MC

December

2020

Volume 6

ED
HECK

N 19
o

Editorial
Amateurism
Review
Poor evidence of direct anticoagulant (DOAC)
DOAC and increased thrombosis without APS
Candidates of New Products
COVID-19 Vaccine Candidates
CONTENTS （December 2020, Vol. 6, No. 19）

Editorial
Amateurism

53

Review
Warfarin is the standard treatment for non-valvular atrial fibrillation
DOAC may induce more thrombosis in patients without APS

54

Candidates of New Products
COVID-19 Vaccine Candidates: Efficacy and Safety
Is frequent neurotoxicity related to new technologies?

64

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December 2020/ Vol.6 No.19

60

M
C

ED

Editorial

HECK

Amateurism
Translated from the Editorial in Med Check(in Japanese) Nov 2020 ; 20 (92) ： 123

Some readers of this bulletin say that thein this issue contains full of unfamiliar

content is difficult and too specialized, or

terms again and again: subunit, spike, lipid

they are tired of reading articles with too

nanoparticle, vector, adjuvant, etc. We feel

many letters. Since this is a drug bulletin thatlike we can hear our readers screaming

covers medical and pharmaceutical sciences,“I have a headache”. However, please takeit requires readers to have some basic

enough time and read them carefully. Evenknowledge about these areas. In addition,

if you don’t understand it by reading it once,

our articles include unfamiliar statistical

you would understand the important points if

terms and numbers, and names of recently

you go back to the articles from time to timedeveloped drugs, which are often long andand read them again.

confusing. That may be one of the reasons
why they are discouraged from reading ourarticles.

The translator (from English to Japanese)of "Representation of the Intellectual" by

The opening message of the first issue

Palestinian-American literary critic Edwardof the predecessor of this bulletin, "Check-

W. Said, said in his postscript that "Whatup your medicines to save your life (launchedkind of person does Said think as a desirable

in January, 2001), said "this book explains

intellectual? The person is not an expert who

about diseases and medicines used foris bound by one field but an amateur whothem, and whether they are good or bad incan freely cross each field." Said does not say

plain language." In addition, the editorial ofthat training of professional skills is wasteful.

the succeeding bulletin, Med Check No. 57

He said "In the current education system,(January, 2015) states that "We would likethe higher the level of education, the more

to make it easy to understand so that lay

those who receive education are confined topeople and the mass media can also read oura narrow area of knowledge." He warns ofbulletin."

professional idiots.

We will do our best to describe complicated contents in a plain and easy-to-

We would like to publish easy-to-understand language, keeping our originalunderstand articles in this bulletin, cherishingintention in our mind.

the spirit of amateurism that "can cross each

However, the article on vaccine (candidate)field freely".

MED CHECK

December 2020/ Vol.6 No.19 ・ Page 53

Review

The 2020 annual theme: Criticism on treatment guidelines series (13)Warfarin is the standard treatment for
non-valvular atrial fibrillation

The usefulness of direct anticoagulants (DOACs)
has not been proven
Translated and revised from Med Check(in Japanese) Mar 2020 ; 20 (88):30-34
Med Check Editorial Team

Summary● Until 2010, warfarin, a vitamin K antagonist, was the only oral anticoagulant for the management of non-valvularatrial fibrillation. The dose of warfarin is titrated by the level of the prothrombin time-international normalized ratio(PT-INR). Although PT-INR range of 2.0 to 3.0 is recommended as optimal in general, we recommend the rage of 1.5

to 2.2 in order to minimize the overall risk of stroke (including hemorrhagic and ischemic) and major hemorrhage.
● There are serious limitations in randomized controlled trials (RCTs) of direct oral anticoagulants (DOACs), including
dabigatran, apixaban, rivaroxaban, and edoxaban. The U.S. Food and Drug Administration (FDA) identified falsified
data especially in the RCTs of apixaban (ARISTOTLE). After excluding the RCTs on apixaban, meta-analysis results of
RCTs on DOAC denied many of the initial analysis results which showed superiority of DOAC to warfarin.
● We found 6 studies and 12 cohorts that compared the outcomes including hemorrhagic and ischemic strokeor other major bleeding between DOAC and warfarin with 6 months or more of follow-up period and were
not directly funded by pharmaceutical companies. Meta-analysis of these studies showed that DOAC did not
significantly reduce the risk of ischemic stroke, systemic thrombosis or overall mortality. The risk of major bleedingand hemorrhagic stroke was significantly reduced, but that of gastrointestinal bleeding was increased. It is highly
possible that increased bleeding is related to the recommended PT-INR range of 2.0 to 3.0, which is too high, andmore bleeding might have occurred in the warfarin group due to excessive use of warfarin.
● Controlling PT-INR at the range of 1.5 to 2.2 with warfarin is most appropriate for the treatment of non-valvularatrial fibrillation.
Conclusion: There is no evidence that direct oral anticoagulants (DOACs) are superior to warfarin
to prevent ischemic stroke in the management of non-valvular atrial fibrillation.
It is appropriate to use warfarin to control PT-INR at the range of 1.5 to 2.2.

Keywords:
vitamin K inhibitor, apixaban, dabigatran, rivaroxaban, ischemic stroke, hemorrhagic stroke, gastrointestinal bleeding, total deathfactor, such as heart failure, hypertension, old age (65Introduction
Prevalence of patients with non-valvular atrial

years and older, especially 75 years and older), diabetes,

fibrillation increases with age [1,2]. Incidence of stroke

history of stroke and vascular diseases. If non-valvularand coronary heart disease, cardiovascular mortality

atrial fibrillation is added, risk of various diseases

and overall mortality increases with each additional risk

especially of ischemic stroke increases greatly [1-4].

Page 54 ・ MED CHECK

December 2020/ Vol.6 No.19

Warfarin has tradit ionally been the only oral
anticoagulant used for reducing ischemic stroke in

Figure 1: Differences in action between warfarin
and DOAC

patients with atrial fibrillation in Japan. However, since
March 2011, direct oral anticoagulants (DOAC) (or nonvitamin K antagonist oral anticoagulants: NOAC) have beenmarketed one after another in Japan.
We reviewed their efficacy and safety, and foundthat all DOACs had major flaws in the methods ofthe randomized controlled trials (RCTs) and that they
could not be used safely [5-7]. In addition, we criticallyreviewed the evidence base of recommending the rangeof 2.0 to 3.0 as the optimal PT-INR for warfarin use andfound that the optimal range of PT-INR should be 1.5 to
2.2 [5,8].
The Japanese Circulation Society stated that "DOAC ispreferable to warfarin if there is an equivalent level ofsleeping pills, and regular break during work or sports
and diaphragmatic breathing are also recommended.

indication" [1]. European guidelines have also expresseda preference for NOACs over VKA in stroke prevention

The appropriate PT-INR is 1.5-2.2.

for AF patients, especially if newly initiated [9]. DOACs

In addition to such non-pharmacological treatment,

include a direct thrombin inhibitor, dabigatran, andanticoagulant therapy should be given to prevent

direct factor Xa inhibitors, such as apixaban, rivaroxaban

ischemic stroke. In order to determine the true optimaland edoxaban. About five years have passed since werange of PT-INR, we searched and found 3 Japaneseexamined these drugs in 2015, so we tried to update thestudies (5 papers) [10-14] and 5 randomized controlled

review.

trials (RCTs) [15-19] analyzed in the Cochrane Review[20] and a series of studies by Hylek et al. [21-23]. We

Atrial fibrillation is a risk factor for stroke andexamined these in detail to identify the optimal range ofischemic disease

PT-INR at which incidence of ischemic stroke + systemic

Patients with atrial fibrillation were 2.8 times more
likely to have a stroke than those without, but were also

embolic event + major hemorrhage (IS / SEE / MH) was
lowest.

2.3 times more likely to die of cardiovascular disease

From Japanese papers, the optimal range of PT- INR

and 1.4 times more likely to die from all causes [4]. Thiswas estimated to be 1.5 to 2.2. In the Cochrane review,

is because non-valvular atrial fibrillation is the result

the optimal range was stated as 2.0-3.0. However, theof ischemia of the myocardium, and hypertension andtarget range of PT- INR of the report (BAATAF study) [16]coronary diseases are also caused by ischemia thatwhich showed the lowest incidence of IS/SEE/MH was 1.5

damages the endothelium of blood vessels causing

to 2.7. In this study PT-INRs of the warfarin group were

inflammation and thrombi. Therefore, it is not surprisingin the target range 83% of the time. In a retrospectivethat people with atrial fibrillation are more likely to havecohort study by Hylek et al., the lowest incidence ofother heart diseases and higher total mortality.

stroke (ischemia + bleeding) was between 2.0 and 2.5 [23].
In addition, the weighted average of the annual rate of

The fundamental treatment should be stressmajor bleeding in RCTs in which target PT-INR was mild

reduction with adequate sleep

was 1.1 % per year [16,19]. In particular, in a study [16]Therefore, reducing tissue ischemia due to sustained
excessive stress is very important not only for atrial

in which targeted PT-INR was 1.5 to 2.7 and 83% of thetime was within the range, annual rate of major bleeding

fibrillation itself but also for the prevention of its

was the lowest (0.86%). On the other hand, the weighted

complications. For that purpose, it is important to takeaverage of the annual rate of major bleeding in RCTs inenough rest with sufficient sleep time without using

which target PT-INRs were in the rage of 2.0 to 3.0 or
MED CHECK

December 2020/ Vol.6 No.19 ・ Page 55

Reviewhigher [15,17,18] and the RE-LY study [24], the annual

will examine whether this information is true or not,rate of major bleeding was 3.2%.

because it contradicts with our previous meta-analysis.

This shows that not only in Japan but also in Europe

There are 3 points to be considered.

and the United States, where the target PT-INR is in the(1) Were the studies conducted in a fair manner ?

range of 2.0 to 3.0, there is a great risk of bleeding. In(2) Were ischemic stroke and total mortality reduced in

the RCT using the warfarin group with the target PT-INR

addition to bleeding?

range of 2.0 to 3.0 as the control group, the risk of major(3) Target PT-INR range of 2.0 to 3.0 is too high andbleeding or cerebral hemorrhage was about 3 times

induces more bleeding.

higher than that of the warfarin group with the milder
target PT-INR range.

Results changed by excluding apixaban RCTTherefore, it is considered that the RCT with 2.0 to 3.0

The Phase 3 RCT that was the basis for the approvalas the target PT-INR range of warfarin use will definitelyof apixaban (Bristol Myers Squibb and Pfizer) is thegive an advantageous result for DOAC. Moreover, since

ARISTOTLE trial. There is a detailed report [32] which

the PROBE method was used in the RE-LY study, theanalysed the US FDA's report on the ARISTOTLE trial,

warfarin group was poorly controlled, and the trial could

including any violations such as data falsification or false

be discontinued should there be any signs of bleeding in

information reporting, protocol violations, violation of

the dabigatran group, which is further advantageous forrecord collection, adverse event reporting and safety

the DOAC group.

assessments.
From their reanalysis of the 22 meta-analyses, they

Meta-analysis results "DOAC is better" is misleading

found that 32 of 99 analyses (32%) yielded results that

The results of a meta-analysis of RCTs on DOAC

would change the conclusions of the initial analysis

comparing with warfarin published in 2014 [25] and(Table1). Of the 32 affected estimates, 31 (97%) no longer

the results of a systematic review and meta-analysis offavored apixaban for the prevention of serious medical

Cochrane [26,27] also conclude that DOAC is better thanissues, and 1 (3%) favored the control. [33]warfarin. These results are also introduced in Japanesereview articles [28,29].

As shown in Table 1, our reanalysis results of thedirect Xa factor inhibitor RCTs from the Cochrane's

There are 2 reports on meta-analysis of observational

review excluding the ARISTOTLE study show thatstudies comparing DOAC with warfarin [30,31] . Boththe assessment of DOAC in ischemic stroke/systemic

focused solely on bleeding, and concluded that among

embolism, cerebral hemorrhage and all strokes (ischemic

DOACs, apixaban and dabigatran had less risk of bleeding

stroke + hemorrhagic stroke) changed from "significantly

than warfarin, and no difference with rivaroxaban. We

effective" to "no significant difference"..

Table 1: Impact of exclusion of ARISTOTLE (from RCTs reviewed by Cochrane)

OR: Odds ratio, 95% CI: 95% confidence interval, NS: not significant, DOAC: Direct oral anticoagulant.
*a: In the edoxaban trials, the total mortality was greatly lower than that in the warfarin group, so this may have affected the overall results.

Page 56 ・ MED CHECK

December 2020/ Vol.6 No.19

No observational study shows superiority of DOAC
Two meta-analysis reports of observational studies

hemorrhage and cerebral hemorrhage) was significantly

lower in DOAC (Table 2).

comparing DOAC with warfarin [30,31] focused only on

Especially in the elderly aged 80 years and overbleeding. Moreover, many of the reports collected and(or 85 years and over) , DOACs significantly increased

analyzed were those that reported bleeding events after

gastrointestinal bleeding by 2-fold and total mortality byshort-term observation and were funded by apixaban

24% compared with warfarin group (Table 3).

manufacturers (Bristol Myers Squibb and Pfizer). Therefore,

There may be 2 major reasons why hemorrhagic

we extracted 12 cohorts from 6 reports [34-39] andstroke was less common in the DOAC group. One is thatanalyzed them after excluding those that reported only

gastrointestinal bleeding is generally more frequent than

bleeding, those that followed-up for less than 6 months,

hemorrhagic stroke, so it is possible that gastrointestinal

and those that were directly funded by pharmaceutical

bleeding occurred earlier and hemorrhagic stroke wascompanies. As a result of comparing the DOAC group andapparently less while using DOAC.

the warfarin group, there was no significant difference

Secondly, as we already pointed out several times

in ischemic stroke / systemic embolism, ischemic stroke,in this paper, hemorrhagic events occur about 3 times

and total mortality while the incidence of gastrointestinal

more frequently in the warfarin group if the target PT-

hemorrhage was significantly higher in DOAC, and

INR is set at the range of 2.0 to 3.0 than milder target

the incidence of hemorrhagic stroke (subarachnoidal

such as 1.5 to 2.7 as in the BAATAF trial.

Table 2: Meta-analysis results of observational studies.

DOAC might have been discontinued at the time when gastrointestinal hemorrhage was noticed. This may be the reason why hemorrhagic stroke
was apparently reduced in the DOAC group. Moreover, if warfarin was used with the targeted PT-INR range of 1.5 to 2.2 instead of 2.0 to 3.0,
hemorrhagic events might have occurred much less frequently, without increasing ischemic stroke,systemic embolism and deaths from all causes.

Table 3: Meta-analysis results of elderly subgroup ( ≧ 80 or 85)

Gastrointestinal bleeding is common among people aged 80 to 85 and over, leading to an increase in total mortality. Controlling PR-INR at therange of 1.5 to 2.2 with warfarin treatment may further reduce hemorrhage such as gastrointestinal bleeding. *a: See reference [40]

MED CHECK

December 2020/ Vol.6 No.19 ・ Page 57

Review
DOAC is only harmful to antiphospholipid antibody

Because the RCTs based on which apixaban was

syndromeapproved have falsified data, by excluding such trials,

As mentioned in another article in this issue [41] ,evidence for the efficacy and safety are greatly changed.

DOAC increases thrombosis and even bleeding in

Not only the Japanese but also the European Guidelines

antiphospholipid antibody syndrome.

which recommend DOAC over warfarin are not reliable.
For the prevention of ischemic stroke in patients with
non-valvular atrial fibrillation, we strongly recommend

In practice
No randomized controlled trials nor observational

treatment with warfarin with target PT-INR range of 1.5

studies with no bias or low risk of bias have shown

to 2.2 in order to minimize the harm of hemorrhage andevidence that DOAC prevents ischemic stroke andprevent ischemic stroke.

reduces hemorrhagic events more than warfarin.

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MED CHECK

December 2020/ Vol.6 No.19 ・ Page 59

Review

DOAC may induce more thrombosis than
warfarin in patients without APS
Translated and revised from Med Check(in Japanese) Nov 2020 ; 20 (92):134-135
Med Check Editorial Team

Summary● Randomized controlled trials (RCTs) and observational studies have confirmed that direct oral anticoagulants(DOAC) increase thrombosis, especially arterial thrombosis, in patients with antiphospholipid antibody syndrome(APS).

● We examined whether this also applies to the evaluation of DOAC when used for non-valvular atrial fibrillation(NVAF).

● A living body works with a well balanced excitatory and inhibitory systems, and receptors also have subtypesof excitatory and inhibitory systems. A selective agonist or antagonist of excitatory system likely to cause harm bydisrupting the balance.
● Blood coagulation function has a coagulation system as excitatory system and an anticoagulation system as
inhibitory system. In the early stage of bleeding, positive feedback promotes coagulation, and as coagulation
progresses, negative feedback ends coagulation. DOAC is a selective inhibitor of Xa or thrombin, namely theselective inhibitor of the excitatory system, while warfarin inhibits both the excitatory system (Factors II, X, VII and IX
in coagulation pathways) and the inhibitory system (protein C pathway).

● Strong platelet aggregation effect of DOAC has been shown in animal experiments. This is suspected to be
associated with selective inhibitory action of DOAC.
● Antiphospholipid antibodies promote coagulation. Individuals with any antiphospholipid antibodies are alsopresent at a substantially high rate in the general population, and higher in the elderly or those with heart diseases.
Therefore, even if APS is not diagnosed, patients with NVAF, which is common in the elderly, may be prone to havethrombosis like those with APS.

Keywords:
antiphospholipid antibody syndrome (APS), rivaroxaban, warfarin, non-valvular atrial fibrillation, coagulation, anticoagulation,
protein C, feedback, platelet aggregation

recommended in patients with antiphospholipid

Introduction
It has been reported that when DOAC is used forsyndrome, particularly high-risk patients (those who

antiphospholipid antibody syndrome (APS), the risk oftest positive for all 3 antiphospholipid tests--lupus

thrombosis is 7.4 times higher than that of warfarin [1]anticoagulant, anticardiolipin antibodies, and anti-beta

in RCT and 12.1 times higher [2] in observational studies,

2 glycoprotein I antibodies) in many countries including

mainly for arterial thrombosis such as ischemic stroke

UK [3].

and myocardial infarction.
Considering the evidence, DOACs are notPage 60 ・ MED CHECK

December 2020/ Vol.6 No.19

However, none of the guidelines for the treatmentof non-valvular atrial fibrillation in many countries

,including in Japan, change the indication of

Figure 1: Differences in action between warfarin

and DOAC

DOAC in prevention of stroke and systemicembolism in patients with non-valvular atrial
fibrillation with one or more risk factors [4].
Considering that the risk of arterial
thrombosis is extremely high (about 10 times
higher) , the onset of thrombosis in APS ismainly related to pharmacological action
rather than pharmacokinetics.
Therefore, we investigated whether DOAC
might increase thrombosis compared withwarfarin in indications other than APS
patients.
Selectivity of drug action and feedback（same as Figure1 in P.55)

function
A living body works with a well balanced excitatory
system (catecholamine, serotonin, etc., or sympathetic

Figure 2: Positive and negative feedback ofhemostatic function

nervous system) and inhibitory system (GABA, etc.,
or parasympathetic nervous system) . For example,

catecholamine predominates in emergencies, but GABA
is also secreted to reduce overexcitement to prevent
excitotoxicity.
Also, when a substance acts on a receptor in vivo,
another subtype of receptor usually suppresses the main
action so that it does not work too strongly.
A selective agonist or antagonist of excitatory system
do not act on the receptors of the inhibitory system,so the balance of action may be lost and the harm may
increase. This may be the major reason why angiotensin
receptor blo ckers (ARB) are more harmful thanangiotensin converting enzyme inhibitors.

FB: feedback, The hemostatic / coagulation function consists of
the interaction between the coagulation pathways (left) and theanticoagulation pathway (right). Initially, the resulting thrombin
promotes coagulation with positive feedback (omitted in the figure), andPositive and negative feedback in coagulation
and anticoagulation pathway

as coagulation progresses, thrombin stimulates the protein C pathway(anticoagulation pathway) to suppress VIII, VII, and V, and also suppresses
platelet aggregation (negative feedback).

In the blood coagulation function, a coagulation
pathways is the excitatory system. On the other hand,an anticoagulant pathway is the inhibitory system thatsufficiently produced, the anticoagulant protein C

works to control not to coagulate too much. Hemostasis

pathway is activated and the aggregation of factors VIII

can be completed normally by both pathways working

and V, and platelets is suppressed. This is a function of

in a well-balanced manner when necessary (Figure. 1 andnegative feedback [5,6].

Figure. 2 ).

In the early stages of bleeding, thrombin mainly
activates factors VIII and V, and provides positive

When it is necessary to stop bleeding rapidly, positive
feedback promotes hemostasis, and when hemostasis
progresses, negative feedback ends coagulation.

feedback to promote the intrinsic pathway.
As hemostasis progresses, when thrombin is
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December 2020/ Vol.6 No.19 ・ Page 61

Review
Dif ferences in action between DOAC andHowever, when thrombin is suppressed by DOAC,

warfarin

the protein C pathway is not activated indefinitely, so

Let's confirm the sites of action of DOAC and warfarin(Figure. 1 and Figure. 2).

various factors that are normally suppressed (particularly
factor VIII) are not suppressed, and platelet aggregation

Of the DOACs, Xa inhibitor such as rivaroxaban,promoted by factor VIII is not suppressed. This is

apixaban and edoxaban inhibits only the factor Xa which

probably the number one reason why DOACs increase

produces the final product, thrombin. Dabigatran inhibits

thrombosis with or without a thrombus predisposition

only thrombin. Both are selective inhibitors only for thesuch as APS or protein C deficiency.

excitatory system that do not inhibit the anticoagulant
pathway.

DOAC strongly aggregates platelets

On the other hand, warfarin inhibits some factors of

DOAC caused frequent arterial thrombosis especiallycoagulation pathway (excitatory system), such as factors

in APS patients [1]. Experiments have been conducted

II and X (in common pathway), VII (in extrinsic pathway),using normal mice to ligate blood vessels or injure theand IX (in intrinsic pathway), as well as protein C pathway

inner surface of vessels and compare the effects ofwhich plays pivotal role in anticoagulant pathway

dabigatran, warfarin and control on on the formation of(inhibitory system). In other words, warfarin is a non-arterial thrombi, mainly thrombi caused by platelets t [8].

selective inhibitor.

No difference was observed between warfarin thecontrol, but dabigatran enhanced platelet aggregation,

Proposed mechanisms of thrombosis by APS

arterial thrombus formation and stabilization [8]. The

Antiphospholipid syndrome (APS) is defined byresult of the experiment reportedly coincides withclinical manifestations that include thrombosis and/the discussion in the previous section that DOAC canor fetal loss or pregnancy morbidity in patients withenhance platelet aggregation with or without thrombus

antiphospholipid antibodies (aPL) . Antiphospholipid

predisposition.

antibodies are directed primarily toward phospholipid

On the other hand, as mentioned at the beginning,binding proteins rather than phospholipid per se, withwarfarin inhibits the extrinsic, intrinsic, common, andthe most common antigenic target being β2-glycoprotein

anticoagulant pathways of coagulation in a well-balanced

I (β2GPI). Laboratory diagnosis of aPL depends upon themanner, and also suppresses platelet aggregation.

detection of a lupus anticoagulant (LA), which prolongs

Because of this, it can be thought that excessive

phospholipid dependent anticoagulation tests, and/or

thrombus formation is avoided with warfarin.

anticardiolipin and anti-β2-glycoprotein I antibodies [7].
Anti-β2GPI antibodies are central to the pathogenesisof APS, and recognize β2GPI bound to the surface ofPatients with non-valvular atrial fibrillation also
has a risk of thrombosis.

endothelial cells, monocytes, and immobilized platelets, in

DOAC is likely to cause platelet aggregation with orsome cases leading to cellular activation and expression

without predisposition of thrombosis. Moreover, evenof procoagulant activity. Other mechanisms by which aPL

without positive for all 3 antiphospholipid antibody

have been proposed to effect a hypercoagulable state

tests, just positive for only one of them increase a risk

include inhibition of the anticoagulant activity of proteinof thrombosis [9]. APS is diagnosed if you have some

C and S, inhibition of the ability of β2GPI to inhibit vonantiphospholipid antibody and have arterial or venous

Willebrand factor-dependent platelet aggregation, andthrombosis, thrombocytopenia, recurrent miscarriage,

in animal models causes tissue factor and complement-

etc. However if you have antiphospholipid antibody but

mediated neutrophil activation etc [7].

have not developed thrombosis, you are not diagnosed
with APS.

Inhibiting thrombin and factor Xa

In northern Italy, some antiphospholipid antibody is

DOAC does not suppress extrinsic or intrinsic

detected in 15.1% of the general population, and it ispathways, but it eventually inhibits thrombin, so

more frequent in older people, especially if they havecoagulation to the common pathway is suppressed.

heart disease [10]. Therefore, the percentage of potential

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December 2020/ Vol.6 No.19

antiphospholipid antibody-positive individuals should
be higher in patients with non-valvular atrial fibrillation
than in the general population, and they are more likely
to develop thrombosis with DOAC.
Conclusions
Even if APS is not diagnosed, many elderly patientswith non-valvular atrial fibrilation are presumed to bepotentially antiphospholipid antibody-positive, and areprone to form thrombi like patients with APS. Therefore,
the use of DOAC is inappropriate in patients with nonvalvular atrial fibrilation.

References
1) Pengo V, Denas G, Zoppellaro G et al. Rivaroxaban vs warfarin in high-riskpatients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371.
PMID:30002145
2) Sato T, Nakamura H, Fujieda Y et al. Factor Xa inhibitors for preventing recurrent
thrombosis in patients with antiphospholipid syndrome: a longitudinal cohort
study. Lupus. 2019 Nov;28(13):1577-1582. PMID:31635559
3) MRHA,
https://www.gov.uk/drug-safety-update/direct-acting-oral-anticoagulants-doacsincreased-risk-of-recurrent-thrombotic-events-in-patients-with-antiphospholipidsyndrome4) Steffel J, Verhamme P, Potpara TS et al The 2018 European Heart Rhythm
Association Practical Guide on the use of non-vitamin K antagonist oral
anticoagulants in patients with atrial fibrillation. Eur Heart J et al 2018 Apr
21;39(16):1330-1393 PMID: 29562325
5) HirshJ and Brain EA, Hemostasis & Thrombosis: A conceptual approach. 2nd
Edition, Churchill Livingstone Inc. New York 1983
6) Liu L. Protein C/S Deficiency
https://step1.medbullets.com/hematology/114066/protein-c-s-deficiency
7) Chaturvedi S, McCrae KR. The antiphospholipid syndrome: still an enigma.
Hematology Am Soc Hematol Educ Program. 2015;2015:53-60. PMID: 26637701
8) Petzold T, Thienel M, Konrad I et al Oral thrombin inhibitor aggravates platelet
adhesion and aggregation during arterial thrombosis. Sci Transl Med. 2016 Nov
30;8(367):367ra168. PMID: 27903864
9) Sato T and Kato M. Comparison of efficacy of ribaroxaban and warfarin on
Rheumatology (in Japanese): 2019：61(4)：396-399.
10) Selmi C, Santis M, Battezzati PM et al. Anti-phospholipid antibody prevalence
and association with subclinical atherosclerosis and atherothrombosis in thegeneral population. Int J Cardiol. 2020 Feb 1;300:209-213. PMID:31757648

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December 2020/ Vol.6 No.19 ・ Page 63

Candidates of New Products
COVID-19 Vaccine Candidates: Efficacy and Safety
Is frequent neurotoxicity related to new technologies?
Translated and revised from Med Check(in Japanese) Nov 2020 ; 20 (92):127-131
Med Check Editorial Team

Summary●There are over 200 vaccine candidates against COVID-19 under development, including those produced by newtechnologies, and several phase III trials are now ongoing.
●In an infection experiment with animals including macaques, infection was not well prevented, while antibody wasproduced in the blood, largely preventing aggravation. However, long-term efficacy is unknown.
●Only up to phase II trials have been published by Oct. 20, 2020 in which only increase in circulating antibody andadverse events were examined for 2 months. It is totally unknown whether the vaccine candidates actually prevent
infection or aggravation, and increased antibody is sustained over a long time.
●In a clinical trial for one vaccine candidate, 2 cases of transverse myelitis or multiple sclerosis were reported.
Neurotoxicity is often associated with vaccines, but in this trial, extremely high incidence, 120/100,000 personyears, was observed. It is highly likely that the new technology for vaccine production is closely associated with theneuropathy, and thus causal relation should be greatly suspected.
Conclusion: There is no evidence for preventive effect yet, but high incidence of neuropathy.
Stringent monitoring on safety and efficacy is essential.

Keywords:
subunit, inactivation, RNA, DNA, viral vector, vaccine candidate, adjuvant, transverse myelitis, multiple sclerosis

Technologies for producing antigen for COVID-19

Introduction
Vaccine candidates against COVID-19 are developed

vaccine candidates are roughly classified into 4

at an unprecedented speed. According to the recent

traditional and 3 new ways. This article explains about

information from London School of Hygiene and Tropicalthese 7 technologies and status of development, andMedicine (as of Oct. 12), currently 248 vaccine candidates

examine their safety.

are under development and 49 clinical trials are ongoingin the world [1].

Vaccine and vaccine candidates (number of vaccine or

The biggest characteristic of the vaccine and vaccine

candidate as of Dec.17, 2020)

candidates under development is that many are producedby new technologies. One of them is to use viral vector

Traditional technologies

against Ebola virus [2,3] , which is approved only

① Using live attenuated virus (4 candidates)

tentatively for human. The other technologies use RNA
or DNA, which is approved for veterinary medicine, but② Using inactivated and non-proliferative whole virus

not for preventive vaccines against infection in human.

particle (18 candidates, 1 approved)

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③ Using virus-like particle which is composed ofNote 1: In humans, protein is usually produced based onproteins synthesized by gene recombination with noa blueprint, mRNA, which is made by translating genetic

genetic materials (19 candidates)④ Using proteins (subunits) , which are believed toplay the most crucial role in infection and aggravation.
They are produced through genetic engineering and are

information in DNA. However, as genes in SARS-CoV-2
is RNA, for DNA vaccines, fragments of DNA is produced
by reverse translation (reverse transcription) of singlestranded RNA to double-stranded RNA.
・Protein production in humans: DNA → mRNA → protein
・Protein production in SARS-CoV-2 : (m)RNA → protein

used as antigens (80 candidates). As SARS-CoV-2 infects

・RNA method: mRNA in lipid nanoparticle → protein

human cells by binding its spike to receptor ACE2, a・DNA method: mRNA → DNA → mRNA → protein

part of the spike or the whole spike is used as antigen.

・Viral vector method: mRNA in virus → protein

New technologies

are injected to mice or macaque, and increase in IgG

There are roughly 3 new technologies. In all of them,level, neutralizing antibody in the blood, is mainly

genetic material (RNA or DNA) is inserted into the humanstudied. Each animal is infected with SARS-CoV-2 about 4

body to synthesize the whole spike protein or a main

weeks post inoculation, and viral loads of SARS-CoV-2 inpart of the spike protein. The difference among the threenasal swab and broncho-alveolar lavage (BAL) fluid wereis as follows.

measured. Animals were dissected 1 week post infection① Using RNA itself

for pathological examination of the lungs and were

For RNA vaccine candidates (35 candidates, 1 approved),messenger RNA (mRNA) (Note 1), which carries genetic

compared with the control (saline, vehicle or other vaccine
candidates).

information of the virus, is used. If naked mRNA is

Since SARS-CoV-2 enters the body and infects throughinjected into the body, it is degraded by ribonuclease

the nose, IgA antibody (Note 2) at nasal and oral mucosa(RNase, an enzyme which breaks RNA) . In order tois supposedly essential for preventing infection. However

prevent it, mRNA is encapsulated in lipid nanoparticle

for most vaccine candidates, only IgG antibody (Note 2) inand injected. Lipid nanoparticle and RNA itself act as

the blood was measured in animal infection experiments,

adjuvants (see Harm of adjuvants).

but not secretory IgA antibody at nasal mucosa.
For example, in a viral vector vaccine candidate② DNA vaccine candidates (23 candidates)

developed by the University of Oxford and AstraZeneca

Transcription (or one kind of reverse translation) of[5], almost no difference in viral load in the nose andRNA of viral protein to DNA is performed by reverse

pharynx was found between the vaccinated and control

transcriptase. Plasmid DNA (circular DNA) encoding themacaques, while viral load in BAL fluid was reduced,

spike gene under a mammalian promoter is injected toand pneumonia improved significantly at 7 days post

the human body. A target protein is synthesized in the

exposure. Animals were infected with the virus 4 weeks

human cell when mRNA is translated from the DNA.

after vaccination, which is the time when antibody titerreached its peak. No animal study confirmed how long

③ Viral vector vaccine candidates (non-replicating viral
vector: 34 candidate and 1 approved, replicating viral vector:
23 candidates)

antibody titer is sustained after inoculation.
For a vaccine candidate developed by Can Sino, China[6] , an animal experiment was conducted, in which

Genetic information (RNA) of target protein is inserted

mice and ferrets were infected with the virus after they

to virus with low toxicity (non-replicating or replicating),

received the candidate not only by the intramuscularsuch as adenovirus. It acts as a vector when it is infectedroute, but also by the oral and intranasal routes.

to the body to synthesize target protein in the humanIntramuscular inoculation suppressed viral replication

cells.

in the lungs, but not adequately in the nose. Intranasal
and oral administration controlled virus almost totally

Findings from animal experiments
In animal experiments, vaccine candidates for humanin nose swabs and the lungs especially of ferrets. In thisstudy, symptom scores and pathological changes in the
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December 2020/ Vol.6 No.19 ・ Page 65

Candidates of New Products
lungs were not reported, and secretory IgA antibody inphase III trials are conducted, all of which with viral

the nose was not measured.

vectors. According to the COVID-19 vaccine tracker

The authors discuss that intranasal administration(https://covid19.trackvaccines.org/vaccines/) , Phase III

should be considered for human clinical trial. However,clinical trials are ongoing as of Dec. 17, 2020: 2 subunit,

in the phase I and phase II trials (Note 3), intramuscular

1 VLP, 1 DNA, 2 RNA, 5 viral vector, 4 inactivated.

administration was used, implying that there was somekind of inconvenience with intranasal administration.

Of the 3 large-scale phase III trials, the first one is
ChAdOx1 nCoV-19 developed by the University of Oxford

Moreover, in most animal experiments, animals wereand AstraZeneca. The trial started on August 17th in

infected with the virus at about 4 weeks post inoculation,

the U.S., involving 30,000 participants [9]. The second isand none of them has confirmed the long-term effect.

Ad26.CoV.S developed by Janssen in the U.S [10]. A phase

From these experiments, it is unknown how long

III trial has been conducted since September 7th in theneutralizing antibody persists.

U.S., Brazil and other Latin American countries, enrolling
60,000 participants. The third is Ad5-nCoV developed

Note 2: Immunity in the body includes innate immunity,

by Can Sino in China [11]. The trial has been conducted

cell-mediated immunity, in which lymphocytes ( Tsince September 15th in Pakistan, involving 40,000

cells) kill virus-infected cells, and humoral immunity,

participants.

in which antibodies developed in the mucosa andAs of October 12th, results from only phase I and II

blood protect against infection. Antibodies are made oftrials have been published, but not yet from phase III

protein called immunoglobulin (Ig) and are produced by
one of the lymphocytes, B cells. In infectious diseases,
immunoglobulin A (IgA), G (IgG) and M (IgM) are mainly
produced. IgA is mainly secreted on the surface of thetrials.
Outcomes reported in phase I and II trials include
IgG antibody titer for up to about 2 months, increase in

mucosa in the nose, bronchus, mouth and gastrointestine,

neutralizing antibody and adverse events. No trial has

and prevents viral invasion. IgM increases in the blood atreported whether vaccine candidate protects against

the beginning of infection and decreases when infection

infection or mitigates aggravation.

is cured. IgG neutralizes virus in the blood. The frequently

In the protocol of the phase I/II trials by the University

used term “neutralizing antibody” refers to an antibodyof Oxford and AstraZeneca [9], “vaccine efficacy rate”

that neutralizes (inactivates) virus in the blood, mainly IgG,
and does not mean IgA antibody secreted in the mucosa.
Note 3: For treatment clinical trials, phase I trials involveis included as an outcome, but it is not reported in the
study. In this study, IgG antibody titer reached peak atday 28 after the first inoculation, and it was lower at day

healthy volunteers, while phase II trials enroll a small

56. In participants who received the second dose at day

number (about 10 to 100) of patients, with illness in order28, slightly increased IgG antibody titer was observed,

to roughly estimate efficacy and safety. Phase III trials

but it again went down at day 56 (4 weeks after the second

include a large number of participants with illness (about

inoculation). It is quite doubtful that IgG antibody persists

100 to 1,000 patients) to confirm efficacy and safety. On thein the blood.

other hand, for clinical trials of vaccine candidates, fromphases I to III, all the participants are healthy. Phase I and II
trials of COVID-19 vaccine candidates enroll several dozens
and several hundreds of healthy volunteers, respectively.

Incidence rates of COVID-19 and changes in antibody
titer should be confirmed over a half year to one year
without waiting for results of phase III trials. Secretory

Phase III trials involved thousands to tens of thousands

IgA antibody at the nasal mucosa should be measured asof healthy volunteers to examine whether the substancewell.

would actually prevent infection, and a rare but severe
adverse reaction would occur.

Multiple sclerosis and transverse myelitis
In the phase I/II trials by the University of Oxford

No evidence for preventive effect in clinicaland AstraZeneca [12], headache was reported in 40%

trialsparticipants who were pretreated with paracetamol andCurrently (as of Oct. 12, 2020), 39 phase I and II trials
and 10 phase III trials are ongoing. Total 3 large-scale
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December 2020/ Vol.6 No.19

60% participants without paracetamol pretreatment in
the vaccine candidate group.

It should be noted that transverse myelitis wasreported in 2 participants (one each in July and in

infected with COVID-19 have died in this age group, it
can be said that the harm far outweighs benefits.

September). The affected participant who was reported inJuly was later diagnosed with multiple sclerosis [13]. The

Note 4: Nerve consists of nerve cells and nerve fibers (axon)

New York Times reported AstraZeneca’s comment that

extending from them. Nerve fibers include myelinatedthe volunteer was later determined to have “a previously
undiagnosed case of multiple sclerosis, unrelated to thevaccine” [14]. However, this is questionable.
Multiple sclerosis is a chronic inflammatory
demyelinating disease (Note 4) of central nervous

nerves wrapped in sheath called myelin sheath (spiralmembrane structure) and unmyelinated nerves without
sheath. When autoantibody is developed against myelin
sheath, it is melted and nerve fibers become exposed.
This is called demyelination, which slows or stops nerve
impulses.

system (CNS). It is characterized by multiple lesions withevidence for dissemination in time and disemination in

N o t e 5 : F o r e x a m p l e , i f f i r s t l y, i n f l a m m a t i o n a n dspace (Note 5). If there is a demyelination in only a single

demyelination of nerves occur in the spinal cord andpart, it is not diagnosed as multiple sclerosis.
If the participant has had a demyelinating disease of
CNS before vaccination and transverse myelitis occurred
after vaccination, this fulfills a diagnostic criteria for
multiple sclerosis. This contradicts with the fact that thesecondly, in another time, it occurs at other sites of thecentral nervous system such as the cerebrum, cerebellumor optic nerve in a patient, it is considered that multiple
lesions occureed with evidence for dissemination in timeand disemination in space.

participant was diagnosed with “transverse myelitis” after

Note 6: For calculation of incidence rate, the numerator

vaccination, but not with multiple sclerosis. Therefore,

is the number of cases identified during a specified

it is highly likely that transverse myelitis occurred after

interval, and the denominator is the number of a defined

vaccination, followed by demyelinating disorders in otherparts of CNS, and this lead to the diagnosis as multiple
sclerosis. Or even if transverse myelitis was the second
demyelinating disorder, the association with the vaccine
candidate should be suspected. In either way, objective

population. Longer the duration of observation is, greater
the number of infected people would become. Therefore,
the duration of observation should be taken into account.
If 100 persons are observed for 2 years, the denominatorshould be 100 persons × 2 years=200 person-years.
Likewise, if 1,000 persons are observed for a short period,

assessment is not possible because AstraZeneca has not

such as 0.2 years, it would also be 200 person-years

reported any details about this case.

(1,000 persons × 0.2 years=200 person-years). As trials of

The New York Times also reported "The condition israre, but serious, and experts said that finding even one
case among thousands of trial participants could be a
red flag. Multiple confirmed cases, they said, could be

COVID-19 vaccine candidates have just started, although
18,000 participants have been enrolled, the duration ofobservation is still shorter than 0.1 year in average, or only
1,600 person-years.

enough to halt AstraZeneca’s vaccine bid entirely." . They
make reasonable points.

10-60 times higher incidence

According to the New York Times, as of September

Autoimmune diseases often occur after infection, and11th, 18,000 participants have received this vaccine

also after vaccination, which creates a condition similar

candidate [14] . However, considering the time of

to infection.

observation, this is still about 1,600 person-years (NoteHPV vaccine is an example of a vaccine with high6). Two persons per 1,600 person-years is equivalent toincidence rate for autoimmune disease, and especiallyabout 120/100,000 person-years.

high incidence of neuropathy has been an issue. In a

The population of people aged 20-29 in Japan is aboutclinical trial for one of the HPV vaccines, Gardasil, female

12 million, and their mortality rate from COVID-19 isparticipants around 20 years of age were observed forlow (only 2 among 42,246 confirmed COVID-19 patients). If

2 years (about 40,000 person-years). Total morbidity forall 12 million received this vaccine candidate, 14,000 of

multiple sclerosis or optic neuritis was 17/100,000

them may develop multiple sclerosis and/or transverse

person-years until the 7th month, and 21/100,000

myelitis. Considering that 2 out of 42,246 people

person-years from the 8th month until the end of the
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December 2020/ Vol.6 No.19 ・ Page 67

Candidates of New Products
second year [16,17].

alum. Gardasil contains “AAHS (amorphous aluminum

This morbidity is 4-20 times higher than that ofhydroxyphosphate sulphate)” as adjuvant. It also contains

women in the same age group who spontaneously

DNA and RNA as impurities which are stabilized anddevelop multiple sclerosis (about 1-5/100,000 person-

protected from endogenous nuclease digestion by

years).

binding to the AAHS [20].

Total incidence of multiple sclerosis in general

For inactivated vaccine candidates and subunit vaccine

population, both men and women in all age groups iscandidates, traditional adjuvants, such as Alum adjuvants

about 2-12/100,000 person-years [18]. Therefore, the(aluminum hydroxide) and surfactant, are used.

incidence of multiple sclerosis in the clinical trial of

On the other hand, vaccine candidates produced

AstraZeneca's COVID-19 vaccine candidate is 10-60

by new technology, such as RNA, DNA or viral vector

times higher than that of spontaneous multiple sclerosis,

vaccines, no specific adjuvant is mentioned. This issuggesting that multiple sclerosis observed in the clinicalbecause RNA or DNA itself, fragments of vector virus

trial was not spontaneous.

RNA/DNA, and lipid nanoparticles that encapsulate them

If the vaccine candidate was used for 100 million

act as adjuvants [21].

people in the world, 120,000 people would have

Severe disability caused after receiving HPV vaccine

transverse myelitis or multiple sclerosis. On thewas strongly associated with new adjuvants andother hand, it is unknown how many serious cases ofresidual DNA/RNA. Due to the way vaccine candidates

COVID-19 it would prevent. Without waiting for another

for COVID-19 are manufactured, it is highly likely thatcase of transverse myelitis, it can be assumed that harm

unavoidable alien substances, such as DNA, RNA, virus,

outweighs benefits.

lipid nanoparticles, would exhibit unknown toxicity as
adjuvants. In order not to repeat the tragedy of HPVHarm of adjuvantsvaccine, careful toxicity study with animals should be1) Adjuvants essentially cause tissue damage

conducted and stringent monitoring is essential.

In order to produce immunity to prevent infection
and aggravation by pathogen, “antigen” is not enough,Other harms

but in addition, adjuvants are often needed to enhance1) Antibody-dependent enhancement (ADE)

immunity.

A typical case of ADE has been reported with Dengue

In spontaneous infection, bacteria have strong toxicity

fever. In Dengue fever, when a person is infected withand enter the human body by damaging the cells. In virala certain strain of Dengue virus, she/he would develop

infection, infected cells are destroyed by cytotoxic T cells

antibody. However, if she/he is secondly infected withand leucocytes which treat them are destroyed. Thendifferent strain of Dengue virus, she/he might develop

intranuclear DNA and RNA are released and bind withsevere symptoms of the disease.

protein to act as an adjuvant and enhance immunity.

When vaccinated persons are infected with Dengue

In vaccines, in order for aluminum (Alum) to act asvirus, they developed severer symptoms than when thean adjuvant and enhance immunity, aluminum particles

unvaccinated persons are infected with the same disease.

must first injure tissues. Then leucocytes are gathered toThis is just like experiencing severe symptoms whentreat them and breaks, and DNA and RNA are released to

one is naturally infected with a strain of virus slightly

bind with protein forming DNA- or RNA-protein complex.

different from the first infection.

This becomes a stable foreign object to be an actual

For vaccine candidates against SARS-CoV and MERS-

adjuvant [19,20]. In other words, at first, adjuvants must

CoV, cases of ADE were reported in animal experiments.

injure tissues.

Because of that, safe and effective vaccine has not yet
been developed.

2) RNA and DNA are strong and direct adjuvants.

As of now, ADE has not been reported in animal

Cervarix contains monophosphoryl lipid A (MPL) ,experiments for COVID-19 vaccine candidates [23] .

a derivat ive of lipid A (major toxic component ofHowever, rigorous monitoring is needed in clinical trials

lipopolysaccharide) from Salmonella endotoxin andand in practice.

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December 2020/ Vol.6 No.19

2) Fragments of bases might have cytotoxicity

entered the third phase, based on the designed number

In the process of manufacturing vaccine candidates byof years and participants, it has reached only 110

the new technologies, bases that do not exist naturally

person-years. If one person experienced a severe adverse

might be produced as RNA, DNA or viral vectors arereaction, this is equivalent to 900/100,000 persons,degraded [21]. Just like an anticancer agent, 5-FU, anda high incidence rate. More information should be

antivirals, favipiravir (Avigan) and remdesivir (Veklury),

published.

these bases are taken into the human cells when RNA
is synthesized and might act as cytotoxic agents [21,24].

Postscript 2:

They might exert mitochondrial toxicity, causing

According to the New York times

myopathy, lactic acidosis, pancreatitis, liver disorder,

https://www.nytimes.com/interactive/2020/science/such as fatty liver and neuropathy, which can be fatal [21].

coronavirus-vaccine-tracker.html?auth=login-

Such toxicity remains unknown with vaccine candidates

email&login=email

against COVID-19 as they have not been applied to

6 vaccines are approved for limited use and 2 vaccines

human use. However, it has been confirmed in animal

are approved for full use as of Dec. 18, 2020.

experiments for other substances [21].
In practice
As of now, harm of vaccine candidates against

References
1) Vaccine Center at the london School of Hygine & Tropical Medicine, COVID-19

COVID-19 seems to outweigh benefit. Therefore, theyvaccine tracker

should not be used until appropriate information is2) FDANews release, First FDA-approved vaccine for the prevention of Ebola virus

published and their safety and efficacy are confirmed.

https://www.fda.gov/news-events/press-announcements/first-fda-approved-vaccine-

https://vac-lshtm.shinyapps.io/ncov_vaccine_landscape/#
disease, marking a critical milestone in public health preparedness and response

Even if you are recommended to receive the vaccination,

prevention-ebola-virus-disease-marking-critical-milestone-public-healthyou should refuse it.

recommended for approval in the European Union

3) EMA Press release: New vaccine for prevention of Ebola virus disease
https://www.ema.europa.eu/en/news/new-vaccine-prevention-ebola-virus-diseaserecommended-approval-european-union

Postscript 1:
Just before the final proof of this article, the media

4) Redding L, Weiner DB DNA vaccines in veterinary use. Expert Rev Vaccines. 2009
Sep;8(9):1251-76. PMID: 19722897
5) Doremalen N, Lambe T, Spencer A et al. ChAdOx1 nCoV-19 vaccination prevents

reported that clinical trials for COVID-19 vaccine and

SARS-CoV-2 1 pneumonia in rhesus macaques bioRxiv preprint doi: https://doi.

antibody drug candidates were paused [25,26]. Janssen

6) Wu S, Zhong G, Zhang J et al A single dose of an adenovirus-vectored vaccine(Johnson & Jonson’s subsidiary company) paused a phaseorg/10.1101/2020.05.13.093195.
provides protection against SARS-CoV-2 challenge. Nat Commun. 2020 Aug
14;11(1):4081. PMID: 32796842

III clinical trial of its vaccine candidate developed by

7) Zhu FC, Li YH, Guan XH et al. Safety, tolerability, and immunogenicity

viral vector technology on October 13 [10]. Then, Eli Lilly

escalation, open-label, non-randomised, first-in-human trial. Lancet. 2020 Junof a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-

decided to pause a clinical trial of its monoclonal antibody

13;395(10240):1845-1854. Epub 2020 May 22.PMID: 32450106

drug candidate on October 14th.

adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or

For Janssen’s vaccine candidate, the phase III trial

8) Zhu FC, Guan XH, Li YH et al. Immunogenicity and safety of a recombinantolder: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2020
Aug 15;396(10249):479-488. Epub 2020 Jul 20.PMID: 32702299

had just started on September 7th, and was designed9) AstraZeneca Phase III Double-blind, Placebo-controlled Study of AZD1222 for theto continue until March, 2023, involving 60,00010) Janssen Vaccines & Prevention B.V. A Study of Ad26.COV2.S for the Prevention

Prevention of COVID-19 in Adults https://clinicaltrials.gov/ct2/show/NCT04516746

participants [10], but it was paused after one month. The

of SARS-CoV-2-Mediated COVID-19 in Adult Participants (ENSEMBLE) https://manufacturer has not reported what kind of illness had11) CanSino Biologics Inc. Phase III Trial of A COVID-19 Vaccine of Adenovirus

been observed. However, there is no doubt that it was

clinicaltrials.gov/ct2/show/NCT04505722
Vector in Adults 18 Years Old and Above https://clinicaltrials.gov/ct2/show/
NCT04526990

a serious adverse reaction associated with the vaccine

12) Folegatti PM, Ewer KJ, Aley PK et al. Safety and immunogenicity of the ChAdOx1

candidate. Reuters introduced a comment of one expert

blind, randomised controlled trial. Lancet. 2020 Aug 15;396(10249):467-478. PMID:

nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-“If it was something like prostate cancer, uncontrolled

32702298

diabetes or a heart attack – they wouldn’t stop it for

growingany of those reasons. This is likely to be a neurologicalevent.” [25] We agree with his comment.
As Janssen’s trial was paused one month after it13) Nature News. COVID-vaccine results are on the way-and scientists’ concerns arehttps://www.nature.com/articles/d41586-020-02706-6
14) NewYork Times. AstraZeneca, Under Fire for Vaccine Safety, Releases Trial
Blueprints 2020/9/11
https://www.nytimes.com/2020/09/19/health/astrazeneca-vaccine-safetyblueprints.html

MED CHECK

December 2020/ Vol.6 No.19 ・ Page 6915) multiple sclerosis/ optic-spinal neuritis(in Japanese) https://www.nanbyou.or.jp/
entry/3807
16) HamaR Stop HPV vaccine MedCheck 2013:13(52):29-43. (in Japanese)17) Hama R, Tanida N. Risk analysis of Autoimmune disease after HPV vaccination
The Informed Prescriber 2013:28(5):89-99.
18) Hama R personal communication.
19) Ishii K Adjuvant and DNA from host's cells
http://www.ifrec.osaka-u.ac.jp/jpn/research/upload_img/Ken% 20Ishii_Nat% 20Medic
ine% 20% E8% A7% A3% E8% AA% AC.pdf
20) Hama R What is adjuvant in HPV vaccine: a comprehensive review. MedCheck
2014:14(53):47-67.
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Vaccines (Basel). 2019 Apr 24;7(2):37. PMID: 31022829
22) Ulrich H, Pillat MM, Tárnok A.Cytometry A. Dengue Fever, COVID-19 (SARSCoV-2), and Antibody-Dependent Enhancement (ADE): A Perspective. Cytometry A
2020 Jul;97(7):662-667. Epub 2020 Jun 7.PMID: 32506725
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10.1038/s41586-020-2798-3. PMID: 32967006
24) Nakanishi T,Hama R Favipiravir (Trade name Avigan) Most probably no efficacy
on COVID-19, and harmful. Med Check in English 2020：6（18)：46-50.
25) Reuters 2020/10/13,
https://jp.reuters.com/article/uk-health-coronavirus-johnson-johnson/jj-pausescovid-19-vaccine-trials-due-to-unexplained-illness-in-participant-idUKKBN26Y02L26) Reuters 2020/10/14
https://jp.reuters.com/article/us-health-coronavirus-eli-lilly/eli-lilly-pauses-trial-of-

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2020

Vol.6

No.18

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, Keiko
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