small rise (thesecond peak) of 480,000 people was recorded on the 11th of October. The number once again
dropped to 320,000 on the 5th of November, but this situation did not last. Another upward trend
began, exceeding 450,000, and this was the beginning of the eighth wave that began on the 1st ofDecember 2022.
The eighth wave was predicted to peak on the 19th of December 2022, with about 590,000
cases, before being followed by a gradual downward trend and convergence. However, in responding to the criticism by the WHO, China announced on the 14th of January 2023, their number of in-June 2023

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61（ 49 ）Fig. 1. Global transition of conﬁrmed cases and deaths of COVID-19 (7-day average)

fected cases and deaths after the 8th of December. Consequently, Fig. 1 shows that the number of
newly infected cases peaked on the 26th of December 2022 at more than 6 million, including 5.88
million in China. Since China stopped releasing information on the daily number of new cases anddeaths on the 9th of January 2023, the graph in Fig. 1 shows a markedly sharp drop. This steep drop
is considered to be hugely artiﬁcial and of no scientiﬁc signiﬁcance whatsoever.
The GCDL database allows for a country-speciﬁc review of SARS-CoV-2 variants attributable to new infections. The third peak of the third wave (which took place on the 11th of January2021), recognized at the time of publication of the authorsʼ 2021 review1), was mainly due to theepidemics of the Epsilon (B.1.427, B.1.429) and Iota (B.1.526)25) variants in the United States, byoutbreaks of the Alpha variant (B.1.1.7) from the United Kingdom in European countries, and theGamma variant (P.1) in Brazil. The subsequent sharp fourth wave (peaking on the 28th of April62（ 50 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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June 20232021), was caused by an epidemic of the Delta variant (B.1.617.2) in India26). The gentle ﬁfth
wave which occurred between July and October of 2021 (peaking on the 21st of August), shows
how several subtypes of the Delta variant raged across the United States. The following small
peak in November–December 2021 is also evidence of a small epidemic caused by multiple lineages of the Delta variant in the United States, and several European countries such as Germany,
France, and the United Kingdom.
Before the small peak following the ﬁfth wave had fully subsided, an explosive sixth waveof outbreaks — caused by the highly infectious Omicron variant (B.1.1.529)27), and ﬁrst detectedin South Africa in mid-November — broke out in the United States and European countries (including the United Kingdom, France, Germany, Italy, Spain, and Denmark). In addition, fromearly January of 2022, the outbreak caused by the Omicron variant spread to Asian countries such
as India, Malaysia, and Japan, as well as to Latin American countries such as Brazil and Mexico.
The spread of the sixth wave of the epidemic was remarkably rapid. By the 28th of February2022, the cumulative number of COVID-19 cases worldwide reached 437 million and the cumulative number of deaths 5.99 million.
The ﬁrst peak of the sixth wave (on the 25th of January 2022), was mainly due to the Omicron variant BA.1 lineage. As shown in Table 1, of the 3.42 million cases worldwide, the UnitedStates accounted for 20.1%, or 686,000 cases, and France for 10.1%, or 344,000 cases. The incidence rates in Italy, Germany, and the United Kingdom ranged from 3.1 to 5.1%. In Japan, the incidence rate was 1.3%, in Vietnam 0.5%, and in South Korea it was 0.2%. The second peak (onthe 17th of March 2022) was caused mainly by the BA.2 lineage28). The composition ratio of this1.81 million cases peak was quite diﬀerent from that of the ﬁrst peak: South Korea showed asharp increase to 387,000 (21.4%), Vietnam increased to 254,000 (14%), and Germany increased
to 220,000 (12.1%), France decreased to 4.0%, Italy showed a slight decrease, the United Kingdom and Japan both showed slight increases, and the United States showed a marked decrease to
33,000 (1.8%).
The ﬁrst peak of the seventh wave (on the 23rd of July 2022), was caused largely by the Omicron variant BA.5 lineage29). While the number of cases in the United States once again increased
to 126,000 (12.3% of the world total of 1.03 million), the number of cases in Japan surprisingly
jumped to 126,000 (12.2% of the world total). France and Italy also showed slight increases in
numbers. On the other hand, South Korea and Vietnam showed a sharp decrease in the number ofcases, down to 61,000 (5.9%) and 650 (0.1%), respectively. Germany and the United Kingdom
also showed downward trends in case numbers. The second peak of the seventh wave (occurringon the 11th of October 2022) showed only a small number of cases (475,000) worldwide, but thestrains caused by this peak were a mixture of BQ.1 and BA.2.75 lineages, in addition to the BA.5
lineage. By country, Germany and France accounted for 21.8% (103,000) and 11.7% (56,000), respectively, of the worldwide total. At the same time, the United States and Japan showed a de-June 2023

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63（ 51 ）Table 1. Conﬁrmed cases at the peaks of the 6th and 7th waves of COVID-19 in each country

crease in the number of cases, with South Korea also showing a declining trend. Thus, throughout
the Omicron variant epidemics, the lineages and the major endemic countries changed.
Table 2 shows the epidemic period and the number of newly infected cases at the peak ofeach of the above-mentioned ﬁrst to eighth waves. If the number of new cases at the peak of theﬁrst wave caused by the original B.1 strain from Wuhan, Hubei Province, China, is 1.00, then thethird peak of the third wave caused by the Alpha variant from England is 7.64, and the fourthwave caused by the Delta variant from India is 9.69. These numbers indicate that the infectivity(spreading power) was gradually enhanced. The Omicron variant of South African origin caused
an explosive outbreak of 40.11 in the ﬁrst peak of the sixth wave. Thus, the Omicron variant was
found to have markedly enhanced infectivity. The reason for the low magniﬁcation after the second peak of the sixth wave is that nearly 500 million people (6% of the world population) were
infected with COVID-19 by the time of the ﬁrst peak of the sixth wave, and 25–60% of the population (as described below) in the United States and Europe in particular were infected with
COVID-19. Therefore, this could be considered as an indication that collective immunity to infection had been established and that the spread of infection had essentially slowed down.
2) Global deaths due to COVID-19
The lower portion of Fig. 1 shows a graph of the number of deaths worldwide due to
COVID-19. It also shows a markedly diﬀerent pattern from that of the number of newly conﬁrmed cases in the upper portion. The dissimilarity is thought to be due to diﬀerences in thestrength of infectivity and virulence (toxicity) of the variants causing each wave of the epidemic.

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Table 2. Transition of the global COVID-19 pandemic

Table 3 shows the results of the analysis of lethality rate, the number of deaths relative to thenumber of newly conﬁrmed cases, on the peak date of each wave of deaths. The lethality rate wasremarkably high at 8.7% in the ﬁrst wave caused by the Wuhan strain (indicated as A in thegraph), but it was reduced to 2.5% by the third peak in the third wave (indicated as C). This wascaused mainly by the Alpha variant of British origin. A further reduction to 1.7% occurred in the
fourth wave (indicated as D), and was due predominantly to the Delta variant of Indian origin.
During the ﬁrst peak of the sixth wave (indicated as G) of the explosive epidemic of the Omicron
variant that spread from South Africa to the rest of the world, the lethality rate was remarkably
low at 0.4%. Comparing these numbers of new cases and deaths, the diﬀerences suggest that the
Omicron variant (which caused the global pandemic from early January of 2022) was characterized by remarkably high infectiousness but remarkably low virulence (toxicity) leading to death,and that the primitive Wuhan strain (which caused the initial epidemic) was characterized by low
infectiousness but remarkably high virulence (toxicity).

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65（ 53 ）Table 3. Transition of global lethality rate with COVID-19

3) COVID-19 infection status in countries around the world
The cumulative numbers of conﬁrmed cases and deaths along with the rates of morbidity andlethality of COVID-19 for the top 20 countries in the world as of the 31st of December 2022, areshown in Table 4. The total number of conﬁrmed cases worldwide was calculated to be approximately 665 million, representing 8.3% of the total population of approximately 8 billion people.
The total number of deaths was about 6.7 million, and the lethality rate was calculated to be
1.0%. It should be understood that this is an analysis of the global situation excluding China,
since it is based on ﬁgures prior to the 14th of January 2023 (at which time, China revised andpublished the number of cases and deaths in response to the WHOʼs criticisms).
In the United States, which has the largest number of infected persons in the world, the numberof conﬁrmed cases reached more than 100 million, or 30.7% of its approximately 335 million population. The number of deaths in the United States is approximately 1.12 million, resulting in alethality rate of 1.1% — which is higher than the world average. In India, the second largest country
based on the number of infected, the number exceeds 44 million. However, with a population ofover 1.4 billion people, the morbidity rate is as low as 3.2%, and the lethality rate is calculated to be
1.2% (since the number of deaths is 530,000). In comparison, France, the country with the thirdlargest number of infected cases, 39.3 million people were infected. Nevertheless, France, with apopulation of 65.5 million, has the highest morbidity rate in the world at 60%. The incidence rate of
ten countries, including South Korea, the Netherlands, and Germany, as shown in the footnote ofTable 4, is more than 25%. The lethality rate is found to be higher than the world average in eight
countries, including Mexico (4.6%), Indonesia (2.4%), and Brazil and Iran (1.9%).
i) Number of infected cases and deaths in the United States
The United States has suﬀered the most severe health consequences from COVID-19, andthe transition of the numbers of conﬁrmed cases and deaths is shown in Fig. 2. The ﬁrst case de-66（ 54 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Table 4. Global situation of COVID-19[as of December 31, 2022: top 20 countries]

tected in the United States was in a person returning from China, just ten days after the Chinese
government reported the outbreak in Wuhan City to the WHO on the 11th of January 2020. On the
12th of April — which was at the peak of the ﬁrst wave of the epidemic — more than 30,000 cases
per day were recognized. This was the highest number in the world. The United States recorded
the highest number of cases in the second and third waves of the global outbreak, as well as in theﬁfth wave and the ﬁrst peak of the sixth wave. On the 12th of January 2022, in particular, near the
peak of the ﬁrst wave of the sixth outbreak, 1.27 million new cases per day (7-day average:
810,000 on the 17th of January 2022) were recorded.
In the United States, the peak day of the number of deaths is observed seven to twenty days
after the peak day of the number of newly conﬁrmed cases during each COVID-19 epidemic.
Table 5 shows the transition of the lethality rate calculated by dividing the number of deaths on
the peak day of deaths by the number of newly conﬁrmed cases on the peak day of newly conﬁrmed cases. The epidemic variants during each epidemic wave are also included in Table 5. The

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67（ 55 ）Fig. 2. Transition of conﬁrmed cases and deaths in the USA (7-day average)

peak date of deaths in the ﬁrst wave was the 15th of April 2020, with 2,624 deaths. The peak date
for newly conﬁrmed cases was the 9th of April, with 36,022 cases, resulting in a lethality rate of
7.3%. In the second wave, there were 1,422 deaths on the 5th of August and 74,944 cases on the
24th of July, with a lethality rate of 1.9%. The highest number of deaths was recorded in the third
peak of the third wave on the 20th of January 2021, with 4,389 deaths and a lethality rate calculated to be 1.4% — since there were 302,978 cases on the 8th of January. In the subsequent ﬁfth
wave, there were 3,493 deaths on the 16th of September and 235,250 cases on the 3rd of September, resulting in a lethality rate of 1.5%. During the ﬁrst peak of the sixth wave, there were 4,091
deaths on the 28th of January 2022 and 1.27 million cases on the 12th of January, resulting in a le-68（ 56 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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thality rate of 0.3%; in the ﬁrst peak of the seventh wave, there were 1,174 deaths on the 8th ofJune and 228,960 cases on the 1st of June, with a lethality rate of 0.5%.
From these results, the original Wuhan strain (B.1), which caused the ﬁrst wave of the epidemic, was less infectious but signiﬁcantly more virulent. The Alpha and Delta variants of the
fourth and ﬁfth waves, respectively, were more infectious but less virulent, and the Omicron variant BA.1 lineage which caused the ﬁrst peak of the sixth wave was signiﬁcantly more infectious
but much less virulent. The Omicron variant BA.2.12.1 lineage and the mixed BA.2 lineage ofthe seventh waveʼs ﬁrst peak, as well as the Omicron variant BA.5 lineage28) and the mixed BA.4
lineage of the seventh waveʼs second peak, were also considered to have decreased virulence.
In the United States, after the peak of the ﬁrst peak of the seventh wave, which was dominated by the BA.2.12.1 lineage, the number of newly conﬁrmed cases decreased rapidly, and theBF.7 and BQ.1 lineages, which were derived from the BA.5 lineage, began to increase as the outbreak subsided. In mid-September 2022, when the epidemic began to shift to the second peak of
the seventh wave, the BQ.1.1 lineage, the BN.1 lineage derived from the BA.2 lineage, and the
XBB lineage, a hybrid between the derived lineages, were all mixed30,31), but the number of
newly conﬁrmed cases did not increase and there was a subsequent lull for about one month. In
early November, a major change in the composition of the epidemic lineages was observed: thesum of the BQ.1 and BQ.1.1 lineages exceeded 25%, the BF.7 and BA.4.6 lineages 6–8%, andthe BA.5.26, XBB and BN.1 lineages 2%, as the BA.5 lineage decreased to less than 50%. The
sum of the BQ.1 and BQ.1.1 lineages exceeded 50% in early December, and the BA.5 lineage30)
accounted for less than 25% of the total.
In the United States, almost all pandemic restrictions were lifted, and life returned to normal
Table 5. Transition of newly conﬁrmed cases and deaths in the USA

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69（ 57 ）in late November of 2022 with less than 40,000 new cases per day. Yet, by the beginning of December, the number of new cases had begun to rise again, indicating the arrival of the eighthwave. The BQ.1 and BQ.1.1 lineages accounted for more than 60% of the total, and the newly
emerged XBB.1.5 lineage accounted for 18%, the XBB and BA.5 lineages 5% each, and theBN.1 and BF.7 lineages 3% each, revealing an increasingly complicated aspect in terms of variant lineage compositions of the epidemic.
As a historical, yet oddly appropriate, sidenote, in Europe and the United States, there is acustom of naming creatures that transcend human knowledge after myths and legends. The
BA.2.75 lineage is, therefore, also named “Centaurus”, which in Greek mythology is a halfhuman, half-beast creature in which the neck of a horse is replaced by the upper half of a humanbody. “Centaurus” is considered the “father” of a race of beastly mythical creatures in Greek mythology. The BA.2.75 lineage is said to be three times more infectious than the BA.5 lineage, so
the name may be somewhat ﬁtting. The hybrid lineage XBB, which is the result of the crossbreeding of the BA.2.75 and the BA.2.10.1 lineages, is named “Griﬃn” (Greek mythology: amonster with the wings and upper body of an eagle and the lower body of a lion). The lineage
XBB.1.5 is named “Kraken”, which is the name of a Nordic Sea monster, regarded as a giant octopus or squid, and some believe it to be a real giant squid of modern times — a monster that suddenly pulls an entire cruise ship into the depths of the sea during a peaceful voyage. The BQ.1.1
lineage is also named “Cerberus” (Greek mythology: a dog monster, a guard dog of the underworld, with three dog heads and three serpent tails), which may be reminiscent of a derived virus
lineage that has accumulated a variety of mutations. The XBB.1.16 lineage, which has spreadaround the world since its appearance in early January 2023 and has become a major epidemicstrain in India and other countries, is named not after a beast but after an alpha star in the constellation Boötes, Arcturus.
ii) Transition of conﬁrmed cases in ﬁve European countries and Russia
In Europe, the number of deaths during the ﬁrst wave of the COVID-19 pandemic was signiﬁcantly higher, and there were reports of a shortage of coﬃns to adequately deal with the increased number of deaths in Italy and Spain. The transition of the conﬁrmed cases in ﬁve European countries (the United Kingdom, France, Italy, Spain, and Germany), and in Russia, is shownin Fig. 3. It should be noted that the numbers on the vertical axis showing the number of conﬁrmed cases in each country diﬀer. Also note that the appearances around the third wave (before
the 24th of February 2021) and the ﬁfth wave (the 12th of September 2021) are diﬀerent in eachcountry. There is a date gap in the arrival of the ﬁrst peak of the sixth wave, as well as marked
diﬀerences in the presence and intensity of the second peak of the sixth wave. There are also
marked diﬀerences in the presence and intensity of the ﬁrst and second peaks of the seventh
wave. Even among countries belonging to the same EU group, the status of COVID-19-related

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vaccine adherence, patient isolation, social activities such as public dining, and the wearing ofmasks all diﬀered, along with diﬀerences in public commuting restrictions and the acceptancepolicies of medical facilities for patient admissions may have all inﬂuenced the manifestations of
the epidemic waves.
Another inﬂuencing factor is thought to be due to the virulence (toxicity) of the Omicron
variant that caused the sixth wave, which was conﬁrmed to be weak. This, and additional societal
measures created to compensate for economic losses, ease restrictions on the behavior of citizens,and improve the movement of people both domestically and abroad all surely played contributoryroles. This may have also resulted in the introduction of variants or lineages that were prevalent
in regions other than Europe alone. In Russia, it is doubtful whether or not the situation after thesixth wave in January of 2022 has been accurately assessed; therefore, detailed information on
the seventh and eighth waves has not been obtained.
iii) Transition of conﬁrmed cases and deaths in India
India has a population of 1.4 billion, and the COVID-19 epidemic diﬀers greatly from one
region to another, such as Uttar Pradesh in the north central region, Maharashtra in the central
western region, and Tamil Nadu in the southeastern region. Diﬀerent measures were taken in different states. Although it may be inappropriate to generalize about all regions in a single ﬁgure,this review treats India as a single country, and the number of newly conﬁrmed cases and deaths
are shown in Fig. 4.
India was not aﬀected by the ﬁrst wave of the global COVID-19 epidemic, and a slow epidemic wave with a peak in mid-September was recorded over a 6-month period from mid-June to
mid-December of 2020 — which corresponded to the period between the global second wave andthe second peak of the third wave. As previously mentioned, the prevalent virus during this period were derivatives of the B.1 (B.1.1.32, B.1.1.8, B.1.113, etc.), B.4 and B.6 lineages which differed from those in other countries, but in late December, the Alpha variant of British origin and
the Beta variant of South African origin became mixed in the population. By then, however, theoutbreak had subsided, thereby avoiding a global third wave of triadic epidemics from early October of 2020 to mid-February of 2021.
From the beginning of March 2021, the number of cases infected with the Kappa variant(B.1.617.1) began to increase, and this was replaced by the Delta variant (B.1.617.2) in midApril. The number of the conﬁrmed cases continued to increase rapidly, reaching a peak of
412,000 cases on the 6th of May 2021, and was then followed by a rapid decline to 40,000 casesby late June. Subsequently, the Delta variant spread worldwide, but in India, when the global
ﬁfth-wave peak was recorded on the 21st of August 2021, the number of new cases stabilized at
30,000 to 40,000 per day; by the end of November, the number of new cases had dropped further
to less than 10,000.

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71（ 59 ）Fig. 3. Transition of newly conﬁrmed cases in 5 countries of EU and in Russia (7-day average)

During the ﬁrst peak of the global sixth wave caused by the Omicron variant BA.1 lineage,in which the number of newly infected cases increased rapidly from mid-December 2021, India
recorded 338,000 new cases at that peak on the 21st of January 2022. However, the subsequent
second peak in March of 2022 had less than 2,000 new cases, and the number of new cases had
subsided. During the ﬁrst peak of the seventh wave, 20,000 new cases were recorded on the 20thof July 2022, but by the time of the second peak in early October, the number of new cases was
still down to less than 2,500. In the eighth wave after November 2022, the number of new cases72（ 60 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Fig. 4. Transition of newly conﬁrmed cases and deaths in India (7-day average)

had settled even further to less than 500.
The number of deaths from COVID-19 in India correlated with the number of conﬁrmed
cases, but the 1,290 deaths on the 15th of September 2020 represented 1.4% of the 90,123 newly
conﬁrmed cases — this was a lower rate compared to the global lethality rate of 2.4%. The 4,529
deaths reported on the 18th of May 2021, the peak of the fourth wave, which was mainly in India,
represented 1.7% of 267,334 newly conﬁrmed cases, and the 1,733 deaths reported on the 1st of
February 2022, the ﬁrst peak of the sixth wave, represented 1.1% of 161,386 newly conﬁrmed
cases at that time — this latter number was an extremely low death rate.
The number of new cases and deaths in India diﬀered greatly between Uttar Pradesh, thestate with the largest population in the north-central portion of the country, and Maharashtra, an
industrial area in the central-western portion of the country. The reasons for this depended on

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73（ 61 ）whether state governments had implemented measures to prevent the spread of infection or not.
This special situation in India will be analyzed in a subsequent review32) by the authors.
The authors had an opportunity to meet with Mr. Sanjay Kumar Verma, the Indian Ambassador to Japan. We learned that India, with a population of 1.4 billion people, had suﬀered greatly
from the May 2021 outbreak caused by the Delta variant, but that at the time of the January 2022
global outbreak caused by the Omicron variant, the number of new infections in India was only atabout 340,000. This is in comparison to the number of approximately 1.36 million new infections in
the United States at that time. The number of newly infected cases per million population was 4,004
in the United States and only 238 in India — this is less than one-sixteenth the morbidity rate. Furthermore, the number of new cases per day in India has been kept below 20,000 since then.
In India, the number of new cases of infection continues to increase since March 2023 due tothe mitigation of infection control measures, with nearly 1,900 daily cases recorded, and the Omicron variant XBB.1.16 accounted for more than 90% of the cases. The WHO designated33) thislineage as a Variant of Interest (VOI) on April 17th.
iv) Transition of conﬁrmed cases in six Asian countries
Regarding the situation in Asia other than India, Fig. 5 shows the transition of newly conﬁrmed COVID-19 cases in Indonesia, Malaysia, Thailand, the Philippines, Vietnam, and South
Korea. It should be noted that the vertical axis scale numbers on some of the graphs (Vietnam andSouth Korea) are diﬀerent from those of the other countries, and the presence or absence of epidemics, as well as the timing of the arrival of each wave is diﬀerent among the countries — eventhose located relatively close to each other. These diﬀerences in the waves of epidemics among
Asian countries are related to the transition of the causative variants of SARS-CoV-2.
Indonesia, with the worldʼs fourth largest population of about 280 million, was spared from theimpact of the ﬁrst global wave. After a small outbreak in the second wave, there was a third wave
with a peak of about 13,000 new cases on the 1st of February 2021. The fourth wave, caused by the
Delta variant, arrived about two months later from India, and a peak of about 49,000 cases was recognized on the 19th of July 2021. Indonesia was spared from the ﬁfth global wave, but the peak of
the sixth wave caused by the Omicron variant BA.1 lineage was observed on the 20th of February
2022 (one month later than the ﬁrst global peak) with about 56,000 newly conﬁrmed cases. The
peak of the seventh wave, caused by the BA.5 lineage, was observed on the 10th of August, with
only about 5,500 new cases. The eighth wave, with a peak of 6,645 cases on the 22nd of November,
was caused by a mixture of the BA.5 (21%), BQ.1 (24%) and XBB (46%) lineages.
Malaysia, with a population of about 33 million, was spared from the eﬀects of the global
ﬁrst and second waves, but the third wave peaked at about 4,700 cases on the 3rd of February
2021. A small peak of about 7,700 cases in the fourth wave, caused by the Alpha and Beta variants, occurred on the 4th of June. The ﬁfth wave, caused by the Delta variant, peaked at 21,800
cases on the 30th of August, while the sixth wave, caused by the Omicron variant BA.2 lineage,

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Fig. 5. Transition of newly conﬁrmed cases in 6 Asian countries (7-day average)

peaked at 30,500 cases on the 10th of March 2022. Subsequently, the seventh wave, with the BA.5
lineage, peaked at 4,300 cases on the 22nd of July, and the eighth wave, with the mixed BA.5
(26%), BA.2.75 (26%), and XBB (38%) lineages, peaked at 3,900 cases on the 9th of November.
Thailand has a population of approximately 72 million, and the COVID-19 epidemic has followed a very similar course to that of Malaysia, with the ﬁfth wave peaking on the 18th of August2021 — with approximately 22,000 cases due to the Delta variant. The sixth wave was a complex
epidemic divided into ﬁve peaks. The ﬁrst peak on the 15th of January 2022 was small, consistingof 7,900 cases due to the BA.1 lineage. All of the second peak on the 2nd of March with 23,400

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75（ 63 ）cases, the third peak on the 5th of April with 26,000 cases, the fourth peak on the 24th of April
with 19,131 cases, and the ﬁfth peak on the 25th of May with 6,497 cases were due to the BA.2
lineage. The seventh wave showed a gentle peak of about 2,000 cases per day — due to the BA.5
lineage — for 3.5 months from mid-June to late October. The eighth wave showed a maximum of
about 700 new cases per day, due to the BA.2.75 lineage.
The Philippines, with a population of approximately 114 million, was spared the ﬁrst global
wave, but the second wave showed a moderate peak of up to 4,400 cases per day over a threemonth period from the 20th of July to the 25th of October 2020. The Philippines was also sparedfrom the third wave, but the fourth wave, due to the Delta variant, showed a ﬁrst peak on the 15thof April 2021 with 10,800 cases, and a second peak on the 10th of June with 6,500 cases. The ﬁfth
wave, also caused by the Delta variant, showed a peak of 21,000 cases on the 12th of September.
The following sixth wave showed a sharp peak of 34,800 cases on the 17th of January 2022,
caused by the BA.2 lineage, and then dropped below 1,000 cases on the 5th of March. During theseventh wave, the ﬁrst peak of 4,000 cases, due to the BA.5 lineage, was seen on the 11th of August, followed by a second peak of 2,300 cases, due to the BA.2 (48%) and BA.5 (47%) lineages,on the 27th of September. After that peak, from early November to around the 10th of December,there were about 1,000 new cases a day, due to the BA.2 (37%) and XBB (50%) lineages; thereafter, things subsided.
Vietnam and South Korea were signiﬁcantly less aﬀected by the ﬁrst through fourth wavesof the global outbreak; however, the ﬁfth and sixth waves in Vietnam and the sixth, seventh, andeighth waves in South Korea were remarkable in terms of infection spread. Vietnam has a population of about 98 million, and the gentle ﬁfth wave caused by the Delta variant peaked at 13,000
cases on the 3rd of September 2021, followed by a continuing gentle peak trend, with 10,000–
20,000 new cases per day, due to the same variant from mid-November 2021 to early February of2022. Under such circumstances, a sixth wave explosive outbreak suddenly occurred, with a peakof 273,400 new cases due to the Omicron variant BA.2 (89%) and BA.1 (8%) lineages on the 17thof March. After the steep peak subsided to 4,000 cases on the 5th of May, the number of new cases
due to the BA.5 lineage was about 2,000 per day during the seventh global wave. Thereafter, theBA.2 and BA.2.75 lineages appeared at a certain frequency. There has been no eighth wave.
South Korea, with a population of approximately 51 million people, had set up a quarantine
system early on in response to the outbreak of COVID-19 in Wuhan, China, and had escaped theeﬀects of the ﬁrst through fourth waves of the global pandemic. This was achieved due to a highrate of PCR testing and high vaccination rates. However, more than 1,000 cases per day had beenrecognized since mid-July of 2021. The ﬁfth wave, caused by the late-arriving Delta variant,reached a small peak of 6,850 cases on the 16th of December. The sixth wave arrived in mid-January of 2022 and spread rapidly, reaching a steep peak of 405,000 cases on the 17th of March —due to a mixture of the Omicron variant BA.1 (43%) and BA.2 (56%) lineages. Thereafter, there76（ 64 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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was a drop to about 7,000 new cases on the 24th of June. Shortly thereafter, the seventh wave, due
to the BA.5 lineage, arrived. This wave reached a peak of 135,300 cases on the 22nd of August,followed by a drop to 20,000 cases on the 11th of October. Following the seventh wave, the number of cases began to increase once again, and an eighth wave was recorded on the 23rd of December, with a peak of 67,300 cases. The eighth wave was due to a mixture of the BA.5 (45%),
BA.2.75 (38%), and BQ.1 (13%) lineages.
The ﬁve Asian countries shown in Fig. 5, excluding South Korea, are in close proximity toeach other, but their COVID-19 epidemics diﬀer markedly. This might be due to diﬀerences inpublic policies to prevent the spread of COVID-19, diﬀerences in medical systems, diﬀerences invaccination status, as well as other factors. Even waterfront quarantine policies and operations
may have been contributing factors inﬂuencing the diﬀerences in the presence and extent oftransmission from COVID-19-endemic countries (such as Europe, the United States, and India).
Vietnam, in particular, has a unique history in that it escaped the outbreak of the Alpha and Delta
variants. However, the Omicron variant caused a signiﬁcantly larger number of new cases in Vietnam than in other countries. Another diﬀerence was observed in Vietnam, in that the seventh
wave never manifested in the country — yet seventh and eighth waves struck the other countries.
South Korea was the ﬁrst country in the world to thoroughly strengthen its epidemiology bymeans of COVID-19 testing using PCR technology. South Korea also took the leading position in
the world in terms of vaccination rate. The spread of the Alpha and Delta variants was controlled
by securing and managing the use of COVID-19 therapeutic agents at the national level. The outbreak of the Omicron variant, however, could not be controlled, and the sixth wave of outbreaks
occurred — recording more than 400,000 new cases per day. This was followed by both the seventh and eighth waves, which also recorded a large number of new cases.
v) Transition of the conﬁrmed cases and deaths of COVID-19 in Japan
Transition of the number of newly conﬁrmed cases and deaths of COVID-19 in Japan isshown in Fig. 6. Comparative analysis of these trends with those of the global epidemic shows
considerable diﬀerences, reﬂecting Japanʼs unique infection control measures. On the 11th of January 2021, corresponding to the peak day of the third wave of the global outbreak, approximately
4,900 new cases and 48 deaths were recorded in Japan — these were due mainly to the B.1.1.214
lineage variant. On the 28th of April, corresponding to the peak day of the fourth global wave, andreﬂecting the explosive spread of the Delta variant in India, approximately 5,800 new cases and
51 deaths were recorded in Japan — mainly due to the Alpha variant, indicating a small outbreak.
The ﬁfth wave in Japan coincided with the timing of the Tokyo Olympics and Paralympics.
The Delta variant caused more than 10,000 new cases per day, reaching a peak of about 26,000 new
cases per day on the 20th of August 2021 (four days before the opening of the Paralympics). However, the number of newly conﬁrmed cases rapidly declined thereafter, eventually subsiding in earlyJune 2023

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77（ 65 ）October of 2021. This steep peak of increase and decrease has been commented on as being the result of the success of Japanʼs COVID-19 countermeasures; in reality, it was a convergence of the
spread of infection caused by mutations of the virus that caused the outbreak. The Delta variant
AY.29 lineage was the main epidemic strain during this ﬁfth wave, but it was later clariﬁed that theaccumulation of mutations leading to the AY.29 lineage damaged the gene for an enzyme that repairs mutations detrimental to the survival (growth) of the virus, with further mutations in the AY.29
lineage resulting in death of the virus. In other words, the AY.29 lineage is considered to be the endof the phylogenetic tree through which the virus evolved by means of mutations.
Another fact demonstrating that the commentary about Japanʼs COVID-19 countermeasures
being successful was incorrect is recognizable by the rapid increase in the number of new cases ofthe sixth wave caused by the Omicron variant BA.1 lineage (which began in early January of 2022).
On the 3rd of February, the peak day of the ﬁrst peak of the sixth wave, the daily number of newly
conﬁrmed cases exceeded 104,000, and on the 22nd of March, it dropped to about 20,000. That
number, however, rose again, reaching a peak of about 57,000 during the second peak on the 13th ofApril and 46,000 during the third peak on the 11th of May — these were mainly due to the BA.2 lineage. The number of deaths corresponding to the peak of the ﬁrst peak was 322 on the 22nd of February, while that of the second peak was 65 on the 26th of April, and that of the third peak was 50 on
the 18th of May. This indicates a decrease in the ratio of deaths to newly infected cases, and suggeststhat the virulence of the causative virus of COVID-19 decreased over time.
The quiescence of the sixth wave was slow, with the second and third peaks being due to thealternation and complexity (e.g., mixing of the BA.2.12.1 lineage) of the causative lineages. The
epidemic was considered to be under control on the 20th of June, when the number of newly conﬁrmed cases fell below 10,000. However, a rapid increase in the number of newly conﬁrmed
cases was observed once more in early July, whereupon the seventh wave, the largest wave everrecorded, hit its ﬁrst peak of about 250,000 cases on the 10th of August and then a second peak of
about 260,000 cases on the 19th of August. At the second peak of this wave, Japan had the highest
number of newly conﬁrmed cases in the world (South Korea was second with approximately
130,000, and the United States was third with approximately 78,000 cases). The fact that Japan
recorded the highest number of cases in the world was surprising. Furthermore, 250,000 new
cases per day was an alarming situation, as this was also an indication that 0.2% of the population
was infected. Fortunately, although the BA.5 lineage variant that caused the seventh wave of theepidemic was signiﬁcantly more infectious, its infectious symptoms were limited mainly to inﬂammation of the pharynx; it rarely caused more severe symptoms such as dyspnea due to inﬂammation of the lower respiratory tract (as were the cases with the Alpha and Delta variants ofthe fourth and ﬁfth waves, respectively) and very few patients became seriously ill.
The lethality rates in each wave were calculated from the number of newly conﬁrmed cases
and the number of deaths at the peak of the ﬁrst wave to the second peak of the seventh wave of78（ 66 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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Fig. 6. Transition of newly conﬁrmed cases and deaths in Japan (7-day average)

the COVID-19 epidemic in Japan and are shown in Table 6. Referring to the main variant and lineage that caused each epidemic wave, the lethality rate was remarkably high at 4.1% in the ﬁrst
wave caused by the Wuhan strain B.1 — the original strain of SARS-CoV-2. The lethality rate
was also high at 3.0% in the fourth wave, in which the Alpha variant accounted for 88% of thecases, while the lethality rate was 0.3%, one-tenth of the previous wave, in the ﬁfth wave where
the Delta variant accounted for 92% of the cases. Thereafter, the lethality rate was 0.3% in theﬁrst peak of the sixth wave, when 96% of the causative virus was the Omicron variant BA.1 lineage. Those in the second and third peaks, where the BA.2 lineage predominated, and in the ﬁrst

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79（ 67 ）and second peaks of the seventh wave, in which the BA.5 lineage predominated, were remarkably
low at 0.1%. However, even though the lethality rate was low, the number of newly conﬁrmed
cases was increasing quite remarkably — there was concern that the number of deaths per day
might exceed 300 persons. In particular, it is important to note that the cause of death during thistime was not due to severe illness caused by COVID-19 itself (such as the worsening of respiratory symptoms), but instead due to the worsening of patientsʼ preexisting disease (which wasoften the cause of general ill health, due to COVID-19 infection).
The epidemic of the seventh wave subsided rapidly, and the number of newly conﬁrmed
cases dropped to about 13,000 on the 10th of October 2022. However, the number began to increase again in late October, and by mid-November, the number of newly conﬁrmed cases exceeded 100,000 per day. This was, again, the highest number in the world, with South Korea occupying second place. This clearly indicated the arrival of the eighth wave. Although BA.5 was
Table 6. Transition of COVID-19 endemic waves in Japan

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the predominant lineage of the eighth wave, a mixture of the BA.2.75 and BQ.1 lineages accounted for about 10% of the cases — thereby complicating the picture. The number of new cases
eventually peaked at about 210,000 on the 28th of December, and was then followed by a downward trend.
In Japan, under the “Act on the Prevention of Infectious Diseases and Medical Care for Patients with Infectious Diseases” (abbreviated as “Infectious Disease Law”)34), COVID-19 has
been classiﬁed as a “new inﬂuenza etc.” disease35), which corresponds to a “Class II infectious
disease” of high severity in the classiﬁcation of infectious diseases. As a result, a wide range ofmeasures and regulations were implemented due to the situation of the high lethality rate of 4.1%
(as shown in Table 6) caused by the original Wuhan strain (B.1 lineage). These measures continued to be enforced throughout the duration of the low lethality rate of 0.1% caused by the eighthwave epidemic strain (BA.5 lineage). During this period, the exhaustion of medical institutions
put under extreme pressure and severe economic losses due to excessive societal measures andregulations were considered to be problematic.
It was argued36) that the current COVID-19 situation should be treated as a general infectious
disease equivalent to a “Class V Infectious Disease”, which is the same as a less severe seasonal
inﬂuenza (under the Infectious Disease Law). Therefore, COVID-19 will be placed into this category of “Class V Infectious Disease” as of May 8, 2023. However, the eighth wave of COVID-19
showed a big surge from mid-October of 2022 to the end of February in 2023 with a major peakof more than 280,000 new cases per day. Even at the end of March 2023, more than 5,000 new
cases per day were occurring. The entire nation must be aware that COVID-19 is an infectious
disease that is easily changeable, unpredictable, and should not be taken lightly.
vi) Interference with global COVID-19 trend survey
The prevalence of various SARS-CoV-2 variants and lineages, trends in COVID-19 cases
worldwide, have been compiled and provided in real time by Johns Hopkins University, theWHO, as well as other organizations and governments. This information is a valuable source andindicator in making infection control policy decisions. However, on the 7th of December 2022,
China (the country of origin of COVID-19, and the most populous country in the world) reversed
its previous “zero-Covid policy” and lifted strict containment regulations, including urban lockdowns and movement restrictions37). As a result, an explosive and serious outbreak of infection
occurred, with an estimated 4.8 million new cases and 25,000 deaths per day38). However, according to the oﬃcial announcement by the Chinese government, the number of newly infected people was 3,000 to 4,000 per day and the number of deaths was 1 to 5 per day, and there continued
to be a marked discrepancy from the actual reality of the situation. It was assumed that the government was concealing the reality of the situation in order to avoid criticism for its failure in infection control policy. Moreover, since the government has not accurately disclosed the actual re-June 2023

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81（ 69 ）ality of the infection situation in China itself, which diﬀered by one full order of magnitude fromthat of the rest of the worldʼs infection environment, there seems to be no longer any point in analyzing the actual situation of infection in other countries in detail. If China prides itself on being aworld power, it should know that the concealment of such a serious matter is a source of ridiculeand extreme loss of trust in the world — there is an inherent responsibility to accurately disclose
information and cooperate with the rest of the world in controlling the infection.
In response to the extraordinary number of new cases of infection in China, countries aroundthe world have naturally tightened the inspection of travelers entering their countries from China.
The Chinese government has raised objections to such measures, calling them unscientiﬁc. This
type of reasoning, however, is itself not consistent with the methodology or principles of science,
because countries around the world need to accurately evaluate and determine the variant/lineageof SARS-CoV-2 entering their borders by travelers from China and prevent the spread of suchstrains within their own countries. Therefore, rigorous testing is essential. The WHO, which had
maintained a tolerant attitude toward Chinaʼs COVID-19 countermeasures, issued a statement39)
condemning the Chinese governmentʼs underestimation of the actual situation in response to its
announcement. In response to that statement, the Chinese government changed40) the total number of deaths since the 7th of December 2022 from 38 to approximately 60,000. No matter what
the reason, it is scientiﬁcally unacceptable for any government to inﬂate the oﬃcial death toll bya factor of 1,600 in response to a condemnation statement.
In addition, a researcher at Peking University estimated that 64% of the Chinese population
had been infected with COVID-19 since the 7th of December 2022 suspension of the “zeroCovid policy”. This equates to 900 million cases. As shown in Table 4 of this review, the cumulative number of infected people worldwide up to the end of December 2022 was 665 million.
Therefore, we must now add about 1.35 times that total number of infected people to this discussion. Even more unreasonably, oﬃcials from the Chinese Center for Disease Prevention and Control (CCDC) announced that the actual number of people infected was more than 1.1 billion, or 80%of the nationʼs population, and that about 12,000 people died in a single week in January of 2023.
According to the announcement on the oﬃcial website41) of the CCDC on the 25th of January2023, the peak number of positive PCR test results was 6.94 million per day on the 22nd of December of the previous year. However, this number dropped to 15,000 on the 23rd of January
2023. The number of outpatients experiencing pyrexia also peaked at 2,867,000 per day on the
23rd of December 2022, but decreased to 63,000 on the 23rd of January 2023. Additionally, thenumber of hospitalized patients also peaked at 1,625,000 on the 5th of January 2023, but decreased to 248,000 on the 12th of January 2023. The number of severely ill patients decreased
from 128,000 on the 5th of January 2023 to 36,000 on the 23rd of January 2023. Similarly, at the
beginning of 2023, the number of hospitalized patients who died decreased from 4,273 per day on
the 4th of January to 896 per day on 23rd of January, according to the oﬃcial report. The center82（ 70 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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also reported that the outbreak strains in China were of the Omicron variant BA.5.2 and BF.7 lineages, and that no new variant or lineage had been found.
On the other hand, Airﬁnity, a UK-based health data research institute, published an estimate38) on the 17th of January 2023, that Chinaʼs COVID-19 epidemic wave had already peaked,
with 4.8 million new cases per day and an estimated maximum daily death toll of 36,000 on the
26th of January 2023. Since the 1st of December 2022, it estimates that 99.5 million people havebeen infected and 608,000 people have died. The discrepancy from the oﬃcial announcement of
the CCDC mentioned above is large, and there is debate as to which is more credible. It is notpossible to add any of the ﬁgures to the data compiled by Johns Hopkins University, and theWHO, etc., at this stage.
The accurate investigation of the global trends of COVID-19, which is considered to be thelargest pandemic in human history, was obstructed by the concealment of the actual situation in
China (where the number of infected people and deaths is expected to be the highest in theworld). Valuable and carefully compiled epidemiological data on infectious diseases — acquired
at great cost in human suﬀering and loss of life — have become a collection of meaningless records, making it impossible to discuss the actual situation of the eighth wave of the epidemic of
COVID-19 worldwide or use such information for predictive purposes in future epidemics.

2. Trends in COVID-19 Therapeutics
1) Status of COVID-19 therapeutic agentsThe status of approval of drugs for the treatment of COVID-19 in the United States, Europe,
and Japan, as well as WHO recommendations, are shown in Table 7. The United States Department of Health & Human Services (HHS) issued42) a “Public Health Emergency (PHE) Declaration” in response to the high number of new cases and deaths in the early years of the disease. In
response to this, a number of drugs have been approved as EUA drugs6) under the jurisdiction of
the FDA from early on. Japan has been following the United States in granting special approval
for emergency for EUA drugs, and in November of 2022, the MHLW granted special approval for
ensitrelvir on its own. The European Medicines Agency (EMA)43) appears to review and approve
COVID-19 drugs, based on diﬀerent criteria than the WHO and the FDA.
i) Remdesivir
With regard to remdesivir, the WHO in its COVID-19 Treatment Guidelines44) published on
the 20th of November 2020, recommended against its use for the treatment of hospitalized patients, regardless of the severity of symptoms. The reason for this is explained by the fact that in
the Solidarity Trial45) conducted by the WHO itself and in three other randomized comparison trials (RCTs), remdesivir did not provide evidence worthy of recommendation regarding lethality,

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83（ 71 ）Table 7. Approval/authorization of therapeutic drugs for COVID-19

need for ventilation, improvement in clinical symptoms, or other important clinical outcomes.
Even more to the contrary, the U.S. FDA changed the usage of remdesivir for treatment from theprevious EUA action to an oﬃcial New Drug Application (NDA)-approved item on October 22ndof the same year — after receiving data from the manufacturer, Gilead Science, Inc. As a result of
this change, remdesivir can still be manufactured, marketed, and clinically used as an approved
drug after ending the “EUA item” status in the United States. In addition, on the 21st of January2022, the drug was approved for use in non-hospitalized adult patients with mild to moderate disease, as well as pediatric patients (age 12 years and older, weighing 40 kg or more). These ap-

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provals are in addition to the already existing indication for severely hospitalized patients.
In Europe, clinical use of the investigational drug as “compassionate use” was initiated in
April of 2020, and the EMA completed its review in mid-May. It recommended approval to theEuropean Community (EC) on the 25th of June 2020. Based on the recommendation, on the 3rd ofJuly, the EC provisionally approved remdesivir for the treatment of COVID-19 pneumonia in
adults and adolescents (age 12 years and older) who are also undergoing oxygen treatment. On
November 20th of the same year, the WHO expressed its opposition to the use of remdesivir, but
the EMA issued an update to explain the validity of the approval. In January of 2022, the indication expansion for severe COVID-19 not requiring supplemental oxygen treatment, began to beconsidered. On the 8th of August, the indication was oﬃcially approved for use in adults and children (weighing 40 kg or more) in cases with or without the need for supplemental oxygen treatment. The WHO revised its guidelines on the 22nd of April 2022, changing the use of remdesivir
from “opposed” to “conditionally recommended”.
In Japan, a special approval for emergency was granted on the 7th of May 2020, for administration to patients with moderate disease or worse, requiring oxygen administration. On the 7th ofJanuary 2021, administration to patients with moderate disease who do not require oxygen administration, was also approved. Due to the limited supply worldwide, the MHLW purchased the
product and distributed it to medical institutions. On August 12th of the same year, the productwas covered by insurance and has been in general distribution since the 18th of October. The dosage for adults with pneumonia caused by SARS-CoV-2 (and children weighing 40 kg or more), is
200 mg on the ﬁrst day, followed by 100 mg on the second and subsequent days. For children
weighing at least 3.5 kg and less than 40 kg, the dosage is 5 mg/kg on the ﬁrst day, then 2.5 mg/kg
on and after the second day, given once daily by intravenous infusion. It should be noted that, thetotal duration of administration should not exceed 10 days. Remdesivir was listed on the National
Health Insurance (NHI) drug price list on the 5th of August 2021; a bottle containing 100 mg is
priced at 63,342 yen. Since the usual treatment is 5 days, one treatment course per patient will administer a total dose of 600 mg, resulting in drug costs of approximately 380,000 yen (equivalent
to $3,472 at the exchange rate on the same day).
ii) Molnupiravir
Molnupiravir46), developed by Merck & Co., Inc. of the United States, is a prodrug used as
an anti-COVID-19 drug. It has oral absorption that gives rise to β-D-N4-hydroxycytidine, which
is a nucleoside that inhibits RNA polymerase of SARS-CoV-2. The EUA application was submitted to the U.S. FDA on the 11th of October 2021. The application is based on the results of an interim analysis of a global phase-III study (NCT04575597) conducted in 1,550 adult patients witha conﬁrmed diagnosis of COVID-19 within 5 days of onset of illness, with mild to moderate disease, who were not hospitalized. The results of the interim analysis of 775 patients were pre-June 2023

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85（ 73 ）sented on the 5th of August 2021. It showed that patients treated with molnupiravir had an approximately 50% reduction in risk of hospitalization and death compared to those treated withplacebo. The interim analysis of the trial conducted at 78 sites in 15 countries, including threesites in Japan, showed that the primary endpoint of hospitalization plus death at 29 days in themolnupiravir group of 7.3% (28 cases/385 cases) was signiﬁcantly (p ＝ 0.0012) lower compared
to 14.1% (53 cases/377 cases) in the placebo group. Adverse events were observed in 40% of patients in the placebo group and 35% in the molnupiravir group.
Based on these results, the Independent Data Monitoring Committee recommended early termination of the trial. Merck & Co., Inc. announced that it ﬁled an EUA application at this stage.
However, the ﬁnal results of the trial, which were submitted to the FDA on the 30th of November
2021, showed that the eﬃcacy rate of the primary endpoint, which was estimated at 50% in theinterim analysis, had dropped to 30%. This result negated the original “game-changer” expectation, and the Councilʼs vote on the EUA special measure was narrowly approved by a vote of 13
to 10. The EUA approval date was set for December 23rd of that same year, one day after the approval of the nirmatrelvir/ritonavir combination (which was ﬁled late by Pﬁzer). The National Institutes of Health (NIH), in its COVID-19 treatment guidelines revised47) on the 24th of February2022, states that the drug is expected to be eﬀective against the Omicron variant but recommends
that it be used only when other treatments are not appropriate, given the low eﬃcacy of the drug.
The EUA special measure for molnupiravir in the United States has been harshly criticizedas an example of the collapse of the worldʼs long-established system for reviewing new drug applications. The EUA application for molnupiravir was ﬁled on the 11th of October 2021, but in thepress release48) of the 9th of June 2022 from the HHS, two months before the interim analysis of
the clinical trial used in the application conducted on August 5th, it stated that the HHS had madean advance reservation to purchase 1.7 million case doses of the drug for $1.2 billion based on
the assumption that the FDA grants EUA or routine approval for the drug. This press release by
the HHS, which is the agency with power over the FDA, puts strong pressure on the FDAʼs review of the drug by making such an announcement before the process is completed. Hence, thepress release was criticized for inducing bias into the review process. This is an example of how
scientiﬁc review for drug approval can be subverted for political purposes.
Even though it has been announced that molnupiravir is approved or licensed for use in 30
countries around the world (including Japan, ten Asian countries such as India, Thailand, and thePhilippines, and South Africa), it is interesting to note the diﬀerent responses in diﬀerent countries. In Europe, the EMA has been collecting information on molnupiravir since the 25th of October 2021. It issued a warning on the 19th of November for use in the EU as an unapproved drug,
and received an application for approval on November 23rd. Despite new data being received andreviewed on the 14th of December 2021, the drug is still unapproved as of the 13th of March 2023.
Meanwhile, in the United Kingdom, regulators reportedly granted accelerated approval for the86（ 74 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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drug on the 4th of November 2021. On the other hand, according to a Reuters report on the 24th ofDecember, the French government cancelled an order for molnupiravir after discovering that thedrugʼs clinical eﬃcacy was lower than originally reported.
In Japan, Prime Minister Kishida announced on the 12th of November 2021, that a total of
1.6 million case doses were pre-ordered at a cost of around 137 billion yen (equivalent to $1.2
billion), with each case costing around 85,000 yen (equivalent to $74500). With the aim of special
approval for emergency at a December 24th Council meeting (the product was already imported
in anticipation of its clinical use starting on December 27th), the Council approved the drug asscheduled. The MHLW announced the special approval for emergency purposes on the same day.
All of these measures were exceptional, including the importation of the drug product while theapproval review was underway, and this was a case in which all the conventional principles andrules for the approval review of new drugs in Japan had been violated. This was a response to apandemic in which a state of emergency was declared by the government, and it is believed thatthe government decided that it was not necessary to comply with the conventional principles andrules in terms of national crisis management in order to protect the lives of the people.
The approved molnupiravir 200 mg capsule formulation is to be administered orally at a doseof 4 capsules twice daily, for 5 days, to patients 18 years of age or older who have risk factors forsevere infection caused by SARS-CoV-2 and who are otherwise considered to require administration of the drug. The drug is not indicated for use in pregnant women and children under 18 yearsof age. In Japan, MSD K.K. is the manufacturer and distributor, and Kyorin Pharmaceutical Co.,
Ltd. is the promotional partner. However, COVID-19 is designated as a Class II infectious disease under the Infectious Disease Law, and the full cost of its treatment is borne by the nationaltreasury. As of the 15th of January 2022, molnupiravir (product name “Lagevrio Capsules
200 mg”) is distributed nationwide by the MHLW through approximately 13,000 medical institutions and 12,000 pharmacies registered as distribution sites.
According to the published data49) of the MHLW, the number of cases in which governmentsecured molnupiravir was administered, from the start of clinical administration on the 27th ofDecember 2021 to the 15th of September 2022, reached 619,621 cases. The capsules were listed
in the NHI Drug Price Standard on the 18th of August 2022, and since the capsules became available for general distribution to medical institutions and pharmacies from the 16th of September,the distribution of the government-secured portion purchased through the registration center was
terminated. The daily drug price for an adult dose (800 mg twice daily) is 18,862.4 yen, or 94,312
yen (equivalent to $69747) for a 5-day treatment. The remaining capsules purchased from the government treasury are not allowed to be transferred to other institutions, or disposed of.
Although review regarding the approval of molnupiravir had been underway since the 10th ofNovember, Korea announced that molnupiravir for 242,000 patients had been pre-ordered on the27th of December 2021. The EUA was issued on the 23rd of March 2022, in response to the emer-

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87（ 75 ）gency situation of the dramatic increase in cases of the Omicron variant. Australia and New Zealand reportedly purchased molnupiravir for 300,000 and 60,000 case doses, respectively. In all ofthese countries, the existing drug approval system is in a state of collapse, as they are deviatingfrom the normal approval system and making advance reservations to secure their own portion
before others. Actions seem to be based on political decisions, without waiting for proper or adequate evaluation of eﬃcacy and safety by their own regulatory authorities. In the Philippines, theﬁrst EUA for molnupiravir was issued to Faberco Life Sciences Inc. on the 22nd of December
2021, followed by EUAs to multiple additional companies — one company each day, on January
14th, 24th, and 28th, and two more companies on the 31st of January 2022.
Merck & Co., Inc. announced, in October of 2021, a non-exclusive patent license agreement
for pharmaceutical companies wishing to manufacture generic versions of molnupiravir. This was
subject to emergency approval by local regulatory authorities, with the aim of accelerating the
supply of molnupiravir for low- to middle-income countries around the world. Merck & Co., Inc.
has licensed the rights, through the Medicines Patent Pool (MPP), to ﬁve companies such as Cipa
Limited, Dr. Reddyʼs Laboratory, Emcure Pharmaceuticals, Hetero Healthcare Labs, and Sun
Pharmaceutical Industries. In India, three phase-III clinical trials (involving 1,200 patients) were
initiated in May and June of the same year, using domestically produced molnupiravir for
COVID-19. In all three trials, the control group was treated with ivermectin, 12 mg for 5 consecutive days, conﬁrming that ivermectin is the standard therapy for COVID-19 in India.
In India, molnupiravir was approved by EUA in December of 2021, but the domestic situation has been complicated. For example, Biophore India, located in New Delhi, announced on the
22nd of January 2022, that it had obtained a license from the MPP for the manufacture of active
pharmaceutical ingredients (API) for manufacturing and would supply API not only to India but
also to other countries. Currently, more than ten companies, including Optimus Pharma, Zenith,
Natco Pharma, Azista Industries, etc., apart from the ﬁve companies under contract with Merck &Co., Inc., are manufacturing molnupiravir capsules in India and more than 500 products are being
sold by dozens of pharmaceutical companies. A box of 40 capsules of 200 mg oral capsule ispriced at 2,400 rupees (about $2900) and can be purchased and taken without a prescription. As
mentioned above, the price for one case in Japan (40 capsules of 200 mg oral capsule) is $69747,
which is about 24 times the price in India.
Meanwhile, the National Task Force of the Indian Council of Medical Research (ICMR) for
COVID-19, which prepares guidelines for COVID-19 treatment in India, issued a statement on
the 13th of January 2022, opposing the inclusion of molnupiravir in the guidelines due to safetyconcerns. The guidelines50) aﬀected the entire country, making it likely that molnupiravir would
no longer be used in India. However, the situation soon changed, and in the Covid Guidelines for
India dated February 16, 2022, it was indicated that “usage of molnupiravir in mild to moderate
COVID-19 patients without risk factors is strongly opposed, but that it is conditionally recom-88（ 76 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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mended as an option only for mild to moderate COVID-19 patients with risk factors (especiallyobesity) that would make them severely ill and who are vaccinated and treated at home.”
According to an announcement on the 3rd of February of 2022 from Merck & Co., Inc., itplanned to ship more than 4 million case doses of molnupiravir to more than 25 countries worldwide, including 3.1 million case doses to the U. S. Government (HHS reserved an additional 1.4
million case doses on the 9th of November 2021, for $1 billion) within a short time frame. The
company had also announced that it would supply 3 million case doses through UNICEF to 100
low- to middle-income countries around the world in the ﬁrst half of 2022, and that it planned to
manufacture 30 million case doses of molnupiravir by the end of 2022.
In its revised guideline for the treatment of COVID-19 issued on the 3rd of March 2022, theWHO included51) a chapter on molnupiravir, stating that it should only be recommended for thetreatment of non-severe COVID-19 patients (excluding pregnant and lactating women, and children) who are at signiﬁcantly higher risk of hospitalization. On the 14th of the same month, theWHO also announced that it would conduct a safety study in low- and middle-income countries
to investigate the safety of molnupiravir in the treatment of mild-to-moderate COVID-19.
iii) Nirmatrelvir/Ritonavir Combination (Paxlovid®)
Nirmatrelvir [investigational code; PF-07321332 (Pﬁzer)]52) is a ﬂuorinated peptide analog that
inhibits the 3CL protease (3CLPRO), known as the main protease, which cleaves between the glutamine and the next amino acid residues of the precursor polyprotein formed by translation from thegenomic RNA of SARS-CoV-2 to generate multiple functional proteins. The absence of functional
proteins inhibits the replication of SARS-CoV-2. To prevent degradation of nirmatrelvir by CYP3A
in the body, ritonavir, which is included in existing anti-HIV drugs, is taken at the same time.
The drug is indicated for the treatment of SARS-CoV-2 infection. The dosage is 300 mg nirmatrelvir and 100 mg ritonavir twice daily for 5 days for adults, and children (12 years or older,weighing 40 kg or more), who have risk factors for severe infection and otherwise qualify fortreatment with this drug. A patient formulation, Paxlovid Pack® (Paxlovid), consisting of two
nirmatrelvir 150 mg tablets and one ritonavir 100 mg tablet, is available.
In the United States, an interim analysis (1,379 of 2,246 targeted patients) of a phase-III trial(NCT04960202) conducted since the 13th of July 2021, showed an 89% reduction (p＜0.0001) in
hospitalization or death in patients with mild to moderate disease within three days of onset. The
results were announced on the 5th of November 2021. Based on these results, an EUA application
was ﬁled with the FDA on November 17th, and the FDA issued53) the EUA approval on December
22nd, one day earlier than the previously ﬁled application for molnupiravir. In its December 30th
revision of the guideline54), the NIH noted that the combination drug is expected to be eﬀective incases of the Omicron variant. It was strongly recommended that ritonavir, which inhibits CYP3A,
be used cautiously due to interactions with a wide variety of drugs. On November 18th, the day

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89（ 77 ）after the EUA application was ﬁled, in the United States, the Biden administration announced that
it would purchase 10 million case doses of Paxlovid, for $5.3 billion, in the same manner as formolnupiravir.
The European EMA received an Application for Marketing Authorization (AMA) with certain
conditions on the 10th of January 2022. It recommended marketing authorization to the EC on January 27th, and issued a marketing authorization valid throughout the EU on January 28th. The United
Kingdom Medicines Agency approved the use of Paxlovid on the 1st of January 2022, and stockpiling has reportedly begun. A preliminary order for 500,000 case doses has been placed by Australia.
In South Korea, the Ministry of Food and Drug Safety granted emergency approval on the same day
after a rapid 5-day review, but fearing criticism announced on the 27th of December 2021 that it had
reserved 362,000 case doses of Paxlovid in advance. As outlined above, the securing of Paxlovid
has become an important issue for administrations in many countries around the world. Also inJapan, Prime Minister Kishida was working hard to secure the drug, urgently reporting that 2 million case doses had been reserved in advance for national treasury purchase. On the 14th of January2022, a special approval application was submitted. Paxlovid was then granted a special approval
for emergency for the treatment of COVID-19 on the 10th of February 2022.
The Paxlovid packages of the governmentʼs treasury purchase were distributed to medical
institutions nationwide from the 28th of February, and after the 22nd of April, the MHLWʼs Novel
Coronavirus Infectious Disease Control Headquarters distributed the drug, through registration
centers, to medical institutions and pharmacies. The drug was prescribed for the treatment of patients in both inpatient and outpatient settings (including at home care). In particular, since there
are many contraindications and precautions against concomitant use of this drug, it is necessary
to check all medications being taken by each patient at the time of prescription. According to the
MHLWʼs published data49), the number of cases in which Paxlovid was administered, from thedate of its special approval to the 15th of March 2023, reached 101,464. Then, in an announcement dated the 20th of March 2023, it was notiﬁed55) that the government-secured portion (government-purchased packages) would not be allocated to medical institutions and pharmacies. The
reason was because the drug was placed on the NHI drug price list and distributed to the generalpublic from the 22nd of March.
Nirmatrelvir, discovered from peptidomimetics drug exploratory research, is an inhibitor ofPRO
which excises multiple active proteins from the polyprotein precursors produced by
3CL
SARS-CoV-2 in cells after infection. The origin of drug exploratory research in this area can betraced back to the structural analysis study56) of 3CLPRO of SARS-CoV in 2003. In a study using
crystallized 3CLPRO of SARS-CoV-2, existing GC373 and its prodrug GC376 are irreversibly
bound57) to the target cysteine residue at the active center of a protease and inhibitory activity results. Nirmatrelvir is an analog of GC373, in which the aldehyde group covalently bound to thecysteine residue of 3CLPRO is replaced by a nitrile group, and shows excellent inhibitory activity.

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Nirmatrelvir is metabolized by CYP3A4 in vivo after oral administration, but its metabolism isinhibited by ritonavir taken at the same time (nirmatrelvir has been conﬁrmed to exist in its active
form in plasma). Although ritonavir has no anti-SARS-CoV-2 activity, its inhibition of CYP3A4
may increase blood levels of various drugs. There are dozens of drugs that are thereby contraindicated or require precautionary measures in order to use. Therefore, when administering ritonavir
to patients with underlying medical conditions, it is necessary to take additional measures such as
discontinuing routine daily medications that patients require for other underlying conditions.
iv) Ensitrelvir
Shionogi & Co., Ltd. started a phase-I clinical trial58) of S-217622, an inhibitor of 3CLPRO
developed in collaboration with the International Institute for Zoonosis Control of Hokkaido University, on the 22nd of July 2021, and a phase- II/III trial59) on the 27th of September. The study
uses a placebo as a control and is designed to evaluate eﬃcacy and safety for oral administrationof S-217622, once daily for 5 days, in patients with mild or asymptomatic COVID-19 infection.
The antiviral activity of S-217622 against the Omicron variant has been under investigation since
the 8th of December 2021. Results were announced on the 20th of December, showing that it has
excellent activity to both Omicron and similar existing variants.
On the 7th of February 2022, Shionogi & Co., Ltd. reported60) the completion of the analysisof the phase-IIa portion (comprised of 69 target cases) of the ongoing phase-II/III clinical trial of
S-217622. S-217622 has CYP3A4 inhibitory activity, and unlike nirmatrelvir, which is also a
3CLPRO inhibitor, it does not need to be combined with ritonavir (which inhibits CYP3A4) and isadministered orally as a single drug. After three doses (i.e., on day 4), viral titers were 60–80%
lower than in the placebo group. As for the eﬀect on clinical symptoms, the investigators reported
that COVID-19 treatment showed a trend toward improvement in clinical symptoms typicallycharacteristic of COVID-19. No cases of severe disease requiring hospitalization were reported,
nor any serious or adverse events requiring discontinuation of the drug.
On the 25th of February 2022, Shionogi & Co., Ltd. submitted61) an application to the
MHLW for manufacturing and marketing approval of S-217622 in Japan. The company had initially hoped to apply under the “Conditional Early Approval System”. However, on the 20th ofMay, the “Act on Securing Quality, Eﬃcacy and Safety of Products Including Pharmaceuticals
and Medical Devices (Pharmaceutical Aﬀairs Law)”62) was revised and this revision created a
new “Emergency Approval System”. The company requested urgent approval under this new system. The drug has been given the generic name ensitrelvir, and its fumarate tablet was named,
Xocova Tablets 125 mg. The urgent approval request was discussed by the Second Committee on
New Drugs held on the 22nd of June. Discussions for approval or disapproval were held at a joint
meeting of the Committee and the Pharmaceutical Aﬀairs Department of the Pharmaceutical Affairs and Food Sanitation Council held on the 20th of July. However, the review by the Pharma-

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91（ 79 ）ceuticals and Medical Devices Agency (PMDA) concluded that, although a trend toward a decrease in viral load after drug administration was observed, eﬃcacy for the proposed indicationof the drug could not be veriﬁed. It was decided that they would continue deliberations following
the submission of data from the phase-III portion of the trial, which was still in progress at thattime.
Despite the establishment of the “Emergency Approval System”, the drug was not approvedat this joint meeting. Discussions were based on conventional deliberation policy by conventional
committee members, and it was determined that even though reductions in viral load required foran original antiviral drug were observed, the eﬃcacy results obtained were not based on conventional clinical evaluation methods. The “Emergency Approval” application was rejected. Thereafter, the Japanese Association for Infectious Diseases and the Japanese Society of Chemotherapy
submitted a proposal63) under the names of the presidents of both societies, to the Minister of
Health, Labour and Welfare on the 2nd of September. In that proposal, while Japan was under thesevere infection environment of the seventh wave of COVID-19, they requested urgent approvalof oral drug formulations that could be used for mild cases.
The primary eﬃcacy endpoint of the phase-III clinical trial of ensitrelvir was the time to recovery of ﬁve symptoms: (1) malaise or fatigue, (2) feverishness or pyrexia, (3) runny or stuﬀynose, (4) sore throat, and (5) cough. The preliminary results of the study demonstrated that theexperimental group showed a time reduction of overall symptoms resulting in 167.9 hours of experienced symptoms, compared to 192.2 hours in the placebo group. The PMDA, which conducted the review, concluded that there was suﬃcient data to infer that the drug was eﬀective.
The results were once again submitted to a joint meeting of the Second Committee on New Drugs
and the Pharmaceutical Aﬀairs Department of the Pharmaceutical Aﬀairs and Food Sanitation
Council, which was held on the 22nd of November 2022, and emergency approval64) for the drug
was granted.
Ensitrelvir is the ﬁrst oral drug that can be used by patients with mild disease and can also betaken by patients who are not at risk for severe disease. The Japanese government had concluded
an agreement with Shionogi & Co., Ltd., to purchase one million case doses of the drug if it is approved. Following the urgent approval of the drug, the MHLWʼs Novel Coronavirus Infectious
Disease Control Headquarters issued a notice65) on the distribution of the drug to medical institutions and pharmacies. The drug is the property of the MHLW, and both in-hospital and out-ofhospital prescriptions are registered at the Xocova Registration Center, which has been established on behalf of the MHLW. The distribution of the drug will only be made to medical
institutions and pharmacies that have a “record of prescribing Paxlovid”, registered with the “Xocova Registration Center”, established by the Ministry. After the Cabinet meeting on the 13th ofDecember 2022, the Minister of Health, Labor and Welfare announced that a contract for the purchase of an additional 1 million case doses of the drug had been made, and a stockpile of 2 mil-

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lion case doses in Japan is said to be ready. According to the MHLWʼs press release49), the drug
has been administered to 37,198 patients through 3,459 hospitals and 9,159 pharmacies nationwide from the time of its approval, up to the 15th of March 2023. According to Shionogiʼs press
release66), the drug was listed in the NHI Drug Price Standard on March 15th and began general
distribution on March 31st, at a price of 7,407.4 yen per 125 mg tablet. The cost of the drug willbe ¥51,851.8 (equivalent to $38869 at the exchange rate on the same day) per course of treatment.
However, since the cost of the drug will, for the time being, be borne by the national treasury, individuals will not have to pay for it.
On the other hand, Shionogi & Co., Ltd. has started the international development of
S-217622, and announced that it has been included in the ACTIV-2d program (SCORPIO-HR
study; NCT05305547) promoted67) by the U.S. National Institutes of Health. Based on the resultsof a phase-II/III study conducted in Japan, the U.S. FDA has approved the study. The study will
evaluate the eﬃcacy of a 5-day course of treatment to prevent deterioration in SARS-CoV-2 positive patients with at least one risk factor, starting within 5 days of onset of disease. Approximately 1,700 patients from Europe, North America, South America, Africa, and Asia are expected
to be enrolled in the randomized, double-blinded, placebo-controlled study, with a 2 : 1 ratio of
patients receiving S-217622 to those receiving a placebo. The company has also announced that it
has initiated an eﬃcacy trial for prevention of the disease in family members living with COVID19 patients, and plans to collect approximately 2,000 patients in Japan and the United States bySeptember of 2023.
v) Monoclonal antibody drugs and others
As a treatment for COVID-19, a neutralizing antibody was developed that speciﬁcally binds
to the spike protein on the surface of the causative SARS-CoV-2 virus, blocking viral entry into
host cells. Several pharmaceutical companies have produced monoclonal antibodies and conducted clinical trials using established monoclonal antibody production methods.
An EUA application, for bamlanivimab (the ﬁrst monoclonal antibody drug approved by theFDA) was submitted by the Eli Lilly & Co. on the 6th of October 2020. The results used for theapproval process were from the interim analysis of a comparative study68) involving a phase-II/III
trial (NCT04427501) that was conducted from the 17th of June 2020. The comparative study analyzed two study arms of bamlanivimab (one alone, and one in combination with etesevimab) inaddition to a placebo-controlled arm. The EUA was granted for bamlanivimab monotherapy on
the 9th of November 2020. However, as mentioned above, multiple variants of COVID-19 havebeen attributed to COVID-19 in the United States. Therefore, a single component of bamlanivimab alone is no longer suﬃcient for therapy. As a result, the FDA issued an EUA on the 9th ofFebruary 2021 for combination therapy using bamlanivimab and etesevimab. The EUA for single
use bamlanivimab was withdrawn on the 16th of April 2021.

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93（ 81 ）The combination regimen was speciﬁed to consist of bamlanivimab 700 mg and etesevimab
1,400 mg, administered intravenously at the same time. Its use in adults (and children weighing
40 kg or more) was also supposed to prevent the onset of disease after exposure to the SARSCoV-2 virus. However, the NIH issued a recommendation against the use of this combination
therapy on the 23rd of December 2021 in its revised guidelines69). The basis for this decision was
the Omicron variantʼs mutated spike protein, which renders the combination therapy ineﬀective.
The FDA suspended the EUA on the 24th of January 2022.
The EMA had been reviewing the application for the combination therapy of bamlanivimab
and etesevimab (to be used for prevention of disease exacerbation in high-risk COVID-19 patients not requiring supplemental oxygen) since March of 2021. However, due to quality control
issues and projected market size issues after launch, Eli Lilly & Co. abandoned development of
the project in Europe on the 2nd of November 2021, by withdrawing its application.
The second monoclonal antibody is casirivimab/imdevimab70), developed by Regeneron
Pharmaceuticals Inc., of the United States. Its clinical trial was initiated on the 11th of June 2020,
and an application for EUA was ﬁled with the FDA on the 8th of October, using interim analysis
results. Its EUA was issued on the 21st of November. In Europe, the marketing authorization application was submitted on the 1st of February 2021. After review by the EMA, a recommendation for authorization was issued to the EC on the 11th of November, and marketing authorization
was granted the following day, on November 12th.
In Japan, the drug was referred to as the “cocktail regimen”, and evaluation of safety, tolerability, and pharmacokinetics in Japanese adults was conducted from March of 2021. An application for special approval for emergency was ﬁled on the 29th of June, and special approval was
granted on the 19th of July. The approved dosage is 600 mg of each drug, as a single intravenous
infusion in combination, for mild to moderate patients (adults, and children aged 12 years orolder who weigh more than 40 kg) who do not require supplemental oxygen, but who have risk
factors for worsening. After special approval, the drug was provided by Chugai PharmaceuticalCo., Ltd. to the MHLW and distributed to eligible medical institutions nationwide. Distribution
was through the “Ronapreve Registration Center”, under the authority of the MHLW, for use in
the treatment of eligible patients as mentioned above. Amid the demand for expansion of the
medical care delivery system to cope with the spread of infection in Japan, an application was
ﬁled on the 11th of October 2021. This application was based on the results of the COV-2069 andCOV-20145 studies conducted overseas, and was for pharmaceutical manufacturing and marketing approval intended for “suppression of onset of SARS CoV-2 infection” and a “single subcutaneous injection”. Special approval for emergency was granted for a new “indication” and “dosage
and administration” in November of 2021.
However, the FDA suspended the EUA on the 24th of January 2022, because the NIH guidelines recommended against the use of this combination therapy. In Japan, the MHLWʼs “Guide-94（ 82 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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line for the Diagnosis and Treatment of New-type Coronavirus Infections (COVID-19) ”, Version
7.0 (issued on February 28, 2022)71), in the chapter “Neutralizing antibody drugs” in the drug
therapy section, states, “There are reports that this drug has reduced neutralizing activity against
Omicron variants, and it is not recommended when it is clear that patients are infected with thisvariant or when there is a high probability that they are infected with this variant”. In the public
notice of the MHLW issued on the 25th of August 2022, however, this drug is listed ﬁrst among
the eight drugs recommended to be used against COVID-19, as speciﬁed by the MHLW andbased on the provisions of the “Infectious Diseases Law”. No note is made regarding the decreased neutralizing activity of the drug. There is a clear discrepancy between the MHLW guidance and the notiﬁcation, and there should be concern about the lack of stringency in the handlingof drugs with reduced eﬃcacy.
The third, sotrovimab72), is a spike protein neutralizing antibody created by GSK PLC of theUnited Kingdom, based on antibodies obtained from a patient infected with the SARS (severe
acute respiratory syndrome) in 2003. It recognizes a highly conserved antigenic determinant (epitope) on the SARS-related coronavirus. The epitope does not overlap with the mutated sites of
the Omicron variant; therefore, the neutralizing antibody activity is not considered to be reduced.
The European EMA initiated its review on the 7th of May 2021, and after a council meeting on
the 18th of November that same year, it was recommended that a marketing authorization be issued on December 16th. The EC permitted marketing authorization of the drug on the 17th of December 2021. The U.S. FDA issued an EUA on May 26th of that same year, and the EUA was revised on December 22nd to include an indication for the Omicron variant. In Japan, a special
approval for emergency was issued on the 27th of September 2021, for a single 500 mg intravenous infusion. This infusion is indicated for mild to moderate adult patients and children (aged 12
years and older weighing 40 kg or more) with risk factors for deterioration and not requiring oxygen administration.
In the United States, sotrovimab had been used under an EUA based on the NIH guidelines
revised on the 24th of January 2022, which stated that the neutralizing activity of sotrovimab
against Omicron variant was not reduced. However, the FDA suspended the EUA for sotrovimab
on the 23rd of February, because the neutralizing activity of sotrovimab was found to be decreased
due to the change of the main epidemic strain in the United States to the BA.2 lineage. In Japan,
sotrovimab was also listed as the third monoclonal antibody drug designated by the MHLW; thepublic notice was issued on the 25th of August 2022, and no further action has since been taken.
The fourth neutralizing antibody drug is tixagevimab/cilgavimab73), developed by AstraZeneca PLC of the United Kingdom. In the United States, the FDA issued an EUA for its use on the20th of December 2021. During the clinical development of this drug, eﬃcacy was demonstrated
in a placebo-controlled infection prevention study in more than 5,000 adults. These adults wereunable to receive any COVID-19 vaccines, due to allergic reactions, and the December 20th EUA

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95（ 83 ）was the ﬁrst approval that was given, indicated for SARS-CoV-2 post-exposure prevention. In
Europe, rolling review by the EMA began on the 14th of October 2021. The EMA eventually recommended marketing authorization on the 24th of March 2022, after successive reviews of quality, safety, clinical pharmacology, clinical trial results, and other well-developed data. In Japan,
based on the results of a global phase-III study and a domestic phase-I study, an application for
special approval for emergency was ﬁled on the 9th of June 2022. On August 29th of that same
year, special approval for tixagevimab/cilgavimab was granted74) for the treatment of COVID-19
and for the prevention of SARS-CoV-2 onset in individuals prior to any exposure to the virus.
At the time of the FDAʼs revision of the EUA on the 29th of June 2022, there was no decrease in the neutralizing antibody activity of tixagevimab/cilgavimab against the Omicron variant BA.2, BA.2.12.1, BA.4, and BA.5 lineages; therefore, the drug continued in clinical use.
However, on the 6th of January 2023, with an increase of the XBB.1.5 lineage in the UnitedStates, its use became problematic as the neutralizing activity of the drug against the lineage decreased. On the 26th of January 2023, the FDA issued a notice75) that, as a result of its investigation, it would suspend the EUA-based use of the drug until the number of viruses non-susceptible
to the drug was reduced to 90% or less.
The U.S. FDA issued an EUA on the 11th of February 2022 for bebtelovimab76) of Eli Lilly& Co., as the ﬁfth neutralizing antibody drug. No marketing authorization application to the European EMA, nor special approval for emergency to the Japanese MHLW has been submitted todate. Although the drug initially showed no decrease in neutralizing antibody activity against the
Omicron variants, as the prevalent strains in the United States changed and the proportion of the
BQ.1 and BQ.1.1 lineages increased, the neutralizing activity eventually decreased, and its therapeutic eﬀect became less promising. Accordingly, in an update77) dated November 30th, the FDA
notiﬁed that, while the EUA for this drug will continue, it will not permit its use. As a result, theuse of all monoclonal antibody drugs against COVID-19 has been suspended in the United States.
Use may be permitted again, when the susceptibility of future outbreak strains to neutralizing antibodies is restored.
While the EMA initiated a sequential review of the marketing authorization of tixagevimab/
cilgavimab on the 14th of October 2021, the Council began deliberation on regdanvimab. The latter was applied for by Celltrion Inc. of Korea on October 4th and had been under review since the24th of February 2021. The recommendation for marketing authorization of regdanvimab to theEC was made on November 11th and was granted on November the 12th, 2021. No EUA application to the U.S. FDA, nor special approval for emergency to the Japanese MHLW, has been ﬁled
for regdanvimab to date.
The European EMA has issued78) a warning from the Emergency Working Group on the 9thof December 2022, stating that four monoclonal antibodies (casirivimab/imdevimab, regdanvimab, sotrovimab, tixagevimab/cilgavimab) may be ineﬀective in the current environment when

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used to treat COVID-19 caused by various lineages (BA.4.6, BA.2.75.2, XBB, BQ.1, BQ.1.1,
etc.) of the Omicron variant which spread throughout the EU. Instead, it recommended the use ofantiviral agents (nirmatrelvir/ritonavir and remdesivir).
Tocilizumab is a monoclonal antibody against the interleukin-6 (IL-6) receptor and is already approved for the treatment of rheumatoid arthritis in the United States, Europe, and Japan.
Oﬀ-label use of this drug has been attempted since early on, because it has been recognized that
although the pathogenesis of COVID-19 begins as a viral infection, as the disease progresses, theimmune response becomes abnormally enhanced, resulting in cytokine storm-like symptoms. The
U.S. FDA issued79) an EUA on the 24th of June 2021 and approved (NDA) the drug, for the treatment of adult inpatients, on the 21st of December 2022. In Japan, an additional indication for thetreatment of pneumonia caused by SARS-CoV-2, was approved on the 21st of January 2022. The
drug is to be administered to hospitalized patients requiring oxygen administration, ventilator
management, or external membrane ventilation (ECMO) induction. The dosage and administration of tocilizumab (recombinant humanized form) is 8 mg/kg, once, intravenously, in combination with corticosteroids in adults. If symptoms do not improve, an additional 8 mg/kg dose of tocilizumab can be administered at least 8 hours after the initial dose.
Sarilumab, a monoclonal antibody against the IL-6 receptor, similar to tocilizumab, is usedclinically in Japan for the treatment of rheumatoid arthritis. However, following the approval of
the intravenous formulation of tocilizumab, it may now be used oﬀ-label for the treatment ofpneumonia caused by SARS-CoV-2. Since only the subcutaneous formulation of sarilumab iscommercially available, and the subcutaneous formulation of tocilizumab is not approved for thetreatment of pneumonia caused by SARS-CoV-2, oﬀ-label use of the subcutaneous formulationof sarilumab is not recommended. However, the WHO does not distinguish between tocilizumab
and sarilumab, and strongly recommends80) both drugs as “IL-6 receptor blockers” for the treatment of severe COVID-19. This diﬀers from the treatment principles of the U.S. FDA, the European EMA, and the Japanese MHLW.
Baricitinib is a Janus kinase (JAK) inhibitor developed by Eli Lilly & Co. in the UnitedStates, for the treatment of rheumatoid arthritis. It has been in clinical use in Japan since September of 2017; its anti-inﬂammatory action is expected to reduce the hyperinﬂammatory state andcytokine storm associated with COVID-19. On the 19th of November 2020, the U.S. FDA
added81) an indication for the treatment of pneumonia caused by SARS-CoV-2 (but only in patients requiring oxygen) in combination with remdesivir. On the 28th of July 2021, the U.S. FDA
approved baricitinib alone (not in combination with remdesivir), for the treatment of pneumonia
caused by SARS-CoV-2 (only in patients requiring oxygen). In Japan, in April of 2021, the additional indication of this same drug for pneumonia caused by SARS-CoV-2 was also formally approved. The dosage and administration instructions stipulate that 4 mg should be administeredorally, once daily, to adults, in combination with remdesivir, for a total duration of up to 14 days.

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97（ 85 ）The European EMA initiated its evaluation of baricitinib, for the indication of hospitalized patients requiring oxygen on the 29th of April 2021, but the application was withdrawn on the 7th ofDecember 2022.
vi) Termination of the Declaration of State of Emergency (PHE) in the United States
The HHS declared the COVID-19 outbreak a “public health emergency (PHE)” under the
Public Health Service Act on the 27th of January 2020, but announced82) in a notice dated the 2ndof March 2023 that the declaration would end on the 11th of May 2023. Drugs and vaccines for
COVID-19 are EUA items that the FDA has designated in response to the PHE (with the exception of remdesivir, which has been moved from the EUA category to a normally approved, or
NDA, item), but the rationale for their authorized use will be lost after the declaration formallyends.
The FDA has established and published83) in the Federal Register three categories for the 68
guidelines issued under the Declaration: 22 will be discontinued upon termination of the Declaration, another 22 will remain in eﬀect for 180 days after the termination and then discontinued,
and an additional 24 will be considered for revision for continuation (another 180-day period). By
including the guideline on EUA-measure items in the third category mentioned above, COVID19 drugs and vaccines can remain available for 6 months and thereafter — under new amended
provisions — continue to be used.
In Japan, a number of drugs have been granted special approval for emergency based on
EUA actions of the U.S. FDA. The drugs include three antiviral drugs (remdesivir, molnupiravir,
nirmatrelvir/ritonavir) and three monoclonal antibody drugs (casirivimab/imdevimab, sotrovimab, Tixagevimab/cilgavimab). All of these drugs will require a formal review on the 8th ofNovember 2023 (which is 180 days from May 11, 2023) if the EUA action is not renewed.
2) Clinical development of new COVID-19 therapeutic agents
While various studies are being conducted worldwide on the eﬃcacy and safety of existing
COVID-19 drugs, clinical developments of new drugs are underway, and vigorous reviews84–87)
of their developmental status have been published.
Through the authorsʼ search, there exist 66 compounds in the pipeline, which are listed inTable 8. They are classiﬁed by mechanism of action for treatment or prophylaxis against COVID19. The table does not include vaccines, antibodies, herbal medicines, and other biological products. In particular, clinical trials have been conducted for dozens of monoclonal antibodies, but
all the products that were already on the market and widely used are no longer expected to be effective due to mutations in the target viruses (variants/lineages). There is also concern that the development of new products will lose their eﬃcacy in a short period of time. The development of
most of these types of products has been suspended.
The compounds listed in Table 8 are candidates to continue clinical development in phase-II98（ 86 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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and -III trials, among the approximately 350 substances that have been tested for clinical eﬃcacy
against COVID-19.
The main reason that a very large number of candidates have been suspended or terminatedin development (since approximately the end of 2021), is evolution of the causative organism
SARS-CoV-2 into highly infectious, but less virulent, variants/lineages. Such causative virus
variants/lineages have allowed patients to recover in a shorter period of time with milder symptoms. Diﬀerences in the improvement of symptoms between patients in the test drug and placebo
control groups became diﬃcult to be shown — in some cases, even making it impossible to do so.
In addition, the marked increase of vaccination rates (including repeated inoculations) makes it
diﬃcult to demonstrate the clinical eﬃcacy of investigational drugs. Furthermore, because of themild symptoms and rapid recovery from COVID-19, the number of applicants for clinical trials
has decreased dramatically. This has also necessitated the withdrawal of many drug development
candidates from clinical trials.
The new COVID-19 drugs under development for the treatment of COVID-19 can be categorized according to their mechanism of action. There are a total of 33 antiviral drugs: 13 are cell
entry inhibitors, 12 are replication inhibitors, 5 are main protease inhibitors, and 3 are substancesthat exhibit other actions. The number of drugs related to inﬂammatory reactions and immunity is
Table 8. Therapeutic drugs for COVID-19 under development

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99（ 87 ）also 33 in total: 7 substances that exhibit anti-inﬂammatory eﬀects, 10 immunomodulating substances, 14 substances that protect lung function, and 2 substances that protect vascular function.
Antiviral drugs are eﬀective when administered during the ﬁrst 72- or 96-hour period when
SARS-CoV-2 is infecting and proliferating, but it is impossible to evaluate the true antiviral eﬀect
if administered after the proliferation is complete. In actual clinical trials against COVID-19, theadministration of the test drug within 72 hours of infection is very rare, and the number of trials
completed within 96 hours is also extremely limited. Therefore, to conﬁrm the eﬃcacy of antiviral drugs, it is considered appropriate to evaluate their eﬃcacy in preventing the onset of diseasein family members and other close contacts of infected patients, rather than in the course of thedisease in infected patients. However, it is necessary to take into consideration that the vaccination status of the target population has a signiﬁcant inﬂuence on the evaluation of the eﬀect ofprevention of disease onset.
On the other hand, evaluation of inﬂammatory reactions and immune-related agents is performed in patients with COVID-19 disease that has progressed to lower respiratory tract disorders. This category comprises cases such as pneumonia, hyperimmune states, and is often basedon ICU admission rates, as well as lethality (case-fatality) rates in many severe cases. The sequelae of post-COVID and long-COVID are presumed to be caused by a hyperimmune state, andnovel anti-COVID-19 agents are also being evaluated based on their eﬃcacy in treating various
sequelae of this process.

Conclusion
The authors published a review article on the COVID-19 pandemic in this journal at the endof March in 2021. At that time, the third wave of the global outbreak was converging, and we hadplanned to publish a sequel to the review article one year later in hopes of following up on the
global trends of the pandemic and the clinical evaluation of ivermectin for COVID-19. However,the sixth wave caused by the Omicron variants that spread from the beginning of the year 2022
was a rapidly and complexly changing day-by-day situation — making it extremely diﬃcult to accurately grasp the global trends. On the 14th of September 2022, two years and six months after
the declaration of the pandemic, the WHO announced13) that COVID-19 had shown a tendency to
subside to the point where the declaration was expected to be lifted soon. However, the numberof new cases worldwide could not be reduced and soon there was a shift from the seventh wave
to the eighth wave. During the seventh wave, the number of newly infected cases in Japan was
the largest in the world, followed by South Korea, and the United States. In the case of the UnitedStates, which had shown a marked decrease in case numbers (ranking third in the world) the
number of cases began to rise once more. All of these factors contributed to making a proper
evaluation of the circumstances diﬃcult.

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Nevertheless, while referring to the databases of the WHO16) and Johns Hopkins University17), it was decided that it would be appropriate to write a sequel to the ﬁrst review article andcover the interim period up to the end of December 2022. However, on the 14th of January 2023,
China released revised numbers of cases and deaths in response to criticism by the WHO, andthis made it necessary to further revise the draft creation. The oﬃcial announcement by Chinathat an estimated 64% of the Chinese population was infected with COVID-19, corresponds to
900 million infected people. Since the cumulative number of infected people worldwide according to the WHO and other data up to that point was approximately 670 million, the addition ofChinaʼs oﬃcially announced ﬁgure would increase the cumulative number of patients by approximately 2.4 times; this necessitated a complete change in the discussion points. Furthermore, anoﬃcial of the Chinese Center for Disease Prevention and Control (CCDC) announced that the actual number of patients was more than 1.1 billion, or 80% of the national population, and that the
number of deaths was about 12,000 in one week in January of 2023. This casts doubt on the authenticity of the oﬃcial Chinese announcement on the 14th of January 2023. Therefore, we concluded that it would be more appropriate to complete this review without including the Chinese
data, rather than to be misled by unreliable ﬁgures on the number of cases and deaths.
The reasons for the decline in lethality rates as the pandemic progressed, from the ﬁrst to thethird and fourth waves, include the widespread use of PCR testing, increased vaccination rates, aswell as advances in treatment with anti-COVID-19 drugs. Direct treatment with antiviral drugs,
antibody drugs, anti-inﬂammatory treatment with steroids, and immunomodulatory drugs haveenabled even severely infected patients to be saved. Even more patients have been successfully
saved by respiratory management with ventilators and extracorporeal membrane ventilators(ECMO).
Such treatment successes, however, have been accompanied by a situation in which the eﬃcacy of drugs, like antibody drugs, is weakened by mutations of the prevalent virus strain. In suchcases, their use is discontinued as a countermeasure, and there have been scattered cases of recurrences/relapses after symptoms have resolved with antiviral drug treatments. In addition, some
COVID-19 drugs are contraindicated because of their interactions with a wide variety of drugs
used to treat other diseases (comorbidities are a common concern among many patients). Therefore, there is an intense research eﬀort to develop new anti-COVID-19 agents with high safety
and eﬃcacy potential, with more than 60 drug candidates currently under clinical evaluation.
Many of these candidates are in phase-III clinical trials, and it is hoped that their development
will progress smoothly and that a variety of therapeutic agents based on diﬀerent mechanisms
will become available for clinical use.
On the other hand, the COVID-19 vaccine has made great progress, and according to theWHOʼs tally, 13 billion doses have been administered worldwide by the end of December 2022.
This means that 8 billion people worldwide have received an average of 1.6 doses, which is theJune 2023

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101（ 89 ）achievement of grand-scale social immunity. However, due to the short duration of vaccineinduced immunity and the rapid mutation of the target SARS-CoV-2 virus, protection against infection by vaccination has been incomplete, resulting in renewed and repeated spread of infection. The principle behind vaccination is that although complete protection against infection by
vaccination cannot be expected, vaccination can prevent the worsening of symptoms.
There is no doubt that the vaccines are the ﬁrst line of defense in the prevention of viral
infections. For the purpose of preventing COVID-19 infection, vaccines were developed usingmRNA encoding the genetic information of the spike protein, which exists on the surface of thevirus particles and is involved in binding to human cells (infectivity) and virulence, as the target
antigen. These vaccines are based on a completely diﬀerent principle from conventional vaccine
products that use attenuated or inactivated viruses as antigens, and a large-scale clinical trial overa long period of time would normally be required to conﬁrm safety and eﬃcacy. Unexpectedly,
however, since the WHO declared COVID-19 a pandemic, and there was an immediate need totake measures to prevent infection, mRNA vaccines were urgently approved in countries aroundthe world. In the process, vaccination coverage and frequency of administration became a matterof competition among countries worldwide.
The variant of SARS-CoV-2 that causes COVID-19 has a mutated spike protein, which is thetarget antigen of the mRNA vaccines. Since the eﬃcacy of the ﬁrst mRNA vaccines targeting theoriginal Wuhan strain was reduced, the second mRNA vaccines targeting the mutated alpha anddelta variants that were the epidemic strains of the third and fourth waves were developed. Subsequently, the third mRNA vaccines covering the spike protein of the Omicron variant BA.4 andBA.5 lineages were also eventually developed. Because of the short duration of immunity,
booster vaccinations are given every 6 or 8 months, and the number of people who have received
4 or 5 doses of the vaccine is increasing. On the other hand, the pathological eﬀects of the spike
proteins in vivo are gradually being elucidated, and studies on cardiac and nervous system disorders, called spike protein diseases, are underway. A discussion of the history of the developmentof the vaccine against COVID-19, its widespread use, and its safety and eﬃcacy would require an
extensive summary of the data, so the authors will defer that discussion for other reviews. Therefore, more detailed descriptions of the vaccine are omitted from this review.
Three years have passed since the WHO issued the Public Health Emergency of International Concern (PHEIC) declaration on the 30th of January 2020, for the novel coronavirus infection that spread from China. The WHO Director-Generalʼs Statement, on the 30th of January2023, stated that although the situation has improved, compared to the peak of the outbreakcaused by the Omicron variant a year ago, there have still been 170,000 deaths worldwide overan eight-week span, resultant sequelae from the infection are still frequent and severe, the virus
continues to mutate, and it continues to cause both a high number and high rate of deaths. It was
further stated that the situation has not yet reached a point where the declaration can be lifted be-102（ 90 ）THE JAPANESE JOURNAL OF ANTIBIOTICS

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cause the virus continues to mutate. The statement concludes with seven recommendations fromthe WHO Director-General for current times. Primary among the recommendations are the promotion of vaccination, improved reporting of surveillance to the WHO by individual countries,
and the maintenance of long-term preparatory medical response capabilities. Furthermore, in
opening remarks89) delivered at a March 17th press conference, the Director-General stated thatthe current situation is the best it has ever been and that there is conﬁdence that the COVID-19
pandemic will end this year. It was also stated that although questions have not been resolved regarding the beginning of the pandemic, the China CDC has provided data on samples taken at the
Huanan Seafood Wholesale Market in Wuhan in early 2020 (which have been analyzed by an international group) and expressed regret that this important data should have been shared three
years ago but was covered up. The WHO has reiterated the necessity for China to transparently
share data, conduct the necessary studies, and share the results.
The words of the Director-General of the WHO in his opening remarks are quoted below as
an appropriate conclusion to this review.
“Understanding how the pandemic began is a moral and scientiﬁc imperative, and as we

look back to the beginning of this pandemic, we must continue to look forward to strengthening the worldʼs defenses against future epidemics and pandemics. This is something thateach country must do together, and no one country can do it alone. We can confront ourcommon threats only through a common response based on a shared commitment to solidarity and equity. This is the pandemic agreement that countries are currently negotiating, anagreement in which countries work together, not competitively, to prepare for and respond to
epidemics and pandemics. WHOʼs role is to help countries implement what they have agreed
to. An agreement that captures all the challenges we faced in this pandemic is essential to ensure that the world does not repeat the mistakes made in this pandemic. If we repeat thesame mistakes, we will not forgive ourselves, nor will our children and grandchildren. We
owe it to ourselves to end this pandemic as soon as possible.”
In Japan, COVID-19 has been moved from a strictly regulated Class II infectious disease toa less restrictive Class V infectious disease36), and in the United States, the “public health emergency declaration”42) was lifted in early May 2023. In Europe, various restrictions have been
lifted in the United Kingdom and France, and in Asia, restrictions have been lifted in India, Vietnam, and South Korea.
Under such circumstances, the Director-General of the WHO stated90), at a press conference
held on the 5th of May 2023, following the results of the deliberations of the COVID-19 Pandemic Emergency Committee held the previous day, that the current COVID-19 situation no longer constituted a public health emergency of international concern (PHEIC), and declared an end
to the emergency. It is hoped that a new wave of COVID-19 epidemics will not materialize afterJune 2023

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103（ 91 ）the WHO pandemic declaration is oﬃcially terminated.
Acknowledgments
The authors would like to express their deepest gratitude to Dr. Satoshi Iwata, President of
the Japan Antibiotics Research Association, and Dr. Naruhiko Ishiwada, Editor-in-Chief of The
Japanese Journal of Antibiotics, for allowing us to contribute to this review and encouraging us towrite this article. We are grateful to be allowed to devote a large number of pages for publicationin this review to include large amounts of data from the WHO, the U.S. CDC, and other sources,in accurate and detailed records.
Conﬂict of Interest
None to declare.

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