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Commentary
Why does Japan have so few cases
of COVID-19?
Akiko Iwasaki
1,2
& Nathan D Grubaugh
3
Despite early exposure, its dense and aging
population, and little social distancing
measures, Japan reports low infection and
low death from COVID-19. Here, we specu-
late on and discuss the possible reasons
that may account for this anomaly.
There is a lot of interest brewing as to
why Japan has such low numbers of
confirmed infected cases of the
COVID-19 disease, caused by the SARS-CoV-
2 virus (Fig 1), despite its high population
density (over 6,100 persons/sqkm in Tokyo,
2.4 times higher than New York City) and
large percentage of high-risk individuals
over 65 years of age (about 26%, compared
with 15% in the USA). In Singapore and
Hong Kong, rapid and strict quarantine rules
and contact tracing have helped to “flatten
the curve”. In South Korea, mass testing and
quarantine measures appear to have reduced
the rate of new cases. However, Japan has
not engaged in expansive testing, contact
tracing, or strict quarantine measures and
yet is reporting a slow growth rate of
infected persons and a death rate that is
currently just 1/10
th
of world average. It is
difficult to make direct comparison of infec-
tion rates, because the number of tests per
capita varies dramatically between coun-
tries. However, this low death rate cannot
be simply explained by lack of testing or
reporting, as no surge in death from respira-
tory syndromes has been reported either.
So how has Japan dealt with COVID-19?
The Japanese Cluster Response Team of the
Ministry of Health set forth on March 9
th
a
three-pronged approach.
•early detection of and early response to
infection clusters
•early patient diagnosis and enhancement
of intensive care and the securing of a
medical service system for the severely ill
•behavior modification of citizens (includ-
ing advise to refrain from holding large-
scale events, temporary school closures)
Note that none of these involve strict
social distancing measures taken by other
countries. Why is this? What can we learn
from Japan to help flatten the curve in other
countries?
Here, we discuss several hypotheses and
provide arguments for or against each
hypothesis.
1 Japanese culture is inherently suited
for social distancing, and face mask
use prevents viral spread.
It is certainly true that the Japanese customs
do not involve handshaking, hugging, or
kissing when greeting. In addition, many
Japanese wear cloth or paper face masks
(not the N95 respirators required for exclu-
sion of aerosol viral particles) in the winter
to avoid transmission of respiratory infec-
tions. People use the mask to avoid spread-
ing the infection and also in an attempt to
prevent exposure to infection. However, we
are unconvinced that this is the main or only
reason why COVID-19 is so well contained in
Japan. There is no social distancing in rush
hour trains and buses, or when walking in
crowded streets to school or to work. The
use of face mask is also practiced in other
Asian countries that witnessed higher rates
of infection. A hint to whether this is a valid
hypothesis comes from looking at other
pandemic viral respiratory diseases. The
community R
0
rate for the 2009 pandemic flu
for Japan was 1.28 while USA was 1.7–2.0
(Boelle et al, 2011). Thus, R
0
in Japan was
somewhat lower than the global median R
0
of 1.47. In addition, an observational study
of elementary school children in Japan found
that wearing masks had significant protective
association (odds ratio of 0.859, 95% confi-
dence interval 0.778–0.949) against seasonal
influenza (Uchida et al, 2017). Therefore,
the social practice culture of Japan and mask
use may explain to some extent the lower
number of observed COVID-19 cases, but is
unlikely the only explanation.
2 Japanese people were exposed to a
milder version of SARS-CoV-2 that
conferred herd immunity before the
spread of a more virulent strain of CoV2.
While possible, there is no current
evidence that milder strains of SARS-CoV-2
exist. Nor do we know what sort of antibody
response would develop as a result of expo-
sure to such a hypothetical variant. Phyloge-
netic analysis of SARS-CoV-2 of more than
3,500 SARS-CoV-2 genomes from around the
world, including 29 from Japan, suggests
that the outbreak in Japan was sparked by
several independent virus introductions
primarily from China (https://nextstrain.
org/ncov?f_country=Japan, accessed
7.4.2020) (Hadfield et al, 2018). Further-
more, all of the SARS-CoV-2 genomes are
highly similar; most contain no more than
10 mutations compared to the virus that
started the original outbreak. Thus, it is
highly unlikely that the virus has evolved a
significantly different phenotype, and even
less likely that it was introduced early into
Japan.
1Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. E-mail: akiko.iwasaki@yale.edu
2Howard Hughes Medical Institute, Chevy Chase, MD, USA. E-mail: akiko.iwasaki@yale.edu
3Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
DOI 10.15252/emmm.202012481 | EMBO Mol Med (2020)12:e12481 | Published online 28 April 2020
©2020 The Authors. Published under the terms of the CC BY 4.0license EMBO Molecular Medicine 12:e12481 |2020 1of 3
Notably, early cases in Japan (January–
February) were all linked to virus introduced
from China. Now, in March, the outbreaks
in Japan are linked to introductions from
Europe, and there is a large gap in between
those early introductions in January and the
recent ones in March. While the data are still
limited, this suggests that Japan was able to
control the early outbreaks, keeping cases
down, but is now experiencing a second
wave introduced more recently from
Europe.
3 Japanese people have reduced suscep-
tibility due to ACE2 receptor expression.
SARS-CoV-2 utilizes ACE2 as a receptor
to enter cells. It is theoretically possible that
ACE2 expression in the respiratory tract is
somehow lower in the Japanese population,
though no direct evidence was identified
during studies investigating coronavirus S-
protein binding-resistant ACE2 mutants
among different populations. If anything,
East Asian populations were reported to
have higher allele frequency in the ACE2
variants associated with higher ACE2
expression in tissues (Cao et al, 2020).
However, the only way to find out whether
the expression of ACE2 is indeed different is
through surface protein staining of lung
tissues, which has yet to be done.
4 Japanese people have distinct HLA that
confers immune resistance to CoV2.
Genome-wide association studies
(GWAS) conducted on disease susceptibility
show that HLA is usually the top locus
associated with disease. This is true for
infectious diseases, autoimmunity, or
neurological disorders. HLA stands for
human leukocyte antigen and is also
known as MHC, or major histocompatibility
complex. These genes encode for proteins
that present antigenic peptides to T cells.
HLA class I presents antigenic peptides to
CD8 T cells, while HLA class II presents
peptides to CD4 T cells. HLA genes are the
most highly polymorphic genes in the
human genome. The variety in HLA
enables our immune system to survey for
maximal number of antigen peptides that
are present in pathogens, so as to elicit
robust cellular immune responses. Previous
studies have identified HLA-B*4601 to be
associated with higher risk of developing
SARS disease (Lin et al, 2003), based on a
small number of cases. However, whether
there are any HLA alleles that confer resis-
tance to COVID-19 and whether the allele
frequency is higher in the Japanese popula-
tion are unknown.
5 BCG vaccine used in Japan confers
protection against COVID-19.
Japan, like many other countries including
China, Korea, India, and the Russian
Figure 1. Cumulative number of cases, by number of days since February 1,2020.
Source: https://ourworldindata.org/coronavirus#confirmed-covid-19-deaths-by-country, accessed 6-4-2020, data based on European Centre for Disease Prevention and
Control.
2of 3EMBO Molecular Medicine 12:e12481 |2020 ª2020 The Authors
EMBO Molecular Medicine Akiko Iwasaki & Nathan D Grubaugh
Federation, have mandatory childhood BCG
vaccines against tuberculosis. These coun-
tries have so far a relatively low per capita
death rate from COVID-19 compared to coun-
tries that have no mandatory BCG vaccines
(USA, Spain, France, Italy, The Netherlands).
What further distinguishes Japan is that the
BCG vaccine strain used in Japan, Brazil, and
Russia is one of the original strains, while
further modified BCG strains are used for
vaccinationinEuropeancountries.Thisasso-
ciation between BCG vaccination and appar-
ent low COVID-19 incidence in Japan has
spurred the idea that these two things may be
linked (for more discussions on this topic,
visit https://www.jsatonotes.com/2020/03/
if-i-were-north-americaneuropeanaustral.html
and https://news.yahoo.co.jp/byline/kimu
ramasato/20200405-00171556/).
How would BCG, an attenuated bacterial
vaccine completely unrelated to COVID-19,
provide protection? Michai Netea and collea-
gues hypothesized that the vaccine may
boost “trained immunity” (Netea et al, 2016)
—in other words, certain immune stimuli
may induce a prolonged state of resistance
against pathogens in general, by elevating
the expression levels of resistance factors.
Studies have shown that receipt of BCG
vaccine was associated with a reduction in
all-cause mortality within the first 1–
60 months: The average relative risks were
0.70 (95% confidence interval 0.49–1.01)
from five clinical trials (Higgins et al, 2016).
Furthermore, Netea and colleagues showed
that BCG vaccination reduced the levels of
viremia caused by the yellow fever virus live
attenuated vaccine (Arts et al, 2018), and
post-BCG increase of IL-1bproduction
strongly correlated with lower viremia after
yellow fever virus administration. A placebo-
controlled randomized clinical trial of 1,000
healthcare workers in The Netherlands has
started, and a similar trial is planned to begin
at the Max Planck Institute (de Vrieze,
2020). The outcomes of these trials will help
us to understand whether and how BCG
confers resistance to other pathogens includ-
ing SARS-CoV-2.
Conclusion
There are many other theories to explain the
low number of COVID-19 cases in Japan, yet
we still do not have enough information to
determine the cause of this striking discrep-
ancy. Clearly, we do not understand what
causes these differences. Many of these
hypotheses can be tested as suggested
above, such as examining ACE2 expression
levels in the respiratory tract, GWAS data on
COVID-19 susceptibility, and whether BCG
vaccines indeed confer long-term innate
immune resistance to SARS-CoV-2. The
three-pronged approach by the Cluster
Response Team of the Japanese Ministry of
Health has thus far contained the spread of
COVID-19 by quickly identifying clusters of
infections, testing, and quarantine of the
infected individuals. A word of caution is
whether this approach will work in cases
where super-spreaders ignite a large-scale
transmission, or when there are multiple
clusters that occur throughout the country at
once. Perhaps one of the reasons for the low
number of cases in Japan might relate to lack
of super-spreader events to date. Just within
the last 24 h, Japan has declared the state of
emergency, as Tokyo faces more than 1,000
confirmed cases, more than double the
number a week ago. Perhaps stronger social
distancing measures are required to keep the
curve flattened in Japan.
Acknowledgements
We wish to thank Dr. Hiroshi Iwasaki for research
and providing key resources from Japanese media
and postings. We also thank Dr. Hironori Funabiki
for his informative Twitter postings on this subject.
Conflict of interest
The authors declare that they have no conflict of
interest.
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