MC

December

2022

Volume 8

ED
HECK

N 25
o

Editorial
Unacceptable Proposal:
Experts ignored clinical trials
Review
To be vaccinated, or Not ?
Points You should Know

SARS-CoV-2 vaccines Doubles the Risk of COVID-19!

CONTENTS (December 2022, Vol. 8, No. 25)
Editorial
Unacceptable Proposal: Experts ignored clinical trials
Review
To be Vaccinated, or Not ? Points You should Know
SARS-CoV-2 Vaccines Doubles the Risk of COVID-19!
(1) “Harm-benefit balance” depends on the situation(2) Types of vaccines and adjuvants(3) Healthy vaccinee effect (bias)(4) The doctrine of original antigenic sin and Omicron variants
Figure 6: Types of vaccines and their structures

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Dec. 2022/ Vol.8 No.25

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40
41
43
44
47
51

ED

HECK

Unacceptable Proposal: Experts ignored clinical trials

Editorial

M
CTranslated from the Editorial in Med Check(in Japanese) Nov. 2022 ; 22 (104)：127

Shionogi & Co., Ltd. has developed ensitrelvir (Zocova R), which is expected to be the first SARSCoV-2 therapeutic agent developed in Japan, and applied for approval under the emergency approvalsystem in July. As a result of the review, a reduction in SARS-CoV-2 viral load was observed comparedto placebo, but there was no significant difference in alleviation of clinical symptoms such as fever,headache, sore throat, and cough. Therefore, it was determined that the efficacy could not be estimated,

Editorial

and the approval was postponed. We also think that it was a natural decision

In response to this postponement of approval, on September 2, 2022, the Japanese Association for

Infectious Diseases and Japanese Society of Chemotherapy jointly announced "Emergency medicalcare is collapsing due to the seventh wave of the corona pandemic. Symptomatic medicines are also in
short supply, and there is widespread public concern about accessibility to proper medical care. Japan’s

Ministry of Health, Labor and Welfare (MHLW) should seriously consider applying the emergency
approval system to antiviral drugs that reduce viral load or expanding the indications of approved

antiviral drugs as soon as possible. We urge the MHLW to make a decision."Ensitrelvir is a drug whose

effectiveness has not even been confirmed. Nevertheless, they said that it should be approved because

it can be expected to have an effect on clinical symptoms based only on the antiviral effect that is just apart of the results of clinical trials. Their statement is unscientific and ignores clinical trial results.

Moreover, two executives of the Japanese Association for Infectious Diseases and one executive ofboth societies are doctors involved in the clinical trials, leading to an issue of conflicts of interest. In
addition, it is not surprising that the general public thinks that the MHLW should approve it as soon as
possible because the academic societies, which are groups of medical experts, said so. Their remarks

may mislead public opinion. The role of academic societies, which are groups of experts, should be todisseminate correct information based on scientific and objective facts, but it seems that they are notfulfilling that role at all.

This issue evaluates vaccines against the Omicron BA.1 strain, which has been reported in the

media to be administered after a shorter interval than originally approved. After reading this, you will
be able to decide if you should also get a new BA.5 strain vaccine. We also would like our readers to
spread the correct information obtained from this bulletin to their families and acquaintances.

Note :New approval system implemented from May 2022. Under this system, even before the completion of regular clinical trials, if theharm is not presumed to be too great to make the substance of no use, and if efficacy is presumed, manufacturing and marketing will be
provisionally approved.

MED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 39

Review
To Be Vaccinated or Not? Points You should Know
SARS-CoV-2 Vaccines Doubles the Risk of COVID-19!

Translated and revised from Med Check(in Japanese) Nov. 2022 ; 22 (104)：128-139
Med Check Editorial Team

Four points you should know to assess safety and effectiveness of vaccines
Safety and effectiveness of “SARS-CoV-2 vaccines” are now at the forefront of public attention more thanever before. Our conclusion is that they are not effective at all, but may increase COVID-19 by two times andhave only harm. SARS-CoV-2 vaccination should be avoided as the data suggest.
In this short series on vaccines, we will discuss safety and effectiveness of eachl vaccine. However, let
us first think about important 4 points for evaluating safety and effectiveness of vaccines, which are often
ignored or neglected by regulators and academic authorities, focusing on “SARS-COV-2 vaccines”.
(1) Harm should be minimal, and benefit should outweigh harm: the balance depends on the situation
First of all, a vaccine is given to people who are not infected with the target infection, i.e., healthy people.
Therefore, the harm should be minimal, and benefit should outweigh the harm. This is the major prerequisite.
Moreover, the evaluation is not universal, but contextual: it changes as time and location (country, region)change, and thus it should be always reviewed and revised.
(2) Types of vaccines and whether they contain adjuvant or not
There are various types of vaccines. This article explains about adjuvants (immune enhancer). Adjuvants
essentially have harms because they become effective only when they damage the tissues. When evaluatingharms in clinical trials, it is important to determine whether or not adjuvants are used in the control.
(3) Beware of healthy vaccinee effect (bias)
People who have fever on the day of vaccination or those who are critically ill would avoid vaccination.
Therefore, vaccinated people have better original health status than unvaccinated people. This bias is called"healthy vaccinee effect". In almost all post-marketing observational studies, this bias is ignored, leading
to the distorted evaluation of effectiveness and harm of vaccines. As a result, severer the cases, the more
effective and less harmful, ineffective vaccines would appear to be.
(4) The doctrine of original antigenic sin
SARS-CoV-2 and influenza viruses are characterized by a high rate of mutation. When a human is infectedwith such a virus (hereafter X0) for the first time, strong antibodies are developed against it (X0). Later, if the
body is exposed to the mutated virus (X1), it would fight X1 with the antibodies against X0, and thus it would
be infected with X1. Even if vaccines for a mutant strain is inoculated, the body have already developed
the antibodies against the original strain which it was exposed to by the first vaccination, and only weak
antibodies would be produced against the mutant strain. Therefore, the vaccination would be ineffective.
This phenomenon is called “the doctrine of original antigenic sin”. It was clearly proven in the case of
vaccines targeting the Omicron variants.
Conclusions: SARS-CoV-2 vaccines not only have no proof of efficacy against Omicron variants but also
may increase risk of COVID-19 by two times, and have serious harms. The use of the SARS-CoV-2 vaccines
should be immediately suspended.
Keywords:

Page 40 ・ MED CHECKSARS-CoV-2 vaccine, adjuvant, healthy vaccinee effect, original antigenic sin, omicron variant, mutant strain

Dec. 2022/ Vol.8 No.25

Introduction

by Med Check based on the data from Israel on the risk of
Pfizer’s vaccine for having COVID-19 [7,8]. Fig. 1A is based

Med Check No. 52 and No. 53 featured articles titled ason the survey for the first two doses of SARS-CoV-2 vaccine“Let’s learn more about vaccines” [1,2]. In addition, Med

compared with unvaccinated [7]. Fig. 1B was based on that for

Check No.69 explained about vaccines, including the history,

the 4th dose compared with those with only 3 doses [8]. Thesein another article titled as “To Vaccinate or Not?” [3]figures showed the risk of COVID-19 by the number of days

The question many people may have now is whether or notafter vaccination.

to be vaccinated with vaccines for the Omicron variants. Is theBoth Fig. 1A and Fig. 1B showed the result after adjusting

vaccine effective and safe? This question is at the forefront offor the original health status of vaccinated and unvaccinatedpublic attention more than ever before.

individuals (healthy vaccinee effect) . This adjustment is

As mentioned in the beginning, Omicron adapted bivalent

explained more in detail in the section (3) healthy-vaccinee

vaccines are not effective at all, but harmful, and there are

effect. In other words, the risk of COVID-19 is shown

solid data to prove this. This article explains about thoseas adjusted risk ratio (adRR) by the number of days after

data in the Q & A between a reader and an editor. “Reader”

inoculation. Are you with us so far?

represents you who are reading this article now.

Reader: You mean that original health conditions of thevaccinated and the unvaccinated were adjusted and equalized(1) “Harm-benefit balance” depends on theto compare the risk?

situation

Editor: Yes, that’s right. Fig. 1A showed the risk after the first

Reader: You mentioned that whether benefit outweighs harmand second dose and Fig. 1B showed the risk after 4th doseor not depends on “time and location (country/region)”. Whatcompared with those with 3rd dose. In both A and B, ■ or ■do you actually mean by this?

are on the right side of 1 until day 30 after vaccination. This

Editor: Let me explain with an example of COVID-19. The

means that the vaccinated were infected with SARSCoV-2

clinical trial which concluded that the preventive effect ofmore frequently than the unvaccinated; vaccine did not

the vaccine was 95% was conducted in the U.S. between the

reduce, but increased COVID-19 for a while after vaccination.

end of July and middle of November, 2020. This coincides

Reader: How did it happen?

with the end of the second wave and the beginning of the 3rd

Editor: We will address this issue in the section (3) healthy

wave. During this period, 1 in 50 persons were infected withvaccinee effect (bias) later. In Fig. 1A, adjusted RR ■ (aRR)

COVID-19, and 1 in 3000 died from the disease.

is on the left side of 1 finally after days 31-36 suggesting

As it was the time of such an epidemic situation, SARS-

that the risk of COVID-19 infection declined after 31 days of

CoV-2 vaccines prevented the symptomatic COVID-19 byvaccination. Risk ratio between day 34 and day 36 was 0.12.

95% as well as aggravation during the most effective period

This means that the risk was 0.88 lower than 1.00: the risk

(1.5 months after the second dose) [4-6]. One hundred ten

was reduced by 88%. In other words, the vaccine effectivenesspersons had to be vaccinated to prevent 1 case of COVID-19.

finally reached 88% 1 month after the vaccination.

Reader: During this period, there were not so many

Reader: You mean that it doesn’t work until 1 month after

COVID-19 patients in Japan.

the vaccination?

Editor: Yes, that’s right. During this period, only 1 in 1500

Editor: That’s right. This study was conducted between

persons was infected, one-thirtieth of that in the U.S., and 1

December 20, 2020 and February 1 2021, in the middle of thein about 150,000 persons died from COVID-19. In order toAlpha strain pandemic in Israel. If converted to the Japanese

get the same number of COVID-19 as that in the U.S. clinicalpopulation, average 850,000 persons would have beentrial, 600,000 participants had to be enrolled each in vaccine

infected with COVID-19 every day.

and placebo groups. It is impossible to involve such a large

Reader: It was just like in the Omicron wave in Japan.

number of participants. During this period, 3500 persons had

Editor: Yes, exactly. In February 2021, Israel had entered theto be vaccinated to reduce 1 case of COVID-19 in Japan.

pandemic where 7 in 100 persons had already been infected.

Reader: Is there a post-marketing surveillance study?

Considering simply the state of infection, the benefit of the

Editor: Yes. Fig. 1A and Fig. 1B are both original analysis

vaccine against the original strain (Note 1) also might have
MED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 41

Review
Figure 1: Risk of asymptomatic infection/symptomatic COVID-19 by SARS-CoV-2 vaccines(A) Risk of symptomatic COVID-19 after the first 2 doses is compared with the unvaccinated and shown by the number of days after vaccination. The risk at days 1-20 isadjusted by the risk at day 1 (risk ratio=0.40), and the risk at day 21 and thereafter by the risk at day 21 (risk ratio=0.22). The risk was reduced significantly at day 31 andthereafter as compared with the reference date (day 21). At days 34-36, the risk was 0.12. Based on this the vaccine effectiveness against symptomatic COVID-19 canbe estimated as 88% (1-0.12). However, (B) the risk never became lower than that on the first day after the 4th dose. There is no data at day 31 and thereafter when theeffectiveness was shown in (A). The significant increase at days 28-30 is probably due to harms of the vaccines. See Suppl. Fig 1B which shows significant increased risk after
day 36 up to 6 months.

outweighed the harm in Israel.

In this figure, healthy vaccinee effect (bias) was adjusted,

Reader: At that time, how many people were infected withthe risk did not become lower than that on the first day of

COVID-19 in Japan?

vaccination. In Fig. 1A, the risk started to decrease after day 31

Editor: By the end of 2021, less than 1 in 100 persons hadfrom vaccination, but in Fig. 1B, no such a trend was observed.

been infected. The “benefit” for the vaccine was touted as

It can therefore be concluded that the 4th dose of vaccine wasa preventive effect against COVID-19 infection. But in a

not effective. Furthermore, the increased risk between day 28

country with low infection rates, such as Japan, harm of theand day 30 was significant, suggesting that the 4th dose wasvaccine was highly likely to outweigh the “benefit”; thus

only harmful [Note A].

vaccination was not necessary the best remedy. This was
discussed in detail in MedCheck in English No. 20 [6].
Note 1: SARS-CoV-2 first spread from Wuhan, China. Both Pfizer’s
and Moderna’s vaccines are called “original vaccines” as they were

Note A (added after publication of Issue No.104):
Suppl. Fig. 1A shows the risk of COVID-19 after 4th doseof Pfizer’s vaccine compared with those who received thedesigned to produce spike protein found in the original virus “SARS-

3rd dose four months earlier based on the combined data

CoV-2”. Neutralizing antibodies against the original virus are called(incidence rate ratio: IRR between day 1 to day 30 after“original antibodies”.

inoculation) from the nation-wide survey in Israel [8] andthe data (hazard ratio: HR between day 7 to day 181 after

SARS-CoV-2 vaccines are not effective at all now

inoculation) from the prospective cohort study involving

Reader: In Fig. 1B, the risk stays higher than 1 after 4th dose.

health care workers in Israel [25].

Editor: Yes, Fig. 1B is based on the study in Israel conducted

Suppl. Fig. 1B showed the risk of COVID-19 adjusted byduring the Omicron pandemic from 3 January to 18 February

the incidence rate ratio (IRR) at the day 1 of inoculation

2022. The study compared the infection risk of those who(IRR=0.45) in ref [8]. IRR (0.48) for day14 to 30 day (medianreceived 4th dose of vaccine against the original strain with

22) in ref [8] is just the same as HR (0.48) for d7 to d35

those who received their 3rd dose four months earlier. If the(median 21) in ref [25]. Hence after adjustment by 0.45(0.41

infection rate in Israel during this pandemic was converted to

to 0.50), adHR reached 2.27 (95%CI: 1.79 to 2.87) during 103

the Japanese population, it would have been infected about

to 181 days after 4th dose (median: day 142). This indicatesover 600,000 persons per day.

that SARS-CoV-2 vaccine increased the risk having COVID-19

Page 42 ・ MED CHECK

Dec. 2022/ Vol.8 No.25

by more than double.

Suppl. Figure 1: Risk of COVID-19 # after 4th dose of Pfizer vaccine comparedwith only 3 doses

This phenomenon, increased risk of
COVID-19 in vaccinees, especially after
4 weeks and thereafter of post-4th
dose should be considered as a resultof "antibody-dependent enhancement(ADE)" caused by the SARS-CoV-2 vaccine.

(2) Types of vaccines andadjuvants
Types of vaccines are explained in
Med Check No.92 [9]. This issue shows
Fig. 6 to categorize various typesof vaccines, including SARS-CoV-2
vaccines as well as other vaccines,
and explains the categorization in thecolumn. Here, it focuses on adjuvants.
*: day of inoculation =1, adRR: adjusted risk ratio, adIRR: adjusted incidence rate ratio, 95%CI: 95% confidence

Adjuvants are toxic and damage
the tissue
Med Check No.53 [2] explains about

interval#: asymptomatic infection or symptomatic COVID-19 for data of day 1 to day 30 [8] that are the same as those in
the Fig 1B. COVID-19 data for day 7 to day 181 [25] are on the SARS-CoV-2 infection not particularly defined asasymptomatic or symptomatic.

adjuvants in detail. This article quickly
reviews what adjuvant is.

with antigens, it injures the body, and leucocytes are attracted

Reader: First of all, what is an adjuvant?

to treat it. However, when they treat the adjuvant, they are

Editor: In addition to antigens, an adjuvant is added todestroyed and release their genetic information, DNA. Then,

vaccines to enhance immune response. In other words, it is an

DNA binds to protein in the body and acts as a foreign

immunostimulant.

substance, inducing innate immunity to help build antibody.

Reader: It is added to any vaccines?

In other words, substances that damage the body can work

Editor: No, presence or absence of adjuvants in each vaccine

as adjuvants, but those that have no toxicity to damage thewill be discussed in the next issue.

body cannot work as adjuvants.

Reader: Why do some vaccines contain adjuvants and some don’t?
Editor: Depending on the types of vaccines, vaccination of

Are vaccines with the same harm as adjuvants safe?

antigens alone is not enough to create antibodies in the body.

Reader: So, adjuvants alone can be harmful to the body?

This is probably because in order to induce immune reaction,

Editor: That’s right. In clinical trials of HPV vaccines,

some degree of damage must be done to the body.

Gardasil and Cervarix, an alum adjuvant or a Hepatitis A

When viruses or bacteria enter the body, they release toxin so

vaccine with an adjuvant was used as a control. Then, what dothat they can easily penetrate into the body. In return the bodyyou think was the result?

tries to eliminate them by immune response. An adjuvant acts

Reader: HPV vaccines contain adjuvants. So, if they arelike the toxin, and damages the body to help antigens inducecompared with the control which contains only adjuvants….?

stronger immune response.

Editor: In young women aged 15-24, incidences of adverse

Reader: What substances are used as adjuvants?

events in HPV vaccine group and control group were almost

Editor: The most common adjuvant is aluminum compounds

the same. This result provided the basis for the HPV vaccine

called an “alum” adjuvant. An adjuvant contained in HPV

to be promoted as harmless

vaccines (so-called cervical cancer vaccine) is a derivative ofReader: There was no difference in the incidences, but why

bacteria toxin (lipid A) of Salmonella. When this is injected

can you say that the vaccine is safe? An adjuvant itself has

MED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 43

Review
Figure 2:HPV vaccines increase mortality by 5 times in woman aged
25 or older(See footnote of Fig. 2).

Through the efforts of victims of HPV vaccines andseveral organizations, including Med-Check, thegovernmental recommendation of HPV vaccine wasonce suspended. However, it is very disappointingthat the recommendation was resumed.
Reader: By the way, do SARS-CoV-2 vaccines
contain adjuvants?
Editor: Takeda Pharmaceutical’s Nuvaxovid is avaccine that contains “full-length spike protein”
as an antigen, which is classified as E in Fig. 6 in

The figure is reproduced from the reference [10]. If the age is younger and mortality rate is onefifth in both groups,（13+7）/5=4 persons in HPV vaccine group and（3+1）/5=0.8 persons
in adjuvant group. As a result, the number of death is minimal, and there is no significant
difference（P=0.32）. If death in the control group happens to be 1 person, p value would be 0.69,
suggesting no significant difference.

page 14. In this vaccine, surfactant is added as an
adjuvant. Pfizer’s and Moderna’s vaccines, whichhave been used in Japan, contain no substancewhich is specifically claimed to be an adjuvant.
However, lipid components which compose lipid

harms, right?

nanoparticles are highly likely to be toxic and may act as an

Editor: Yes, it does. However, they are considered to

adjuvant. Considering the intensity of the harm of SARS-

be "safe" because so-called experts have declared so. As

CoV-2 vaccines, it is reasonable to think that they containmentioned above, even if there was no difference with asubstances which act like adjuvants.

harmful adjuvant, it cannot be concluded that the vaccine is(3) Healthy vaccinee effect (bias)

safe.
How can we be sure that it is harmful? I would like toexplain some points. First of all, temporal change should

People who have fever on the day of vaccinationor who are critically ill would not be vaccinated.

be investigated. If a substance has no effect on the body,

By appropriately interpreting the report from Israel [8,incidence (morbidity) of adverse events which occur newly,25], it can be said that the 4th dose of the vaccine against thesuch as autoimmune diseases, is supposed to be constantoriginal strain was not effective as compared with the 3rd

over time. However, in both adjuvant and vaccine groups,

dose (Fig. 1B and Suppl. Fig. 1B). However, this study [8] reports

the incidence of autoimmune diseases significantly increased

that the vaccine reduced asymptomatic infection by 52%,

within 6 months after vaccination, and decreased over time.

symptomatic COVID-19 by 61%, hospitalization by 71%,

Another way to determine the harm is to compare theincidence rate (morbidity) with that of the same age group insevere cases by 64%, and death by 76% between day 14 andday 30 after vaccination.

the general population. Incidence rate (morbidity) of multiple

An ineffective vaccine would never prevent about three-sclerosis and ulcerative colitis in both adjuvant and vaccine

fourths of the death. However, if healthy vaccinee effect wasgroups were significantly higher than those of the same age

not adjusted before calculation, the result can be “cheatedgroup in the general population [10]. This can be evidence forwithout actually lying”.

the harm.

The incidence of COVID-19 per 100,000 persons was only

Reader: What were the differences in mortality?

15 persons in the vaccinated on the day of vaccination while

Editor: There was no difference in mortality in women aged

it was 38 persons in the unvaccinated on the day which was

15-24. However, in women aged 25-45, mortality increased

equivalent to the day of vaccination (Fig. 3). Risk ratio of theby 5-fold over 4 years in the vaccine group as compared to thevaccinated to the unvaccinated was 0.40.

adjuvant group (Fig. 2) [10]. A substance that in.eases mortality

Editor: What do you think about the data of the first day (Fig.

by 5-fold in women aged 25 and above can never be safe for3 □ )?

younger women. Because mortality rate is originally low in

Reader: It looks as if the vaccine worked from the day ofwomen aged 15-24, the difference was simply not so marked

vaccination.

Page 44 ・ MED CHECK

Dec. 2022/ Vol.8 No.25

Figure 3: Trends of incidence rate (/100k) of COVID-19 since first day of inoculation::comparison of vaccinated and unvaccinated (Nation-wide survey in Israel) [7](the incidence on the first day).

However, on day 21 (Fig. 3□ ), it was suddenly halved
to 10. This is statisticallysignificant. On the sameday, the incidence in theunvaccinated was 45 (persons
per 100,000 person-days).

Trick to make ineffective
vaccine appear to
reduce death
Editor: Why did it halve?
Reader: Umm…. Why?
Editor: Yes, it really does. Why do you think the incidence

Editor: I’ll give you a hint. What kind of people were able toin vaccinated people appears to be much lower than that inreceive the second dose?

unvaccinated people?

Reader: Those who had no problem after the first dose. Oh,

Reader: Well…because the vaccinated people were

I see…Among the people who had high fever after the first

healthier?

dose, some would choose to avoid the second dose, right?

Editor: Exactly. What if the patient has a fever on the day of

Editor: Exactly. People who received the second dose were

the scheduled vaccination?

even healthier than those who had the first dose. Risk (riskReader: They would avoid the vaccination.

ratio) on the day of vaccination of the second dose is 0.22. It

Editor: How about those who are critically ill?

was much lower than the risk in those who had the first dose

Reader: They would not be vaccinated, either. I think people(0.40).

who have some kind of illnesses would avoid vaccination.

In Fig. 1A, the risk of COVID-19 on day21 and thereafter

Editor: Even if they have an illness, if their condition iswere adjusted by that on day 21 (explained below) in addition

stable, many of them would be vaccinated. So more precisely,

to the adjustment for day 1 to day 20 by that on day1.

“people who have had serious illness recently would avoid

Based on an Israeli study by Dangan et.al [7], the risk in

vaccination”. After that, the incidence rate (persons per 100,000

the vaccinated group on the day of vaccination was estimatedperson-days) in the unvaccinated stayed at around 40 (persons

by severity. Since there was an adequate number of cases ofper 100,000 person-days) , fluctuating along the increase/

asymptomatic infection and symptomatic COVID-19 fromdecrease in infection in Israel. However, in the vaccinated, thethe first day, the risk and 95% confidence interval (95%CI)

incidence rate gradually increased and between day 8 and day

are directly estimated. However, the risk of hospitalization,

10, it was higher than that in the unvaccinated.

aggravation and death was indirectly estimated, and 95%CI

Reader: That is due to a negative impact of the vaccine?

was not calculated. The rough estimate of risk was shown in

Editor: After vaccination, many people experience fever.

Fig. 4.

When there is fever, it might not be just because of the

If not adjusted by the risk on the first day, the vaccine seems

vaccination, but of COVID-19. When they undergo a test, they

to reduce asymptomatic infection by 38% ((1-0.62) ×100%,might be actually found positive. This is not simply because

hereafter the same calculation method is used), symptomaticthe number of tests conducted have increased, but because

COVID-19 by 60%, hospitalization by 73%, severe disease

they might have been weakened by fever, and they wereby 82%, and death by 87%. However, vaccines would neverinfected and developed symptoms. After that, the incidence

be effective on the first day. Therefore, they must be divided

in the vaccinated gradually decreased. Then, as shown inby 0.62, 0.40, 0.27, 0.18 and 0.13, respectively, to equalize

Fig. 3, between day 17 and day 20, before vaccination of thethe risk (health condition) of the vaccinated and unvaccinatedsecond dose ( □ ), the incidence rate was 19; higher than 15

groups. Not only the risk ratio on the first day, but the risk

MED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 45

Review
Figure 4: The apparent risk of asymptomatic infection or COVID-19 by severity on the day of inoculation

From the data of Dagan et al. [7], we estimated the risks of SARS-CoV-2 infection in SARS-CoV-2 vaccinees on the day of inoculation: The risk ratio
and 95% confidence interval (95%CI) could be directly calculated for asymptomatic infection and symptomatic COVID-19, as events were enough toestimate. However, direct estimation of risk was difficult for COVID-19 hospitalization, severe COVID-19 and death due to COVID-19, because on the
day of vaccination, no event was reported in the vaccination group for hospitalization and no event in both groups for severe case and death. Therefore,
assuming that the increase in the risk of symptomatic COVID-19 from the date of vaccination to 1 to 2 weeks after vaccination also applied to severe andfatal cases, we estimated the risk ratio at the day of inoculation for hospitalization, severe case and death. Because it was impossible for the vaccine tobe effective at the day of inoculation, these low risks in vaccinated people mean that the risk of infection (disease) in vaccinated people is low compared
to unvaccinated people. This means that vaccinated people were healthier than unvaccinated people. It should be noted that the severer the disease, thestronger vaccine apparently works.

ratio thereafter should also be divided likewise.

symptomatic COVID-19 on the first day) and 0.18 (the risk ratio

Reader: Wait a minute. Why do you have to divide?

of severe disease on the first day), the risk ratios are 0.15 andEditor: The health conditions on the day of vaccination are

0.44 and the vaccine effectiveness is as low as 85% and 56%,

different in the vaccinated and unvaccinated groups, right?

respectively.

Suppose the risk (risk ratio) of becoming ill in the vaccinatedReader: How about the 4th dose in Israel?

is 0.5. In other words, the risk of COVID-19 in the vaccinatedEditor: It was reported that the vaccine effectiveness wasgroup is half (0.5) of that in the unvaccinated group.

61% against symptomatic COVID-19, 64% against severe

Therefore, in order to equalize the health conditions of the 2disease, 76% against COVID-19 death between day 14 andgroups (risk ratio: 1.0), 0.5 should be multiplied by 2. Amongday 30. Can you calculate the risk ratio?

the numbers above (0.62, 0.40, 0.27, 0.18, 0.13), 0.40 is taken as

Reader: For symptomatic COVID-19, It is “1 - 0.61 = 0.39”

an example here. The risk ratio of COVID-19 on the first day

and 0.36 (1-0.64) for severe disease and 0.24 (1-0.76) for death.

was 0.40 (1/2.5). Therefore, to equalize the risk of COVID-19

Editor: Correct. It had been confirmed that the degree ofin the vaccinated and unvaccinated groups, 0.4 is divided byhealthy vaccinee effect after the 4th dose was almost the same

0.4 or 0.4 is multiplied by 2.5.

as that after the second dose (Note 2). Then, let’s adjust it byMoreover, the health condition would continue to havethe risk by severity on the first day after the second dose. For

influence thereafter as it does on the first day. Therefore,

symptomatic COVID-19, 0.39 was divided by 0.4 and themultiplying the risk ratio thereafter by 2.5 (or dividing it by 0.4)

adjusted risk ratio is 0.98. It meant that the vaccine was not

is needed for unbiased comparison.

effective at all. How about aggravation?

Reader: But it is said that booster shots would especially

Reader: It is 0.36 divided by 0.18 and it becomes 2.0. Oh no,

reduce aggravation and death, isn’t it?

the risk is not reduced, but doubled?!

Editor: The first Israeli study reported that the vaccine

Editor: Yes, even the risk of death was nearly doubled:

effectiveness after the second dose was 94% against

0.24÷0.13 ＝ 1.85. This suggests that the booster shots did not

symptomatic COVID-19 and 92% against severe diseases.

reduce aggravation and death, but they might rather increase

Reader: What would happen if this result is adjusted by thethose conditions.
This study reported only hospitalization and death fromhealth condition?
Editor: The risk ratios were 0.06 (1-0.94) and 0.08 (1-0.92),

SARS-CoV-2, but not from thrombosis nor myocarditis after

respectively. If they were divided by 0.40 (the risk ratio ofvaccination. The vaccine had no effect on prevention ofPage 46 ・ MED CHECK

Dec. 2022/ Vol.8 No.25

SARS-CoV-2 infection and symptomatic COVID-19, but has

antibody against X1, and thus it is not enough to eliminate X1,

harms. It was estimated that the risk of hospitalization andleading to infection and onset of disease.

death was even higher.

The same phenomenon would happen with vaccines.

It is clear now that in order to assess the vaccine

Coronavirus (SARS-CoV-2) which originates in Wuhan, China

effectiveness by observation studies (Note 3), such as theis called the “original virus” or “original wild type (WT) virus”

Israeli study above; healthy vaccinee effect must be taken into

(B0). Vaccines which had been made so far are called theconsideration. Otherwise, ineffective vaccines would appear“original vaccines” or “original WT vaccines” as they were

to be effective.

designed against the original (WT) virus (B0). If a person A is

Reader: I understand it very well now.

vaccinated with B0, he/she would develop antibodies against
B0 only in the blood, but almost no antibody in the nasal

Note 2: The only available data about the risk is that of asymptomatic
infection/symptomatic COVID-19 on the day of the fourth vaccination(0.45) in the ref [8], which is almost the same as the risk of

mucosa. Then, when the pandemic is driven by the Omicron
BA1, BA2 or BA5 and A is exposed to those viruses, the body

asymptomatic infection/symptomatic COVID-19 on the day of thewould try to counteract them only by the antibodies against B0

second vaccination (0.48) in the ref [7].

in the blood, and thus the Omicron variant would easily enter
the body, causing infection and symptomatic COVID-19.

Note 3: Observational studies are not conducted by intentional
interventions like a randomized controlled study, but are based on
observation of ongoing medical interventions. For example, conditions

This phenomenon is called the doctrine of original
antigenic sin. It was first introduced by Thomas Francis,

of infection and hospitalization or mortality rates in the vaccinated andJr. (1960) [12,13]. Through a series of his studies, he foundunvaccinated are compared. In a cohort study, treated and untreatedthat people of the same age have the same specific antibody

people (groups) are compared. On the other hand, a case-control

against influenza virus, which corresponds to the first seasonal

study compares the proportion of people who were exposed to a

influenza virus that they were exposed to. He confirmed

particular substance before the onset in 2 groups of people: those withthe disease and those without. Both are called observational studies.
Recently, they are often called real world data (RWD), as well.

this by various methods, and introduced the concept of thedoctrine of original antigenic sin [13].

(4) The doctrine of original antigenic sin and

The doctrine of original antigenic sin discussed in

vaccines against the Omicron variant

the MHLW meeting

In the introduction, we have concluded that new vaccines

The doctrine of original antigenic sin is well-known as Dr.

against the Omicron variants have no effect, but only harms.

Yoshimasa Takahashi, Director of Research Center for Drug

The conclusion is based on the phenomenon called “theand Vaccine Development, National Institute of Infectious

doctrine of original antigenic sin”. To fully understand thisDiseases, discussed it in the 31st Health Sciences Council

phenomenon, complicated interpretation of data is necessary,

Vaccine Taskforce (3-24-2022) as follows [14].

but it might confuse our readers. So, we will avoid going into
details with numbers and graphs, but will explain you in a
simpler manner.
When a person (A) is infected with a virus (X0) for the
first time, he/she would develop strong immunity (antibodies)against this virus (X0). In the case of COVID-19, the immunity
is developed in the form of protective antibodies in the
respiratory mucosa, such as in the nose, throat and bronchi,
which is the entry point of the virus, as well as neutralizing
antibodies in the blood.

There is an immune phenomenon called “original antigenicsin” in English. I think this is the state of immunity given by
vaccines etc. with conventional strains, and I think it is thecurrent situation in Japan, but if you inoculate with a mutant
strain type vaccine in such a situation, by definition, it is suchan immune phenomenon that pre-existing immunity prevents
new immunity from being induced against the mutant strain.
However, this phenomenon called original antigenic sin is not aphenomenon that has been confirmed so far in the SARS-CoV-2,
but it is a possible phenomenon as a general theory, and some

Later, if infection with the mutant virus (X1) of X0 causes

reviews have proposed such a hypothesis. Such a situation is mypandemic and A is exposed to X 1, the body would try tocurrent understanding. Above, I have supplemented the topic

defend against X1 with the immunity (antibodies) against X0,of original antigenic sin.

which his/her body remembers. It would develop only little

MED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 47

Review
What happens when a person vaccinated with an

Editor: That’s a good question. It is difficult to give you

original vaccine is infected with BA1

a definite answer as the antibody titer before symptoms of

Dr. Takahashi implies that the doctrine of original antigenic

the Omicron BA1/BA2 began after the 3rd dose was not

sin is not confirmed with SARS-CoV-2. However, is it reallymeasured. However, antibody titer was 2-fold higher for any

so? SARS-CoV-2 vaccines used for the 3rd and 4th doses

variants in those who had symptoms than in those who had

around the world are original vaccines. Many people who hadreceived the 3rd dose [15]. In addition, in all studies, not only

been vaccinated were infected with BA1, BA2 or BA5 of thethat the antibody titer was higher, but it was sustained longer

Omicron variants. Let us think about it through Q&A below.

in people who were infected than in those who had the 3rd
dose.

Editor: Total 27 people were examined, who were vaccinated

In Israel, the 4th dose did not prevent the symptomaticwith the 3rd dose (so-called booster shot) of an original vaccine

COVID-19 by the Omicron BA1 (Fig. 1B and Suppl.Fig 1B).

6 months after the second dose of Pfizer’s original vaccine.

This means that the antibody titer increased after the 3rd or

Which antibody titer do you think was the highest; those

4th dose was not high enough to prevent the symptomatic

against ①original virus, ② BA1, or ③ BA5?

COVID-19 by the Omicron variant.

Reader: Because they were vaccinated with the originalMice pretreated with the original vaccine were given BA1

vaccine, the answer is ① antibody against the original virus.

vaccine and the antibody titer was measured. The antibody

Editor: Correct. Antibody titer against the original virus wastiter for the original virus was 6-fold higher than that for the

6.4 times higher than that against BA1 [15]. Next, another 27

Omicron BA1, and was the highest, showing the similar result

persons who became ill after being infected with BA1 or BA2

as in humans.

of the Omicron variant were studied. About 80% of them had

Reader: How about Takeda’s vaccine? It is also an original

received 3rd doses of the original vaccine, and only 1 person

vaccine, isn’t it?

had received no vaccination. One month (median 29 days) after

Editor: Yes, Takeda’s Nuvaxovid is an original vaccine. Do

infection, which antibody titer was the highest in their bodies?

you think it is effective?

Please remember what was explained for the doctrine of

Reader: I don’t think so, as Pfizer’s and Moderna’s vaccinesoriginal antigenic sin.

are not effective. How about the increased antibody titers after

Reader: It’s ①antibody for the original virus.

BA1 or BA5 vaccines are inoculated? Is it effective?

Editor: That’s right. Do you guess how much more antibody

Editor: That’s the most important point. We will take a lookagainst the original virus was produced after infection withat the evidence which Japan’s Ministry of Health, Labour

BA1/BA2 of the Omicron variant as compared to the antibody

and Welfare (MHLW) referred to for approval, especially how

against BA1; ① 1.5-2 times, ② 3-4 times, ③ 6-13 times?

much increase was observed in the antibody titer. Before that,

Reader: Because it was after being infected with thebesides the increased antibody titer, what else is needed as the

Omicron variant, it must be less than when vaccinated withevidence for preventive efficacy?

the original vaccine. So, it’s ②3-4 times?

Reader: Clinical trials?

Editor: No, it was also 6.4-fold [15]. The report on the

Editor: Yes, that’s right. To objectively prove the efficacy on

special approval for Pfizer’s vaccine for BA1 [16] shows that

reduction of the symptomatic COVID-19 and hospitalization

it was 13.2-fold. So, it was from around 6-fold to 13-fold. By

due to COVID-19, it has to be confirmed by randomized

the way, antibody against BA5 strain (BA5 antibody), which

controlled trials (RCTs).

caused the seventh wave of pandemic, was only about onetwentieth of the antibody against the original virus both after

Exceptional approval granted based only on

the 3rd dose and being infected with BA1/BA2 viruses [15].

antibody test
Reader: Vaccines for the Omicron BA1 and BA5 wereMouse tests with original vaccine proved the same

approved very quickly. Were RCTs conducted?

Reader: Which people had higher antibody titer; people who

Editor: No, RCTs to examine the prevention of symptomatic

had received the 3rd dose or those who had symptoms of the

COVID-19 and hospitalization have not been conducted.

Omicron BA1/BA2?

Exceptional approval was urgently granted only based on the

Page 48 ・ MED CHECK

Dec. 2022/ Vol.8 No.25

antibody test [16]. Its legal basis is on the exceptional

Figure 5: Slight increase of neutralizing antibody titer byapproval system in the revised Pharmaceuticals andBA1 vaccines (comparison with original vaccine)

Medical Devices Law issued on May 20, 2022.
Reader: Zocoba is now being examined in theemergency approval system, right?
Editor: Yes, for an anti-viral agent, Zocoba (seeEditorials) , an RCT was somehow conducted and its

validity was being examined. However, vaccinesfor BA1 and BA5 were put not on the emergency
approval but on the exceptional approval system [18].
“Exceptional approval system” had been established bylaw before May 20, 2022. However, it was revised that
if the efficacy, a requirement for “emergency approval”,
is estimated, the substance is eligible for “exceptional

average 6000 just like the original antibody?

emergency” approval by the revision of the Medicines andEditor: Yes, but unfortunately, with the increased antibody

Pharmaceutical Devices Law on May 20, 2022 [18]. The sixth

titer (average 456) after 4th doses of the original vaccine,wave caused by BA1 and BA2 and the seventh wave by BA5

it showed almost no effect, and thus even if it increases toin 2022, an urgent response was given an importance, and theaverage 711, no effect is expected. The MHLW is supposed to

exceptional approval was granted based only on the increased

be very much aware of this.

antibody titer without confirming the preventive effect byReader: How about Moderna’s BA1 vaccine or Pfizer’s BA5

clinical trials.

vaccine?

Please take a look at how much antibody titers increase in

Editor: The antibody titer after Moderna’s BA1 vaccine wasFig. 5. What is the fraction of BA1 antibody (456) produced

1.74-fold higher than that after the original vaccine (Note 4),

by the original vaccine to the original antibody (5998)?

but as for Pfizer’s BA5 vaccine, no assessment report has been

Reader: One-thirteenth? It is smaller than one-sixth

published, and no data were shown in the package insert［Note B］.

mentioned above.
Editor: Yes, I mentioned earlier 6-fold to 13-fold, and “13”Note B: A bioRxiv preprint paper [26] reported “At 3-5

came from this calculation. Then, is there any difference inweeks post booster shot, individuals who received a 4th

the produced titer of original antibodies between the original

dose with a bivalent mRNA vaccine targeting BA.4/BA.5 had

vaccine and the BA1 vaccine?

similar neutralizing antibody titers as those receiving a 4th

Reader: No, not at all.

monovalent mRNA vaccine against all SARS-CoV-2 variants

Editor: Right. What is the fraction of BA1 antibody (711)tested, including BA.4/BA.5.” (Suppl. Fig. 5)

produced by BA1 vaccines to the original antibody?
Reader: One-eighth. It is only 1.6-fold of that produced by
the original vaccine, and there is only little difference. Is such

Note 4: Some studies on preventive effectiveness on the symptomatic
COVID-19 of Moderna’s vaccines have been published, including
those during the pandemic by the Omicron variant [20-24]. However,a vaccine really effective?

no study reported the risk ratio of symptomatic COVID-19 on the

Editor: That’s where the problem lies. MHLW granted the

day of vaccination, and thus it was not possible to estimate healthy

exceptional emergency approval to the BA1 bivalent vaccine,
because it showed a statistically significant increase of BA1
antibody compared with original SARS-CoV-2 vaccine
and satisfied the condition “efficacy is estimated”. MHLW

vaccine effect which could be estimated in the Israeli studies [7,8].
Healthy-vaccinee effect might occur with Moderna’s vaccines as was
the case in Israel. Therefore, the original vaccine is ineffective against
symptomatic COVID-19 caused by the Omicron variant and so is
Moderna’s BA1 vaccines.

may have wanted to say that it should be approved without
randomised clinical trials before the 8th wave would be

Reader: Why was the approval granted based on such data

prevailing in Japan.

without conducting any clinical trial?

Reader: Is the effect expected if the antibody titer reaches

Editor: We don’t know for sure, but if a large-scale RCTMED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 49

Review
Suppl. Figure 5: Antibody response by original WT vaccine vs BA4/5 bivalentvaccine after 3 doses of original WT vaccine

pandemic in Japan in winter, aswell［Note C］.
Note C:
Around January 10, more than 200
thousand people are confirmedwith SARS-CoV-2 infection every
day and more than 400 people aredying every day in Japan, althoughmany had the 4th dose of SARSCoV-2 vaccines.

A part of the Figure 1B in the ref [26] is extracted showing “comparison of antibody responses induced bya fourth dose of the original wild type (WT ) mRNA vaccine versus a BA.4/BA.5 bivalent mRNA vaccine
as a fourth dose” especially on BA4/5 antibody. No difference on BA4/5 antibody responses was shown.
BA4/5 antibody rise by a BA.4/BA.5 bivalent vaccine was only one fifth of original WT antibody titer.

was conducted, as was practice for existing vaccines, it would

Reader: Will BA1 or BA5 vaccines be effective against the

be confirmed that the vaccines were ineffective. Therefore,

new variant?

the MHLW probably wants to approve the vaccines if “theEditor: No, not at all.

efficacy or effect is estimated” based solely on the antibody
test, hoping that the effectiveness would be proven by studies

No effect, but harm

conducted after the approval.

Editor: Do you think there is no harm if there is no effect?
Reader: No, I don’t think so.

How to make ineffective substances look “effective”?

Editor:As for the effect, the body would acquire theReader: How can you make ineffective substances lookimmunity against the virus or the vaccine which it was first“effective”?

exposed to. When a similar virus enters the body, it tries to

Editor: Do you remember the methods mentioned in the

counteract with the immunity against the original virus or

section (3) ?

vaccine, so it is not effective against the similar one.

Reader: Ah ha, if the effect of an ineffective vaccine is

In addition, the body does not develop a defense systemcompared between the vaccinated and unvaccinated without

against harm even after many doses of vaccines. On theconsidering “healthy vaccinee effect”, it would even appear tocontrary, the harm might become severer each time.

“reduce death”.

Reader: Is it an example of the point (1) for assessment of

Editor: Exactly. The MHLW probably intended to do this.

safety and effectiveness of vaccines: harm-benefit balance

Eventually, observational studies on the preventive effect ofwould change depending on timing?

BA1 and BA5 vaccines on infection will be published like

Editor: Yes, now harm outweighs benefit all over the world,

Israeli studies [8,25]. As a result, the effectiveness of vaccines

and the vaccination should be suspended immediately.

on preventing symptomatic COVID-19, hospitalization,
aggravation and even death might be not just “estimated”, but

Conclusion
SARS-CoV-2 vaccines not only have no proof of efficacy“confirmed”.

against Omicron variants but also may increase risk of
Effective for the 8th wave?

COVID-19 by two times and have serious harms. The

Reader: Is the 8th wave coming?

use of SARS-CoV-2 vaccines should be immediately

Editor: In France and Germany, as of October 24, 2022, thesuspended.

eighth wave has started, and what is worse, a new variant,a subtype of BA5, seems to be spreading. It might cause

Page 50 ・ MED CHECK

Dec. 2022/ Vol.8 No.25

Figure 6:Types of vaccines and their structures

Modified based on the figure 3 in ref [27]Based on a figure in Krammer, F. Nature 2020:586, 516-527. https://doi.org/10.1038/s41586-020-2798-3, a part of the figure and explanation is revised.

Traditional methods of producing antigens (A-G in Fig. 6)

New methods of producing antigens (H-J in Fig. 6)①Attenuated live virus/bacteria (C) :They are called “(attenuated)

There are mainly 3 new methods. All of them have genetic

live vaccines”. They include vaccines for measles and rubella,information to synthesize the whole protein or a part of protein

BCG for tuberculosis, rotavirus vaccine and former polio vaccines.

like spike protein inside of the human body. When injected, they

Although it is rare, vaccine strains of the virus/bacteria may cause

produce the target antigen proteins in the body. The differences arerespective diseases.

as follows.

② Inactivated virus/bacteria (D): Disease-producing capacity is① Using RNA itself (J)destroyed. They include current polio vaccines and vaccines for

In RNA vaccines, messenger RNA (mRNA, Note 5) , which

whooping cough and Japanese encephalitis.

is genetic information of the SARS-CoV-2 virus, is used (the③ Virus-like particle (VLP) -based vaccines (G) : They arebase sequence is partially changed). Bare mRNA is immediately

produced by the recombinant methods, carrying no genome but

decomposed by ribonuclease in the body. In order to prevent this, it

have other component including spike protein on their surface oris encapsulated in lipid nanoparticles. The lipid nanoparticles andother antigen proteins: HPV vaccines (with adjuvants) belongs to

RNA also plays the role of “adjuvants”. Pfizer’s and Moderna’s

this category.

vaccines are in this category.

④ Protein components (subunits) (E/F): that play an important② Using DNA (I)role in infection and aggravation are refined from viruses which

Genetic information (RNA) of viral protein is once transcribed

are cultured and proliferated in a chicken egg (influenza vaccine), or

into DNA by reverse transcriptase (Note 5), and reverse-transcribed

are genetically engineered (by the recombinant methods) and used as

DNA fragments are embedded in a part of circular DNA (plasmid)

antigens (Nuvaxovid/Novavax = Takeda’s SARS － CoV-2 vaccine).

and injected into the human body. This DNA is translated into

As SARS-CoV-2 infects human cells by binding its spikes to
ACE2 receptors, the entire spikes or a part of them are used as
antigens (See Fig. 6 for the structure of SARS-CoV-2 and types ofantigens used for vaccines (candidates) ).

mRNA and the protein of interest is synthesized in the human cells.
③ Using viral vectors (H)Genetic information (RNA) of the protein of interest is embedded
in a low-toxic virus, such as adenovirus, using as a vector, andthey are injected to synthesize the protein inside of the human cells(AstraZeneca’s vaccines).

MED CHECK

Dec. 2022/ Vol.8 No.25 ・ Page 51

Note 5: The human body usually translates genetic information in
DNA and produces mRNA, a blueprint for protein, based on which
protein is produced in the cell. However, as the genes of SARS-CoV-2
is RNA, in DNA vaccine candidates, single-stranded RNA is reversetranslated (reverse-transcribed) into double-stranded DNA to create
DNA fragments.
How protein is produced in human: DNA → mRNA → protein
How protein is produced in SARS-CoV-2:（m）RNA → protein
RNA method: mRNA in lipid nanoparticles → protein production
DNA method: mRNA → DNA → mRNA → protein production

https://www.pmda.go.jp/drugs/2022/P20220912001/672212000_30400A

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Apology：Med Check No.25 was originally scheduled to be issued in December 2022, but it is issued in January 2023.

M
C

ED

2022

Vol.8

No.25

HECK

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, KeikoE d i t o r i a l S t a f f : N A K A N I S H I ,Ta ke a k i ( P h a r m a c i s t ) ; TA K A N O,
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Translators: NAKAMURA, Akari
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Dec. 2022/ Vol.8 No.25 ・ Page 53