Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -

Corman-Drosten ​et al.​, Eurosurveillance 2020 (Updated: 2.12.2020)

External peer review of the RTPCR test to detect SARS-CoV-2

reveals 10 major scientific flaws at the molecular and
methodological level: consequences for false positive results.
Pieter Borger​(1 * )​, Bobby Rajesh Malhotra​(2)​ , Michael Yeadon​(3)​ , Clare Craig​(4)
Kevin McKernan​(5)​ , Klaus Steger​(6)​ , Paul McSheehy​(7)​ , Lidiya Angelova​(8)
Fabio Franchi​(9)​, Thomas Binder​(10)​, Henrik Ullrich​(11)​ , Makoto Ohashi​(12)
Stefano Scoglio​(13)​, Marjolein Doesburg-van Kleffens​(14)​, Dorothea Gilbert​(15)
Rainer Klement​(16)​, Ruth Schruefer​(17)​, Berber W. Pieksma​(18)​, Jan Bonte​(19)
Bruno H. Dalle Carbonare​(20)​, Kevin P. Corbett​(21)​, Ulrike Kämmerer​(22)
* Corresponding Author

ABSTRACT
"In the publication entitled “Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR”
(Eurosurveillance 25(8) 2020) the authors present a diagnostic workflow and RT-qPCR protocol for
detection and diagnostics of 2019-nCoV (now known as SARS-CoV-2), which they claim to be
validated, as well as being a robust diagnostic methodology for use in public-health laboratory
settings.
In light of all the consequences resulting from this very publication for societies worldwide, a group
of independent researchers performed a point-by-point review of the aforesaid publication in which
1) all components of the presented test design were cross checked, 2) the RT-qPCR
protocol-recommendations were assessed with respect to good laboratory practice, and 3)
parameters examined against relevant scientific literature covering the field.
The published RT-qPCR protocol for detection and diagnostics of 2019-nCoV and the manuscript
suffer from numerous technical and scientific errors, including insufficient primer design, a
problematic and insufficient RT-qPCR protocol, and the absence of an accurate test validation.
Neither the presented test nor the manuscript itself fulfils the requirements for an acceptable
scientific publication. Further, serious conflicts of interest of the authors are not mentioned. Finally,
the very short timescale between submission and acceptance of the publication (24 hours) signifies
that a systematic peer review process was either not performed here, or of problematic poor quality.

We provide compelling evidence of several scientific inadequacies, errors and flaws. Considering the
scientific and methodological blemishes presented here, we are confident that the editorial board of
Eurosurveillance has no other choice but to retract the publication."
Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.​, Eurosurveillance 2020 (Updated: 2.12.2020)

CONCISE REVIEW REPORT

This paper will show numerous serious flaws in the Corman-Drosten paper, the significance of which
has led to worldwide misdiagnosis of infections attributed to SARS-CoV-2 and associated with the
disease COVID-19. We are confronted with stringent lockdowns which have destroyed many people’s
lives and livelihoods, limited access to education and these imposed restrictions by governments
around the world are a direct attack on people’s basic rights and their personal freedoms, resulting in
collateral damage for entire economies on a global scale.

There are ten fatal problems with the Corman-Drosten paper which we will outline and explain in
greater detail in the following sections.

The first and major issue is that the novel Coronavirus SARS-CoV-2 (in the publication named
2019-nCoV and in February 2020 named SARS-CoV-2 by an international consortium of virus experts)
is based on in silico (theoretical) sequences, supplied by a laboratory in China [1], because at the time
neither control material of infectious (“live”) or inactivated SARS-CoV-2 nor isolated genomic RNA of
the virus was available to the authors. To date no validation has been performed by the authorship
based on isolated SARS-CoV-2 viruses or full length RNA thereof. According to Corman et al.:

“We aimed to develop and deploy robust diagnostic methodology for use in public
health laboratory settings without having virus material available.”​ [1]

The focus here should be placed upon the two stated aims: a) ​development​ and b) ​deployment of a
diagnostic test for use in public health laboratory settings.​ These aims are not achievable without
having any actual virus material available (e.g. for determining the infectious viral load). In any case,
only a protocol with maximal accuracy can be the mandatory and primary goal in any
scenario-outcome of this magnitude. Critical viral load determination is mandatory information, and
it is in Christian Drosten’s group responsibility to perform these experiments and provide the crucial
data.

Nevertheless these in silico sequences were used to develop a RT-PCR test methodology to identify
the aforesaid virus. This model was based on the assumption that the novel virus is very similar to
SARS-CoV from 2003 as both are beta-coronaviruses.

The PCR test was therefore designed using the genomic sequence of SARS-CoV as a control material
for the Sarbeco component; we know this from our personal email-communication with [2] one of
the co-authors of the Corman-Drosten paper. This method to model SARS-CoV-2 was described in the
Corman-Drosten paper as follows:

“the establishment and validation of a diagnostic workflow for 2019-nCoV screening

and specific confirmation, designed in absence of available virus isolates or original
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patient specimens. Design and validation were enabled by the close genetic relatedness
to the 2003 SARS-CoV, and aided by the use of synthetic nucleic acid technology.”

The Reverse Transcription-Polymerase Chain Reaction (RT-PCR) is an important biomolecular

technology to rapidly detect rare RNA fragments, which are known in advance. In the first step, RNA
molecules present in the sample are reverse transcribed to yield cDNA. The cDNA is then amplified in
the polymerase chain reaction using a specific primer pair and a thermostable DNA polymerase
enzyme. The technology is highly sensitive and its detection limit is theoretically 1 molecule of cDNA.
The specificity of the PCR is highly influenced by biomolecular design errors.

What is important when designing an RT-PCR Test and the quantitative RT-qPCR
test described in the Corman-Drosten publication?

1. The primers and probes:

a) the concentration of primers and probes must be of optimal range (100-200 nM)

b) must be specific to the target-gene you want to amplify

c) must have an optimal percentage of GC content relative to the total nitrogenous bases (minimum
40%, maximum 60%)

d) for virus diagnostics at least 3 primer pairs must detect 3 viral genes (preferably as far apart as
possible in the viral genome)

2. The temperature at which all reactions take place:

a) DNA melting temperature (>92°)

b) DNA amplification temperature (TaqPol specific)

c) Tm; the annealing temperature (the temperature at which the primers and probes reach the target
binding/detachment, not to exceed 2 ̊C per primer pair). Tm heavily depends on GC content of the
primers

3. The number of amplification cycles (less than 35; preferably 25-30 cycles);

In case of virus detection, >35 cycles only detects signals which do not correlate with infectious virus
as determined by isolation in cell culture [reviewed in 2]; if someone is tested by PCR as positive
when a threshold of 35 cycles or higher is used (as is the case in most laboratories in Europe & the
US), the probability that said person is actually infected is less than 3%, the probability that said
result is a false positive is 97% [reviewed in 3]
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4. Molecular biological validations; amplified PCR products must be validated either by running the products
in a gel with a DNA ruler, or by direct DNA sequencing

5. Positive and negative controls should be specified to confirm/refute specific virus detection

6. There should be a Standard Operational Procedure (SOP) available

SOP unequivocally specifies the above parameters, so that all laboratories are able to set up the
exact same test conditions. To have a validated universal SOP is essential, because it enables the
comparison of data within and between countries.

MINOR CONCERNS WITH THE CORMAN-DROSTEN PAPER

1. In Table 1 of the Corman-Drosten paper, different abbreviations are stated - “nM” is specified,
“nm” isn’t. Further in regards to correct nomenclature, nm means “nanometer” therefore nm should
read nM here.

2. It is the general consensus to write genetic sequences always in the 5’-3’ direction, including the
reverse primers. It is highly unusual to do alignment with reverse complementary writing of the
primer sequence as the authors did in figure 2 of the Corman-Drosten paper. Here, in addition, a
wobble base is marked as “y” without description of the bases the Y stands for.

3. Two misleading pitfalls in the Corman-Drosten paper are that their Table 1 does not include
Tm-values (annealing-temperature values), neither does it show GC-values (number of G and C in the
sequences as %-value of total bases).

MAJOR CONCERNS WITH THE CORMAN-DROSTEN PAPER

A) BACKGROUND

The authors introduce the background for their scientific work as: “The ongoing outbreak of the
recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as
virus isolates are unavailable while there is growing evidence that the outbreak is more widespread
than initially thought, and international spread through travelers does already occur”.

According to BBC News [4] and Google Statistics [5] there were 6 deaths world-wide on January 21st
2020 - the day when the manuscript was submitted. Why did the authors assume a challenge for
public health laboratories while there was no substantial evidence at that time to indicate that the
outbreak was more widespread than initially thought?

As an aim the authors declared to develop and deploy robust diagnostic methodology for use in
public health laboratory settings without having virus material available. Further, they acknowledge
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Corman-Drosten ​et al.​, Eurosurveillance 2020 (Updated: 2.12.2020)

that “The present study demonstrates the enormous response capacity achieved through
coordination of academic and public laboratories in national and European research networks.”

B) METHODS AND RESULTS

1. Primer & Probe Design

1a) Erroneous primer concentrations

Reliable and accurate PCR-test protocols are normally designed using between 100 nM and 200 nM
per primer [7]. In the Corman-Drosten paper, we observe unusually high and varying primer
concentrations for several primers (table 1). For the RdRp_SARSr-F and RdRp_SARSr-R primer pairs,
600 nM and 800 nM are described, respectively. Similarly, for the N_Sarbeco_F and N_Sarbeco_R
primer set, they advise 600 nM and 800 nM, respectively [1].

It should be clear that these concentrations are far too high to be optimal for specific amplifications
of target genes. ​There exists no specified reason to use these extremely high concentrations of
primers in this protocol. Rather, these concentrations lead to increased unspecific binding and PCR
product amplification.

Table1: Primers and probes (adapted from Corman-Drosten paper; erroneous primer concentrations are
highlighted)

1b) Unspecified (“Wobbly”) primer and probe sequences

To obtain reproducible and comparable results, it is essential to distinctively define the
primer pairs. In the Corman-Drosten paper we observed six unspecified positions, indicated
by the letters R, W, M and S (Table 2). The letter W means that at this position there can be
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either an A or a T; R signifies there can be either a G or an A; M indicates that the position

may either be an A or a C; the letter S indicates there can be either a G or a C on this
position. This high number of variants not only is unusual, but it also is highly confusing for
laboratories. These six unspecified positions could easily result in the design of several
different alternative primer sequences which do not relate to SARS-CoV-2 (2 distinct
RdRp_SARSr_F primers + 8 distinct RdRp_SARS_P1 probes + 4 distinct RdRp_SARSr_R). The
design variations will inevitably lead to results that are not even SARS CoV-2 related.
Therefore, the confusing unspecific description in the Corman-Drosten paper is not suitable
as a Standard Operational Protocol. These unspecified positions should have been designed
unequivocally.
These wobbly sequences have already created a source of concern in the field and resulted
in a Letter to the Editor authored by Pillonel et al. [8] regarding blatant errors in the
described sequences. These errors are self-evident in the Corman et al. supplement as well.

Table 2: Primers and probes (adapted from Corman-Drosten paper; unspecified (“Wobbly”) nucleotides in the
primers are highlighted)

The WHO-protocol (Figure 1), which directly derives from the Corman-Drosten paper,
concludes that in order to confirm the presence of SARS-CoV-2, two control genes (the
E-and the RdRp-genes) must be identified in the assay. It should be noted, that the
RdPd-gene has one uncertain position (“wobbly”) in the forward-primer (R=G/A), two
uncertain positions in the reverse-primer (R=G/A; S=G/C) and it has three uncertain
positions in the RdRp-probe (W=A/T; R=G/A; M=A/C). So, two different forward primers,
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four different reverse primers, and eight distinct probes can be synthesized for the
RdPd-gene. Together, there are 64 possible combinations of primers and probes!

The Corman-Drosten paper further identifies a third gene which, according to the WHO
protocol, was not further validated and deemed unnecessary:

“Of note, the N gene assay also performed well but was not subjected
to intensive further validation because it was slightly less sensitive.”

This was an unfortunate omission as it would be best to use all three gene PCRs as
confirmatory assays, and this would have resulted in an almost sufficient virus RNA
detection diagnostic tool protocol. Three confirmatory assay-steps would at least
minimize-out errors & uncertainties at every fold-step in regards to “Wobbly”-spots.
(Nonetheless, the protocol would still fall short of any “good laboratory practice”, when
factoring in all the other design-errors).

As it stands, the N gene assay is regrettably neither proposed in the WHO-recommendation

(Figure 1) as a mandatory and crucial third confirmatory step, nor is it emphasized in the
Corman-Drosten paper as important optional reassurance “for a routine workflow” (Table 2).

Consequently, in nearly all test procedures worldwide, merely 2 primer matches were used
instead of all three. This oversight renders the entire test-protocol useless with regards to
delivering accurate test-results of real significance in an ongoing pandemic.

Figure 1: The N-Gene confirmatory-assay is neither emphasized as necessary third step in the official WHO
Drosten-Corman protocol-recommendation below [8] nor is it required as a crucial step for higher test-accuracy
in the Eurosurveillance publication.
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1c) Erroneous GC-content (discussed in 2c, together with annealing temperature (Tm))

1d) Detection of viral genes

RT-PCR is not recommended for primary diagnostics of infection. This is why the RT-PCR Test
used in clinical routine for detection of COVID-19 is not indicated for COVID-19 diagnosis on
a regulatory basis.

“Clinicians need to recognize the enhanced accuracy and speed of the molecular diagnostic
techniques for the diagnosis of infections, but also to understand their limitations. Laboratory
results should always be interpreted in the context of the clinical presentation of the patient,
and appropriate site, quality, and timing of specimen collection are required for reliable test
results”. [9]

However, it may be used to help the physician’s differential diagnosis when he or she has to
discriminate between different infections of the lung (Flu, Covid-19 and SARS have very
similar symptoms). For a confirmative diagnosis of a specific virus, at least 3 specific primer
pairs must be applied to detect 3 virus-specific genes. Preferably, these target genes should
be located with the greatest distance possible in the viral genome (opposite ends included).

Although the Corman-Drosten paper describes 3 primers, these primers only cover roughly
half of the virus’ genome. This is another factor that decreases specificity for detection of
intact COVID-19 virus RNA and increases the quote of false positive test results.

Therefore, even if we obtain three positive signals (i.e. the three primer pairs give 3 different
amplification products) in a sample, this does not prove the presence of a virus. A better
primer design would have terminal primers on both ends of the viral genome. This is
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because the whole viral genome would be covered and three positive signals can better
discriminate between a complete (and thus potentially infectious) virus and fragmented viral
genomes (without infectious potency). In order to infer anything of significance about the
infectivity of the virus, the Orf1 gene, which encodes the essential replicase enzyme of
SARS-CoV viruses, should have been included as a target (Figure 2). The positioning of the
targets in the region of the viral genome that is most heavily and variably transcribed is
another weakness of the protocol.

Kim et al. demonstrate a highly variable 3’ expression of subgenomic RNA in Sars-CoV-2 [23].
These RNAs are actively monitored as signatures for asymptomatic and non-infectious
patients [10]. It is highly questionable to screen a population of asymptomatic people with
qPCR primers that have 6 base pairs primer-dimer on the 3 prime end of a primer (Figure 3).

Apparently the WHO recommends these primers. We tested all the wobble derivatives from
the Corman-Drosten paper with Thermofisher’s primer dimer web tool [11]. The RdRp
forward primer has 6bp 3prime homology with Sarbeco E Reverse. At high primer
concentrations this is enough to create inaccuracies.

Of note: There is a perfect match of one of the N primers to a clinical pathogen (Pantoea),
found in immuno-compromised patients. The reverse primer hits Pantoea as well but not in
the same region (Figure 3).

These are severe design errors, since the test cannot discriminate between the whole virus
and viral fragments. The test cannot be used as a diagnostic for SARS-viruses.
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Figure 2: Relative positions of amplicon targets on the SARS coronavirus and the 2019 novel coronavirus
genome. ORF: open reading frame; RdRp: RNA-dependent RNA polymerase. Numbers below amplicon are
genome positions according to SARS-CoV, NC_004718 [1];

Figure 3: A test with Thermofischer’s primer dimer web tool reveals that the RdRp forward primer has a 6bp
3`prime homology with Sarbeco E Reverse (left box). Another test reveals that there is a perfect match for one
of the N-primers to a clinical pathogen (Pantoea) found in immuno-compromised patients (right box).
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Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

2. Reaction temperature

2a) DNA melting temperature (>92°).

Adequately addressed in the Corman-Drosten paper.

2b) DNA amplification temperature.

Adequately addressed in the Corman-Drosten paper.

2c) Erroneous GC-contents and Tm

The annealing-temperature determines at which temperature the primer attaches/detaches
from the target sequence. For an efficient and specific amplification, GC content of primers
should meet a minimum of 40% and a maximum of 60% amplification. As indicated in table
3, three of the primers described in the Corman-Drosten paper are not within the normal
range for GC-content. Two primers (RdRp_SARSr_F and RdRp_SARSr_R) have unusual and
very low GC-values of 28%-31% for all possible variants of wobble bases, whereas primer
E_Sarbeco_F has a GC-value of 34.6% (Table 3 and second panel of Table 3).

It should be noted that the GC-content largely determines the binding to its specific target
due to its three hydrogen bonds in base pairing. Thus, the lower the GC-content of the
primer, the lower its binding-capability to its specific target gene sequence (i.e. the gene to
be detected). This means for a target-sequence to be recognized we have to choose a
temperature which is as close as possible to the actual annealing-temperature (best
practise-value) for the primer not to detach again, while at the same time specifically
selecting the target sequence.

If the Tm-value is very low, as observed for all wobbly-variants of the RdRp reverse primers,
the primers can bind non-specifically to several targets, decreasing specificity and increasing
potential false positive results.

The annealing temperature (Tm) is a crucial factor for the determination of the
specificity/accuracy of the qPCR procedure and essential for evaluating the accuracy of
qPCR-protocols. Best-practice recommendation: Both primers (forward and reverse) should
have an almost similar value, preferably the identical value.

We used the freely available primer design software Primer-BLAST [12, 25] to evaluable the
best-practise values for all primers used in the Corman-Drosten paper (Table 3). We
attempted to find a Tm-value of 60° C, while similarly seeking the highest possible
GC%-value for all primers. A maximal Tm difference of 2° C within primer pairs was
considered acceptable. Testing the primer pairs specified in the Corman-Drosten paper, we
observed a difference of 10° C with respect to the annealing temperature Tm for primer
pair1 (RdRp_SARSr_F and RdRp_SARSr_R). This is a very serious error and makes the
protocol useless as a specific diagnostic tool.
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Additional testing demonstrated that only the primer pair designed to amplify the N-gene
(N_Sarbeco_F and N_Sarbeco_R) reached the adequate standard to operate in a diagnostic
test, since it has a sufficient GC-content and the Tm difference between the primers
(N_Sarbeco_F and N_Sarbeco_R) is 1.85° C (below the crucial maximum of 2° C difference).
Importantly, this is the gene which was neither tested in the virus samples (Table 2) nor
emphasized as a confirmatory test. In addition to highly variable melting temperatures and
degenerate sequences in these primers, there is another factor impacting specificity of the
procedure: the dNTPs (0.4uM) are 2x higher than recommended for a highly specific
amplification. There is additional magnesium sulphate added to the reaction as well. This
procedure combined with a low annealing temperature can create non-specific
amplifications. When additional magnesium is required for qPCR, specificity of the assay
should be further scrutinized.

The design errors described here are so severe that it is highly unlikely that specific
amplification of SARS-CoV-2 genetic material will occur using the protocol of the
Corman-Drosten paper.
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Table 3: GC-content of the primers and probes (adapted from Corman-Drosten paper; aberrations from
optimized GC-contents are highlighted. Second Panel shows a table-listing of all Primer-BLAST best practices
values for all primers and probes used in the Corman-Drosten paper by Prof. Dr. Ulrike Kämmerer & her team.

3. The number of amplification cycles

It should be noted that there is no mention anywhere in the Corman-Drosten paper of a test
being positive or negative, or indeed what defines a positive or negative result. These types
of virological diagnostic tests must be based on a SOP, including a validated and fixed
number of PCR cycles (Ct value) after which a sample is deemed positive or negative. The
maximum reasonably reliable Ct value is 30 cycles. Above a Ct of 35 cycles, rapidly increasing
numbers of false positives must be expected .

PCR data evaluated as positive after a Ct value of 35 cycles are completely unreliable.
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Citing Jaafar et al. 2020 [3]:

“At Ct = 35, the value we used to report a positive result for PCR, <3% of cultures are
positive.”

In other words, there was no successful virus isolation of SARS-CoV-2 at those high Ct
values. Further, scientific studies show that only non-infectious (dead) viruses are detected
with Ct values of 35 [22].

Between 30 and 35 there is a grey area, where a positive test cannot be established with
certainty. This area should be excluded. Of course, one could perform 45 PCR cycles, as
recommended in the Corman-Drosten WHO-protocol (Figure 4), but then you also have to
define a reasonable Ct-value (which should not exceed 30). But an analytical result with a Ct
value of 45 is scientifically and diagnostically absolutely meaningless (a reasonable Ct-value
should not exceed 30). All this should be communicated very clearly. It is a significant
mistake that the Corman-Drosten paper does not mention the maximum Ct value at which
a sample can be unambiguously considered as a positive or a negative test-result. This
important cycle threshold limit is also not specified in any follow-up submissions to date.

Figure 4: RT-PCR Kit recommendation in the official Corman-Drosten WHO-protocol [8]. Only a “Cycler”-value
(cycles) is to be found without corresponding and scientifically reasonable Ct (Cutoff-value). This or any other
cycles-value is nowhere to be found in the actual Corman-Drosten paper.
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4. Biomolecular validations

To determine whether the amplified products are indeed SARS-CoV-2 genes, biomolecular
validation of amplified PCR products is essential. For a diagnostic test, this validation is an
absolute must.

Validation of PCR products should be performed by either running the PCR product in a 1%
agarose-EtBr gel together with a size indicator (DNA ruler or DNA ladder) so that the size of
the product can be estimated. The size must correspond to the calculated size of the
amplification product. But it is even better to sequence the amplification product. The
latter will give 100% certainty about the identity of the amplification product. Without
molecular validation one can not be sure about the identity of the amplified PCR products.
Considering the severe design errors described earlier, the amplified PCR products can be
anything.

Also not mentioned in the Corman-Drosten paper is the case of small fragments of qPCR
(around 100bp): It could be either 1,5% agarose gel or even an acrylamide gel.

The fact that these PCR products have not been validated at molecular level is another
striking error of the protocol, making any test based upon it useless as a specific diagnostic
tool to identify the SARS-CoV-2 virus.

5. Positive and negative controls to confirm/refute specific virus detection.

The unconfirmed assumption described in the Corman-Drosten paper is that SARS-CoV-2 is

the only virus from the SARS-like beta-coronavirus group that currently causes infections in
humans. The sequences on which their PCR method is based are in silico sequences,
supplied by a laboratory in China [23], because at the time of development of the PCR test
no control material of infectious (“live”) or inactivated SARS-CoV-2 was available to the
authors. The PCR test was therefore designed using the sequence of the known SARS-CoV
as a control material for the Sarbeco component (Dr. Meijer, co-author Corman-Drosten
paper in an email exchange with Dr. Peter Borger) [2].

All individuals testing positive with the RT-PCR test, as described in the Corman-Drosten
paper, are assumed to be positive for SARS-CoV-2 infections. There are three severe flaws
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in their assumption. First, a positive test for the RNA molecules described in the
Corman-Drosten paper cannot be equated to “infection with a virus”. A positive RT-PCR test
merely indicates the presence of viral RNA molecules. As demonstrated under point 1d
(above), the Corman-Drosten test was not designed to detect the full-length virus, but only
a fragment of the virus. We already concluded that this classifies the test as unsuitable as a
diagnostic test for SARS-virus infections.

Secondly and of major relevance, the functionality of the published RT-PCR Test was not
demonstrated with the use of a positive control (isolated SARS-CoV-2 RNA) which is an
essential scientific gold standard.

Third, the Corman-Drosten paper states:

“To show that the assays can detect other bat-associated SARS-related viruses, we used the E
gene assay to test six bat-derived faecal samples available from Drexler et al. […] und Muth
et al. […]. These virus-positive samples stemmed from European rhinolophid bats. Detection
of these phylogenetic outliers within the SARS-related CoV clade suggests that all Asian
viruses are likely to be detected. This would, theoretically, ensure broad sensitivity even in
case of multiple independent acquisitions of variant viruses from an animal reservoir.”

This statement demonstrates that the E gene used in RT-PCR test, as described in the
Corman-Drosten paper, is not specific to SARS-CoV-2.

The E gene primers also detect a broad spectrum of other SARS viruses.

The genome of the coronavirus is the largest of all RNA viruses that infect humans and they
all have a very similar molecular structure. Still, SARS-CoV1 and SARS-CoV-2 have two highly
specific genetic fingerprints, which set them apart from the other coronaviruses. First, a
unique fingerprint-sequence (KTFPPTEPKKDKKKK) is present in the N-protein of SARS-CoV
and SARS-CoV-2 [13,14,15]. Second, both SARS-CoV1 and SARS-CoV2 do not contain the HE
protein, whereas all other coronaviruses possess this gene [13, 14]. So, in order to
specifically detect a SARS-CoV1 and SARS-CoV-2 PCR product the above region in the N gene
should have been chosen as the amplification target. A reliable diagnostic test should focus
on this specific region in the N gene as a confirmatory test. The PCR for this N gene was not
further validated nor recommended as a test gene by the Drosten-Corman paper, because of
being “not so sensitive” with the SARS-CoV original probe [1].

Furthermore, the absence of the HE gene in both SARS-CoV1 and SARS-CoV-2 makes this
gene the ideal negative control to exclude other coronaviruses. The Corman-Drosten paper
does not contain this negative control, nor does it contain any other negative controls. The
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PCR test in the Corman-Drosten paper therefore contains neither a unique positive control
nor a negative control to exclude the presence of other coronaviruses. This is another major
design flaw which classifies the test as unsuitable for diagnosis.

6. Standard Operational Procedure (SOP) is not available

There should be a Standard Operational Procedure (SOP) available, which unequivocally

specifies the above parameters, so that all laboratories are able to set up the identical same
test conditions. To have a validated universal SOP is essential, because it facilitates data
comparison within and between countries. It is very important to specify all primer
parameters unequivocally. We note that this has not been done. Further, the Ct value to
indicate when a sample should be considered positive or negative is not specified. It is also
not specified when a sample is considered infected with SARS-CoV viruses. As shown above,
the test cannot discern between virus and virus fragments, so the Ct value indicating
positivity is crucially important. This Ct value should have been specified in the Standard
Operational Procedure (SOP) and put on-line so that all laboratories carrying out this test
have exactly the same boundary conditions. It points to flawed science that such an SOP
does not exist. The laboratories are thus free to conduct the test as they consider
appropriate, resulting in an enormous amount of variation. Laboratories all over Europe are
left with a multitude of questions; which primers to order? which nucleotides to fill in the
undefined places? which Tm value to choose? How many PCR cycles to run? At what Ct value
is the sample positive? And when is it negative? And how many genes to test? Should all
genes be tested, or just the E and RpRd gene as shown in Table 2 of the Corman-Drosten
paper? Should the N gene be tested as well? And what is their negative control? What is
their positive control?

The protocol as described is unfortunately very vague and erroneous in its design that one
can go in dozens of different directions. There does not appear to be any standardization nor
an SOP, so it is not clear how this test can be implemented.

7. Consequences of the errors described under 1-5: false positive results.

The RT-PCR test described in the Corman-Drosten paper contains so many molecular
biological design errors (see 1-5) that it is not possible to obtain unambiguous results. It is
inevitable that this test will generate a tremendous number of so-called “false positives”.
The definition of false positives is a negative sample, which initially scores positive, but
which is negative after retesting with the same test. False positives are erroneous positive
test-results, i.e. negative samples that test positive. And this is indeed what is found in the
Corman-Drosten paper. On page 6 of the manuscript PDF the authors demonstrate, that
even under well-controlled laboratory conditions, a considerable percentage of false
positives is generated with this test:
Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

“In four individual test reactions, weak initial reactivity was seen however they were negative
upon retesting with the same assay. These signals were not associated with any particular
virus, and for each virus with which initial positive reactivity occurred, there were other
samples that contained the same virus at a higher concentration but did not test positive.
Given the results from the extensive technical qualification described above, it was concluded
that this initial reactivity was not due to chemical instability of real-time PCR probes and
most probably to handling issues caused by the rapid introduction of new diagnostic tests
and controls during this evaluation study.” [1]

The first sentence of this excerpt is clear evidence that the PCR test described in the
Corman-Drosten paper generates false positives. Even under the well-controlled conditions
of the state-of-the-art Charité-laboratory, 4 out of 310 primary-tests are false positives per
definition. Four negative samples initially tested positive, then were negative upon retesting.
This is the classical example of a false positive. In this case the authors do not identify them
as false positives, which is intellectually dishonest.

Another telltale observation in the excerpt above is that the authors explain the false
positives away as "handling issues caused by the rapid introduction of new diagnostic tests".
Imagine the laboratories that have to introduce the test without all the necessary
information normally described in an SOP.

8. The Corman-Drosten paper was not peer-reviewed

Before formal publication in a scholarly journal, scientific and medical articles are
traditionally certified by “peer review.” In this process, the journal’s editors take advice from
various experts (“referees”) who have assessed the paper and may identify weaknesses in its
assumptions, methods, and conclusions. Typically a journal will only publish an article once
the editors are satisfied that the authors have addressed referees’ concerns and that the
data presented supports the conclusions drawn in the paper.” This process is as well
described for Eurosurveillance [16].

The Corman-Drosten paper was submitted to Eurosurveillance on January 21st 2020 and
accepted for publication on January 22nd 2020. On January 23rd 2020 the paper was online.
On January 13th 2020 version 1-0 of the protocol was published at the official WHO website
[17], updated on January 17th 2020 as document version 2-1 [18], even before the
Corman-Drosten paper was published on January 23rd at Eurosurveillance.

Normally, peer review is a time-consuming process since at least two experts from the field
have to critically read and comment on the submitted paper. In our opinion, this paper was
not peer-reviewed. Twenty-four hours are simply not enough to carry out a thorough peer
review. Our conclusion is supported by the fact that a tremendous number of very serious
design flaws were found by us, which make the PCR test completely unsuitable as a
diagnostic tool to identify the SARS-CoV-2 virus. Any molecular biologist familiar with RT-PCR
Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

design would have easily observed the grave errors present in the Corman-Drosten paper
before the actual review process. We asked Eurosurveillance on October 26th 2020 to send
us a copy of the peer review report. To date, we have not received this report and in a letter
dated November 18th 2020, the ECDC as host for Eurosurveillance declined to provide
access without providing substantial scientific reasons for their decision. On the contrary,
they write that “disclosure would undermine the purpose of scientific investigations.” [24].

9. Authors as the editors

A final point is one of major concern. It turns out that two authors of the Corman-Drosten
paper, Christian Drosten and Chantal Reusken, are also members of the editorial board of
this journal [19]. Hence there is a severe conflict of interest which strengthens suspicions
that the paper was not peer-reviewed. It has the appearance that the rapid publication was
possible simply because the authors were also part of the editorial board at
Eurosurveillance. This practice is categorized as compromising scientific integrity.

SUMMARY CATALOGUE OF ERRORS FOUND IN THE PAPER

The Corman-Drosten paper contains the following specific errors:

1. There exists no specified reason to use these extremely high concentrations of primers in
this protocol. The described concentrations lead to increased nonspecific bindings and PCR
product amplifications, making the test unsuitable as a specific diagnostic tool to identify the
SARS-CoV-2 virus.

2. Six unspecified wobbly positions will introduce an enormous variability in the real world
laboratory implementations of this test; the confusing nonspecific description in the
Corman-Drosten paper is not suitable as a Standard Operational Protocol making the test
unsuitable as a specific diagnostic tool to identify the SARS-CoV-2 virus.

3. The test cannot discriminate between the whole virus and viral fragments. Therefore, the
test cannot be used as a diagnostic for intact (infectious) viruses, making the test unsuitable
as a specific diagnostic tool to identify the SARS-CoV-2 virus and make inferences about the
presence of an infection.

4. A difference of 10° C with respect to the annealing temperature Tm for primer pair1
(RdRp_SARSr_F and RdRp_SARSr_R) also makes the test unsuitable as a specific diagnostic
tool to identify the SARS-CoV-2 virus.
Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

5. A severe error is the omission of a Ct value at which a sample is considered positive and
negative. This Ct value is also not found in follow-up submissions making the test unsuitable
as a specific diagnostic tool to identify the SARS-CoV-2 virus.

6. The PCR products have not been validated at the molecular level. This fact makes the
protocol useless as a specific diagnostic tool to identify the SARS-CoV-2 virus.

7. The PCR test contains neither a unique positive control to evaluate its specificity for
SARS-CoV-2 nor a negative control to exclude the presence of other coronaviruses, making
the test unsuitable as a specific diagnostic tool to identify the SARS-CoV-2 virus.

8. The test design in the Corman-Drosten paper is so vague and flawed that one can go in
dozens of different directions; nothing is standardized and there is no SOP. This highly
questions the scientific validity of the test and makes it unsuitable as a specific diagnostic
tool to identify the SARS-CoV-2 virus.

9. Most likely, the Corman-Drosten paper was not peer-reviewed making the test
unsuitable as a specific diagnostic tool to identify the SARS-CoV-2 virus.

10. We find severe conflicts of interest for at least four authors, in addition to the fact that
two of the authors of the Corman-Drosten paper (Christian Drosten and Chantal Reusken)
are members of the editorial board of Eurosurveillance. A conflict of interest was added on
July 29 2020 (Olfert Landt is CEO of TIB-Molbiol; Marco Kaiser is senior researcher at
GenExpress and serves as scientific advisor for TIB-Molbiol), that was not declared in the
original version (and still is missing in the PubMed version); TIB-Molbiol is the company
which was “the first” to produce PCR kits (Light Mix) based on the protocol published in the
Corman-Drosten manuscript, and according to their own words, they distributed these
PCR-test kits before the publication was even submitted [20]; further, Victor Corman &
Christian Drosten failed to mention their second affiliation: the commercial test laboratory
“Labor Berlin”. Both are responsible for the virus diagnostics there [21] and the company
operates in the realm of real time PCR-testing.

In light of our re-examination of the test protocol to identify SARS-CoV-2 described in the
Corman-Drosten paper we have identified concerning errors and inherent fallacies which
render the SARS-CoV-2 PCR test useless.
Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

CONCLUSION

The decision as to which test protocols are published and made widely available lies
squarely in the hands of Eurosurveillance. A decision to recognise the errors apparent in the
Corman-Drosten paper has the benefit to greatly minimise human cost and suffering going
forward.

Is it not in the best interest of Eurosurveillance to retract this paper? Our conclusion is
clear. In the face of all the tremendous PCR-protocol design flaws and errors described
here, we conclude: There is not much of a choice left in the framework of scientific integrity
and responsibility.

REFERENCES

[1] Corman Victor M, Landt Olfert, Kaiser Marco, Molenkamp Richard, Meijer Adam, Chu Daniel KW, Bleicker
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der Veer Bas, van den Brink Sharon, Wijsman Lisa, Goderski Gabriel, Romette Jean-Louis, Ellis Joanna, Zambon
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[2] Email communication between Dr. Peter Borger & Dr. Adam Meijer:​ ​Supplementary Material

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[4] BBC, January 21st 2020:​ ​https://www.bbc.com/news/world-asia-china-51185836​;

Archive:​ ​https://archive.is/0qRmZ

[5] Google Analytics - COVID19-deaths worldwide:​ ​https://bit.ly/3fndemJ

Archive:​ ​https://archive.is/PpqEE

[6] Laboratory testing for COVID-19 Emergency Response Technical Centre, NIVD under
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China CDC March 15th, 2020:​ ​http://www.chinacdc.cn/en/COVID19/202003/P020200323390321297894.pdf

[7] Real-Time PCR Handbook Life Technologies:

https://www.thermofisher.com/content/dam/LifeTech/global/Forms/PDF/real-time-pcr-

handbook.pdf

Nolan T, Huggett J, Sanchez E.Good practice guide for the application of quantitative PCR (qPCR) First Edition
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[8] Trestan Pillonel et al, Letter to the editor: SARS-CoV-2 detection by real-time RT-PCR:
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[9] Kurkela, Satu, and David WG Brown. “Molecular-diagnostic techniques.” Medicine 38.10 (2009): 535-540.

[10] Wolfel et al., Virological assessment of hospitalized patients with COVID-2019

https://www.nature.com/articles/s41586-020-2196-x

[11] Thermofischer Primer Dimer Web Tool:

https://www.thermofisher.com/us/en/home/brands/thermo-scientific/molecular-biology/molecular-biology
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tml

Suplementary material by Kevin Mckernan, Corman-Drosten Primer Dimer Results with Thermofischer
Primer Dimer Web Tool

[12] Primer-BLAST, NCBI - National Center for Biotechnology Information:

https://www.ncbi.nlm.nih.gov/tools/primer-blast/

[13] Marra MA, Steven JMJ, Caroline RA, Robert AH, Angela BW et al. (2003) Science. The

Genome sequence of the SARS-associated coronavirus. Science 300(5624): 1399-1404.

[14] Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome:
https://www.ncbi.nlm.nih.gov/nuccore/MN908947

[15] Borger P. A SARS-like Coronavirus was expected but nothing was done to be prepared. Am J Biomed Sci
Res 2020.​ ​https://biomedgrid.com/pdf/AJBSR.MS.ID.001312.pdf
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Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

https://www.researchgate.net/publication/341120750_A_SARS-like_Coronavirus_was_Expected_but_nothi
ng_was_done_to_be_Prepared​;

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[16] Eurosurveillance paper evaluation / review process:​ ​https://www.eurosurveillance.org/evaluation

[17] Official recommendation of the Corman-Drosten protocol & manuscript by the WHO,published on
January 13th 2020 as version 1.0 of the document:

https://www.who.int/docs/default-source/coronaviruse/wuhan-virus-assay-v1991527e5122341d99287a1b1
7c111902.pdf​; archive:​ ​https://bit.ly/3m3jXVH

[18] Official WHO-recommendation for the Corman / Drosten RT-qPCR-protocol, which directly derives from
the Eurosurveillance-publication, document-version 2-1, published on

17th January 2020:

https://www.who.int/docs/default-source/coronaviruse/protocol-v2-1.pdf?sfvrsn=a9ef618c_2

[19] Eurosurveillance Editorial Board, 2020:

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[20] Instructions For Use LightMix SarbecoV E-gene plus EAV Control, TIB-Molbiol & Roche Molecular
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[21] Christian Drosten & Victor Corman, responsible for viral diagnostics at Labor Berlin:
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[22] Tom Jefferson, Elizabeth Spencer, Jon Brassey, Carl Heneghan Viral cultures for COVID-19 infectivity
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Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

[23] Kim et al.,The Architecture of SARS-CoV-2 Transcriptome:

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[24] ECDC reply to Dr. Peter Borger, 18th November 2020: ​Supplementary Material

[25] Prof. Dr. Ulrike Kämmerer & team, survey & Primer-BLAST table: ​Supplementary Material

Additional literature:

Description RT-PCR RKI Germany, on page 10 of this link:

https://www.rki.de/DE/Content/Gesundheitsmonitoring/Gesundheitsberichterstattung/GBEDownloadsJ/Jo
HM_S5_2020_Studienprotokoll_CORONA_MONITORING_lokal.pdf?__blob=publicationFile

Author's Affiliations:

1) Dr. Pieter Borger (MSc, PhD), Molecular Genetics, W+W Research Associate, Lörrach, Germany

2) Rajesh Kumar Malhotra (Artist Alias: Bobby Rajesh Malhotra), Former 3D Artist / Scientific Visualizations at CeMM - Center for Molecular Medicine of the
Austrian Academy of Sciences (2019-2020), University for Applied Arts - Department for Digital Arts Vienna, Austria

3) Dr. Michael Yeadon BSs(Hons) Biochem Tox U Surrey, PhD Pharmacology U Surrey. Managing Director, Yeadon Consulting Ltd, former Pfizer Chief
Scientist, United Kingdom

4) Dr. Clare Craig MA, (Cantab) BM, BCh (Oxon), FRCPath, United Kingdom

5) Kevin McKernan, BS Emory University, Chief Scientific Officer, founder Medical Genomics, engineered the sequencing pipeline at WIBR/MIT for the
Human Genome Project, Invented and developed the SOLiD sequencer, awarded patents related to PCR, DNA Isolation and Sequencing, USA

6) Prof. Dr. Klaus Steger, Department of Urology, Pediatric Urology and Andrology, Molecular Andrology, Biomedical Research Center of the Justus Liebig
University, Giessen, Germany

7) Dr. Paul McSheehy (BSc, PhD), Biochemist & Industry Pharmacologist, Loerrach, Germany

8) Dr. Lidiya Angelova, MSc in Biology, PhD in Microbiology, Former researcher at the National Institute of Allergy and Infectious Diseases (NIAID),
Maryland, USA

9) Dr. Fabio Franchi, Former Dirigente Medico (M.D) in an Infectious Disease Ward, specialized in “Infectious Diseases” and “Hygiene and Preventive
Medicine”, Società Scientifica per il Principio di Precauzione (SSPP), Italy

10) Dr. med. Thomas Binder, Internist and Cardiologist (FMH), Switzerland

11) Prof. Dr. med. Henrik Ullrich, specialist Diagnostic Radiology, Chief Medical Doctor at the Center for Radiology of Collm Oschatz-Hospital, Germany

12) Prof. Dr. Makoto Ohashi, Professor emeritus, PhD in Microbiology and Immunology, Tokushima University, Japan

13) Dr. Stefano Scoglio, B.Sc. Ph.D., Microbiologist, Nutritionist, Italy

14) Dr. Marjolein Doesburg-van Kleffens (MSc, PhD), specialist in Laboratory Medicine (clinical chemistry), Maasziekenhuis Pantein, Beugen, The
Netherlands

15) Dr. Dorothea Gilbert (MSc, PhD), PhD Environmental Chemistry and Toxicology. DGI Consulting Services, Oslo, Norway

16) Dr. Rainer J. Klement, PhD. Department of Radiation Oncology, Leopoldina Hospital Schweinfurt, Germany
Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

17) Dr. Ruth Schruefer, PhD, human genetics/ immunology, Munich, Germany,

18) Dra. Berber W. Pieksma, General Practitioner, The Netherlands

19) Dr. med. Jan Bonte (GJ), Consultant Neurologist, The Netherlands

20) Dr. Bruno H. Dalle Carbonare (Molecular biologist), IP specialist, BDC Basel, Switzerland

21) Dr. Kevin P. Corbett, MSc Nursing (Kings College London) PhD (London South Bank) Social Sciences (Science & Technology Studies) London, England,
United Kingdom

22) Prof. Dr. Ulrike Kämmerer, specialist in Virology / Immunology / Human Biology / Cell Biology, University Hospital Würzburg, Germany

Author’s Contributions:
PB: Planned and conducted the analyses and research, conceptualising the manuscript.

BRM: Planned and conducted the research, conceptualising the figures and manuscript.

MY: ​Proofreading the analyses and research.

KMcK: Conducted the analyses and research, conceptualized the manuscript.

KS: Conducted the analyses and research.

PMcS: Proofreading the analyses and research.

LA: Proofreading the analyses and research.

FF: Proofreading the analyses and research.

TB: Proofreading the analyses and research.

HU: Proofreading the analyses and research.

MO: Proofreading the analyses and research.

SS: Proofreading the analyses and research.

MDvK: Proofreading the analyses and research.

DG: Proofreading the analyses and research.

RJK: Proofreading the analyses and research.

RS: Proofreading the analyses and research, and the manuscript.

BWK: Proofreading the analyses and research.

RvV: Proofreading the analyses and research.

JB: Proofreading the analyses and research.

KC: Proofreading the analyses and research.

UK: Planned and conducted the analyses and research, conceptualising the manuscript.

Additional Proof-Readers:
Saji N Hameed, Environmental Informatics, University of Aizu, Tsuruga, Ikki-machi, Aizuwakamatsu-shi, Fukushima, Japan

Howard R. Steen, MA Chem. Eng. Cantab, Former Research Manager, Germany

Review Report by an International Consortium of Scientists in Life Sciences (ICSLS) -
Corman-Drosten ​et al.,​ Eurosurveillance 2020 (Updated: 2.12.2020)

Addendum:

Update 2.12.2020:

Author Contribution​ Dr. Michael Yeadon changed to: ​Proofreading the analyses and research.

Author Affiliation​ Kevin Mckernan changed to ​Medicinal Genomics.