Vol.25 (2022/05/12) Positive antibody test rate at our clinic / Infection trends in Japan and the world / Latest information on mutant strains / Information on newly approved vaccines, etc.

[1] Positive rate of COVID-19 antibody tests at our clinic

The positive rate of COVID-2 antibody tests at our hospital has risen sharply to over 20% since mid-February.

This is thought to be because the neutralizing antibody titer declined about six months after the second vaccination, and Omicron strain infection spread there. Among people in the group who visit medical checkups or outpatient clinics, one in four or five people may have a history of infection, including asymptomatic people.
After that, as the number of people receiving the third vaccination increases, it is thought that the antibody positivity rate will not change significantly.

●2021/12/15～2022/1/14 Number of tests: 147 Number of positive cases: 19 Positive rate (%): 12.9
● January 2022, 1 to February 15, 2022 Number of tests: 2 Number of positive cases: 14 Positive rate (%): 215
● January 2022, 2 to February 15, 2022 Number of tests: 3 Number of positive cases: 14 Positive rate (%): 143
● January 2022, 3 to February 15, 2022 Number of tests: 4 Number of positive cases: 14 Positive rate (%): 158

Figure 1: Positive rate of antibody tests at Tokyo Midtown Clinic

The proportion of people receiving the third vaccination has been increasing, as shown in the pie chart below (Grey has received three vaccinations).

Figure 2: Number of vaccinations

Figure 3: Changes in neutralizing antibodies over time at Tokyo Midtown Clinic

[Legend]
Vertical axis: The rate of decrease (%) in neutralizing antibody values ​​from the second blood draw onward, assuming the neutralizing antibody value at the first blood draw is 1%
Horizontal axis: Number of days since the first neutralizing antibody blood collection (Day 1)

[2] Current status of the outbreak in Japan

We can see that since the beginning of 2022, there has been a significant increase in people infected with the Omicron strain.

Figure 4: Number of new cases reported nationwide

Next is the number of PCR tests and the PCR positivity rate.

Figure 5: Number of PCR tests, number of PCR positive cases, and positive rate
Weekly (March 2021, 3 - April 29, 2022)

The number of tests has increased dramatically this year, and the positive rate is now over 30%.
This is a higher figure than during the fifth wave of Delta strain infections.

What can be inferred from this is that there was a bias in that only those who were strongly suspected of being infected were tested, and that there may have been many asymptomatic people who were not tested.
This could mean that the number of infected people was much higher.
We believe that our antibody positivity rate is quite accurate.

(Source) National Institute of Infectious Diseases: COVID-19 Surveillance Weekly Report: Understanding the current situation regarding outbreak trends
2022年第16週（4月18日～4月24日； 4月26日現在）掲載日：2022年5月2日
https://www.niid.go.jp/niid/images/epi/PDF/COVID-19_2022w16.pdf

[3] Global situation

Since the beginning of 2022, the Omicron strain has been spreading around the world, with the number of infected people increasing at an unprecedented rate.

Since the end of the year, the number of COVID-1 patients has increased sharply, especially in Europe and North America. This sudden increase in the number of patients, which has not been seen in any of the previous epidemic strains, was caused by the Omicron strain. This global epidemic peaked on January 24th and has been decreasing since then, but after a temporary increase from early March to March 3th, mainly in Asia and Europe, it has been decreasing again.

Figure 6: Trends in the number of new infections worldwide (2020-day moving average from February 2, 20 to May 2022, 5)

Source:ourworldindata.org/covid-cases

This is a graph showing the change in the number of deaths from coronavirus. The number of deaths worldwide has increased significantly due to the increase in the number of patients, but since peaking on February 2, the number has been declining worldwide.

Figure 7: Trends in the number of deaths worldwide (2020-day moving average from February 2, 20 to May 2022, 5)

(Source) Tokyo Metropolitan Institute of Public Health, "Global spread of novel coronavirus variants (updated May 5nd)"
https://www.tmiph.metro.tokyo.lg.jp/lb_virus/worldmutation/

In the United States, more than 50% of people have a history of infection, raising the possibility that the disease is becoming more like a "common cold."

Nearly 2% of Americans had been infected with the new coronavirus as of February, including three in four children, according to a new report from the Centers for Disease Control and Prevention (CDC).

According to a research report published by the CDC on the 26th, the percentage of people in the United States with detectable, infection-induced antibodies is estimated to have increased from 2021% in December 12 to 34% in February 22. The sudden increase in Omicron strain infections during the winter highlighted the spread of the virus across the United States.

At the height of the winter wave of Omicron infections, the seven-day average of daily confirmed cases exceeded 1, far surpassing the previous record. Given the increase in at-home testing and the lack of access to tests for many people, it is likely that a significant number of people are not being counted as infected.

(Source) THE WALL STREET JOURNAL "US COVID-60 infections approach XNUMX% = CDC"
https://jp.wsj.com/articles/more-than-half-of-people-in-u-s-likely-had-covid-19-cdc-says-11651014914

[4] Regarding mutant strains

The Omicron strain has given rise to numerous mutant strains, including its substrains.

■ "BA.2" spreads around the world
The new coronavirus is changing as it spreads around the world. The virus that is currently spreading the most around the world is one of the Omicron strains, "BA.1." From "BA.2," genes such as the "spike protein," which is the protrusion on the surface of the virus that acts as a foothold when infecting cells, have mutated.

■ 93% of UK voters and 72% of US voters are BA.2
The percentage of newly confirmed cases that are "BA.2" is
In the UK, health authorities say the rate rose to 2022% in the week up to March 3, 27.
In the United States, the Centers for Disease Control and Prevention (CDC) estimates that the infection rate was 2022% for the week ending April 4, 2.

■ In Japan, 5% of respondents chose "BA.93" in May
日本国内では国立感染症研究所が民間の検査会社のデータをもとに全国での「BA.2」の割合を推定したところ、2022年3月半ばの時点で30％程度でしたが、5月の第1週には93％、6月の第1週には100％を占めるとみられるということです。

"BA.1" had almost completely replaced the previous Delta strain by mid-January 2021, a few weeks after community transmission was confirmed in late December 12.

Although the replacement of "BA.2" with "BA.2" is not as rapid as when community-acquired infections were confirmed in Tokyo in mid-February and the virus was replaced by "BA.1," the replacement is still ongoing.

Feature 1: It is more infectious than "BA.1"
The World Health Organization (WHO) says that BA.2 is more infectious than BA.6, the Omicron strain that was the mainstream in the sixth wave. An analysis of Danish data shows that the generation time, or the time it takes for a person to infect others after being infected, is 1% shorter than that of BA.1, and the effective reproduction number, which indicates how many people one person can spread the infection to, is 15% higher.

Feature 2. Is the rate of severe illness low?
The rate of severe symptoms appears to be low, and the WHO has said that analysis from the UK showed there was no difference in the risk of hospitalization between people infected with "BA.1" and "BA.2."

Feature 3. "BA.1" infection → "BA.2" infection
People infected with "BA.1" can still be infected with "BA.2".

■ Effectiveness of vaccines

ワクチンの効果はイギリスの保健当局の研究者がまとめたデータによりますと、発症予防効果は3回目の接種から▽1週間の時点で「BA.1」は71.3％だったのに対し「BA.2」は72.2％で大きくは変わりませんでした。一方▽15週間以上たった時点では大幅に下がり「BA.1」で45.5％「BA.2」で48.4％でした。

According to a government announcement regarding the progress of the third vaccination, as of April 3, approximately 3% of people aged 4 and over in Japan had completed their third vaccination, and around 11% of the entire population.

Atsuro Hamada, a specially appointed professor at Tokyo Medical University who is familiar with the infectious disease situation overseas, said, "The BA.2 strain has been replaced in most countries around the world, and in some European countries, it has been replaced in over 9% of countries. In Japan too, it will be important to take stronger preventive measures while reducing opportunities for contact and to promote additional vaccinations. As the number of infected people in their 20s is particularly high, measures targeting this generation may be the key to whether we can mitigate the resurgence of cases."

■New type "XE" confirmed for the first time in Japan
In addition, a new mutant virus called "XE," a combination of multiple viruses, has been reported in the UK and other countries. It was also confirmed for the first time in Japan during quarantine.

1. Woman on "XE" confirmed at domestic quarantine after arriving at Narita
On April 4, the Ministry of Health, Labor and Welfare announced that "XE" had been confirmed for the first time in domestic quarantine. The infected person was a woman in her 11s who had entered Japan from the United States, who tested positive at the quarantine station after arriving at Narita Airport on March 30. Genetic analysis of the sample at the National Institute of Infectious Diseases confirmed that it was "XE."

2. "XE" ... "BA.1" + "BA.2"
Viruses undergo small mutations and acquire new properties. In addition, when a single person is infected with multiple types of viruses, genetic recombination can occur, creating a new virus that is a combination of multiple viruses.

"XE" is a type that is a combination of multiple viruses, combining "BA.1" and "BA.2" of the Omicron strain. Most of the part containing the spike protein on the surface of the virus, which serves as a foothold for infecting human cells, is "BA.2," and the other parts are "BA.1."

3. "XE" infection spreads 2% faster than "BA.12.6"

■There are other viruses that combine multiple viruses...
There are other types of viruses that are a combination of multiple viruses, including "XD" and "XF," which are a combination of the Delta strain that spread during the "fifth wave" last summer and the Omicron strain "BA.5."

1. "XD": Mostly Delta strains + spike protein is "BA.1"

2. "XF" - some Delta stocks + mostly "BA.1"

3. "BA.4" and "BA.5" also confirmed...
In addition, other types of mutant viruses called "BA.4" and "BA.5" in which the spike protein gene has been mutated have been confirmed in South Africa and other places.

■ Expert: "Basic everyday measures remain unchanged"
The current number of new infections continues to be higher than the peak of the fifth wave last summer. The Ministry of Health, Labor and Welfare's expert meeting has expressed concern about the possibility of a further rebound.
Further advance the administration of additional vaccines
When going out, avoid crowded places and places with poor ventilation that pose a high risk of infection.
▽ Wear non-woven masks correctly, disinfect and ventilate, and avoid crowds
We once again call for thorough implementation of such measures.

(Source) NHK Online, What are the new coronaviruses "BA.2" and "XE"? What you need to know [4/11] (April 2022, 4, 11:19)
https://www3.nhk.or.jp/news/html/20220411/k10013576501000.html

Figure 8: Data on new infections (number of new infections per day in descending order: as of April 1, 2022)

(Source) Tokyo Metropolitan Institute of Public Health, "Global spread of novel coronavirus variants (updated May 5nd)"
https://www.tmiph.metro.tokyo.lg.jp/lb_virus/worldmutation/

[4] Regarding the fourth vaccination

The effectiveness of the vaccine after the third dose is now being questioned, and consideration is now underway regarding the fourth dose.

Figure 9: Effect of the third vaccination

Let's look at the contents of papers on previous overseas cases.

■ How much will antibodies increase after the fourth dose of mRNA vaccine?
Figure 10: Changes in antibody titers when the Pfizer mRNA vaccine was administered three times and then the Pfizer or Moderna vaccine was administered a fourth time (DOI: 3/NEJMc4)

A study evaluating the efficacy and safety of the fourth vaccine in healthcare workers in Israel has been reported.
The vertical axis shows that the antibody titer is higher after the third vaccination than after the second vaccination, and higher after the fourth vaccination than after the third vaccination, but this is not a very significant change.
After the third vaccination, antibody titers decrease over time, but it has been confirmed that they rise again after the fourth vaccination.

Neutralizing antibodies against the Omicron strain are insufficient even after four doses of vaccination
Figure 11: Changes in neutralizing antibody titers against wild-type, Delta, and Omicron strains (DOI: 10.1056/NEJMc2202542)

The amount of neutralizing antibodies (antibodies that actually neutralize the virus) produced after vaccination varies depending on the type of variant.
Originally, Pfizer and Moderna's mRNA vaccines work by producing the spike protein of the new coronavirus (the so-called wild strain) found in Wuhan inside cells, thereby conferring immunity.
However, the Omicron strain has numerous mutations in the spike protein, giving it a significantly different appearance from the wild-type spike protein.
Therefore, although vaccination with the mRNA vaccine produces a large amount of neutralizing antibodies against the wild-type strain, the amount of neutralizing antibodies produced is insufficient to react to the Omicron strain.

■ The fourth vaccine has an infection prevention effect of 4-11%
Figure 12: Changes in cumulative incidence rates in people who received the fourth dose of the vaccine and those who received up to the third dose (DOI: 4/NEJMc3)

In this study, 4% of people who did not receive the fourth dose of the vaccine (those who had received up to the third dose) became infected with the Omicron strain during the observation period, compared to 3% of the Pfizer group and 25% of the Moderna group, and the infection prevention effectiveness was calculated to be 18.3% and 20.7%, respectively, compared to people who had only received the third dose.

Incidentally, in this study, the proportion of asymptomatic infections among medical workers infected with the Omicron strain was higher in the fourth vaccination group (4-25%), but the viral load was higher in the fourth vaccination group compared to the non-vaccinated group, and the risk of spreading the infection to others if infected is probably the same.

Figure 13: Frequency of adverse reactions occurring after the fourth dose (DOI: 4/NEJMc10.1056)

Furthermore, the side effects that occurred after the fourth vaccination were not significantly different from those after the first three vaccinations.

Figure 14: Side effects of the fourth vaccination

As in the past, side effects such as swelling and pain at the injection site, fatigue, muscle pain, headache, fever, and swollen lymph nodes have been observed. There does not appear to be any increase in side effects compared to the first three doses.

■ For people aged 60 and over, the risk of infection is halved and the risk of developing severe symptoms is reduced to one-quarter
Pfizer issued a press release on March 3th announcing the effectiveness of the fourth vaccination administered to people aged 15 and over in Israel.
According to the press release, elderly people who received the fourth vaccine four months or more after the third dose had half the number of infections and one-quarter of the number of people who became seriously ill compared to elderly people who did not receive the fourth dose.
Based on these data, Pfizer has submitted an application to the US FDA (Food and Drug Administration) for a fourth dose of the vaccine for people aged 65 and over.

Next, let's look at the current state of consideration in Japan.

■ Fourth vaccination in Japan: What is the interval and who should receive it?
An expert committee of the Ministry of Health, Labor and Welfare discussed whether the Pfizer and Moderna vaccines should be used for the fourth dose.

Interval: 5 months
Eligibility: People aged 60 or older and those with underlying medical conditions

■ Preparations to be made by the end of May
In March, the Ministry of Health, Labor and Welfare notified local governments to complete arrangements for venues and preparations for sending out vaccination tickets by the end of May.

■Interval between 4th doses overseas
Figure 15: Trends in various countries regarding the fourth vaccination

Fourth vaccination overseas trends
Country (time period)	Target	interval
Israel (Since December last year)	Over 60 years old Risk of severe illness in those aged 18 and over Medical professionals, etc.	4 months
Germany (February~)	Over 70 years old Age 5 years or older and immunocompromised Nursing home residents	3 months
	Medical professionals, etc.	6 months
France (February~)	Over 80 years old Immunodeficiency	3 months
United Kingdom (February~)	Over 75 years old Elderly people in nursing homes Age 12 years or older and immunocompromised	Approximately 6 months
America (February~)	Over 50 years old Immunodeficiency, such as organ transplants	4 months

■ In the US, fourth vaccination approved for people aged 50 and over
On March 3, the U.S. Food and Drug Administration (FDA) announced that it would approve the fourth dose of Pfizer and Moderna's COVID-29 vaccines for people aged 50 and over.

(Source) Yahoo! News "The effect of the fourth vaccination has revealed the limits of the effectiveness of existing COVID-4 vaccines (Katsushi Kutsuna)" (March 3 (Sun) 20:7)
https://news.yahoo.co.jp/byline/kutsunasatoshi/20220320-00287289

NHK "The fourth dose of the coronavirus vaccine: what are its effects and side effects? The interval between doses should be five months" (April 4, 5)
https://www.nhk.or.jp/shutoken/newsup/20220426a.html

[6] Regarding newly approved vaccines

Recently, a new coronavirus vaccine was approved in Japan, the fourth of its kind. Let's take a look at its features.

On April 4th, the Minister of Health, Labour and Welfare approved the manufacture and sale of Nuvaxovid Intramuscular Injection (generic name: Recombinant Coronavirus (SARS-CoV-2) Vaccine), manufactured by Novavax, a US company, the fourth COVID-4 vaccine in Japan. A supply contract has already been signed for 19 million doses, and Takeda Pharmaceutical will manufacture and sell the vaccine at its factory in Hikari City, Yamaguchi Prefecture, following a technology transfer from Novavax, so there are hopes for a stable supply.

"Mechanism of action" from the package insert

The vaccine consists of purified, full-length SARS-CoV-2 rS nanoparticles stabilized in the prefusion conformation. The addition of the saponin-based Matrix-M adjuvant promotes activation of the innate immune system and enhances S protein-specific immune responses. These two vaccine components are believed to provide protection against COVID-2 infection by inducing B and T cell immune responses (including neutralizing antibodies) against the S protein.

The target population for vaccination is people aged 18 or over. For the first vaccination, 3 mL of the vaccine is administered at three-week intervals without alternating with other products. The necessity of additional vaccinations will be determined "based on the epidemic situation and individual background factors, etc." The third vaccination can be administered at least six months after the second vaccination.

In clinical trials, initial immunization showed a 3% prevention rate in a Phase III trial involving 90.4 people conducted in the US and Mexico, and an 1% prevention rate in a Phase III trial involving 5 people conducted in the UK. The serum neutralizing antibody titers in Japanese people in domestic clinical trials did not differ significantly from data obtained overseas.

Regarding booster immunization, the geometric mean value (GMT) of serum neutralizing antibody titers was 2 14 days after the second vaccination, 724.2 180 days after, and 69.4 3 days after the third vaccination.

Regarding the vaccine's effectiveness against the currently prevalent Omicron strain, the Ministry of Health, Labour and Welfare stated that "although the neutralizing antibody titer was slightly low, a certain level was observed."

Figure 16: Summary of adverse reactions to the Novavax vaccine (from the package insert)

(Source) m3.com "Novavax's COVID-4 vaccine approved by the Ministry of Health, Labor and Welfare, becoming the fourth type approved in Japan"
Manufactured and sold domestically by Takeda Pharmaceutical Co., Ltd. (Tuesday, April 2022, 4)
https://www.m3.com/news/iryoishin/1036337