Vol.23 (2021/09/24) Positive antibody test rate at our clinic / Latest trends in Japan and the world / Decreasing mortality rate after vaccination / Breakthrough infection and neutralizing antibodies / Third vaccination, etc.

[1] Antibody positivity rate at our clinic

We check the positive rate of new infectious antibodies every month during health checkups and outpatient visits.
●From July 7th to August 15th, there were 8 tests, 14 positive cases, and a positive rate of 246%.
●From July 8th to August 15th, there were 9 tests, 14 positive cases, and a positive rate of 386%.
There appears to be an increase in asymptomatic infections with the Delta strain.

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

[2] Japan’s outbreak situation (number of new positive cases, number of serious cases)

The fifth wave has passed its peak, but the number of cases is still high.

Figure 2: Trends in the number of new positive cases (as of September 2021, 9)

Source: Ministry of Health, Labor and Welfare "Domestic outbreak situation, etc."
https://www.mhlw.go.jp/stf/covid-19/kokunainohasseijoukyou.html#h2_1

Figure 3: Trends in the number of seriously injured people (as of September 2021, 9)

Source: Ministry of Health, Labor and Welfare, Domestic outbreak situation, etc. (as of September 2021, 9)
https://www.mhlw.go.jp/stf/covid-19/kokunainohasseijoukyou.html

[3] Global outbreak situation (number of new positive cases, number of deaths, number of vaccinations, etc.)

This is the number of new infections per 10 people. Compared to the UK and US, Japan and the EU have fewer cases.

Figure 4: Trends in the number of new positive cases per 10 people Comparison of the United States, the United Kingdom, the EU, and Japan (as of September 2021, 9)

Next is the number of deaths per 10 people in 7 days. The number of infected people is about the same in both the UK and the US, but the number of deaths is low and under control in the UK. The numbers are lower in the EU and Japan.

Figure 5: Trends in 10-day deaths per 7 people Comparison of the US, UK, EU, and Japan (as of September 2021, 9)

However, when comparing in Asia, the number of new infections in Japan is as high as in Thailand and Vietnam, but for some reason, India is low. We can see that the number in Japan has been declining. China has hardly reported any cases.

Figure 6: Trends in the number of new positive cases per 10 people Comparison of Japan, India, Thailand, China, South Korea, and Vietnam (as of September 2021, 9)

Looking at the number of deaths, we can see that Japan's numbers are much lower than those of Thailand, Vietnam, and other countries.
This explains why a lockdown was implemented in Vietnam, especially since the number of deaths is so high compared to the number of infected people.

Figure 7: Trends in 10-day deaths per 7 people Comparison of Japan, India, Thailand, China, South Korea, and Vietnam (as of September 2021, 9)

Next is the vaccination rate. This is a graph showing how many doses have been administered per 100 people.
Japan's population is increasing rapidly, surpassing the US and reaching the same level as the EU.
Israel and China are at the top of the list.

Figure 8: Trends in vaccine doses administered per 100 people Comparison of the UK, Israel, US, EU, China, India, and Japan (as of September 2021, 9)

The most important information is whether the number of deaths due to COVID-19 has increased compared to average years.
The bar graph below shows the number of excess deaths per 100 million population.
As has been said before, Peru has the highest number of deaths. Brazil, Italy, Spain, the UK and the US also clearly acknowledge excess deaths.
Looking at the bottom, we can see that Singapore, the Philippines, Japan, Australia, and Taiwan have fewer deaths than usual. It can be said that public health control as a whole has been good.

Figure 9: Excess deaths per million population (as of September 100, 2021)

Source: FINACIAL TIMES Coronavirus tracker: the latest figures as countries fight the Covid-19 resurgence (as of September 2021, 9)
https://www.ft.com/content/a2901ce8-5eb7-4633-b89c-cbdf5b386938

[4] It is true that the mortality rate after vaccination has decreased.

The conclusion of the comparison between June and July 2021
●Of the total 141,303 confirmed cases of COVID-65 in July, 135,350 (96%) were under the age of 70. Compared to June, the number of infected people in July decreased among those aged 65 and over, but increased among those under XNUMX.

●Comparing the case fatality rates of people who tested positive for COVID-0.60, the case fatality rate in July decreased from 0.15% to 65% for all ages compared to June, decreased from 4.1% to 2.4% for the elderly (65 years and older), and decreased from 0.076% to 0.047% for those under XNUMX.

●ワクチン接種による新型コロナウイルス感染陽性者の致死率への影響をみると、高齢者における死亡者は、未接種者は3,289人中93人（2.83％）、1回の接種で1,148人中27人(2.35％)、2回の接種で983人中12人(1.22％）であった。

You will notice that the number of infected people is different between unvaccinated people, those who have received one dose, and those who have received two doses.
The mortality rate among the elderly has also declined significantly.

Figure 10

Source: Ministry of Health, Labor and Welfare, 50th COVID-3 Infection Countermeasures Advisory Board (September 9, 1), Document 2021-7, "Number of COVID-XNUMX positive cases and deaths by age group - Also examining vaccination by age group - (July XNUMX)"
https://www.mhlw.go.jp/content/10900000/000826597.pdf

[5] Japanese study on neutralizing antibodies in infected and vaccinated individuals

A team from Toyama University conducted a study using a method called CRNT on people infected with the new coronavirus (SARS-CoV-2) and those who received the SARS-CoV-2 vaccine.

The median antibody level in COVID-19 convalescent patients was 35.0 U/mL (interquartile range 7.63-137.0 U/mL).
The median antibody level after two doses of the vaccine was also high at 2 U/mL (interquartile range 2,112-1,275 U/mL), 3,390 times higher than that of convalescent COVID-19 patients.
* Antibody levels vary greatly depending on COVID symptoms

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

[6] Overseas data on neutralizing antibodies after infection and vaccination

This test examines the effectiveness of antibodies against each strain of the virus, and although it is not a test that is normally performed in medical institutions, it can be used as a reference.

●The virus strains used were the A.1 variant, B.1, B.1.1.7, and N501Y strains.

●The antibody titer in serum samples from convalescent patients was 91-168.

●The antibody titers in serum samples from mRNA-1273 vaccine recipients were 804-1709.

● The effectiveness of antibodies varied depending on the virus strain. Antibody titers were found to be 1273-9 times higher than those of convalescent patients after receiving the mRNA-10 vaccine.

Figure 11: Neutralizing antibody responses to SARS-CoV-2 mutant strains

*The graph has a logarithmic scale. One increase in scale is 1 times.

Source: JAMA Network Neutralizing Antibodies Against SARS-CoV-2 Variants After Infection and Vaccination (Research Letter) JAMA. 2021 May 11;325(18):1896-1898
https://jamanetwork.com/journals/jama/fullarticle/2777898

[7] Even low levels of antibodies in infected individuals may be meaningful

There is concern that COVID-19 variants may escape from neutralizing antibodies acquired by recovered or vaccinated individuals, but this study has found that recovered COVID-19 patients acquire antibodies that cross-link to the variants. It has also been discovered that the quality of these antibodies (neutralizing specific activity and cross-reactivity) improves over time.
Therefore, even if people who have already been infected have low antibody levels, it is still considered meaningful from the perspective of infection prevention.

Figure 12: Changes in antibody quantity and quality over time in infected individuals

The results of this research were published in Immunity on July 2021, 7.
“Temporal Maturation of Neutralizing Antibodies in COVID-19 Convalescent Individuals Improves Potency and Breadth to Circulating SARS-CoV-2 Variants”

Source: Japan Agency for Medical Research and Development (AMED) press release: Discovery that the quality of neutralizing antibodies against novel coronavirus variants improves over time (July 2021, 7)
https://www.amed.go.jp/news/release_20210705-02.html

[1] When an infected person is vaccinated, neutralizing antibodies increase even after one dose, and the neutralizing antibodies do not decrease easily after two doses.

In non-infected individuals, neutralizing antibodies do not increase significantly after the first vaccination, increase after the second vaccination, but decrease significantly after three months.

Figure 13: Neutralizing antibody titers in infected individuals (left) and non-infected individuals (right)

The left shows the neutralizing antibody response of an infected person, and the right shows the neutralizing antibody response of a non-infected person.
V0はワクチン前、V1_20は1回目接種20日後、V2_20は2回目接種20日後、V2_90は2回目接種90日後です。
It appears that those who have already been infected have a good immune and antibody response.

Source: International Journal of Infectious Diseases Faster decay of neutralizing antibodies in never infected than previously infected healthcare workers three months after the second BNT162b2 mRNA COVID-19 vaccine dose
https://www.ijidonline.com/article/S1201-9712(21)00683-4/fulltext

[9] Global standardization of binding and neutralizing antibodies has begun.

In the future, evaluation will be based on BAU and IU.
At our clinic's outpatient clinic, we already have a certificate format in English that indicates antibody titers in BAU and IU.

First of all, the Abbott antibody kit, which we also use in our clinic, is top class in terms of both sensitivity and specificity.

Figure 14

In order to standardize antibody tests conducted around the world, WHO first created a standard serum and had it tested simultaneously at research institutions around the world.
The results are as follows, and the neutralizing activity IU and binding activity BAU of the standard serum were both defined as 1000.
In the future, it will be necessary to indicate the results of each test kit and the corresponding IU and BAU.

Figure 15

According to "WHO/BS.2020.2403 Establishment of the WHO International Standard and Reference Panel for anti-SARS-CoV-2 antibody," when serum after infection was confirmed,
- Serum concentration in convalescent patients with mild infection is about 20-30 IU
- Convalescent serum from moderate infection is about 150 IU
• Convalescent serum from severe infection was around 1000 IU.

Source: National Institute of Health Sciences, Corona Diagnostic Drug Team, Antibody Testing Division: Department of Biopharmaceuticals, Department of Pharmaceutical Safety Science, "Overseas trends regarding performance evaluation of novel coronavirus antibody test kits and the establishment of standard products" (July 2021)
http://www.nihs.go.jp/dbcb/COVID19/COV2_antibody_assay_international_trends_200712.pdf

[10] A study on the level of neutralizing antibodies and subsequent COVID-19 prevention effects.

It also includes previous data on Delta shares, which is helpful.

First of all, the diagram is difficult to understand, but Convalescent is convalescent serum, BNT162b2 is the Pfizer vaccine, and mRNA-1273 is the Moderna vaccine.

The Pfizer vaccine is about 95% effective in preventing infection, and about three times as effective at neutralizing it.
The Moderna vaccine is also about 95% effective in preventing infection, and its neutralizing effect is about four times higher.
We know that some vaccines are less effective.

Figure 16: Relationship between neutralization and preventive effect

In the following figure b, we can see that after 250 days, the neutralizing effect drops from 4 times at first to 1 time (1/4).
However, this only indicates that the 95% preventive efficacy is reduced to 89%, and does not represent a change in neutralizing antibody titers.
In reality, neutralizing antibody titers will decrease by more than 1/4.

Looking at the graph of the initial 95% preventive efficacy in Figure C, we can see that the preventive efficacy for mild infections differs from that for severe infections. The preventive efficacy for mild infections drops from 250% to about 95% in 75 days. However, the preventive efficacy for severe infections only drops from 250% to about 100% in 97 days.
250 days (approximately 8 months) after vaccination, it is clear that mild infections still occur, but severe infections are unlikely to occur.

Figure 17: Prevention of aggravation

Source: Nature Medicine Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection
https://www.nature.com/articles/s41591-021-01377-8

[11] Regarding breakthrough infections

The Ministry of Health, Labour and Welfare's website has a very easy-to-understand explanation.

■What is breakthrough infection?
No vaccine against any infectious disease is 100% effective. It is possible to become infected even after receiving the vaccine, which is called a "breakthrough infection." In the case of the COVID-2 vaccine, sufficient immunity is expected to be acquired about two weeks after receiving the second vaccination, so if you become infected after that, it is called a breakthrough infection.

■Why you can still get infected even if you have immunity
There are some infectious diseases that you cannot get "again" once you have had them, and others that you can get repeatedly. The former include measles and chickenpox, while the latter include influenza and rotavirus gastroenteritis. Vaccines are available for these infectious diseases, but breakthrough infections are rare for the former and common for the latter. What is the difference?

In the case of measles and chickenpox, after the virus enters through the mucous membranes of the nose or throat, it multiplies in the tonsils and nearby lymph nodes, and then spreads throughout the body via the bloodstream (viremia), causing symptoms such as fever and rash, and the onset of the disease (onset of the disease). In other words, there is an incubation period of 10 days or 2-3 weeks between the time the virus enters the body and the onset of the disease. In people who have already had the disease or have been vaccinated twice and are therefore immune, the antibodies in the blood block the virus that enters the body, so the person does not develop the disease.
Even if the amount of antibodies has decreased in a person, when the person is infected and the virus enters the body through the mucous membranes of the nose or throat, the body is stimulated to resume antibody production, and by the time the virus enters the bloodstream, sufficient amounts of antibodies are produced. Therefore, the person will not develop the disease again.

On the other hand, in the case of influenza, the virus that invades the mucous membranes of the nose and throat immediately begins to multiply there, damaging the mucous membranes of the respiratory tract, causing illness (onset of symptoms) within a few days. Even if you have been vaccinated and have antibodies in your blood, it is difficult to prevent infection of the mucous membranes of the respiratory tract, and it is not enough to prevent onset of illness. However, the antibodies do prevent the disease from becoming severe by blocking the infection from seeping into the lungs and causing pneumonia.

Like the influenza virus, the new coronavirus also grows in the mucous membranes of the nose and throat and becomes ill within a few days. If the infection spreads to the lungs, there is a risk of the disease becoming severe. The antibodies in the blood are not very effective in preventing infection in the mucous membranes of the nose and throat, but they are effective in preventing the disease becoming severe in the lungs (Figure 18).

Figure 18

In general, the effectiveness of vaccines in preventing respiratory infections is ranked as follows: "effectiveness in preventing the disease from becoming severe > effectiveness in preventing the disease from becoming infected > effectiveness in preventing infection."

■ Breakthrough infections that have increased due to the Delta strain
Viruses mutate repeatedly, and those that undergo changes that are favorable to them eventually become the mainstream viruses. Not only has the Delta strain of the virus become more infectious, but it is also thought to be less susceptible to the immunity gained through vaccines.
Pfizer and Takeda/Moderna's mRNA (messenger RNA) vaccines are highly effective vaccines that are 94-95% effective in preventing disease against conventional strains of the virus, and in Israel (where the Pfizer vaccine is used), they have been reported to be 91.5% effective in preventing infection itself (*1).

However, it has since been almost entirely replaced by the Delta strain in Israel, resulting in its effectiveness in preventing disease and infection dropping to 64% (on the other hand, its effectiveness in preventing hospitalization remains high at 93%)(※2).

■ As the epidemic spreads, mutations will continue to occur one after another.
Mutations of viruses occur with a certain probability, and the more infected people there are as the epidemic spreads, the more mutations there will be. If a mutant strain emerges that is more infectious or has acquired properties that allow it to escape the immunity provided by the vaccine, it will eventually replace the existing one, and the fight against COVID-19 will never end.
The most effective way to prevent the emergence of troublesome mutant strains is to thoroughly implement infection prevention measures, including vaccination, and prevent the spread of the epidemic.

■ Breakthrough infections increase over time after vaccination
Even if you acquire immunity and develop antibodies by actually contracting the disease or receiving a vaccine, the amount of antibodies will gradually decrease if you do not have the opportunity to use them. Even if the amount of antibodies is low, they are produced immediately after infection, so it is often enough to prevent the disease from becoming severe, but it is not enough to prevent the onset of the disease or infection.

The decline in the effectiveness of the vaccine in Israel (the effect of preventing the onset of the disease and infection itself) mentioned earlier is due to the replacement of the Delta strain with the virus, and also to the fact that about six months have passed since the completion of the second vaccination. Therefore, some countries, including Israel, have begun the third vaccination in response to the increase in breakthrough infections.

■ Breakthrough infections are mild.
As mentioned above, breakthrough infections in people who have received two doses of the vaccine have increased after the strain was replaced by the delta strain, but the vaccine's effectiveness in preventing severe illness remains at a high level. Based on data from the US CDC, it has been reported that "the risk of death from breakthrough infection of the new coronavirus in people who have been vaccinated is less than 2%" (※0.001).

■ The significance of increasing vaccination rates
If hospitals are overwhelmed with people who become seriously ill with COVID-19, there is a risk that lives that could be saved by being hospitalized and receiving adequate treatment will be lost. In addition, if hospitals are overwhelmed with patients, the lives of patients who need emergency treatment for other illnesses or injuries will also be at risk. However, if many people are vaccinated, medical care will be able to maintain its original function.

In addition, while vaccines alone cannot stop an epidemic, vaccination, when carried out together with other infection control measures, can be of great help in stopping the spread of the disease in society.
That's why vaccination is so important.

■ Even those who have been vaccinated should continue to take precautions against infection
If you have been vaccinated, you will avoid becoming seriously ill in most cases even if you have a breakthrough infection. However, you can still be infected, and even if you are infected, you may not develop symptoms, so you may not even realize you have it.

If you talk without wearing a mask or go to crowded places where there are three C's, you risk spreading the virus to others. As long as vaccinations are not fully underway, I would like you to continue taking the same infection control measures as before to prevent the spread of infection to those who are infected.

(Reference material)
*1: Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data
*2: Explanation About the Effectiveness of the Vaccine for Coronavirus in Israel
*3: A Statistical Analysis of COVID-19 Breakthrough Infections and Deaths

Source: Ministry of Health, Labor and Welfare "Breakthrough infection after vaccination" Why are both vaccines and infection prevention measures necessary? | COVID-2021 Vaccine Q&A (August 08, 27)
https://www.cov19-vaccine.mhlw.go.jp/qa/column/0006.html

[12] Is the COVID-19 breakthrough infection related to pre-infection neutralizing antibody titers?

Among Israeli medical workers (1497 people) who received the Pfizer vaccine, neutralizing antibody titers were examined for 39 people who developed breakthrough infections after being regularly checked using PCR tests.
The neutralizing antibody titer in the infected group within one week before SARS-CoV-2 detection was 1 times lower than that in the non-infected control group. Most breakthrough infections were mild or asymptomatic, but 0.36% of them had symptoms lasting for more than 19 weeks.
85% of those tested were alpha strains.
*The paper was published in July and contains a lot of information prior to the Delta stock market.

In Figure A below, the antibody titers of people who had breakthrough infections were around 150-200. The maximum antibody titers in Figure B were similar. Looking at the maximum titers, the maximum antibody titers of people who did not have breakthrough infections appear to be about six times higher than those of people who did have breakthrough infections.

Although we cannot directly compare their antibody testing method with Abbott's antibody testing method, it is possible that some people may develop mild breakthrough infections, especially when the Abbott antibody titer is around 500-600 to begin with.

Figure 19: Comparison of neutralizing antibody titers between breakthrough infected and non-infected individuals

Source: he NEW ENGLAND JOURNAL of MEDICINE Covid-19 Breakthrough Infections in Vaccinated Health Care Workers
https://www.nejm.org/doi/10.1056/NEJMoa2109072

[3] What about the third vaccination?

The NHK article goes into great detail.

After two doses, the Pfizer and Moderna vaccines have been confirmed to be more than 2% effective in preventing the onset of the current novel coronavirus, while the AstraZeneca vaccine is approximately 90% effective.

Figure 20

The Middle Eastern nation of Israel has begun administering the third dose of the vaccine to people aged 60 and over. This is because the number of COVID-3 infections is on the rise again due to the highly contagious "Delta strain" mutant virus. At one point, the number of new infections per day had dropped to single digits, but due to the highly contagious "Delta strain" mutant virus, it has increased again, with more than 1 new infections reported every day.

Figure 21

In Israel, more than 16% of people aged 8 and over have received two doses of the vaccine. However, as there are a significant number of cases of severe illness even among those who have completed the vaccination, it has been decided that a third dose will be administered to people aged 2 and over, and vaccinations for these people have begun.

In Israel, most people have received the vaccine developed by pharmaceutical giant Pfizer and others, and will receive the same vaccine for the third time.
Those eligible for the third dose are people aged 3 or older who have been in the country for more than five months since their second dose. Meanwhile, the Israeli government has not yet mentioned a third dose for people aged 2 or younger.

The British government plans to start vaccinating people aged 70 and over from September.
German health authorities have decided to administer a third booster dose of the COVID-9 vaccine to elderly people and others who have completed their vaccination starting in September.
Swedish health authorities have also announced plans to administer the third dose of the vaccine to people at high risk of developing severe symptoms, such as those aged 80 and over, as early as this autumn.
In Japan, Minister of Regulatory Reform Kono has indicated that he expects the third vaccination to be administered next year. Experts also point out that "it is possible that additional vaccinations will be administered in about six months."

"It is said that the immunity provided by the vaccines currently in use will weaken after about six months. Although the mechanism is different, influenza vaccines are said to be effective for about six months. It is conceivable that a booster shot of the COVID-19 vaccine will be administered after about six months as well."

■ What is the effect of the third vaccination?
Pfizer is conducting clinical trials to determine how much the vaccine's effectiveness can be increased by a third dose, as there are an increasing number of mutant viruses that are resistant to the vaccine and the vaccine's effectiveness decreases over time.

Figure 22

7月28日にファイザーが公表した資料によりますと、3回目の接種をした人はウイルスの働きを抑える中和抗体の値が、従来の新型コロナウイルスや、変異ウイルスの「ベータ株」に対しては、2回目の接種後と比べ、5倍から10倍に増えたほか、変異ウイルスの「デルタ株」に対しても18歳から55歳の場合、5倍以上に、65歳から85歳の場合は、11倍以上に増えたということです。

Regarding the effectiveness of the vaccines currently in use, the FDA and the Centers for Disease Control and Prevention (CDC) issued a joint statement stating, "Individuals who have been fully vaccinated are protected from severe illness and death even from mutated viruses, including the delta strain. At this time, fully vaccinated individuals do not need additional vaccinations," and said they will determine the need for further vaccinations in the future based on scientific knowledge.

Dr. Fauci, the US government's chief medical adviser, has also expressed the view that "people who are immunosuppressed, such as those who have undergone organ transplants or chemotherapy for cancer, may need additional vaccinations."

American pharmaceutical company Moderna has stated that it believes that additional vaccinations with its new coronavirus vaccine will be necessary in the future due to the spread of highly contagious mutant strains of the virus, such as the "delta strain."

Figure 23: Moderna Press Release

On the 5th, Moderna released information about the effectiveness of its COVID-XNUMX vaccine and the status of development of a new vaccine to combat mutated viruses.
According to the report, the Moderna vaccine's effectiveness in preventing the onset of the disease six months after administration was confirmed to be 6%, maintaining a high level.

On the other hand, with the spread of mutated viruses, such as the highly contagious "delta strain," the government stated that "the effectiveness of the vaccine will likely decrease in the future," and that even those who have completed two doses of the vaccine will be required to receive a third vaccination from autumn this year onwards.

Source: NHK, COVID-3 vaccine: Is a third dose necessary? How effective is it? (August 2021, 8)
https://www.nhk.or.jp/shutoken/newsup/20210803b.html

[3] What is the actual effect of a third booster vaccination?

First, in a paper in which several medical workers were given the third dose, antibody titers were found to have recovered two weeks after the third vaccination.

Figure 24: Changes in antibody titers against non-mutated and beta-mutated strains after the second and third vaccinations

Source: medRxiv A third COVID-19 vaccine shot markedly boosts neutralizing antibody potency and breadth
https://www.medrxiv.org/content/10.1101/2021.08.11.21261670v1

またイスラエルの論文では、7月30日から8月31日の60歳以上で2回のワクチン接種後の1,137,804名の登録データを確認したところ、3回目非接種者は3回目の接種を受けて12日以上たった人と比較して、感染リスクは11.3倍あり、重症感染は19.5倍でした。
Furthermore, the effect was not as pronounced within 3 days of the third vaccination.

Figure 25: Number and ratio of cases of infection and severe symptoms among those who have received the third dose and those who have not

Source: The NEW ENGLAND JOURNAL of MEDICINE Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel
https://www.nejm.org/doi/full/10.1056/NEJMoa2114255

[15] Regarding additional vaccinations

The World Health Organization (WHO) has called for the postponement of vaccinations until the end of September, citing concerns that it could affect supplies to developing countries where vaccinations have not yet progressed, and this is causing controversy.

On September 9, the medical journal The Lancet published a paper stating that instead of giving a third dose, priority should be given to vaccination in unvaccinated countries, such as those in Africa.
"There is a need to consider primary vaccination on a global scale as an absolute priority."
"Any eventual benefit of a booster shot is unlikely to outweigh the benefit of providing initial protection to those who have not yet been vaccinated. If we can get the vaccine to where it will be most effective, we could hasten the end of the pandemic while limiting the further evolution of variants."

Source: Courrier Japon "Stop it!" on the third dose: Researchers oppose additional COVID-3 vaccine shots
https://news.yahoo.co.jp/articles/f9b0cfe2388606ac966f00336e588abe7f9ea56e

Global vaccine disparities will be a major issue.