Vol.10 (2020/6/25) Global situation / Infection risk due to relaxed entry / Report from China: Antibody levels are declining / etc.

[1] COVID-19 cases are still increasing around the world

The number of cases is increasing every day around the world (more than 15 new cases each day). The current center of infection is shifting to Central and South America.

(Figure 1) Trends in the number of cases worldwide (as of June 2020, 6)

Source: Johns Hopkins University "CORONAVIRUS RESOURCE CENTER"
https://coronavirus.jhu.edu/map.html

The number of deaths worldwide is also increasing in Latin America.
The total number of people infected so far is approaching 900 million, with 46 deaths.

(Figure 2) Changes in the number of deaths worldwide (as of June 2020, 6)

(Figure 3) Global distribution of cases and deaths (as of June 2020, 6)

Source: FINANCIAL TIMES “Coronavirus tracked: the latest figures as countries start to reopen”
https://www.ft.com/content/a26fbf7e-48f8-11ea-aeb3-955839e06441

[2] Special lecture by Professor Nishiura: "Risks of relaxing entry restrictions, simulation"

Professor Susumu Nishiura, a professor of hygiene in the Department of Social Medicine at the Graduate School of Medicine, Hokkaido University, who has been analyzing the COVID-19 pandemic using mathematical models, has pointed out that international travel is a major infection risk in Japan after the state of emergency is lifted.
How many people would need to enter Japan from countries with high infection rates to cause a large-scale outbreak?
The mathematical model shows only one hypothesis. Even if the state of emergency is lifted, we need to understand that there are still risks lurking and think about the new normal.

Using the "branching process model," we can calculate the probability that the infection will disappear when a single infected person invades somewhere. Here, we will use a realistic value of "19" for the R (effective reproduction number) of COVID-1.6. Let's assume that these are the values ​​when various countermeasures are being implemented in Japan and people's behavior is changing.
The parameter that represents the variation is set to "0.1." This corresponds to "about 10 in 1 infected people will develop a secondary infection." Until now, epidemiological data observed in Japan has suggested that "2 in 5 people will develop a secondary infection," but a statistical estimate by a team at the London School of Tropical Medicine and Hygiene and others has shown that the figure is "approximately 1 in 2 people."
Based on these "1.6" and "0.1" values, if one person infected with COVID-19 enters the country and that person's contacts are not tracked and are allowed to move freely, the probability that the virus will die out naturally without causing an epidemic is q = 1 (or 0.9226%). This is the "extinction probability." With that one person's entry, the probability of an epidemic occurring is only about 92.3%.

Setting: Calculate the probability of causing a large-scale epidemic in Japan when entering from a country or region with an infection rate of 3% (alternatives are 0.1% and 1%) equivalent to "Level 0.0005" in the Ministry of Foreign Affairs' "Infectious Disease Risk Information," i.e. a country or region that is subject to a ban on entry. The infection rate was calculated in three stages while assuming the destination country. "3%" corresponds to South Korea and China, etc., where the epidemic has been almost controlled. "0.0005%" is Russia and Brazil, for example, in recent times. "0.1%" is a state where the risk of infection is extremely high and Japanese people were rescued by charter flights (about 1% in Wuhan, China).

The calculation is based on the probability of 1000 people entering the country per day (alternatives are 2000, 4000, and 8000 people per day). If multiple flights arrive, especially from the United States or China, a situation could easily arise in which 1 to 2000 people enter the country per day.

■ Calculation results of epidemic probability

(Table 1) Simulation results by Professor Nishiura

90日間の入国者数が、9万人、18万人、36万人、72万人は、1日の入国者数で言うと、1000人、2000人、4000人、8000人に対応しています。
For example, if passengers have a 0.1% chance of being infected, allowing everyone into the country without quarantine will result in a near 100% chance of a large-scale epidemic. If people are detained, this goes down slightly, and if they are detained and undergo PCR testing, it goes down even further. Even so, if the number of people entering the country is large, it will be impossible to prevent a large-scale epidemic.
If the infection rate were higher, at "1.0%," even if we conducted quarantine and PCR tests, there would be almost a 100% chance of a large-scale epidemic. "No matter what we do, the situation is tough," and if we resume travel to these countries, an epidemic will definitely occur unless we take appropriate measures domestically. Such entry into the country may have occurred when the pandemic was spreading within the country, for example, from early to mid-March. If there are a lot of people entering the country, an epidemic will occur.
On the other hand, if travel were to resume between countries with a low infection rate of 0.0005%, such as China and South Korea, it would be fine as long as there were not too many people entering the country. However, if there were too many people entering the country, the risk of an epidemic would exceed 25% without quarantine. We can see that this situation can be prevented by implementing quarantine or "quarantine + PCR."

I ask that people who travel across borders not be subjected to unjustified discrimination and that foreign nationals not be treated unfairly. The pandemic is an obstacle that the whole world must overcome, and I hope that politicians will make efforts to ensure that no one is disadvantaged too much in any one area, while we all become smarter.

Source: m3.com "Let's think together about international travel during the pandemic ◆ Vol.1 June 2020, 6"
https://www.m3.com/open/iryoIshin/article/780507/

[5] According to Forbes magazine, Japan was ranked XNUMXth safest country by AI.

While the ways in which measures against COVID-11,400 are being taken vary greatly from country to country, one initiative is visualizing each country's level of safety by comprehensively analyzing each country's efforts from both quantitative and qualitative perspectives using over XNUMX pieces of data.
Japan was ranked 5th safest country (as of June 2020).
This indicator is just one of many in the world, but from a global perspective, it may be said that Japan has (as a result) been able to control the COVID-1 pandemic.

(Figure 4) Top 20 Safe Countries for COVID-XNUMX

Source: Forbes “The 100 Safest Countries In The World For COVID-19” 2020/6/13
https://www.forbes.com/sites/johnkoetsier/2020/06/05/the-100-safest-countries-in-the-world-for-covid-19/#53a7f14468c5

1.Switzerland, 2.Germany, 3.Israel, 4.Singapore, 5.Japan
6.Australia, 7.China, 8.Australia, 9.New Zealand, 10.South Korea
11.United Arab Emirates, 12.Canada, 13.Hong Kong, 14.Norway, 15.Denmark
16.Taiwan, 17.Saudi Arabia, 18.Hungary, 19.Netherlands, 20.Vietnam

[4] How should we interpret the report from China that COVID-19 antibodies turn negative several months after infection?

There has long been interest in COVID-19, including whether immunity can be developed or whether it is a disease that can be contracted multiple times.
On this point, infectious disease specialist Dr. Kutsuna Masashi has published an article based on the latest research papers.

A report from China on antibodies in the acute phase (when the virus is detectable in respiratory samples) and recovery phase (8 weeks after discharge from hospital) was published in Nature Medicine.
Antibodies are produced in the body as a result of the body's immune response and are one of the weapons used to attack foreign substances such as microorganisms.
The higher the amount of antibodies, the greater the resistance to the pathogen, and thus is an indicator of immunity.
The study reported this time compared antibody titers (amount of antibodies) in 37 asymptomatic and 37 symptomatic infected individuals during the acute and recovery phases.
According to this, antibodies in COVID-19 patients, both asymptomatic and symptomatic, have already begun to decline during the recovery phase.

(Figure 5) Changes in antibody titers and neutralization rates in COVID-XNUMX patients during the acute and recovery phases

Source: https://doi.org/10.1038/s41591-020-0965-6

In the COVID-8 recovery phase (40 weeks after discharge from hospital), IgG antibodies appear to be negative in 12.9% of asymptomatic infected individuals and XNUMX% of symptomatic individuals.

(Figure 6) Percentage of COVID-XNUMX patients whose antibodies become negative during the recovery phase

Source: https://doi.org/10.1038/s41591-020-0965-6

Until now, it was thought that antibody testing could be used to assess how many people have recovered from COVID-0.1, but if there is a certain percentage of people whose antibodies decline early, it becomes difficult to know how to assess those who have already been infected. The commonly reported assessment method of "XNUMX% of people in Tokyo are antibody positive" assumes that people who test positive for antibodies once will remain positive for a long period of time, but in fact it only picks up "people who currently have antibodies" and may not pick up people whose antibodies decline over time after infection.

(Figure 7) Anamnestic immune response (created by Dr. Kutsuna)

It is still unclear whether people can be infected with COVID-19 multiple times.

It is possible that those who test negative for these antibodies may be reinfected with COVID-19. It is too early to say anything about this.
Antibodies are an indicator of the "humoral immunity" of human immunity, but human immunity consists of not only "humoral immunity" but also "cellular immunity," and antibodies, which are an indicator of humoral immunity, only look at one part of the immunity.
Furthermore, experiments on rhesus monkeys have confirmed that once an infection occurs, the next time the monkey is exposed to the virus, a rapid and large amount of antibodies are produced from memory cells, resulting in an anamnestic immune response that prevents the onset of the disease.
In the case of COVID-19, if reinfection occurs within a certain period of time, this previous antibody response may be able to prevent onset of the disease even if the antibody test is negative.

It is known that human coronaviruses can cause reinfection even after one infection, which is thought to be due to an early decline in antibodies. However, reinfection appears to shorten the period of viral shedding and reduce symptoms. If humans are infected with the new coronavirus multiple times, its pathogenicity may gradually decrease with each infection, and in the future it may circulate between humans and animals as one of the pathogens causing colds.

We need to wait for further information to find out whether the current "life of coexisting with COVID-19" is temporary or something we must accept as permanent, but in any case, what we can do at this stage remains the same. Let's continue to steadily take individual infection prevention measures, such as avoiding the three Cs and washing our hands frequently.

Source: Yahoo! News: Article by infectious disease specialist Dr. Masashi Kutsuna
https://news.yahoo.co.jp/byline/kutsunasatoshi/20200621-00184351/

Original publication: Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections
Nature Medicine (2020) Letter Published: 18 June 2020
https://www.nature.com/articles/s41591-020-0965-6

[5] Antibody prevalence in the general population and in medical facilities in Europe, especially Belgium

[Excerpt from BMJ NEWS]

In Belgium, which has one of the highest infection rates in Europe, a survey was conducted on antibody possession rates among medical staff working at key hospitals and the results were recently published in a paper.

(Figure 8) Covid-11 infection rates in 19 European countries

Source: Wise J. Covid-19: Risk of second wave is very real, say researchers. BMJ.
2020;369:m2294. Published 2020 Jun 9. doi:10.1136/bmj.m2294
https://www.bmj.com/content/369/bmj.m2294

The positive COVID-3,056 antibody rate among 6.4 employees at a Belgian medical institution was XNUMX%.

Although Belgium has a high death toll, the infection rate (antibody positivity rate) among staff at one major hospital was 6.4%.
As shown in Figure 8, the infection rate (antibody possession rate) in Belgium was 8%, so the rate was not particularly high among medical professionals, but the results showed that the antibody possession rate was three times higher if there was an infected person in the household.

In addition, even among those who tested positive for antibodies, one in six had no symptoms, and there was no difference between those who worked directly caring for coronavirus patients or not.
This paper reiterates the importance of following the basics of infection prevention.

Furthermore, the paper also presents data showing the relationship between subjective symptoms and positivity rate, and the high antibody positivity rate among people with olfactory disorders is striking.

(Figure 9)

Source: Hospital-Wide SARS-CoV-2 Antibody Screening in 3056 Staff in a Tertiary Center in Belgium [published online ahead of print, 2020 Jun 15]. JAMA.
2020;10.1001/jama.2020.11160. doi:10.1001/jama.2020.11160
https://jamanetwork.com/journals/jama/fullarticle/2767382

[500] Hypothesis based on XNUMX antibody tests in Tokyo: The number of infected people in Tokyo is...

Following China and Belgium, we will introduce a pioneering case of antibody testing in Tokyo, Japan.
As Dr. Kutsuna's article states, there is a possibility that antibodies may decrease even in people infected with COVID-8 during the recovery phase, so it cannot be denied that the number of infected people in Tokyo may be higher than the number stated in the article that follows (XNUMX people).

■ Antibody testing in Tokyo: Positive rate is 0.6%

A team led by Professor Emeritus Tatsuhiko Kodama (Project Leader for Cancer and Metabolism) of the University of Tokyo's Research Center for Advanced Science and Technology conducted random antibody tests for the new coronavirus at general medical institutions in Tokyo on May 5st and 1nd. The results showed that three of the 2 samples taken from people in their teens to 10s were positive (90%).
The antibody tests conducted were highly reproducible and stable, and did not react to the four types of cold coronaviruses.
Health, Labor and Welfare Minister Katsunobu Kato also recently announced that of 4 samples randomly selected from blood donations collected in Tokyo and six Tohoku prefectures in April, three positive cases (6%) were found in Tokyo and two positive cases (500%) in Tohoku.
The government plans to conduct antibody tests on a scale of 6 by June. Until now, it was unclear how widespread the infection was in Tokyo, which has the highest number of infected people in the country.
Kodama said that the fact that about 1398 people, or 0.6% of Tokyo's population of 8 million, are infected is a good indicator. The number of infected people in Tokyo is 5070, so this is about 16 times higher.

■ Antibodies are produced differently

Taking hepatitis B as an example, first the IgM type of antibody (the first antibody produced when infected with a pathogen, pink dotted line) appears, followed by the IgG type (produced in earnest after IgM is produced, pink solid line), which leads to recovery. "After that, when neutralizing antibodies (dark blue solid line) appear, the person develops immunity that prevents the infection from recurring."

(Figure 10) From Professor Kodama's slide

"Precise measurements of the new coronavirus have revealed a tendency in Japanese people for the IgM (pink dotted line) reaction to be slow and weak. "When we actually look at the reaction to the new coronavirus, we have found that IgG reacts first, and the IgM reaction is weak," he said. "Looking at the results that have been studied at clinical institutions and will be published in the future, IgM (red dotted line) rises quickly in severe cases. In mild cases (depicted by thin lines) and other cases, the IgM reaction is slow. In severe cases, the IgM reaction occurs normally."

(Figure 11) From Professor Kodama's slide

(Figure 12) From Professor Kodama's slide

■ Hypothesis of the SARS-X epidemic

"People who say they're only suffering from mild symptoms have already been infected with various coronavirus subtypes. There may be more of these people in East Asia. There is a possibility that they are particularly prevalent along the coast."
"In such cases, there is no IgM reaction, but an IgG reaction occurs. The sequence of the new coronavirus is also rapidly evolving. It is known that antibodies against SARS (Severe Acute Respiratory Syndrome) from 2002-03 also react to the new coronavirus."
"Is it possible that a different coronavirus (SARS-X) has actually been circulating in East Asia since the SARS epidemic?"
"As a result, it is possible that infections in East Asia may have provided immunity that would have produced IgG first compared to Western countries."
"However, this is still an academic hypothesis, so academic research will continue while observing the response of the new coronavirus."

In the future, large-scale antibody testing will be used to diagnose and determine the severity of the disease, and research will be conducted to determine whether the silent spread of SARS-X had given Japanese people prior immunity to the new coronavirus.

Source: Yahoo! News "8 people infected in Tokyo" Estimated from antibody tests Did SARS-X protect Japan from COVID-XNUMX?
https://news.yahoo.co.jp/byline/kimuramasato/20200520-00179344/

■ In the world's papers, IgM antibodies have come out first. (Unlike in Japan!)

After infection with the new coronavirus, IgM antibodies are produced about one week, and IgG antibodies, which have a high affinity for the virus, appear about two weeks later, and the number of infected people whose virus disappears is increasing.

(Figure 13)

Source: Nature “A pneumonia outbreak associated with a new coronavirus of probable bat origin”
Nature 579, 270-273(2020)
https://www.nature.com/articles/s41586-020-2012-7
https://www.ric.u-tokyo.ac.jp/topics/2020/ig.html（上記図13）

[7] The possibility of an asymptomatic person infecting others is "extremely rare"

When large-scale antibody testing is conducted, it is expected that asymptomatic infected people (asymptomatic infected people) will be identified to a certain extent. However, according to the WHO, it is known that the possibility of asymptomatic infected people infecting others is low, so there is no need to be worried about the antibody test itself.

At a press conference on the novel coronavirus disease (COVID-6) held on June 9 (Swiss time), the World Health Organization (WHO) stated that with regard to the possibility of asymptomatic infected individuals transmitting the virus to others, "based on the data we have at present, it remains extremely rare" (explaining the reason for this, "We have received many reports from various countries that have investigated the infection routes in detail, and these include asymptomatic infected individuals, but secondary transmission by asymptomatic infected individuals has not been confirmed," and added that "most of these reports have not been published in papers." They then stated, "We will continue to closely monitor this data and hope to arrive at a more definitive answer based on more reports.").

Source: Medical Tribune, "COVID-2020 is 'extremely rare' in asymptomatic individuals, WHO holds press conference, June 06, 09"
https://medical-tribune.co.jp/news/2020/0609530570/?_login=1#_login
https://twitter.com/WHO/status/1270013794366812160

[8] A large-scale antibody testing project for the new coronavirus has begun

Once again, how many people are (or have been) infected with COVID-19 (including asymptomatic cases)?
As one effort to investigate this, plans are underway for large-scale antibody testing.

■ Steering Committee of the Council for Users of the Novel Coronavirus Antibody Testing Machine (abbreviation: Council Steering Committee)

The Council Steering Committee will carry out the following academic tasks to enable practical personnel at institutions that have introduced, or are considering introducing, equipment aimed at quantitatively, fully-automatically, safely, and in large numbers to detect antibodies to SARS-CoV2, to share information on diagnosis, treatment, epidemiology, and basic science.

This project was launched by researchers from three university hospitals (University of Tokyo Hospital, Keio University Hospital, Osaka University Hospital) and three research institutes (University of Tokyo RCAST, University of Tokyo Radioisotope Center, Tokyo Metropolitan Institute of Medical Science) with the aim of measuring two types of antibodies (IgM and IgG) against SARS-CoV2 and clarifying their significance in diagnosis, progression, and severity assessment (approved by the ethics committees of each institution). It consists of domestic epidemiological and clinical surveys, and quantitatively measures IgG and IgM in a large number of cases across the nation.

In preliminary studies conducted so far, many patients infected with the new coronavirus in Japan did not show an early increase in IgM, while almost all patients showed an increase in IgG by the second week after infection. Based on these results, it is hoped that measurements will be conducted on as many samples as possible as early as possible to clarify the significance of this antibody test.

■ Preliminary measurement results of IgG and IgM antibodies in Japan

In a preliminary study, more than 9% of patients were IgG positive from the XNUMXth day after the estimated onset of symptoms. However, if the measurement date is earlier than this, IgG may be negative. On the other hand, it is becoming clear that even in PCR-positive patients, IgM does not become high in the early stages after infection in many cases (XNUMX-XNUMX%). In patients in whom IgM does not easily increase, it is necessary to consider whether immunity is well established.

The neutralizing activity of the antibodies being measured this time is unknown. Therefore, we will have to wait for future research to see whether antibody-positive individuals will acquire an "immunity passport" as reported in the media. In particular, it is known that many people have weak IgM responses to COVID-19 infections, and there are concerns that reinfection may occur due to poor immune function. It is also known that even if IgG levels increase, the condition may worsen if the neutrophil/lymphocyte ratio is high, and that reinfection can occur even if the virus has disappeared once.

Source: The University of Tokyo Radioisotope Center website
https://www.ric.u-tokyo.ac.jp/topics/2020/ig.html

In preparation for a second wave, we await the results of these surveys and other research as soon as possible.