Tackling covid-19 with public healthperspective

Minato Nakazawa, Ph.D.
Professor, Department of Public Health,Graduate School of Health Sciences,
Kobe University<minato-nakazawa@people.kobe-u.ac.jp>
February 4, 2022

1

Interaction between human andenvironment in human ecology

Human
ActionUsing materials,
effects by
Counterphysical/chemicalactionenvironment

Medicine
Agriculture

Parasitism
Food
Symbiosis Development,
waste disposal

Biologicalenvironment
February 4, 2022

Physical/chemical
environment

What is human infectious diseases?
●"Infectious diseases" from ecological perspective– Among the symbiosis (mutualism, commensalism,

parasitism), a kind of parasitism– The life and reproduction of parasites depend on
host's life (differently by macro-/micro-)– Host-parasite co-evolution
Antimalarial genes in malaria endemic area
– Thalassemia in Eastern Mediterranean– Sickle cell anemia in Sub-Saharan Africa●
Hypoferremic adaptation hypothesis: relatively lower ironconcentration in serum than in liver found in malaria-endemicarea●

February 4, 2022

Fundamental mechanism of infectious
diseases (3 factors + alpha)Immune hosts (due to innate, naturally acquired after
infection, artificially acquired=vaccinated) are not susceptible

Susceptible
host
Entrance to host: skin, mucosa,
blood, mouth, ...

Route ofinfection
Direct (contact, droplet, ...)
Indirect (fomite, vector)

Patients (as next
source of infection)

Transmission of pathogens (virus,
bacteria and macro-parasites)

Source ofinfection

Reservoir

Patients, carrier (asymptomatic patients),
animals (for zoonosys), soils, etc.

Effects by environmental conditions The most critical factors:* Transmissibility (infectiousness)(temperature, wind, rainfall, etc.)* Severity (virulence)
February 4, 2022

Route of infection
Route of transmission

Characteristics

Contact

Requires direct/indirect contact* Indirect = infected fomite, blood or body fluid* Direct = skin or sexual contact

Food- or water-borne

Ingestion of contaminated food (outbreaks may be large
and dispersed, depending on distribution of food)

Airborne (droplet, droplet
nuclei, micro-droplet)

Inhalation of contaminated air* Droplet = large droplets by cough (eg. flu)
* Droplet nuclei = Dried particle from droplets (eg. measles)* Micro-droplets = small suspended droplets (eg. covid-19)

Vector-borne

Dependent on biology of the vector (mosquito, tick, snail,etc), as well as the infectivity of the organism

Perinatal

Similar to contact infection; however, the contact may occur
in utero during pregnancy or at the time of delivery

February 4, 20225

Transmissibility (Infectiousness)
Reproduction number and generation time●●

The relative proportions of immune Unit time = generation timeand susceptible persons in a
population can determine whether TIME
t
t+1
t+2
the infection will take hold in thecommunity or die out quickly
When substantial proportion isimmune (herd immunity
situation), an infected person will
R =4
be less likely to spread thepathogen0●R0 (basic reproduction number) is
the average number of secondary
cases that occur from a single
index case in a susceptible
population–●

If R0 < 1, the outbreak will dieout unless fueled by external
re-infections

R0=4
Rt=1

DiseasePrimary mode oftransmission

R0

Measles

Airborne

15

Pertussis(whoopingcough)

Airborne droplet

15

Diphtheria

Saliva6

Smallpox

Social contact

6

Polio

Fecal-oral

6

RubellaAirborne droplet

6

Mumps

Airborne droplet

5

HIV/AIDS

Sexual contact

3

SARS

Airborne droplet

3

Ebola

Bodily fluids

2

Rt (effective reproduction number)1918 flu
Airborne droplet
is the value of reproduction
Susceptible
Transmission
2009 flu
Airborne droplet
number that takes into account the
COVID-19
Airborne droplet
No transmission
Immunemix of immunity and social
interaction at any point in time asan outbreak progresses
Note: If average R is same, control efficacy may largely differ by

February 4, 2022

variance.

02
1.5
1.4-3?

6

Terms to describe individual infection
Incubation period
Latent orPre-infectious
periodClinical symptoms

Infectious period

serial intervalFirst infection

Onset

Primary caseSecond infection
generation time

February 4, 2022

Onset

Secondary case
7

The nature of R0 and Rt
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●

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The reproduction number reflects the
biologic potential of the infectious agent
and the social intercourse that leads tosituations in which transmission mightoccur– If directly transmitted disease patient
is too sick to move, there will be few
contact with susceptible host, resultsin low reproductive number
R0 varies by population (due to behavioral
difference by age and so on)
Even if R0 is low, some social networks
within a population may form a subset
with rapid spread of infection. (eg. a few“superspreaders” such as needlesharers transmitting a blood-borne
infection can suffice to spark an outbreak)Superspreading is not always an attributeof person, sometimes a condition of the
field setting (in the case of COVID-19).

February 4, 2022

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●

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While Rt>1, epidemic continues
Eventually Rt becomes 1 or below, because theproportion of susceptible people decreases orcontrol measures are implemented
If Rt=1 (endemic equilibrium), the prevalence of
infection remains level over time as new
susceptibles are added to the population to balance
those who acquire immunity–
Rt = 1 = R0 x ps, where ps is the proportion of
the population susceptible to infection atequilibrium, thus R0 = 1/ps
Basic strategy to reduce transmission is isolation of
infected persons.
Related strategy is quarantine to restrict contacts
among people who are not yet ill but alreadycontacted with infected persons(For bioterrorism by smallpox, ring-vaccination is tobe conducted to reduce Rt)
In Japan, restriction of behavior to fill the conditions
for superspreading events was taken to reduce R t
as a countermeasure against COVID-19 outbreak.
8

Example of SARS, and if
vaccine would be available?
●●

The strategy of isolation and quarantine worked well against SARS–SARS nearly became pandemic in 2003, rapidly spread from China to 37 countries (infected more than
8000 people, CFR was almost 10%).
–
Canadian officials quarantined more than 23000 people who had been in contact with SARS cases,
about 100 persons for every identified case of SARS. Movement of those under quarantine wasrestricted until 10 days after the last contact–
SARS was emerging disease in 2003 and thus no vaccine existed
If vaccine would be available, Rt depends on vaccine efficacy (Ve) and coverage (Vc)–

Rt = R0 (1 – Ve x Vc) ↔ Rt/R0 = 1 - Ve x Vc ↔ Vc = (1 - Rt/R0)/Ve–

Rt < 1 ↔ Vc > (1 – 1/R0)/Ve

When R0 is large, to succeed in curtailing the epidemic, high efficacy and coverage are needed (If R 0 is
10 and Ve is 95%, Vc has to be larger than 95% needed to reduce Rt below 1; (1 – 1/10)/0.95 = 0.947…
≈ 0.95)–In the case of measles, R0 is 15. Even if Ve is 100%, Vc has to be larger than 93% to reduce Rt below 1;(1 – 1/15)/1 = 0.933… ≈ 0.93–
If R0 is 2 and Ve is 95%, Vc needs to be larger than 53% to reduce Rt below 1; (1 –1/2) /0.95 = 0.526… ≈0.53.
The same relationship may stand for not only vaccination but also naturally acquired immunity after infection.
Vaccine efficacy corresponds to the proportion of immunized by single infection and coverage corresponds tothe proportion of people ever infected and recovered (herd immunity threshold)–●February 4, 2022

9

Severity (virulence)●

The common indicator of severity is CFR (Case Fatality Risk). It's the number of deaths caused by adisease divided by the number of confirmed cases of that disease. Different from mortality.
CFRs for SARS, MERS, Spanish flu and Asian flu were 10%, 35%, 3% and 0.5%, respectively.
–
It is widely misunderstood that the CFR of seasonal flu is "less than" 0.1%. Actually, the estimates ofconfirmed cases of seasonal flu in Japan is about 10 million, and the number of death due to seasonal
flu is 2000 to 3000, so that CFR of seasonal flu ranges 0.02-0.03%.
–
The CFR of COVID-19 ranges from 1 to 10% (For omicron variant, it may be less than 1%, butalmost surely higher than 0.1%).
●
The wide range of CFR is caused by large difference of examination ability, medical capacity, andthe age distribution of the patients.
●
Like in South Korea and Germany, extensive RT-PCR examination for many people leads to large
number of confirmed patients, subsequently smaller CFR estimates. In South Korea, younger
patients with lower fatality shared majority of positives, which made CFR lower.
●
Like in Italy and France, if the number of patients went beyond the medical capacity with rapid
increase (so-called "overshoot" in Japan, analogously with "overshoot" in ecology, which means
excess population growth beyond the carrying capacity), CFR goes higher.
In the case of COVID-19, as above mentioned, CFR depends on examination and medical capacity, so thatthe meaning of CFR is difficult to interpret. Based on the data from China, where the examination
coverage was already assessed, estimated CFR ranged from 3% to 6% and the confirmed cases wereconsidered to share about 10% of all infected patients, Infection Fatality Risk (IFR) was suggested as
0.3-0.6%. IFR may be applicable as universal indicator of disease severity (Nishiura 2020).
–●–

The IFR of seasonal flu seems to range from 0.005 to 0.01%.

February 4, 2022

10

Roughly estimating CFR of COVID-19

February 4, 2022

11

The origin of human infectious diseases●

5 Stages from animal pathogen to specialized pathogen of humans (Wolfe et al.
2007) (http://www.nature.com/nature/journal/v447/n7142/full/nature05775.html)

February 4, 2022

Preparedness for the emergence ofhighly virulent pathogens●

Human-to-human transmission of highly virulent pathogen may cause
catastrophic mass dying such as medieval plague and 1917-9 Spanish
flu, and the possible spread may be more rapid considering the fasttransfer of human and material due to globalization, so that WHO, CDCs
in each country and Health authorities have prepared action plans.
– Ring vaccination against small pox (in case of bio-terrorism)––

Strategic stock of prepandemic vaccine and specific medicine against
pandemic flu.
Against novel influenza, mutated from highly virulent bird flu such as H5N1
and H7N9,●●Phase specific action plans– (Emergence) Strengthening quarantine to prevent invasion– (After invasion) Prefecture-wide school closure just after the first casedetection in each prefecture to prevent spreading of the epidemic– Treatment plan for ever-spread situation
Reducing reproduction number to make the peak height lower and the timing of
the peak delayed, as community mitigation strategy

February 4, 2022

Preparedness for "the next pandemic"
after the pandemic flu 2009
Discussion by the specialists in USA in 2019
（ https://www.centerforhealthsecurity.org/event201/ )●Discussion by the specialists in Germany in 2012
（ https://dserver.bundestag.de/btd/17/120/1712051.pdf）●
Both indicated the possible pandemic by a novel corona virus– Most patients show mild symptoms– Severe cases show high fatality– No medicine nor vaccine (even pre-pandemic vaccine for flu)
exists●However, preparation was not enough.
– WHO lacked no funding base for future pandemic.
– Some governments started to prepare, but did not implement
any strategic plan for it.
●

February 4, 2022

COVID-19
Then, in the end of 2019, novel
corona virus, emerged in China,caused epidemic of severe atypical
pneumonia there.
●
It has quickly spread over the world,
pandemic has continued for morethan 2 years.
●

February 4, 2022

The pathogen of COVID-19(Lai C-C et al. https://doi.org/10.1016/j.ijantimicag.2020.105924)●

The pathogen of COVID-19 is the 7 th corona virus of which host is
human, SARS-CoV-2– 4 of 7 corona viruses of which hosts are human cause common
cold– The other 3 are SARS-CoV, MERS-CoV, and currently prevailing
SARS-CoV-2 (in early 2020, it has been called as 2019-nCoV).
The virus genomes of SARS-CoV and SARS-CoV-2 are the samefor 80% of all loci. Among the CoVs of which hosts are bat, the oneof which genome is almost 100% similar to SARS-CoV-2 exists.
●
SARS-CoV did host-switch from bat → other animal → human→ human●
MERS-CoV did host-switch from camel → human (→ human)●
SARS-CoV-2 did host-switch from bat (→ Malayan pangolin) →human → human
https://doi.org/10.1038/s41586-020-2169-0

February 4, 2022

16

The feature of COVID-19(except for omicron variant)
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●

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Long latent period (median 5 days; Linton et al. 2020
[https://www.mdpi.com/2077-0383/9/2/538]), (for omicron, median 2-3 days)
Median serial interval was 4 days (for omicron, 2-3 days)→ Shorter than latent period → About half of infection occurs during latent period(Nishiura et al., 2020 [https://dx.doi.org/10.1016%2Fj.ijid.2020.02.060])→ Suggests difficulty of contact tracing (asymptomatic patients is difficult to follow)
80 % of patients has no or mild symptoms, 20% become severe.
The risk of severe symptoms / deaths is different by age. Elderly and the people
with underlying disease show higher fatality, but young people without underlying
disease also suffer from severe symptom and death at non-negligible probability(the paper in Lancet on 24th Jan 2020)
After hospitalization, it takes about 20 days until recovery or death.
(Later, hospitalization period has been shorten.)
Until mid-2020, vaccine and medicine didn't exist → Respirator or ECMO wasneeded to rescue severe cases → Fatality largely depends on the medical standard
and medical system.
Early development and implementation of vaccines and medical treatments(especially antibody drugs) contributed to the decrease of fatality, but not enough.

February 4, 2022

17

Variants of SARS-CoV-2
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(CDC) https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/variant-surveillance/variant-info.html(WHO) https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/(Pango Lineage) https://cov-lineages.org/(Nextstrain) https://nextstrain.org/sars-cov-2/(JAMA) Viewpoint "Genetic Variants of SARS-CoV-2-What Do They Mean?" 9 Feb 2020
https://doi.org/10.1001/jama.2020.27124(NEJM) Clinical implications of basic research "Emergence of a Highly Fit SARS-CoV-2 Variant" 31 Dec 2020
https://www.nejm.org/doi/full/10.1056/NEJMcibr2032888(Vaccines) "Emerging SARS-CoV-2 Variants and Impact in Global Vaccination Programs against SARS-CoV-2/COVID-19"
11 Mar 2021 https://dx.doi.org/10.3390%2Fvaccines9030243

RNA virus, easy to suffer from mutation, but mutation is slower than HIV
Variant means the virus with different infectiousness and/or severity due to 1 or more mutation in
genotype.
When mutation causes the change in amino-acid sequence, the epidemiologic nature (infectiousness /severity / immunogenecity) may change.
(eg.) N501Y is the change of the 501st amino-acid from N (asparagine) to Y (tyrosine) in spike protein.
Variants may include one or more such changes in amino-acid sequence.
Variants are named in several different systems– Name with country name such as UK variant (though it's not recommended) means the first country
reported the variant.
– Pango Lineage: B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.1.529, ...
– Nextstrain: 20I (V1), 20H (V2), 20J (V3), 21A/21I/21J, 21K/21L/21M, ...
– WHO (for VOC): Alpha, Beta, Gamma, Delta, Omicron, ...
February 4, 2022

18

Age dependency of CFR (in early 2020)
Age-specific CFRs in Mainland China
up to 11 Feb 2020.
https://doi.org/10.46234/ccdcw2020.032
Confirmed
cases(https://www.mhlw.go.jp/bunya/kenkou/kekkaku-kansenshou04/dl/infu100608-03.pdf

0-4yr 0.0007%
5-9yr 0.0003%
10-14yr 0.0001%
15-19yr 0.0001%
20-29yr 0.0005%
30-39yr 0.0009%
40-49yr 0.0031%
50-59yr 0.0066%
60-69yr 0.0147%
70yr+ 0.0282%

Deaths CFR(%)

0-9yr

416

0

0

10-19yr

549

1

0.2

20-29yr

3619

7

0.2

30-39yr

7600

18

0.2

40-49yr

8571

38

0.4

50-59yr

10008

130

1.3

60-69yr

8583

309

3.6

70-79yr

3918

312

8.0

80yr+

1408

208

14.8

All

44672

1023

2.3

February 4, 2022

Age-specific CFR of Pandemic flu 2009
– MHLW data in Japan–

NY city H1N1pdm2009(https://doi.org/10.1371/journal.pone.0011677)
0-17yr 0.0008-0.0012%
18-64yr 0.0081-0.0132%
65yr+ 0.0094-0.0147%

19)

WHO Timeline (until 9 Sep 2020)
https://www.who.int/news-room/detail/29-06-2020-covidtimeline
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/interactive-timeline
31 Dec 2019

First report of unusual cluster of atypical pneumonia to WHO from Wuhan, China

1 Jan 2020

WHO asked China health officials to collect information, IMST started

5 Jan 2020

WHO publicly announced the details of cluster of new atypical pneumonia in Wuhan

9 Jan 2020

WHO announced that the cause of new atypical pneumonia was new coronavirus

13 Jan 2020

In Thailand, imported case from China was first confirmed. WHO opened the protocol of RTPCR to detect the new coronavirus

16 Jan 2020

Japan's MHLW announced the bus driver case as 2nd confirmed outside China

22-23 Jan 2020

WHO's committee discussed whether PHEIC (Public Health Emergency with International
Concern) should be issued or not, but didn't approved

24 Jan 2020

The first case in Europe was confirmed in France

30 Jan 2020

WHO announced PHEIC

13 Mar 2020

WHO secretary general Dr. Adanom stated the change of epicenter from China to Europe

Mar-Apr 2020

Lockdowns were done in many European countries

8 Jun 2020

NZ announced the complete elimination of COVID-19 from the nation

13 Jul 2020

UN predicted potential chronic starvation attacking 130 million in the world until the end of2020 (in the report of "Food Security and Nutritional Status in the World")

31 Jul 2020

WHO and IHR committee judged the continuance of PHEIC

2 Sep 2020

WHO announced the clinical therapy guidance including evidence-based corticosteriods

8-9 Sep 2020

WHO began to review the efficacy of IHR as a response to COVID-19

February 4, 2022

20

Asymptomatic vs severe cases●●●

About 80% of infections cause asymptomatic or mild, 20% become severe.
– Risks to get severe or to die differ by age. Patients with higher age or underlying disease
show higher risk of death. However, young patients without any underlying disease also show
considerable risk of death (Lancet paper [https://doi.org/10.1016/S0140-6736(20)30183-5] on
24th Jan 2020 suggested). However, there were many wrong messages.
– The time from admission to hospital to discharge or death was about 20 days in early 2020.
Recently shorter due to the change of discharge criteria.
– More than 80% of patients show some kinds of symptoms 2 months after onset. (https://jamanetwork.com/journals/jama/fullarticle/2768351, research letter on 9th July 2020,
JAMA)
Large difference in CFR by country– Whole body management with respirator and/or ECMO is needed to keep the severe patients
alive.
– CFR is higher in countries or regions with lower medical standard.
– Public health strategy also differs by country.
Variants show different infectiousness and/or severity and thus tackling strategy should differ for
new variants from previous virus strains.
– B.1.1.7 (alpha) shows higher risk to get severe in youth than original SARS-CoV-2.
– B.1.1.529 (omicron) easily infects children and adolescents in schools, very different fromprevious SARS-CoV-2.
February 4, 2022

21

Reproduction Number (R) of COVID-19
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R ＜ 1 means suppression of epidemic.
R0 of other infectious diseases– Measles (transmission occurs airborne) has 12-18(Guerra et al. 2017; https://doi.org/10.1016/S1473-3099(17)30307-9)– SARS has about 3 with superspreading events within hospital or airplane.
– MARS has less than 1 except for nosocomial infection.
https://www.who.int/csr/disease/coronavirus_infections/risk-assessment-august-2018.pdf– Spanish flu has about 2– Seasonal / 2009 pandemic flu has 1.1-1.5
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670001/
COVID-19 (original) has 1.4-2.5, estimated by WHO based on Wuhan data on 23rd Jan 2020.
– Much higher estimates: 6.47 (Tang B et al. 2020, https://doi.org/10.3390/jcm9020462)– Overdispersion (very large variance of R0 by patients)●
Grantz et al. [https://hopkinsidd.github.io/nCoV-Sandbox/DispersionExploration.html]●
Nishiura et al. [https://doi.org/10.1101/2020.02.28.20029272]●
Bi et al. [https://doi.org/10.1016/S1473-3099(20)30287-5]●
Hellewell et al. [https://doi.org/10.1016/S2214-109X(20)30074-7]●
Zhang et al. [https://doi.org/10.3390/ijerph17103705]●
Althouse et al. [https://arxiv.org/abs/2005.13689]●
Sneppen et al. [https://doi.org/10.1101/2020.05.17.20104745]●
Endo et al. [https://wellcomeopenresearch.org/articles/5-67]
Some variants showed higher transmissibility. Omicron variant has about 2-3, but serial interval ismuch shorter than original virus and previous variants, and thus doubling time is very short.
February 4, 2022

22

Routes of infection(probably both routes below exist)●●

Random link route – can be prevented by hand-wash,
hygiene, keeping social distance– Droplet (airborne): Large droplets from patients reachsomebody else by conversation within 2 m– Contact: Fomite with droplets from patients has
infectiousness for several hours– Oral-Fecal: Virus is excreted from patients into feces.
Touching something after defecation without handwash makes fomite
Scale-free route– Suspended micro-droplets in 3Cs environment cause
cluster infection (super-spreading event)●
Closed space (poor ventilation)●
Crowded (high population density)●
Close contact with conversation– Specialists in Japan have focused on this route since
February 2020, which led anti-3C campaign by
MHLW.
– Shared appeal by 239 researchers in July 2020 makethe possibility of airborne infection popular
https://doi.org/10.1093/cid/ciaa939
February 4, 2022

Random link = equal probability for all

Scale free = super-spreading events
23

The purposes and performances ofvarious testing
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Presumption in 2020:– No perfect testing– Even if the infection is detected earlier, effective initial treatment to prevent getting severe or death is notestablished
Situation slightly changed since 2021: Effective initial treatment has gradually been establishedThe performance of testing is usually assessed by the combination of sensitivity and specificity.
– To calculate the sensitivity and specificity, the test results must be obtained from the patients and non-patients
who are already diagnosed by the gold standard method– In COVID-19 testing, RT-PCR is the gold-standard and thus it's impossible to assess its performance
RT-PCR: Detecting the amplified the 2 RNA sequences which are specific for SARS-CoV-2. As alreadymentioned, gold standard method. But getting naso-pharyngeal swab or saliva can fail to pick the viral RNA frompatients, and thus one-time testing's sensitivity is 80% [https://doi.org/10.7326/M20-1495], specificity is almost
100% (at least 99.99%), but there are false-positive cases due to the errors in labeling samples or contamination– Nasal swab and pharyngeal swab: Used from Jan 2020. Healthcare professionals face the risk of infection at
the time of sampling– Saliva: Self-sampling is possible. It can be kept for several hours at room temperature
Antigen test of naso-pharyngeal swab or saliva using immunochromatography: Purpose is same as RT-PCR. Onsite rapid testing is possible, but the performance such as sensitivity and specificity (largely varies by the kit) ispoorer than RT-PCR.
Antibody test of serum using immunochromatography or ELISA: Purpose is to know the past experience of
infection. Antibodies remain for several months after recovery, but it gradually increases after infection and does
not exist just after the infection. Not suitable to detect the current infection. Among 2 types of antibodies, IgM candevelop soon, IgG later.
February 4, 2022

24

When RT-PCR should be applied
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(A) When doctor judged the needs of confirmatory diagnosis based on clinical examination showing high possibility of
infection such as pneumonia.
– Definitely needed. If confirmed, the patients have to be hospitalized and carefully monitored to apply respirator orECMO when the symptoms become severe.
●
Recommended by WHO since early 2020. In Japan, about 300 patients could not get this testing during 3
weeks in March 2020. In January 2022, many symptomatic people could not get any diagnosis/treatment byphysician due to rapid increase of new cases of the 6th wave of epidemic.
(B) Testing the people who contacted with patients proved by contact tracing– To prevent the spreading from presymptomatic patients by isolating them.
●
Recommended by WHO since early 2020.
●
Some countries did, but others could not do so.
●
When the new cases increase too rapidly, this testing become impossible due to capacity limit of contact tracing.
– Some papers recommended isolation of symptomatic people with close contact before testing. It's effectively
preventing the spread, shown by the result of mathematical models.
(B') Many papers recommended frequent testing of the healthcare workers who have high risk of infection.
(eg. https://www.imperial.ac.uk/mrc-global-infectious-disease-analysis/covid-19/report-16-testing/)(C) Area-wide screening or widely available free testing– If prevalence is very low, positive detection proportion is very low. If the situation becomes more or less endemic(prevalence becomes high), widely available free testing is desireble.
– Because of imperfect sampling efficacy, there remains the possible false-negatives and thus it's not recommended
as screening measure.
– For early isolation for presymptomatic patients to prevent the spread from them, conducted in many countries, since
early 2020, such as Iceland, China, South Korea, Germany, some states in USA, etc. (Japan has never done untillate 2021)– China conducted this in some cities (eg. 10 million in Wuhan) to confirm the elimination (though temporarily)
February 4, 2022

25

Effectiveness of Digital Contact Tracing
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Type (B) testing becomes difficult when the newly found cases (especially with unknown link) increased, because manual contact
tracing requires huge time and effort of the professionals of health center, which exceed the capacity soon.
If we can easily find the people who had close contact with the infected case, even after propagation of epidemic, type (B) testing
can more effectively detect the infected cases than type (C) testing, and thus type (B) testing may have higher priority than type(C) testing.
There may be a solution. It's the use of big data automatically collected by smartphone apps
(https://www.cnbc.com/2020/03/27/coronavirus-surveillance-used-by-governments-to-fight-pandemic-privacy-concerns.html)– China seems to have enhanced the information collection system using GPS tracking and surveillance camera since Beijing
Olympic. The report 11 from the group of Imperial College used the population movement data from GPS record by Baidu.
– South Korea has a strong regulation based on the law of infection control, by which the movement of the infected cases using
GPS data is visualized and opened to public.
– In Singapore, the smartphone app "TraceTogether" is recommended to install for everybody. When the smartphone with theTraceTogether running comes close each other, the other's information without location information is automatically detectedusing bluetooth and recorded with time in each smartphone. The information is kept for 21 days within each smartphone.
When a person is proved to be infected, it's possible to find all close contactees of the person during previous 21 days.
– Apple and Google cooperated to develop API to keep proximity information using Bluetooth without location/privacy as well as
Trace Together, equipped in iOS and Android. They allowed each country to develop only one application using this API.
●
Very early application releases were done by Australia and Switzerland.
●
UK once developed their unique application and provided it for the public at GitHub, but due to the less performance, gave
up it and moved to Apple/Google API.
●
Germany developed an application to use Apple/Google API at GitHub platform.
●
Japan released COCOA in June 2020, which was linked with the national patient database called "HER-SYS", speciallydeveloped for COVID-19. However, the registration of the COVID-19 patients to HER-SYS was delayed andincomplete, and additional man-power in health center was required for manual contact tracing from patients andhigh-risk people with close contact. In addition, there were many bugs in COCOA, so that it wasn't effectively working.
According to the paper by Fraser et al. (Ferretti et al., 2020 [https://science.sciencemag.org/content/368/6491/eabb6936]), "digitalcontact tracing" using smartphone app may enable the suppression of epidemic to avoid "overshoot" without "lockdown". They
also discussed ethical issue in that paper, too.

February 4, 2022

26

Needed epidemiological studies,suggested in early 2020●

Lipsitch M, Swerdlow DL, Finelli L (2020) Defining the epidemiology of
Covid-19 – Studies Needed. New England Journal of Medicine, 382:
1194-6, 26 Mar. https://www.nejm.org/doi/full/10.1056/NEJMp2002125

February 4, 2022

27

How to tackle COVID-19
●

●

●

●

Human's technology against infectious diseases= Preventive medicine (vaccine and Non-Pharmaceutical Interventions [=NPIs])+ Medical care (effective drug to cure and life-saving treatment)
Against emerging infectious disease, at least during early days, there is no vaccine nor
effective drug to cure
→ Human can do nothing but the NPIs and the life-saving treatment→ Life-saving treatment such as respirator and ECMO is hardly available in LMICs.
For COVID-19, development of effective vaccines and drugs succeeded very early.
– Efficacy of mRNA vaccines was very high. Especially hospitalization and death could
be prevented more than 90% by 2 doses. However, significant loss of immunity
occurred after half year and thus 3rd (booster) dose is promoted. Immunity against
omicron variant was relatively poor.
– There are some drugs to prevent symptoms, getting severe and death and/or toshorten hospitalization, but efficacy is not so high. Injection of antibody-based drugs
shows relatively higher efficacy, but expensive and not perfect.
NPIs include behavioral changes by language and social organization– Decreasing the chance of face-to-face contact– Lockdown– Remote working– "New normal"s such as always wearing face-mask, frequent hand-washing, ...

February 4, 2022

Behavioral changes as NPIs
●

●

●

●

●

Since 2007, US-CDC stated the necessity of NPIs as community mitigation measure under pandemic situation.
NPIs can reduce reproduction number and the peak height of epi-cuve and postpone the peak timing. By doing
so, CDC aimed to prevent the number of patients exceeding the medical capacity.
The report No.9 from Imperial College of London examined the effect of various NPIs on COVID-19 using
micro-simulation model. [https://www.imperial.ac.uk/media/imperial-college/medicine/sph/ide/gida-fellowships/
Imperial-College-COVID19-NPI-modelling-16-03-2020.pdf]– Predicted epi-curves were compared among several NPIs such as the mitigation strategy by weak restrictionof behavior such as school closure and the suppression strategy by stay-at-home and lockdown (of city
functions such as public transportation)●
School closure itself was not effective. However, it may be effective against omicron variant.
– Any mitigation strategy led to the rapid increase of patients exceeding the capacity of medical care. In thesecond wave of epidemic, many patients will die by the lack of medical care.
– To prevent the large number of death due to the lack of medical care, repeated application of suppression
strategy was inevitable.
– The most difficulty was the decision of when suppression can be lifted.
The timings of lifting suppression varied by country.
– Only after no newly reported cases continued for several days, lift the suppression: China, NZ, Taiwan– Soon after daily new cases decreased to the level within medical treatment capacity: USA, Europe, Japan, ...
Behavioral restriction partly violates basic human rights and gives damage to economic activities.
→ Compensation for economy is needed→ Comprehensive prediction based on several scenarios is required
Public health specialists should address such comprehensive intervention policy. Specialists in Taiwan and NZ
did so. Advisory committee (as the representative of specialists) in Japan didn't.
February 4, 2022

29

Situation until 30 Jan 2022
https://covid19.who.int/
●

●

●

●

●

●

Until 30 Jan 2022
Until 8 Dec 2021
Until 20 Dec 2020
Cumulative cases:
373,229,380–
Until 8 Dec 2021: 267,184,623
順 Country Cum.cases Country Cum.cases Country Cum.cases
位–
Until 20 Dec 2020: 74,879,038
1 USA
73,531,094 USA
49,106,224 USA
17,314,834–
Until 10 Nov 2020: 50,459,886–
Until 9 Oct 2020: 36,754,395
2 India
41,302,440 India
34,666,241 India
10,031,223
Cumulative deaths:
5,658,702
3 Brazil
25,214,622 Brazil
22,157,726 Brazil
7,162,978–Until 8 Dec 2021: 5,277,327
4 France
18,574,875 UK
10,610,962 Russia
2,819,429–
Until 20 Dec 2020: 1,676,236
5 UK
16,468,526 Russia
9,925,806 France
2,401,113–
Until 10 Nov 2020: 1,257,523–
Until 9 Oct 2020:
1,064,838
UK showed relapse after
NZ and Taiwan succeeded the containment several
lifting almost all NPIs
times, but experienced several relapse by imported
since summer 2021
cases.
← It was criticized as
Until the end of 2020, Mongolia, Uganda, Vietnam, Lao"barbaric experiment"
PDR, Cambodia, PNG, Solomon Islands, where hadsmall number of cases and less aging population, had
Cumulative deaths until 30 Jan 2022 and rough CFR
zero death.
Rank Country
Cum. Deaths rough CFR(%)–
All those showed many cases in 2021,
subsequently considerable number of deaths.
1
USA
875,755
1.19
Most small oceanic countries such as Vanuatu, Samoa,
2
Brazil626,524
2.48
Tonga had only a few cases with no death. FSM has no3
India495,050
1.20
cases. Due to rigid border control and quarantine.
Fiji and New Caledonia had many cases and deaths.
4
Russia331,349
2.79
February 4, 2022

5

Mexico305,762306.22Governmental responses by country（ https://www.coronanet-project.org/）●●

https://www.nature.com/articles/s41562-020-0909-7
The database of 96,739 COVID-19 related governmental responses
from 198 countries in total. Manually classified and scored.

PolicyClosure of shopping malls
Restriction commercial business
Closure of retail stores
Closure of personal grooming
Primary school closure
High school closure
Higher education closure
Restriction of other business
Sanitizer policies
Closure of restaurants
Quarantine at homePre-school closure
Mobilization of volunteers
Other health staff
Restriction of mass gatherings
Test production
Mobilization of doctors
Mobilization of nurses
Internal border restrictions
Limited quarantine
Other health resources
Social distancing
Other health facilities
Other health resources
Mobilization of ventilators

February 4, 2022

Median activity index
1.7
1.7
1.5
1.4
1.3
1.2
1.1
1.1
1
1
1
1
0.9
0.9
0.9
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8
0.8

In USA, mask policy was enhanced
since Jan 2021.

31

What kind of factors may determine
governmental responses?
●●●

Age structure– LMIC shows lower IFR than HIC, because theproportion of youth population is high.
– HIC is aged, so that IFR tends to be high eventhough the medical standard is high.
The extent of avoidance of economic restriction
by the government– Under the government which does not want to
restrict economic activities, testing, isolation,
treatment, contact tracing, behavioral restriction
and quarantine are suppressed.
– Taking responses such as testing requires
materials and equipment, which costs much.
– Taking responses affects the mental and socioeconomic aspects, to inactivate socio-economic
activities.
The extent of social gap– Poor people living in slum and ethnic minority arevulnerable (less immune against invading
pathogen and inaccessibility to medical care)– If the government focuses less on social justice,response against pandemic becomes inactive.

February 4, 2022●

The responses by LMICs tend to bepolarized to either of the following 2
strategies– (L-strategy) Less restriction on
economic activity, let the infection
expand to establish early herd
immunity. If the age structure is young
and there are many competing causesof death, the IFR by COVID-19 may
be socially acceptable.
– (P-strategy) Due to lack of the lifesaving medical facilities such as
respirator and ECMO, the government
strictly conducted quarantine andborder control to prevent the invasionof pathogen totally since very earlystage of pandemic. → Succeeded in
Polynesian and Micronesian countries.
Especially FSM's cumulative numberof patients is still zero.
32Changes of newly reported cases for selected
countries by 5 strategies
●

●

●

●

●

Japan (black): NPIs with special
emphasis to prevent 3Cs. Suffering 6 thwave now.
Less controls (orange) = L strategy:
Only if the newly reported cases
exceeds the capacity of medical facility,
conduct strong NPIs including
lockdown. Vaccination started earlier
but coverage was not so high → Brazil,
USA, India, Sweden, Russia, UK,
France, Italy, ...
Middle level controls (light blue):
Based on extensive testing and contact
tracing, early isolation introduced,
followed by lockdown if necessary →Germany (insufficient isolation andquarantine), South Korea, Iceland,
Singapore, New Zealand and Taiwan(early lockdown until suppression)
Strong controls (green): Similar
testing-based isolation and lockdown
were done earlier → Mongolia,
Uganda, Vietnam, Lao PDR, Cambodia
Strongest controls (yellow) = P
strategy: Preventing invasion by rigid
quarantine and border control →Solomon Islands, Vanuatu, FSM, ...
February 4, 2022

33

Changes of newly reported cases in several
Asia-Oceania countries and USA

February 4, 2022

34

Comparison between Bhutan and Nepal

Nepal Bhutan
BhutanHealthmonitoring

Schoolrestrictions
The situation until 31 Dec 2021.
In 2022, Bhutan suffers rapid propagation of cases.

Business
restrictions

Nepal
Mask policies
Business
Schoolrestrictions
restrictions
February 4, 2022

35

Comparison among China, Japan andSouth Korea (NPIs until Apr 2021)
China

February 4, 2022

Japan

South Korea

36

The reason why the spread of COVID-19
was so slow in East Asia (personal view)●●●

Infection via random link route may occur
from a primary case to 0-2, at most 3.
– East Asian countries including Japan
culturally had longer inter-individual
distance (wider personal space).
Greetings is not done by handshake, kissand hug, but by bow and nodding.
– Relatively rich water resources contributed
to establishment of hand-washing habits
using soap.
– In Japan, the importance of handwashing
was emphasized since January 2020.
Due to the 3 reasons shown above, thenumber of transmission from primary case to
secondary cases is mostly 0 or 1 in East Asia,
but mostly 1 or 2 in Europe or USA.
Average of "0 or 1" is less than 1, but averageof "1 or 2" is more than 1, which differentiates
epidemic. The former shows R < 1 and theepidemic will shrink, but the latter shows R >1 and the epidemic will continue to spread.

February 4, 2022

●

●

●

●

Western countries asked people
to keep inter-individual distancelarger than 2 m since Spring
2020, to reduce R.
In addition, Japan and Malaysia
did campaign to avoid 3Cs
situation to prevent theoccurrence of cluster infection(super-spreading events).
There were many countries in
East Asia to suppress by strict
quarantine and/or by doing
contact-tracing and isolation.
Taiwan succeeded containmentand suppression due to testing,isolation and quarantine.
37

The 6 waves of epidemic curve in Japan
●
●
●

●

●

●

●

●

IHR 2005 states the importance of minimizing the effect of response on global traffic and trade.
Originally "wave" refers the sudden increase of patients from imported cases.
The very first wave is often ignored now. It was originated in the traveler from China to Japan in January to February
2020, and was suppressed by the anti-cluster campaign. It was confirmed by genotyping of virus.
So-called 1st wave occurred in late March 2020 by many return migrants from Europe and USA.
–
Prof. Oshitani stated the reason of rapid increase of untraceable patients was hidden cluster. He judged that contact
tracing and isolation were impossible. → Specialists committee suggested issuing emergency condition statement.
●
Emergency call has been issued since 7th April 2020. The government requested to reduce face-to-face contact
by 80%.
●The imported cases from Europe and USA were too large to suppress by anti-cluster measure, which led to thefirst wave.
The essential problems in anti-cluster measure–
Prohibiting the most business activities with compensation may be possible, but some essential workplaces such as
hospital and care facility have to continue, in which avoiding 3Cs is almost impossible. Such workplaces showed
many cluster infections.
–Long-lasting mild suppression of behavior without compensation is impossible for human-being. Rather short-term
strict suppression with compensation seems better.
The 2nd wave occurred in July-August 2020. Lifting of emergency statement for the 1st wave was done after successful
suppression in most prefectures, but lifting was in much earlier stage in Tokyo, led to relapse with additional imported
cases from Europe and USA.
Due to lifting the restriction of immigration since October 2020, "GoTo" campaign, especially "go to eat", lifting the
restriction of mass-gathering events, and other factors, the number of daily new cases suddenly increased since October
2020, which led to the 3rd wave in winter 2020-2021, the management of medical systems faced the risk of collapse.
The 4th wave occurred in spring 2021, the 5th wave occurred in summer 2021, largely due to the delta variant and Tokyo
Olympic. From September to December 2021, suppression continued, but largely due to the invasion of omicron variant,the 6th wave has come to Japan in January 2022.
February 4, 2022
38

Changes of daily new reported cases by prefecturesin Japan (Red: preventive NPIs, Navy: lifting)February 4, 2022

39

Behavioral restriction should be continued
until elimination as "new normal"
●
●
●

●
●

●

The government has to establish the infrastructure to enable remote working.
Mass gathering events should be restricted. Especially with close contact or conversation.
Needed behavioral change– To prevent infection from oneself●
If feel ill, never go out. Test if past close contact with patients and/or suspicious symptoms such as the
body temperature being higher than 37.5 degree C or SPO 2 being less than 90%●
Conversation should always done with face-mask even asymptomatic.
– To the contrary, mask is not necessary in outside, keeping quiet, and no symptom.
– To prevent random link infection●
Frequent hand-washing with soap or sterilization of hand by alcohol●
Keeping inter-individual distance more than 2 meters●
Avoiding face-to-face conversation without mask
– To prevent cluster infection events●
Avoiding 3Cs●
Ventilation. To check the extent, monitoring CO2 levels is usefulhttps://doi.org/10.1021/acs.estlett.1c00183●
https://www.who.int/docs/default-source/coronaviruse/getting-workplace-ready-for-covid-19.pdf
Never stigmatize the infected patients
Almost all behavioral restriction can be lifted after elimination, except for border control, quarantine andsurveillanceThis is the challenge: Can human adapt to new biological environment by establishing the new normal
through social organization, language and technology?
February 4, 2022

40

Vaccination: Once effectively suppressed pandemic,but omicron variant broke the protection

February 4, 2022

41

Using language adequately,
act against infodemic
●

●

●

●

●
●

Enormous amount of information filled the world by the globalization of information network with multichannel– For lay people, it's very difficult to judge correctly what is the right information– Some politician intentionally spread wrong information
WHO has the website for infodemic management
https://www.who.int/teams/risk-communication/infodemic-management/
The Editorial of Lancet Infectious Diseases stated very important thing ("The Covid-19 infodemic"
https://doi.org/10.1016/S1473-3099(20)30565-X， 17 July 2020)– "… sometimes deliberately misleading reactions, such as those of US President Donald Trump or Brazilian
President Jair Bolsonaro. Such miscommunication is not helped by mass media, which are often guilty offavouring quick, sensationalist reporting rather than carefully worded scientific messages with a balanced
interpretation. The outcome is erosion of public trust and a sense of helplessness, the perfect conditions
for the spread of harmful misinformation that begins a vicious circle"– "Although we have long worked with authors and media outlets to create factually correct, unbiased stories
fit for public consumption, perhaps now is the time for a more proactive response. Journals (including thisone) should consider actively countering misinformation about themselves and the work that they publish."
The Editorial of New England Journal of Medicine stated ("Dying in a Leadership Vacuum"
https://www.nejm.org/doi/full/10.1056/NEJMe2029812， 8 Oct 2020)– "Our current leaders have undercut trust in science and in government, causing damage that will certainly
outlast them. Instead of relying on expertise, the administration has turned to uninformed “opinion leaders”
and charlatans who obscure the truth and facilitate the promulgation of outright lies"
Fact check is very important, but it's difficult for lay people.
To revive the trustworthiness of scientific information, regular polite explanation from the single responsible
authority is effective, as done in NZ and Taiwan.
February 4, 2022

42