Vol.21 (2021/06/11) Antibody-positive patients at our clinic / Latest trends in Japan and the world / Neutralizing antibodies / Vaccination of those already infected / Summary of tests by time of infection, etc.

[1] Antibody positivity rate at our clinic

The antibody positivity rate from April 4th to May 15th decreased slightly, but remains higher than the data released by the government.

Figure 1: Antibody positivity rate at our clinic

The above antibodies indicate SARS-CoV-2 infection (whether you have been infected with a coronavirus before) and do not react to the COVID19 vaccine. Neutralizing antibodies react after vaccination. In the future, we plan to list both types of information together. (For more information on neutralizing antibodies, see Chapter 4.)

[2] The situation in Japan

The peak of the fourth wave has passed, but the trough has not yet come, and it is clear that we need to be careful.

Figure 2021: Number of new positive cases and number of people requiring hospitalization (as of June 6, 10)

Source: Ministry of Health, Labor and Welfare "Domestic outbreak situation, etc."
https://www.mhlw.go.jp/stf/covid-19/kokunainohasseijoukyou.html

[3] Global situation

It is clear that the number of new infections in Japan is close to that in the United States, the United Kingdom, and Europe. This is probably due to the effect of the vaccine. (Compared by the number of patients per 10 population)

Figure 2021: Trends in the number of new infections (Comparison between the EU, US, UK, and Japan; as of June 6, 10)

Comparing Asian countries, the number of patients in India has decreased, while the number in Taiwan has increased (compared by the number of patients per 10 population).

Figure 2021: Comparison of new infection numbers (Japan, Thailand, Taiwan, South Korea, and India; as of June 6, 10)

The number of people vaccinated.
This shows how many doses are being administered per 100 people. Japan is finally seeing an increase in vaccinations.
It appears to be 4-5 months behind the US and UK.

Figure 2021: Trends in the number of people vaccinated (Comparison between the UK, Israel, US, EU, and Japan; as of June 6, 10)

Source: Financial Times Coronavirus tracked: see how your country compares
(Figures 3,4, XNUMX) https://ig.ft.com/coronavirus-chart/
(Figure 5) https://ig.ft.com/coronavirus-vaccine-tracker/

[4] What is a neutralizing antibody?

New neutralizing antibody tests are useful after vaccination

1) Regarding virus structure

The spike protein (S) on the outermost side is involved in infecting cells. Other proteins include the envelope protein (E), membrane protein (M), and nucleocapsid protein (N), as well as RNA.

Figure 6: Structure of the new coronavirus (National Institute of Infectious Diseases)

2) Regarding vaccines

The new coronavirus (SARS-CoV-2) uses the spike protein to attach to cells.
Most of the new vaccines work by producing antibodies against this spike protein, blocking (neutralizing) its function.
The Pfizer and Moderna vaccines are messenger RNA vaccines. The AstraZeneca and Johnson & Johnson vaccines are viral vector vaccines. When administered, all of these vaccines produce spike proteins in the body and induce antibodies against them.

3) Antibodies and antibody testing

Previous antibody tests have used the virus's nucleocapsid protein (N) as an antigen.
It is used to determine whether a person has been infected with the new coronavirus (SARS-CoV-2).
Neutralizing antibodies are antibodies that bind to the virus and interfere with (neutralize) the virus's ability to infect cells. Antibodies against the spike protein (S) are examples of neutralizing antibodies. By measuring neutralizing antibodies, we can measure whether the vaccine has worked and how well the vaccine protects against the virus.

4) Summary

Until now, antibody tests have been used to check for a history of novel coronavirus infection (COVID-19).
The new neutralizing antibody test will examine the effectiveness of the vaccine and its ability to prevent infection.
Conversely, people who have had COVID-19 will test positive for both antibody and neutralizing antibody tests. However, the antibody titer will decrease over time.
For those who have not had a history of infection and have been vaccinated, neutralizing antibodies alone will increase after two weeks. After two doses of the vaccine, neutralizing antibodies will increase significantly.
It has been reported that people with a history of infection can experience a sufficient rise in neutralizing antibodies with just one vaccination. For this reason, it is worth testing for neutralizing antibodies early on.

[5] Neutralizing antibodies appear to persist for some time.

Professor Yamanaka Takeharu of clinical statistics at Yokohama City University and his colleagues reported the results of a large-scale study measuring neutralizing antibodies 19 months after infection in COVID-12 survivors at a press conference held on May 5. "Although there was a slight decrease from six months after infection, the majority of COVID-20 survivors still had enough neutralizing antibodies to block infection 6 months later. In addition, neutralizing antibodies against mutant strains tended to decrease compared to conventional strains, with the decrease being particularly noticeable in mild and asymptomatic cases," he said.

● The positive rate after one year was 1%
The analysis showed that for the conventional strain, the neutralizing antibody positivity rate at 12 months after infection was 97%, a slight decrease from the 6% at 98 months, but the majority still maintained sufficient antibodies to block infection.

Figure 6: Neutralizing antibody positivity rate 12 and XNUMX months after natural infection (conventional strain)

● Mutant strain: The rate in the mild and asymptomatic group is declining, at 68.7-79.1%.
Regarding mutant strains: The neutralizing antibody positivity rate for the UK strain was 6% at 88.4 months and 12% at 84.4 months. Similarly, it was 85.6% and 81.6% for the Brazilian strain, 75.2% and 74.8% for the South African strain, and 80.4% and 75.2% for the Indian strain. The decline in the neutralizing antibody positivity rate after 12 months was also small for mutant strains.

Figure 6: Neutralizing antibody positivity rate 12 and XNUMX months after natural infection (summary of mutant strains)

Source: Medical Tribune, "Coronavirus neutralizing antibodies persist even one year after infection: Results of large-scale survey reported - Yokohama City University" (May 1, 2021, 05:21)
https://medical-tribune.co.jp/news/2021/0521536481/

[6] Neutralizing antibody tests and comparison of results

The antibody titers for coronavirus neutralizing antibodies vary depending on which company's product is used to perform the test.

[Major manufacturers and product names]

• Roche Elecsys® Anti-SARS-CoV-2 S
• Abbott Architect SARS-CoV-2 IgG II

Since different manufacturers use different testing methods, it is difficult to compare data between companies, but the following paper provides some insight.

Figure 9: Distribution of neutralizing antibody reaction status by testing company

Source: OXFORD ACADEMIC Clinical Chemistry
Commercial Serology Assays Predict Neutralization Activity against SARS-CoV-2
Clin Chem. 2021 Jan 30;67(2):404-414
https://academic.oup.com/clinchem/article/67/2/404/5934505

The median neutralizing antibody levels in patients with positive results were as follows:

Figure 10: Summary of median and cutoff values

S/C and COI roughly correspond to a certain number of times each company's cutoff value (positive determination standard value).
The cut-off value for Roche is 1AU, and the cut-off value for Abbott is 50AU.
Assuming the medians are close, Roche's 25.5 AU is comparable to Abbott's 340 AU.
This ratio is not necessarily equal for all values.

[7] Increase in neutralizing antibodies after administration of the Pfizer vaccine

Neutralizing antibodies were also produced against the mutant strain.

A research team led by Professor Takeharu Yamanaka of the Department of Clinical Statistics at the Yokohama City University Graduate School of Medicine has revealed that the COVID-19 vaccine currently being administered induces the production of neutralizing antibodies against not only conventional strains but also various mutated strains, and is expected to be effective in terms of humoral immunity.

<Key points of the research results>

• The effectiveness of the Pfizer vaccine was investigated in 111 Japanese vaccine recipients (105 uninfected and 6 infected) from the perspective of the rate of neutralizing antibodies (humoral immunity).
• Utilizing the company's unique rapid antibody measurement system, the "hiVNT COVID-7 Mutant Panel," neutralizing antibodies against a total of eight strains, including conventional strains and seven mutant strains, were measured.
• Among previously uninfected people who received two doses of the vaccine, 2% had neutralizing antibodies against the conventional strain, and 99-501% had neutralizing antibodies against the three currently circulating strains carrying the N3Y mutation (strains first identified in the UK, South Africa, and Brazil).
• Utilizing the company's unique rapid antibody measurement system, the "hiVNT COVID-7 Mutant Panel," neutralizing antibodies against a total of eight strains, including conventional strains and seven mutant strains, were measured.
• Among previously uninfected people who received two doses of the vaccine, 2% had neutralizing antibodies against the conventional strain, and 99-501% had neutralizing antibodies against the three currently circulating strains carrying the N3Y mutation (strains first identified in the UK, South Africa, and Brazil).
• There was no trend toward a decrease in the positivity rate of neutralizing antibodies against the strains of concern originating from India.
• Approximately 8% (9/93; 105%) of the participants tested positive for neutralizing antibodies to all eight strains.
• There were individual differences in how neutralizing antibodies increased. In particular, there were a certain number of people who did not produce neutralizing antibodies against the mutant strain after only one vaccination.

Source: Nikkei Newspaper, "Yokohama City University reveals that approximately 9% of COVID-2021 vaccine recipients possess neutralizing antibodies against the current mutant strain" (May 5, 12, 14:32)
https://www.nikkei.com/article/DGXLRSP610093_S1A510C2000000/

[8] People who have already been infected have lower levels of neutralizing antibodies than those who have been vaccinated, so they still need to get vaccinated.

However, it appears that a single dose is enough to produce a sufficient amount of neutralizing antibodies.

1) Previously presented paper: How much do antibodies increase in previously infected medical workers after the first vaccination?

People who have already been infected with COVID-19 can significantly increase their antibody levels with just one dose of the vaccine.
In those who were not infected or whose antibody titers had not yet increased, the antibody titers increased to about 2X two weeks after the first vaccination, but in asymptomatic and symptomatic infected individuals, the antibody titers increased to 1000X from the seventh day.
Therefore, it was thought that a single dose of the vaccine would be sufficient for those who were already infected, even if they were asymptomatic.

Figure 11: SARS-CoV-2 antibody responses after a single dose of vaccine in healthcare workers

Source: JAMA
Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2. JAMA. Published online March 1, 2021. https://jamanetwork.com/journals/jama/fullarticle/2777171

2) Similar reports have also come out in Japan.

Yoshitomo Morinaga, professor of microbiology at Toyama University, qualitatively evaluated the antibodies acquired by both participants using the neutralizing antibody test (CRNT) method established by the university, and quantitatively evaluated them using a commercially available antibody test. The results revealed that the amount of antibodies in SARS-CoV-2 vaccine recipients was about 19 times that of patients in the convalescent stage of COVID-60. In addition, although the antibodies acquired after vaccination tended to have a lower neutralizing ability against mutant strains than conventional strains, it is possible that the higher amount of antibodies complements the neutralizing ability against mutant strains.

Serum samples were used from 482 patients (19 COVID-74 patients, 2 SARS-CoV-179 negative cases, and 229 unscreened cases) who visited the university hospital and Toyama City Hospital.
The median antibody level in COVID-19 convalescent patients was 35.0 U/mL (interquartile range (IQR) 7.63-137.0 U/mL). However, neutralizing activity against mutant strains (UK and South African strains) was below the reference value in about half of the patients.

Serum samples were collected from 2 employees (aged 740-20) at the university hospital who had received the SARS-CoV-69 vaccine Tojinameran. The median antibody level was high at 2,112 U/mL (IQR 1,275-3,390 U/mL), 19 times higher than that of convalescent COVID-60.3 patients. In addition, although the neutralizing ability of antibodies against the mutant strain was lower than that of the conventional strain, all were above the standard value.

Source: Medical Tribune, "Vaccinated people have 60 times more antibodies than infected people" (June 2021, 06, 04:17)
https://medical-tribune.co.jp/news/2021/0604536705/

paper:
Correlation of the commercial anti-SARS-CoV-2 receptor binding domain antibody test with the chemiluminescent reduction neutralizing test and possible detection of antibodies to emerging variants
https://www.medrxiv.org/content/10.1101/2021.05.25.21257828v1

3) Data from Abbott's neutralizing antibody test

Green indicates uninfected individuals, purple indicates infected individuals. From the left, before vaccination, after the first vaccination, and after the second vaccination.
The uninfected individuals (green) reached an antibody titer of 2 AU, which is considered to be effective in generating neutralizing antibodies, after the second vaccination, while the infected individuals (purple) reached an antibody titer of 1 AU after the first vaccination.
Vaccination can be considered successful if the Abbott Neutralizing Antibody Test reaches 4200 AU.

Figure 12: Distribution of IgG(S-RBD) antibody responses to mRNA SARS-CoV-2 vaccination in individuals with and without prior SARS-CoV-2 infection.

Source: Nature medicine
Antibody responses to the BNT162b2 mRNA vaccine in individuals previously infected with SARS-CoV-2
https://www.nature.com/articles/s41591-021-01325-6

[9] The Japanese Society of Vaccines recommends using the AstraZeneca vaccine

AstraZeneca's (AZ) SARS-CoV-2 vaccine "Bakiszebria Intramuscular Injection" (generic name: coronavirus (SARS-CoV-2) vaccine (recombinant simian adenovirus vector)) was approved as a special case on May 5, but vaccinations continue to be postponed. While there are plans to provide some of the AZ vaccine to Taiwan, where the number of SARS-CoV-21 infections is rapidly increasing, the Japanese Society of Vaccines has expressed the view that "it is essential to utilize it in Japan first."

The incidence rate of thrombosis as a side effect was 100 cases per 6.5 million vaccinations.
The AZ vaccine is a new type of vaccine that uses a genetically modified simian adenovirus vector. Overseas clinical trials have shown that it is 19% effective in preventing the onset of COVID-76 and 100% effective in preventing the onset of severe symptoms and death.

Although extremely rare, cases of embolism and blood clots have been confirmed as post-marketing side effects, and the European Medicines Agency (EMA) has reported that as of April 2021, 4, 4 cases of thrombosis (3,400 cases per million doses) have occurred in approximately 222 million doses of the vaccine. Most of these cases have occurred in women under the age of 100, and are said to occur within two weeks of vaccination.

In a Phase I/II trial conducted in Japan, no cases of thrombosis were reported in 192 patients who received the vaccine.
The society argues that "one idea would be for Japan to also select recipients of vaccination taking into consideration factors such as age, gender, and whether or not they have underlying diseases, and to proceed with administering the vaccine."

Features that are different from other vaccines could be an advantage
He also noted that the vaccine can be stored, transported, and managed at normal refrigeration temperatures (2-8°C) for at least six months and can be administered within the existing medical system. He expressed the view that "its characteristics that differ from other SARS-CoV-6 vaccines that have been approved by special exception in Japan could be advantageous," including that 2) it can be administered individually at general clinics in the same way as influenza vaccines, and XNUMX) it is also suitable for home vaccination in remote areas where it is difficult to transport the vaccine in a stable condition.

Source: Medical Tribune "AZ vaccine must first be used in Japan"
https://medical-tribune.co.jp/news/2021/0603536691/index.html

[10] Japan’s centenarian population has accelerated during the COVID-19 pandemic

From 2014 to 2018, the number of people turning 100 years old each year in Japan remained stable at 3, but from 2019 to 2020, the number of people turning 100 years old increased by about 1 compared to previous years.
Due to the large number of deaths, the net increase in 2020 was XNUMX.
The author speculates that this may also be a result of more people staying at home as a measure to combat the COVID-19 pandemic, which has led to a decrease in viral infections.

Figure 13: Annual trends in the number of centenarians in Japan

Bar graph: Population aged 100 and over
Line graph: Number of people who turned 100 or will turn 100 during the year

Information provided by: Dr. Michiyuki Matsuzaki (Dohoku Kinikyo Asahikawa Kita Hospital)
Paper: OXFORD ACADEMIC
Aoki Y (Matsumoto University Graduate School of Health Science, Matsumoto, Japan.), Mehmet SC. The COVID-19 Pandemic Appears to Have Increased Longevity in Japanese Centenarians. Age Ageing. 2021 Apr 28:afab077. doi: 10.1093/ageing/afab077 . Epub ahead of print. PMID: 33909007.
https://academic.oup.com/ageing/advance-article/doi/10.1093/ageing/afab077/6255737

[11] Summary of coronavirus tests by time of infection: Effectiveness of antigen tests

Dr. Yoshi Yamamoto of the National Center for Global Health and Medicine's International Center for Infectious Diseases explained the selection of tests for "infection control" of SARS-CoV-95 and "disease diagnosis" of novel coronavirus disease (COVID-69) at the 5th Japanese Association of Infectious Diseases/7th Japanese Society of Chemotherapy (May 9-2, held online).

● In terms of infection control, the value of simple, low-cost antigen tests will be reassessed.
The hospital conducts high-throughput polymerase chain reaction (PCR) tests for screening at admission, POCT (FilmArray) for emergency admission, Outpatient care, and antigen testing (Espline) for the emergency outpatient department.

Although antigen testing is slightly less sensitive than NAT, it consumes less medical resources and may be easier to detect SARS-CoV-2 than less frequent highly sensitive PCR testing (Figure). In addition, it has been reported that the positive predictive rate of viral culture-positive cases was 73.3% for PCR testing and 90.0% for antigen detection.

In cases where the possibility of COVID-19 is high, nucleic acid amplification tests such as PCR will be conducted repeatedly to aim for a definitive diagnosis.
*Antigen tests will be positive during the infectious period, so antigen tests are sufficient on-site.

Figure 14: Relationship between viral load, test sensitivity, and test frequency

(BMJ 2021; 372: n208) https://pubmed.ncbi.nlm.nih.gov/33536228/

Source: Medical Tribune, "How to Choose the Right Test for COVID-2021" (June 06, 02 05:15)
https://medical-tribune.co.jp/news/2021/0602536642/index.html