RNA sequence standards in the COVID-19 rRT-PCR test - current and future
Dear Medicines and Healthcare products Regulatory Agency,
What synthetic 3'-deoxyribose nucleic acid (RNA) sequence or sequences (e.g. N Gene; Genbank accession: MN908947.2) are supplied as reference standards for the real time reverse transcriptase chain reaction (rRT-PCR) test or tests used for detecting the putative virus SARS-Cov-2 that are either in production or being validated by the National Institute of Biological Standards and Controls (NIBSC)?
Specifically this request relates to the sequences of:
1. The Research reagent for SARS-CoV-2 RNA NIBSC code: 20/110
2. The 1st WHO International Standard for SARS-CoV-2 RNA
Yours faithfully,
J Grove
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Our Ref: FOI 20/523
Dear J Grove,
RE: REQUEST UNDER THE FREEDOM OF INFORMATION ACT 2000
Thank you for your enquiry which we received on 4 December 2020.
I confirm that your request is now being handled under the Freedom of Information Act and you should receive a reply within 20 working days from our date of receipt.
If you need to contact us again about this request, please quote the reference number above.
Kind Regards,
MHRA Customer Service Centre
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU
Telephone 0203 080 6000
Dear MHRA Customer Services,
For clarification this request should have stated ribonucleic acid (RNA) rather than "3'-deoxyribose nucleic acid (RNA)" (a nonsensical chemical descriptor).
It is the RNA sequence (i.e. the standard that is the substrate for the Reverse Transcriptase enzyme) and not any DNA (2'-deoxyribose nucleic acid) sequence that is being requested.
Sorry for the mistake.
Yours sincerely,
J Grove
FOI 20/523
Dear J Grove,
In response to your e-mail dated 4th December 2020, the information requested can be found in the WHO report for the collaborative study for the establishment of the WHO International Standard for SARS-CoV-2 RNA. The link to the report is on the WHO website at https://www.who.int/publications/m/item/...
If you are dissatisfied with the handling of your request, you have the right to ask for an internal review. Internal review requests should be submitted within two months of the date you receive this response and addressed to: [MHRA request email]
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Kind Regards
MHRA Customer Service Centre
Medicines and Healthcare products Regulatory Agency
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Telephone 020 3080 6000
Dear MHRA Customer Services,
Thanks for the information provided yet it is unclear whether the proposed International Standard that will be produced is Candidate 1 (NIBSC code 20/146) or Candidate 2 (NIBSC code 20/138). The publication from the World Health Organisation (WHO) states the following:
Proposal
It is proposed that Candidate 1, the inactivated SARS-CoV-2 England isolate, NIBSC code 20/146 is established as the WHO International Standard for NAT based assays detecting SARS-CoV-2 RNA with an assigned potency of 7.40 Log10 IU/ampoule (7.70 Log10 IU/mL following reconstitution). Proposed Instructions for Use (IFU) for the product are included in Appendix 5.
There are approximately 2500 ampoules (0.5 mL/ ampoule) available for distribution. It is recommended that the International Standard is stored at -20˚C.
Furthermore, it is proposed that Candidate 2, the chimeric LVP containing SARS-CoV-2 RNA, NIBSC code 20/138 is made available as a Working Reagent calibrated to the International Standard for SARS-CoV-2 RNA within this study. The potency of the reagent is 6.73 Log10 IU/mL, with 95% confidence limits of 6.58 to 6.88 (n = 30). Proposed Instructions for Use (IFU) for the product are included in Appendix 6.There are approximately 2000 ampoules (0.5 mL/ ampoule) available for distribution. It is recommended that the International Standard is stored at -20˚C.
The information requested as a Freedom of Information Act 2000 request was for the sequences of:
1. The Research reagent for SARS-CoV-2 RNA NIBSC code: 20/110
2. The 1st WHO International Standard for SARS-CoV-2 RNA
The current response details that there are two international standard candidates with NIBSC code 20/138 (having four sequences with GenBank accessions of MW059032, MW059033, MW059034 and MW059035 as described Appendix 6) and NIBSC code 20/146 (having a single sequences with GenBank accession of MW0590326 as described Appendix 5).
There has been no sequence information provided for the current standard (SARS-CoV-2 RNA NIBSC code: 20/110).
Please provide the information requested namely which MHRA code relates to the which international standard (i.e. is the new standard being produced 20/138 or 20/146?) and the GenBank accession for SARS-CoV-2 RNA NIBSC code: 20/110.
This is NOT an internal review, that will come later if there is no further information provided for this request, thank you.
Yours sincerely,
J Grove
Dear J Grove,
Thank you for your email.
The First International Standard for SARS-CoV-2 RNA is NIBSC product code
20/146, inactivated SARS-CoV-2 virus. Sequence is available in Genbank
acc. no. MW059036
Candidate 2 evaluated in the collaborative study in link provided at the
bottom of this email trail is NIBSC product 20/138. This is an equimolar
mix of 4 constructs each one containing a portion of the SARS-CoV-2
genome. The four sequences are available in Genbank acc. no. MW059032,
MW059033, MW059034 and MW059035.
The decision was taken during the 73th WHO ECBS meeting which took place
last December and the Executive Summary is available here:
[1]https://www.who.int/groups/expert-commit...
Regarding product 20/110, this is indeed in Neil's Division, as Nicola
suggested. However, I can help with the information on the sequence as it
was made by us as well. The sequences of the 4 constructs used to produced
20/110 are deposited in Genbank accession numbers MT299802, MT299803,
MT299804, and MT299805.
Kind Regards
MHRA Customer Service Centre
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 020 3080 6000
Dear Medicines and Healthcare products Regulatory Agency,
Please pass this on to the person who conducts Freedom of Information reviews.
I am writing to request an internal review of Medicines and Healthcare products Regulatory Agency's handling of my FOI request 'RNA sequence standards in the COVID-19 rRT-PCR test - current and future'.
I am writing to request an internal review of Medicines and Healthcare products Regulatory Agency's handling of my FOI request 'RNA sequence standards in the COVID-19 rRT-PCR test - current and future'.
Many thanks for the sequence information associated with the NIBSC codes 20/110, 20/146 and 20/138.
The original request was for all of the RNA standards (though the specific ones were requested which may have been confusing). Please provide the sequence information for the reagent "Research reagent for SARS-CoV-2 RNA (NIBSC code: 19/304).
Thank you.
A full history of my FOI request and all correspondence is available on the Internet at this address: https://www.whatdotheyknow.com/request/r...
Yours faithfully,
J Grove
Thank you for your email. This auto-response is to inform you that your
email has been received and will be reviewed by our Customer Service Team.
We will respond to you as soon as possible.
Please note that we may not respond if your query:
• contains offensive language
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• is illegible
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• is for information only
Medicines and Healthcare products Regulatory Agency
10 South Colonnade,
Canary Wharf,
London
E14 4PU
gov.uk/mhra
Stay connected
For information on how the Agency uses your personal data and your data
protection rights, please see our three centres’ Privacy Notices: MHRA,
CPRD and NIBSC.
The UK has left the EU, and the transition period ends on 31 December
2020. Our [1]guidance and information can be accessed here.
References
Visible links
1. https://www.gov.uk/government/collection...
Dear J Grove,
Thank you for your email.
We confirm that an internal review is being carried out on FOI 20/523.
Please note the deadline for reply for Internal Reviews is 20 working days from our date of receipt and the date for this request is 10 February.
Kind Regards
MHRA Customer Service Centre
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 020 3080 6000
Dear J Grove,
Thank you for your email.
Please find attached the response to your Internal Review request.
Yours sincerely
MHRA Customer Service Centre
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 0203 080 6000
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Bartholomeus Lakeman (Account suspended) left an annotation ()
“Collaborative Study for the Establishment of a WHO International Standard for SARS-CoV-2RNA” is a draft which “may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any website”. And indeed, of this study one can find neither a verification nor a comment.
This study used an acid-heat inactivated England/02/2020 isolate of SARS-CoV-2 (Candidate 1; NIBSC code 20/146). The preparation has been evaluated in a WHO International Collaborative study. The intended use of the International Standard is for the calibration and harmonisation of NAT-based assays for the detection of SARS-CoV-2 RNA. The viral stock was received at passage 1 and amplified at NIBSC one further passage in Vero-E6 cells (ATCC®CRL-1586) with a MOI of 0.001. The culture supernatant was collected 72 hours post-infection. The infectious titre of the stock was measured as 1.5x106 infectious units/mL by plaque assay.
However, this study does not show by what kind of qualification it was proven that the item (said inactivated virus) obtained in Feb- 2020 (from the UK or Wuhan?) is indeed the SARS-CoV-2. Was it qualified by a RT-PCR test with an unknown Ct value? The item had been deepfreezed (-50 C) and (homoeopathically) diluted for it to be compared to a synthetic version of SARS-CoV-2 (GenBank: MN908947.3) which after been subjected to the same procedure: from multiple labs tests it appeared that these pairs were a mismatch.
Whether this WHO study proves the ribonucleic acid (RNA) sequence remains a question: it did not described it. Instead of the Genbank accession: MN908947.2 WHO has named it with the GenBank accession MW059036.