Oxford/Astrazeneca vaccine ChAdOx1-S [recombinant]: toxicolgy and pharmacodynamics

Graham Crawley made this Freedom of Information request to Medicines and Healthcare Products Regulatory Agency

This request has been closed to new correspondence. Contact us if you think it should be reopened.

Medicines and Healthcare Products Regulatory Agency did not have the information requested.

Dear Medicines and Healthcare Products Regulatory Agency,
Regarding COVID-19 Vaccine AstraZeneca, (ChAdOx1-S [recombinant]) hereinafter called "the vaccine"

Please provide the following information

1. What were the results of study 514559, designed to explore the distribution of the vaccine in mice
2. Which cell types in which tissues does the vaccine viral vector transfect?
3. In transfected cells, for how long do the cells synthesise the spike protein and what limits the synthesis?
4. What is the fate of the transfected vaccine DNA at cell death and cell division?
5. Does the vaccine DNA integrate into the host cell genome: what studies have been done to address this?
6. Regarding the spike protein:
a) Has the spike protein produced by transfected cells been sequenced and what modifications are there compared to the Wuhan spike protein?
b) Does the spike protein generated by the vaccine comprise both S1 and S2 domains?
c) Does the spike protein generated by the vaccine incorporate the furin cleavage site?
d) Have proline or other amino acids been substituted into the spike proteins produced by the vaccine to favour a particular protein conformation and if so:
i) What are the relative binding affinities of the modified spike protein to the ACE2 receptor compared to the original Wuhan spike protein?
ii) Are the substitutions in the S1 or S2 domains or both domains?
e) have soluble proteins, derived from cleavage of intact spike protein or arising from transcription/translation errors, been looked for/detected in the circulation and, if so, what are the biologcal consequences of these proteins?
7. The process-related impurities are divided into three categories: biologically-derived
macromolecules, small molecules and synthetic macromolecules. What are they?
8. The vaccine has been manufactured so that it is unable to replicate in cells. What studies have been carried out which confirm this?
9. What were the results of GLP embryo-fetal development study, Study 490843?
10. In order to interpret safety pharmacolgy and toxicity studies, what are the relative affinities of vaccine generated spike proteins for human, mouse, ferret and monkey ACE2 receptors?
11. As the vaccine is more akin to a prodrug generating potentially both membrane bound and soluble spike protein, why have no genotoxicity, including Ames test, and carcinogenicity studies been conducted?

Yours faithfully,

Graham Crawley

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Thank you for your email.  This auto-response is to inform you that your
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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...

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Our Ref: FOI 21/714

Dear Graham Crawley,

RE: REQUEST UNDER THE FREEDOM OF INFORMATION ACT 2000

Thank you for your enquiry which we received on 24 June 2021.

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.

Please be aware that we publish FOIs replies and these are redacted and are located on our website at the following link below.
https://www.gov.uk/government/collection...


Kind Regards,

MHRA Customer Service Centre

Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 0203 080 6000

show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

FOI 21/714
Dear Mr Crawley
 
Thank you for your email.
 
The temporary authorisations of the Pfizer/BioNTech, Oxford/AstraZeneca
and Moderna vaccines was done through an expedited rolling review. A
‘rolling review’ can be used to complete the assessment of a promising
medicine or vaccine during a public health emergency in the shortest time
possible. This is done as the packages of data become available from
ongoing studies on a staggered basis. The temporary authorisation under
Regulation 174 permits the supply of identified vaccine batches, based on
the safety, quality and efficacy data submitted to MHRA. These
authorisations do not constitute a marketing authorisation.
 
All vaccines are tested through three phases of clinical trials to ensure
they meet the gold standard. Phase 1 trials are with a small group of
people to make sure there are no safety concerns and determines the
appropriate dosage for the best immune response. Phase 2 trials are
conducted on a larger group of people to check the vaccine works
consistently and that the immune response is sufficient. Phase 3 trials
test the vaccines on thousands of people for scientists to assess if the
vaccine is producing immunity that will prevent disease. Usually, these
phases are run in sequence, but in an effort to find a safe and effective
Covid-19 vaccine as quickly as possible, once safety has been ascertained
through Phase 1, Phases 2 and 3 are being run in parallel. Extensive
checks and balances are required at every stage of the development of a
vaccine, and this is no different for a Covid-19 vaccine. No stages in the
vaccine development processes were bypassed.
 
Information on the study conducted using the Pfizer/BioNTech vaccine and
its results are available in a peer-reviewed journal, the New England
Journal of Medicine (NEJM). A link to this is provided below:
[1]https://www.nejm.org/doi/full/10.1056/NE...
 
The temporary authorisations for use of the COVID-19 vaccines in the UK
followed a rigorous scientific assessment of all the available evidence of
quality, safety and effectiveness by the UK regulator, the Medicines and
Healthcare products Regulatory Agency (MHRA). The MHRA expert scientists
and clinicians reviewed data from the laboratory pre-clinical studies,
clinical trials, manufacturing and quality controls, product sampling and
testing of the final vaccine, and also considered the conditions for its
safe supply and distribution. The decision was made with advice from the
Commission on Human Medicines (CHM), the government’s independent expert
scientific advisory body. Regarding the MHRA approval of the
Pfizer/BioNTech and the Oxford/AstraZeneca COVID-19 vaccines, further
information (including information for physicians and recipients of the
vaccine, and Public Assessment Reports [PARs] for each vaccine) are
available on the MHRA website. Links to these are provided below:
[2]https://www.gov.uk/government/publicatio...
[3]https://www.gov.uk/government/publicatio...
[4]https://www.gov.uk/government/publicatio...
 
Please note that a marketing authorisation was granted for the
Pfizer/BioNTech vaccine (Comirnaty) following a European Commission (EC)
decision on 21 December 2020 (PLGB 53632/0002). Further information is
available on the European Medicines Agency (EMA) website, a link to this
is provided below:
[5]https://www.ema.europa.eu/en/medicines/h...
 
Please also note that a marketing authorisation was granted for the
Moderna vaccine on 31 March 2021 following an EC Reliance Procedure (PLGB
53720/0002). Further information is available on the MHRA website and the
EMA website, links to these are provided below:
[6]https://www.gov.uk/government/publicatio...
[7]https://www.ema.europa.eu/en/medicines/h...
 
A marketing authorisation has been granted for the Janssen Covid-19
vaccine on 28 May 2021. Further information is available via the below
link:
[8]https://www.gov.uk/government/publicatio...
 
In addition, the European Commission, following recommendations from the
European Medicines Agency (EMA), have granted a marketing authorisation
for the Oxford/AstraZeneca vaccine. Further information is provided below:
[9]https://www.ema.europa.eu/en/medicines/h...
 
As with any vaccine or medicine, COVID-19 vaccines require continuous
safety monitoring and that the benefits in protecting people against
COVID-19 outweigh any side effects or potential risks. This is a process
known as safety monitoring (pharmacovigilance). This ensures that any
potential medium and long term safety issues are promptly and adequately
evaluated. As part of our signal detection processes, all adverse reaction
reports received are individually assessed and cumulative information
reviewed at regular intervals. Be reassured that the MHRA is working in
collaboration with partners in the health system to rapidly assess all
available safety data in real time and communicate any emerging issues, as
necessary.
 
Throughout this global pandemic, we have always been guided by the latest
scientific advice. Having studied evidence on both the Pfizer/BioNTech and
Oxford/AstraZeneca vaccines, the Joint Committee on Vaccination and
Immunisation (JCVI) has advised that we should prioritise giving as many
people in at-risk groups their first dose, rather than providing two doses
in as short a time as possible.
 
The four UK Chief Medical Officers agree with JCVI that at this stage of
the pandemic prioritising the first doses of vaccine for as many people as
possible on the priority list will protect the greatest number of at risk
people overall in the shortest possible time and will have the greatest
impact on reducing mortality, severe disease and hospitalisations and in
protecting the NHS and equivalent health services.
 
This is because the evidence shows that one dose of either vaccine
provides a high level of protection from Covid-19. 
 
For both vaccines, data provided to MHRA demonstrate that whilst efficacy
is optimised when a second dose is administered both offer considerable
protection after a single dose, at least in the short term. For both
vaccines the second dose completes the course and is likely to be
important for longer term protection.
 
The NHS across the UK will prioritise giving the first dose of the vaccine
to those in the most high-risk groups. Everyone will still receive their
second dose and this will be within 12 weeks of their first. The second
dose completes the course and is important for longer-term protection.
 
The JCVI’s independent advice is that this approach will maximise the
benefits of both vaccines allowing the NHS to help the greatest number of
people in the shortest possible time.  It will ensure that more at-risk
people are able to get meaningful protection from a vaccine in the coming
weeks and months, reducing deaths and starting to ease pressure on our
NHS.
 
The following Department of Health and Social Care (DHSC) webpage for the
independent report ‘Optimising the COVID-19 vaccination programme for
maximum short-term impact’ from the Joint Committee on Vaccination and
Immunisation (JCVI) provides the rationale for the government’s
implemented dosing strategy: 
[10]https://www.gov.uk/government/publicatio...
 
Further, the scientific basis from the JCVI concerning the current
evidence on efficacy after single doses of the Pfizer/BioNTech,
Oxford/AstraZeneca and Moderna vaccines is available in the public domain
and is provided below:
[11]https://www.gov.uk/government/publicatio...
 
 
If you have a query about the information provided, please reply to this
email
 
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: [12][MHRA request email]
 
Due to the ongoing Covid-19 situation, we are not able to accept delivery
of any documents or correspondence by post or courier to any of our
offices
 
Please remember to quote the reference number above in any future
communications.
 
If you were to remain dissatisfied with the outcome of the internal
review, you would have the right to apply directly to the Information
Commissioner for a decision. Please bear in mind that the Information
Commissioner will not normally review our handling of your request unless
you have first contacted us to conduct an internal review. The Information
Commissioner can be contacted at:
 
Information Commissioner’s Office
Wycliffe House
Water Lane
Wilmslow
Cheshire
SK9 5AF
 
Yours sincerely
 
 
MHRA Customer Service Centre
 
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 0203 080 6000
 

show quoted sections

Dear MHRA Customer Services,
Thank you for your long reply in which you failed to answer any of my questions, either directly or in the references provided. Please provide answers to my questions

Yours sincerely,

Graham Crawley

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

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
• has already been answered in a previous reply to you
• is illegible
• is selling or promoting a product
• 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...

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

MHRA Customer Services would like to recall the message, "FOI 21/714 - Freedom of Information request - Oxford/Astrazeneca vaccine ChAdOx1-S [recombinant]: toxicolgy and pharmacodynamics".

show quoted sections

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

FOI 21/714 & 21/715
Dear Mr Crawley
 
Thank you for your email.
 
The temporary authorisations of the Pfizer/BioNTech, Oxford/AstraZeneca
and Moderna vaccines was done through an expedited rolling review. A
‘rolling review’ can be used to complete the assessment of a promising
medicine or vaccine during a public health emergency in the shortest time
possible. This is done as the packages of data become available from
ongoing studies on a staggered basis. The temporary authorisation under
Regulation 174 permits the supply of identified vaccine batches, based on
the safety, quality and efficacy data submitted to MHRA. These
authorisations do not constitute a marketing authorisation.
 
All vaccines are tested through three phases of clinical trials to ensure
they meet the gold standard. Phase 1 trials are with a small group of
people to make sure there are no safety concerns and determines the
appropriate dosage for the best immune response. Phase 2 trials are
conducted on a larger group of people to check the vaccine works
consistently and that the immune response is sufficient. Phase 3 trials
test the vaccines on thousands of people for scientists to assess if the
vaccine is producing immunity that will prevent disease. Usually, these
phases are run in sequence, but in an effort to find a safe and effective
Covid-19 vaccine as quickly as possible, once safety has been ascertained
through Phase 1, Phases 2 and 3 are being run in parallel. Extensive
checks and balances are required at every stage of the development of a
vaccine, and this is no different for a Covid-19 vaccine. No stages in the
vaccine development processes were bypassed.
 
Information on the study conducted using the Pfizer/BioNTech vaccine and
its results are available in a peer-reviewed journal, the New England
Journal of Medicine (NEJM). A link to this is provided below:
[1]https://www.nejm.org/doi/full/10.1056/NE...
 
The temporary authorisations for use of the COVID-19 vaccines in the UK
followed a rigorous scientific assessment of all the available evidence of
quality, safety and effectiveness by the UK regulator, the Medicines and
Healthcare products Regulatory Agency (MHRA). The MHRA expert scientists
and clinicians reviewed data from the laboratory pre-clinical studies,
clinical trials, manufacturing and quality controls, product sampling and
testing of the final vaccine, and also considered the conditions for its
safe supply and distribution. The decision was made with advice from the
Commission on Human Medicines (CHM), the government’s independent expert
scientific advisory body. Regarding the MHRA approval of the
Pfizer/BioNTech and the Oxford/AstraZeneca COVID-19 vaccines, further
information (including information for physicians and recipients of the
vaccine, and Public Assessment Reports [PARs] for each vaccine) are
available on the MHRA website. Links to these are provided below:
[2]https://www.gov.uk/government/publicatio...
[3]https://www.gov.uk/government/publicatio...
[4]https://www.gov.uk/government/publicatio...
 
Please note that a marketing authorisation was granted for the
Pfizer/BioNTech vaccine (Comirnaty) following a European Commission (EC)
decision on 21 December 2020 (PLGB 53632/0002). Further information is
available on the European Medicines Agency (EMA) website, a link to this
is provided below:
[5]https://www.ema.europa.eu/en/medicines/h...
 
Please also note that a marketing authorisation was granted for the
Moderna vaccine on 31 March 2021 following an EC Reliance Procedure (PLGB
53720/0002). Further information is available on the MHRA website and the
EMA website, links to these are provided below:
[6]https://www.gov.uk/government/publicatio...
[7]https://www.ema.europa.eu/en/medicines/h...
 
A marketing authorisation has been granted for the Janssen Covid-19
vaccine on 28 May 2021. Further information is available via the below
link:
[8]https://www.gov.uk/government/publicatio...
 
In addition, the European Commission, following recommendations from the
European Medicines Agency (EMA), have granted a marketing authorisation
for the Oxford/AstraZeneca vaccine. Further information is provided below:
[9]https://www.ema.europa.eu/en/medicines/h...
 
As with any vaccine or medicine, COVID-19 vaccines require continuous
safety monitoring and that the benefits in protecting people against
COVID-19 outweigh any side effects or potential risks. This is a process
known as safety monitoring (pharmacovigilance). This ensures that any
potential medium and long term safety issues are promptly and adequately
evaluated. As part of our signal detection processes, all adverse reaction
reports received are individually assessed and cumulative information
reviewed at regular intervals. Be reassured that the MHRA is working in
collaboration with partners in the health system to rapidly assess all
available safety data in real time and communicate any emerging issues, as
necessary.
 
Throughout this global pandemic, we have always been guided by the latest
scientific advice. Having studied evidence on both the Pfizer/BioNTech and
Oxford/AstraZeneca vaccines, the Joint Committee on Vaccination and
Immunisation (JCVI) has advised that we should prioritise giving as many
people in at-risk groups their first dose, rather than providing two doses
in as short a time as possible.
 
The four UK Chief Medical Officers agree with JCVI that at this stage of
the pandemic prioritising the first doses of vaccine for as many people as
possible on the priority list will protect the greatest number of at risk
people overall in the shortest possible time and will have the greatest
impact on reducing mortality, severe disease and hospitalisations and in
protecting the NHS and equivalent health services.
 
This is because the evidence shows that one dose of either vaccine
provides a high level of protection from Covid-19. 
 
For both vaccines, data provided to MHRA demonstrate that whilst efficacy
is optimised when a second dose is administered both offer considerable
protection after a single dose, at least in the short term. For both
vaccines the second dose completes the course and is likely to be
important for longer term protection.
 
The NHS across the UK will prioritise giving the first dose of the vaccine
to those in the most high-risk groups. Everyone will still receive their
second dose and this will be within 12 weeks of their first. The second
dose completes the course and is important for longer-term protection.
 
The JCVI’s independent advice is that this approach will maximise the
benefits of both vaccines allowing the NHS to help the greatest number of
people in the shortest possible time.  It will ensure that more at-risk
people are able to get meaningful protection from a vaccine in the coming
weeks and months, reducing deaths and starting to ease pressure on our
NHS.
 
The following Department of Health and Social Care (DHSC) webpage for the
independent report ‘Optimising the COVID-19 vaccination programme for
maximum short-term impact’ from the Joint Committee on Vaccination and
Immunisation (JCVI) provides the rationale for the government’s
implemented dosing strategy: 
[10]https://www.gov.uk/government/publicatio...
 
Further, the scientific basis from the JCVI concerning the current
evidence on efficacy after single doses of the Pfizer/BioNTech,
Oxford/AstraZeneca and Moderna vaccines is available in the public domain
and is provided below:
[11]https://www.gov.uk/government/publicatio...
 
 
If you have a query about the information provided, please reply to this
email
 
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: [12][MHRA request email]
 
Due to the ongoing Covid-19 situation, we are not able to accept delivery
of any documents or correspondence by post or courier to any of our
offices
 
Please remember to quote the reference number above in any future
communications.
 
If you were to remain dissatisfied with the outcome of the internal
review, you would have the right to apply directly to the Information
Commissioner for a decision. Please bear in mind that the Information
Commissioner will not normally review our handling of your request unless
you have first contacted us to conduct an internal review. The Information
Commissioner can be contacted at:
 
Information Commissioner’s Office
Wycliffe House
Water Lane
Wilmslow
Cheshire
SK9 5AF
 
Yours sincerely
 
 
MHRA Customer Service Centre
 
Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 0203 080 6000
 

show quoted sections

Dear MHRA Customer Services,
Please reply immediately to this request. By law you should have replied by 23/07/2021

Yours sincerely,

Graham Crawley

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

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
• has already been answered in a previous reply to you
• is illegible
• is selling or promoting a product
• 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...

MHRA Customer Services, Medicines and Healthcare Products Regulatory Agency

Dear Mr Crawley

Thank you for your email.

A response was sent below to you on 7 July.

Yours sincerely


MHRA Customer Service Centre

Medicines and Healthcare products Regulatory Agency
10 South Colonnade, Canary Wharf, London E14 4PU Telephone 0203 080 6000

show quoted sections