Ref. Ares(2021)496499 - 21/01/2021
Public Assessment Report
Authorisation for Temporary Supply
COVID-19 Vaccine AstraZeneca, solution for
injection in multidose container
COVID-19 Vaccine (ChAdOx1-S
[recombinant])
Department of Health and Social Care (DHSC)
AstraZeneca AB
COVID-19 Vaccine AstraZeneca, solution for injection in multidose
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LAY SUMMARY
COVID-19 Vaccine AstraZeneca, solution for injection in multidose container
COVID-19 Vaccine (ChAdOx1-S [recombinant])
This is a summary of the Public Assessment Report (PAR) for COVID-19 Vaccine
AstraZeneca, solution for injection in multidose container.
It explains how this product was
assessed and its authorisation recommended, as well as its conditions of use. It is not
intended to provide practical advice on how to use this product.
This product will be referred to as COVID-19 Vaccine AstraZeneca in this lay summary for
ease of reading.
For practical information about using COVID-19 Vaccine AstraZeneca, patients should read
the
Information for UK recipients on COVID-19 Vaccine AstraZeneca or contact their doctor
or pharmacist.
What is COVID-19 Vaccine AstraZeneca and what is it used for?
COVID-19 Vaccine AstraZeneca is a vaccine indicated for active immunisation of individuals
18 years of age and older for the prevention of coronavirus disease 2019 (COVID-19).
How does COVID-19 Vaccine AstraZeneca work?
COVID-19 Vaccine AstraZeneca stimulates the body’s natural defences (immune system)
and causes the body to produce its own protection (antibodies) against the virus. None of the
ingredients in this vaccine can cause COVID-19.
How is COVID-19 Vaccine AstraZeneca used?
The pharmaceutical form of this medicine is a solution for injection and the route of
administration is intramuscular injection. COVID-19 Vaccine AstraZeneca will be given to
you by an authorised practitioner as an intramuscular injection into the muscle at the top of
the upper arm (deltoid muscle).
You will receive 2 injections of COVID-19 Vaccine AstraZeneca, each of 0.5ml. You will be
told when you need to return for your second injection of COVID-19 Vaccine AstraZeneca.
The second injection can be given between 4 and 12 weeks after the first injection.
For further information on how COVID-19 Vaccine AstraZeneca is used, refer to the
Information for UK recipients on COVID-19 Vaccine AstraZeneca a
nd Information for
Healthcare Professionals on COVID-19 Vaccine AstraZeneca available on the Medicines and
Healthcare products Regulatory Agency (MHRA) website.
This vaccine can only be obtained with a prescription.
If a person has any questions concerning the vaccine, they should ask the administering
healthcare practitioner.
What benefits of COVID-19 Vaccine AstraZeneca have been shown in studies?
COVID-19 Vaccine AstraZeneca has been given to approximately 24,000 individuals aged
18 years or older in four ongoing clinical trials in the UK, Brazil and South-Africa. Most
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were equally allocated to COVID 19 Vaccine AstraZeneca or a control (another vaccine not
targeting SARS-CoV-2 or a placebo).
In a pre-specified preliminary analysis, those who received the vaccine had a reduction in the
rate of COVID-19 illness compared to those who received the control (30 cases of COVID-
19 illness in the vaccinated group compared to 101 cases in the control group). These results
were observed two weeks or more after the second dose in study participants with no
evidence of prior SARS-CoV-2 infection.
A similar benefit was observed in participants who had one or more other medical conditions
that increase the risk of severe COVID-19 disease, such as obesity, cardiovascular disorder,
respiratory disease or diabetes.
What are the possible side effects of COVID-19 Vaccine AstraZeneca?
The most common side effects with COVID-19 Vaccine AstraZeneca (which may affect
more than 1 in 10 people) were tenderness, pain, warmth, redness, itching, swelling or
bruising where the injection is given, generally feeling unwell, feeling tired (fatigue), chills
or feeling feverish, headache, feeling sick (nausea), joint pain or muscle ache. In clinical
studies, most side effects were mild to moderate in nature and resolved within a few days
with some still present a week after vaccination
For the full list of all side effects reported with this medicine, see Section 4 of the
Information for UK recipients on COVID-19 Vaccine AstraZeneca or the
Information for
Healthcare Professionals on COVID-19 Vaccine AstraZeneca available on the MHRA
website.
Why was COVID-19 Vaccine AstraZeneca approved?
It was concluded that COVID-19 Vaccine AstraZeneca has been shown to be effective in the
prevention of COVID-19. Furthermore, the side effects observed with use of this product are
considered to be similar to those seen for other vaccines. Therefore, the MHRA concluded
that the benefits are greater than the risks and recommended that this medicine can be
authorised for temporary supply during the COVID-19 pandemic.
What measures are being taken to ensure the safe and effective use of
COVID-19 Vaccine AstraZeneca?
All new medicines approved require a Risk Management Plan (RMP) to ensure they are used
as safely as possible. An RMP has been agreed for the use of COVID-19 Vaccine
AstraZeneca in the UK. Based on this plan, safety information has been included in
the Information for UK Healthcare Professionals and the Information for UK recipients,
including the appropriate precautions to be followed by healthcare professionals and patients.
All side effects reported by patients/healthcare professionals are continuously monitored.
Any new safety signals identified will be reviewed and, if necessary, appropriate regulatory
action will be taken. The MHRA has also put in place an additional proactive safety
monitoring plan for all COVID-19 vaccines to enable rapid analysis of safety information
which is important during a pandemic.
Other information about COVID-19 Vaccine AstraZeneca
Authorisation for the temporary supply of COVID-19 Vaccine AstraZeneca was granted in
the UK on 29 December 2020.
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The full public assessment report for COVID-19 Vaccine AstraZeneca follows this summary.
This summary was last updated 31 December 2020.
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TABLE OF CONTENTS
I
INTRODUCTION ......................................................................................................... 6
II
QUALITY ASPECTS ............................................................................................................. 9
III
NON-CLINICAL ASPECTS .............................................................................................. 15
IV
CLINICAL ASPECTS ......................................................................................................... 24
V
USER CONSULTATION ................................................................................................... 56
VI
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION ....................................................................................................... 56
TABLE OF CONTENT OF THE PAR UPDATE ....................................................................... 57
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I
INTRODUCTION
This report is based on the information provided by the company in a rolling data submission
procedure and it covers the authorisation for temporary supply of COVID-19 Vaccine
AstraZeneca. At the time of writing the company have provided sufficient information to
make a decision on the vaccine but final reports for all studies have not yet been received: in
addition, a reproductive toxicology study is ongoing.
Quality aspects of the vaccine are reviewed on a batch-specific basis.
In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China and
in January 2020, a novel coronavirus was discovered as the underlying cause. Infections by
the virus, named SARS-CoV-2, and the resulting disease, COVID-19, have spread globally.
On 11 March 2020, the WHO declared the COVID-19 outbreak to be a pandemic.
The number of COVID-19 cases in the UK now stands at more than 2 million and over
70,000 deaths have been attributed to the disease. The elderly and those with pre-existing
medical conditions are at particular risk of severe disease and death from COVID-19. A new
variant of SARS-CoV-2 has recently been identified which has a higher transmission rate
than the other variants in circulation. Currently there is no evidence that this variant causes
more severe disease or higher mortality. Vaccination is the most effective medical
intervention to decrease risk and reduce spread of the SARS-CoV-2 virus.
The Department of Health and Social Care (DHSC) is leading the Government’s deployment
of vaccinations against COVID-19. In order to save lives, and to reduce the number of people
who need hospital treatment due to COVID-19, the DHSC have sought to deploy a safe and
effective vaccine as soon as possible. In a letter dated 24 November 2020, the DHSC
requested authorisation, on a temporary basis, of its proposed supply of a vaccine
manufactured by AstraZeneca AB named “COVID-19 Vaccine AstraZeneca”, under
Regulation 174 of the Human Medicines Regulations 2012, (“the Regulations”).
Development of COVID-19 Vaccine AstraZeneca was initiated by the University of Oxford
with subsequent transfer of development activities to AstraZeneca AB. In a subsequent letter
dated 22 December 2020, and in light of knowledge of the new variant of SARS-CoV-2, the
DHSC requested MHRA to consider the time interval between initial and booster doses of
vaccine in which efficacy has been demonstrated, in order to provide operational flexibility
and to enable a larger proportion of the population to receive a first dose in a shorter
timeframe.
Following an extensive review of the quality, safety and efficacy data, COVID-19 Vaccine
AstraZeneca has been authorised for temporary supply in the UK for the following
indication: active immunisation of individuals ≥18 years old for the prevention of
coronavirus disease 2019 (COVID-19). COVID-19 Vaccine AstraZeneca is a solution for
injection stored at 2 – 8°C intended for intramuscular administration (IM). A single 4 mL vial
contains 8 doses (each 0.5 mL) and a single 5 mL vial contains 10 doses (each 0.5 mL).
The SARS-CoV-2 virus uses proteins on its outer surface, called spike (S) proteins, to enter
the cells of the body and cause disease. The active substance of COVID-19 Vaccine
AstraZeneca is a monovalent vaccine composed of a single recombinant, replication-deficient
chimpanzee adenovirus (ChAdOx1) vector that codes for the S glycoprotein of SARS-CoV-2
(ChAdOx1-S [recombinant]). Following vaccine administration, this vector enters into the
cells of the body and produces the S glycoprotein of SARS-CoV-2 which is then expressed
on the surface of the cells. Expression of the spike protein induces neutralising antibodies and
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T-cells to be raised against it. Should the body then become infected with SARS-CoV-2, the
immune system will recognise the SARS-CoV-2 virus and attack it.
The authorisation is for specific batches of the vaccine, after confirmation that detailed
conditions are met. The
Conditions for Authorisation for COVID-19 Vaccine AstraZeneca
are published on the MHRA website.
The MHRA has been assured that acceptable standards of Good Manufacturing Practice
(GMP) are in place for this product at all sites responsible for the manufacture, analysis,
assembly and batch release of this product.
A Risk Management Plan (RMP) and a summary of the pharmacovigilance system have been
provided with this application and are satisfactory.
This batch, and any future batches, of COVID-19 Vaccine AstraZeneca are subject to
Qualified Person (QP) certification and batch evaluation by an independent control
laboratory before the vaccine is released into the UK.
The COVID-19 Vaccine Benefit Risk Expert Working Group (Vaccine BR EWG) have met
several times to review and discuss the quality, safety and efficacy aspects in relation to
batches of COVID-19 Vaccine AstraZeneca.
The Vaccine BR EWG gave advice to the Commission of Human Medicines (CHM) on 29
September 2020, 14 October 2020, 10 November 2020, 7 December 2020, 10 December
2020, 17 December 2020, 22 December 2020, 24 December 2020, 29 December 2020 and 31
December 2020, regarding the requirements for authorisation for the temporary supply of
COVID-19 Vaccine AstraZeneca. The requirements for quality, safety and efficacy were
considered, taking into account the urgent public health need and risk to life, the pandemic
situation and limited options for prevention and treatment of COVID-19. As well as data on
quality, safety, efficacy and the timing of the second dose, specific conditions on the product
were discussed to ensure adequate standards of quality and safety are met.
The CHM concluded that the proposed supply of COVID-19 Vaccine AstraZeneca for active
immunisation to prevent coronavirus disease 2019 (COVID-19), in individuals 18 years of
age and older, is recommended to be suitable for approval under Regulation 174 provided the
company meets the
Conditions for Authorisation for COVID-19 Vaccine AstraZeneca set out
by the MHRA.
Authorisation for the temporary supply of COVID-19 Vaccine AstraZeneca was granted in
the UK on 29 December 2020. This report covers data received and reviewed for this
authorisation only. This authorisation is valid until expressly withdrawn by MHRA or upon
issue of a marketing authorisation by MHRA.
Whilst an acceptable level of information has been received to provide assurance that
appropriate standards of quality, safety and efficacy have been met for authorisation of
specific batches for temporary supply under Regulation 174 of the Regulations, it should be
noted that COVID-19 Vaccine AstraZeneca remains under review as MHRA continues to
receive data from the company as it becomes available. This will include, for example, final
study reports for all studies, long-term follow-up efficacy and safety data. Further
information that is received by the MHRA will be reviewed as part of the ongoing
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assessment for this product and updates will be made to this PAR to reflect that in due
course.
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II
QUALITY ASPECTS
II.1
Introduction
This product is a colourless to slightly brown solution provided in a multidose vial of 2
different sizes: 10-dose drug product presentation (5 mL of vaccine) in a 6 mL vial or 10R
vial, and an 8-dose drug product presentation (4 mL of vaccine) in a 5 mL vial.
One dose (0.5 mL) contains COVID-19 Vaccine (ChAdOx1-S recombinant) 5 × 1010 viral
particles (vp), where ChAdOx1-S means the recombinant, replication-deficient chimpanzee
adenovirus vector encoding the SARS-CoV-2 Spike (S) glycoprotein. The adenovirus is a
non-enveloped virus.
The vaccine is produced in genetically modified human embryonic kidney (HEK) 293 cells.
COVID-19 Vaccine AstraZeneca contains genetically modified organisms (GMOs).
In addition to ChAdOx1-S (recombinant) this product also contains the excipients L-
histidine, L-histidine hydrochloride monohydrate, magnesium chloride hexahydrate,
polysorbate 80, ethanol, sucrose, sodium chloride, disodium edetate dihydrate and water for
injections.
The finished product is packaged in multidose vials of either: 5 ml of solution in a 10-dose
vial (clear type I glass) with a halobutyl rubber stopper and an aluminium overseal with a
plastic flip-off cap (in packs of 10 vials); or 4 ml of solution in an 8-dose vial (clear type I
glass) with a halobutyl rubber stopper and an aluminium overseal with a plastic flip-off cap.
Satisfactory specifications and Certificates of Analysis have been provided for all packaging
components. All primary packaging complies with European Pharmacopoeia requirements.
II.2
ACTIVE SUBSTANCE
rINN: not assigned
The active substance is a clear to slightly opalescent solution.
Structure
The active substance, ChAdOx1-S (recombinant), is a recombinant, replication-deficient (E1
and E3 deleted) chimpanzee adenovirus that encodes the SARS-CoV-2 spike protein with a
tissue plasminogen activator (tPA) leader sequence.
Adenoviruses are non-encapsulated, icosahedral particles (virions) between 80 and 100 nm in
diameter, with prominent fibres protruding from the 12 vertices. The viral capsid is
composed of three major proteins (fibre, hexon and penton) with four minor proteins (IIIa,
VI, VIII and IX). The particles contain a single copy of the double-stranded DNA genome.
The manufacturer has provided the DNA sequence of the 35,539 bp ChAdOx1-S
(recombinant) genome.
The expression cassette for the SARS-CoV-2 spike protein fused to the tPA leader uses a
modified human cytomegalovirus (CMV) promoter and a bovine growth hormone
polyadenylation sequence.
The nucleotide sequence of the SARS-CoV-2 spike protein fused to the tPA leader encoded
by ChAdOx1-S (recombinant) have been provided by the manufacturer.
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General properties
Adenoviruses such as ChAdOx1-S (recombinant) are non-encapsulated, icosahedral particles
(virions) between 80 and 100 nm in diameter, with prominent fibres protruding from the 12
vertices. The particles contain a single copy of the double-stranded DNA genome (contains a
transgene to express the SARS-CoV02 virus spike [S] protein).
Viral genome size
The active substance, ChAdOx1-S (recombinant), has a genome size of 35,539 base pairs
(bp).
ChAdOx1-S (recombinant) is not the subject of a European Pharmacopoeia (Ph. Eur.)
monograph.
Manufacture of the drug substance
The manufacturer has provided details of the responsibilities of each facility involved in
manufacture and testing including responsibilities performed by contract laboratories. A
description of the manufacturing process and controls has been provided for each
manufacturing site, including material inputs, critical and non-critical process parameters,
and process outputs. The upstream process consists of working host cell bank vial thaw,
inoculum expansion, infection with working virus seed and further expansion in the
production bioreactor to generate ChAdOx1-S (recombinant). The downstream process
consists of lysis of the production bioreactor cell culture, nuclease digestion of the host cell
DNA, clarification and further processing through a series of purification/concentration steps
to remove process-related impurities and then formulation with excipients and aseptic
filtration.
The comparability between drug substance batches manufactured for the clinical program
and drug substance batches representative of the commercial process has been evaluated.
The data generated indicate consistency between the drug substance described for this
application and that used in the clinical programme.
GMP certificates or a QP declaration have been provided for all relevant manufacturing sites,
testing sites and QP release site. There are no GMP concerns.
Control of Materials
Raw materials are purchased from quality-approved suppliers according to approved
procedures and are either compendial grade (i.e. defined in a Pharmacopoeia) or purchased in
accordance with the vendor’s and/or manufacturer’s written specifications. No materials of
human origin were used in the manufacturing process for COVID-19 Vaccine AstraZeneca
other than the host cells, which are derived from the HEK293 human embryonic kidney cell
line. Materials of animal origin used in pre-GMP virus seed development, GMP cell banking,
virus seed banking and the manufacturing process have been adequately described.
Information, certificates of origin and TSE certificates of suitability have been provided.
Satisfactory descriptions have been provided for all starting materials. Detailed descriptions
are given for the development of the ChAdOx1 adenoviral vector, development of the
recombinant spike protein gene, construction of the intermediate ChAdOx1 nCoV-19 BAC
plasmid, and generation of the host cell line as well as the generation of the viral isolate and
preparation of the research virus seed (RVS).
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Details of the master host cell bank and working host cell bank have been provided as well as
details of the master virus seeds (MVSs), working virus seeds (WVSs) and control cell
cultures. Testing of the cell banks is in line with ICH Q5A (R1) and ICH Q5D. The cell
banks were tested for identity, safety, and purity, and all test results met the acceptance
criteria.
Tests include sterility, mycoplasma, adventitious and endogenous viruses and cell line
species identification. A test for replication competent adenovirus (RCA) is conducted on
every AZD1222 MVS and on every drug substance at the bulk harvest step to confirm the
absence of replication competent adenovirus.
Controls of Critical Steps and Intermediates
Synthesis of the active substance from the designated starting materials has been adequately
described and appropriate in-process controls and intermediate specifications are applied.
The microbial controls (in-process bioburden and endotoxin measurements) used to
demonstrate microbial control of the manufacturing process for drug substance are described
and found acceptable.
Process validation
Drug substance process validation studies are not yet complete, however, the general
validation plans described appear acceptable. Full validation study results must be provided
once available.
Characterisation
Appropriate proof-of-structure data have been supplied for the active substance.
Impurities
All potential known product-related impurities have been identified and characterised. The
process-related impurities are divided into three categories: biologically-derived
macromolecules, small molecules and synthetic macromolecules. These have been
adequately evaluated and described.
Control of drug substance
An appropriate release specification is provided for the active substance. The manufacturer
has provided adequate justification for these limits, based on efficacy and safety
considerations, and/or well-established limits for other medicines (where this is appropriate).
It is agreed that due to the relatively limited manufacturing experience to date the proposed
specifications can be accepted at this time, by taking into account the efficacy and safety
justifications. The specifications will be revisited and revised if appropriate after a suitable
number of commercial batches have been prepared.
Validation of analytical procedure
Validation of the analytical methods used for the control of the drug substance are
satisfactory for ensuring compliance with the relevant specifications.
Batch analyses
Batch release results for all batches used in the clinical trials, along with site of manufacture,
have been provided and show that all batches conformed to the specifications in force at time
of manufacture.
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Batch release data for the commercially manufactured drug substance lots that have been
provided to date are all within specification and no major trends are apparent between the
different manufacturing facilities.
All batch release results are provided and confirmed to be within specification before
approval of each batch under Regulation 174.
Justification of specification
Acceptance criteria for stability and lot release testing are established within limits that
ensure the safety and efficacy of the product and allow for reliable manufacturing and
adequate shelf life needed for continued product supply. Some specifications are further
justified based on manufacturing experience with other adenoviral products and/or
compliance with regulations, guidance, and compendial monographs.
Reference Standard
The reference standard used for routine drug substance and drug product lot release and
stability testing has been described. The reference standard is placed on stability. Preparation
and qualification of the reference standard has been provided and is adequate.
Container Closure System
Suitable specifications have been provided for all packaging used. The two primary container
closure systems for the drug substance have been described and are suitable for the intended
use. Stability testing has shown the primary containers to be compatible with the drug
substance. Long-term storage of the drug substance in the primary containers has been
provided and is adequate.
The primary packaging has been shown to comply with the quality standards of the Ph.Eur.
Stability
The stability data provided are sufficient to support the proposed shelf-life of 6 months for
the drug substance. The company has committed to continue the stability studies.
II.3
DRUG PRODUCT
COVID-19 Vaccine AstraZeneca is a sterile liquid dosage form intended as a multiple-dose
vial for administration by intramuscular injection. The drug product is supplied in
presentations containing either 8 doses or 10 doses per vial. COVID-19 Vaccine AstraZeneca
is manufactured with clear and colourless vials, closed with elastomeric stoppers, and sealed
with aluminium overseals. The drug product vials are packaged 10 vials in a carton.
Pharmaceutical development A satisfactory account of the pharmaceutical development has been provided. The sterile
drug product dosage form was developed to ensure COVID-19 Vaccine AstraZeneca stability
and to meet clinical dose level needs by intramuscular administration. The formulation
composition was developed based on experience with adenoviruses.
All excipients, including water for injection (WFI) comply with the specifications of the Ph.
Eur. None of the excipients are of animal or human origin, nor are any novel. The excipients
are well established for pharmaceutical products.
This product consists of genetically modified organisms (GMO).
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Manufacture of the drug product
A description of the manufacturing method has been provided. Drug product manufacturing
consists of thawing, dilution, mixing sterile filtration, aseptic filling, visual inspection and
labelling. The finished drug product is stored at 2-8°C.
The development of the clinical manufacturing processes have been adequately described.
Comparability studies demonstrate that drug product from each process is comparable and
conform to pre-defined comparability criteria.
A satisfactory batch formula has been provided for the manufacture of the product for
presentations with 8 doses/vial, 5 mL vial size, 10 doses/vial, 6 mL vial size, and 10
doses/vial, 10R vial size.
An appropriate account of the manufacturing process has been provided for each drug
product manufacturer. The manufacturing process has been adequately described and the
manufacturing process controls in place are acceptable.
Controls of critical steps and intermediates
Adequate information on critical process parameters and in-process controls has been
provided. Control of critical process steps for the manufacture of COVID-19 Vaccine
AstraZeneca is described through critical process parameters, in-process controls, and in-
process hold time.
Process validation
Drug product process validation studies are not yet complete, however, the general validation
plans described appear acceptable. Full validation study results must be provided once
available.
Control of excipients
All excipients are of compendial grade and none of the excipients are of human or animal
origin. As the drug product excipients are tested according to compendial methods, no
validation of the analytical procedures is required to be submitted for review.
Control of drug product
The finished product specification is satisfactory. The manufacturer has provided adequate
justification for these limits, based on efficacy and safety considerations, and/or well-
established limits for other medicines (where this is appropriate). It is agreed that due to the
relatively limited manufacturing experience to date the proposed specifications can be
accepted at this time by taking into account the efficacy/safety justifications. The
specifications will be revisited and revised if appropriate after a suitable number of
commercial batches have been prepared.
Analytical procedures
Validation of the analytical methods used for the control of the drug product are satisfactory
for ensuring compliance with the relevant specifications.
Batch analyses
Batch release results for all batches used in the clinical trials, along with site of manufacture,
have been provided and show that all batches conformed to the specifications in force at time
of manufacture.
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Batch release data for the commercially manufactured drug product lots that have been
provided to date are all within specification.
All batch release results are provided and confirmed to be within specification before
approval of each batch under Regulation 174.
Independent Batch testing
Independent batch testing provides additional assurance of quality before a batch is made
available to the market. Independent batch testing is a function that is undertaken by an
Official Medicines Control Laboratory (OMCL) and, under Regulation 174A, the UK
National Institute for Biological Standards and Control (NIBSC) is responsible for this
function.
Independent batch testing is product-specific: it requires specific materials and
documentation from the manufacturer and comprises laboratory-based testing and review of
the manufacturer’s test data. If all tests meet the product specifications a certificate of
compliance is issued by the OMCL. NIBSC has developed the capability and capacity to
undertake the independent batch tests for this product.
Characterisation of impurities There are no new process related drug product impurities in addition to those described for
the drug substance.
Justification of specifications
Acceptance criteria for stability and lot release testing are established within limits that
ensure the safety and efficacy of the product, ensure consistent manufacturing and allow an
adequate shelf life for continued product supply. Some specifications are further justified
based on manufacturing experience with other adenoviral products and/or compliance with
regulations, guidance, and compendial monographs.
Reference standards or materials The reference standard used for the drug substance and the drug product are the same. This is
acceptable as both drug substance and drug product have the same composition.
Container closure system
The container closure system has been well described and complies with the relevant quality
standards of the Ph.Eur.
Stability
Finished product stability studies include batches of the finished product stored in the
packaging proposed for marketing. The manufacturer has provided all stability data available
to date. Based on the results, a shelf-life of 6 months at 2°C to 8°C for the unopened
multidose vials is recommended.
The product should be stored in the original package in order to protect from light. During
use, vials can be handled in room light conditions. It should not be frozen.
Since the vaccine does not contain a preservative, once the stopper has first been punctured,
the vial should be used within 6 hours. After the first dose is withdrawn, the vaccine should
be stored between 2°C to 25°C and used as soon as practically possible. After 6 hours, any
unused vaccine left in the vial should be discarded.
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Suitable post approval stability commitments have been provided to continue stability testing
on batches of COVID-19 Vaccine AstraZeneca. The manufacturer has committed to provide
these data to the MHRA on an on-going basis as it becomes available.
Handling and disposal
Distribution during deployment should be controlled at 2-8°C throughout its shelf life of
6 months.
Further packing down (splitting of packs) of lots to aid deployment, can occur at 2-8°C
within its shelf life. This can also be implemented at ‘room temperature’ (less than 25°C), if
completed within 2 hours, immediately prior to final pre-use distribution (at 2-8°C). GMP
controls are required to ensure there is no detrimental impact to quality, safety or efficacy of
the lots by this processing.
After first use, the vials should be marked with the date and time.
Disposal should take account of the fact that COVID-19 Vaccine AstraZeneca contains a
genetically modified organism (GMO). Any unused vaccine or waste material should be
disposed of in accordance with local requirements. Spills should be disinfected with an
appropriate antiviral disinfectant.
II.4
Regulation 174
Authorisation for temporary supply of COVID-19 Vaccine AstraZeneca under this
Regulation 174 has been given following review of batch specific data by MHRA.
Independent batch release by the National Institute for Biological Standards and Control
(NIBSC) is performed on all batches to be supplied to the UK.
The quality data currently available for COVID-19 Vaccine AstraZeneca can be accepted as
sufficient with specific conditions in place. There are no scientific objections arising from
this review to the authorisation for temporary supply for this product under Regulation 174 of
the Human Medicine Regulations.
III
NON-CLINICAL ASPECTS
III.1 Introduction
In vivo animal safety testing with the vaccine has been conducted and it was well tolerated
with no adverse findings. At the time of writing, the only remaining data expected, that are in
compliance with Good Laboratory Practice (GLP) are from a reproductive toxicity study in
mice. This will be reported in 2021. The primary pharmacology data reviewed do use
COVID-19 Vaccine AstraZeneca.
The following non-clinical information was reviewed for this application.
Primary Pharmacology
Graham, S. P. et al. Evaluation of the immunogenicity of prime-boost vaccination with the
replication-deficient viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19.
npj
Vaccines. 5, 69 (2020)
Study INT-ChAdOx1 nCov19-POT-002 – To determine potency of the CBF manufacturing
batch of COVID-19 Vaccine AstraZeneca in mice
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Study 20-01125 - Assessment of efficacy of SARSCoV-2 vaccine candidates in the ferret
model
Study 6285 – Efficacy of ChAdOx1 nCoV-19 against coronavirus infection in ferrets
van Doremalen, N. et al. ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in
rhesus macaques.
Nature. 586, 578-582 (2020)
Study 6284 – Efficacy of ChAdOx1 nCoV-19 against coronavirus in rhesus macaques
Safety Pharmacology
Study 617078-1158zm – Safety pharmacology study to assess potential effects on vital
systems (cardiovascular, respiratory) of AZD1222 in male mice given a single intramuscular
dose of AZD1222 (GLP)
Pharmacokinetics
Study uno0009/MAB-001 – AdCh63ME-TRAP tissue distribution study by intra-dermal
administration to mice (GLP)
Study uno0014/RMBBioDIST-001- AdCh63 MSP-1 and MVA MSP-1 tissue distribution
study by intra- muscular administration to mice (in-life phase conducted to GLP)
Study 514559 (protocol, study ongoing) – AZD1222 (ChAdOx1-nCovd-19): A single dose
intramuscular vaccine biodistribution study in the mouse (GLP)
Study 0841mv38-001 (protocol, study ongoing) – ChAdOx-1 HBV and MVA-HBV
biodistribution study in BALB/c mice with shedding assessment (GLP)
Toxicology
Study 513351 - AZD1222 (ChAdOx1-nCovd-19): A 6 week intermittent dosing
intramuscular vaccine toxicity study in the mouse with a 4 week recovery (GLP)
Study QS18dl – ChAdOx1 Chik Vaccine or ChAdOx1 MERS: toxicity study by
intramuscular administration to mice (GLP)
Study uno0013 - Mouse toxicity AdCh63 MSP-1 and MVA MSP-1 or a combination of
AdCh63 ME-TRAP and MVA METRAP (GLP)
Study XMM0003 - ChAdOx1 NP+M1 and MVA NP+M1: toxicity study by intramuscular
administration to mice (GLP)
Study 490838 - ChAdOx1-nCovd19: A preliminary intramuscular injection vaccine
development and reproductive study in female CD-1 mice (GLP)
Study 490843 (ongoing) - AZD1222 (ChAdOx1 -nCovd19): An intramuscular vaccine
development and reproductive study in female CD-1 mice (GLP)
Studies that were carried out in accordance with Good Laboratory Practice (GLP) are
indicated above. There are no concerns in relation to GLP. In the study titles above COVID-
19 Vaccine AstraZeneca is sometimes referred to as AZD1222.
III.2 Pharmacology
Immunogenicity studies were conducted in animal models responsive to COVID-19 Vaccine
AstraZeneca in order to evaluate the immunological properties of this COVID-19 vaccine
candidate to support first in human (FIH) clinical trials. COVID-19 Vaccine AstraZeneca has
been shown to be immunogenic in BALB/c, CD-1 mice, ferrets, non-human primate (NHP)
and pig models.
The studies summarised below included evaluation of humoral, cellular and functional
immune responses. It is noted that the number of animals in groups was limited in some
studies.
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In the immunogenicity study, published by Graham et al, 2020, ‘prime-boost’ vaccinated
inbred (BALB/c) and outbred (CD1) mice (9-10 weeks of age) were immunised by
intramuscular (IM) injection of 108 infectious units (IU) of COVID-19 Vaccine AstraZeneca
on 0 and 28 days post-vaccination, whereas, ‘prime-only’ mice received a single dose of the
vaccine on day 28. Results showed a significant increase in antibody titre on prime-boosting
in inbred mice when compared to primed-only mice but there was no boosting response seen
in outbred mice. In both mouse strains the cellular response was primarily driven by CD8 +ve
T cells. The absence of a booster response in outbred mice may have been due to the effect of
a single dose being near to the maximal response. Mice showed Th1-like CD4+ and CD8+ve
T cell responses. Both antibody- and T cell responses are thought likely to contribute to
controlling infection. This study also investigated the immunogenicity of one or two doses of
COVID-19 Vaccine AstraZeneca in pigs. Responses seen in pigs may be more representative
of the likely human response. Pigs showed a booster response in serum antibody and showed
Th1-like CD4+ and CD8+ve T-cell responses which are thought likely to contribute to
controlling infection. In pigs, titres after a single dose of vaccine were similar to those in
asymptomatic humans, whereas those after boosting were comparable to those in patients
who recovered from COVID-19 disease.
Study 20-01125 evaluated the immunogenicity and protective activity of COVID-19 Vaccine
AstraZeneca on challenge with SARS CoV-2. Ferrets can be infected with SARS-CoV-2
after its intranasal application, with virus shedding from the upper respiratory tract occurring
for at least 9 days post exposure; however, they do not show signs of ill health. In this study
no ferrets in either the vaccinated or control groups developed any signs of disease,
indicating that the virus is not pathogenic in ferrets. Nevertheless, antiviral activity of the
vaccine can be shown in this species. Data were presented on immunological analyses of
ferret immune cell populations, cytokine profiles and proportions of IFN-γ producing cells
following immunisation and subsequent challenge with SARS-CoV-2. Ferrets given a single
intramuscular injection of COVID-19 Vaccine AstraZeneca developed neutralising
antibodies, boosted by challenge with SARS-CoV-2. Ferrets given COVID-19 Vaccine
AstraZeneca showed a faster reduction to undetectable limits of SARS CoV-2 virus in nasal
samples than did ferrets not given COVID-19 Vaccine AstraZeneca.
Study 6285 assessed the immunogenicity of COVID-19 Vaccine AstraZeneca and its
protective activity against SARS CoV-2 challenge in ferrets. A vector control group were
given ChAdOx-1 GFP in which the gene insert for the viral spike protein was replaced by
that for Green Fluorescent Protein (GFP) and a further group were assigned as unvaccinated
controls. Twelve ferrets were vaccinated with COVID-19 Vaccine AstraZeneca, six with a
prime only regime and six with a prime and boost doses, 28 days apart. Eight ferrets also
received viral particles of ChAdOx1-GFP, four prime only and four prime boost. Six further
ferrets were immunised with formalin-inactivated SARS CoV-2. Ferrets were challenged
with SARS-CoV-2 via the intranasal route at 4 weeks after their last dose of vaccine (2 weeks
for those given formalin-inactivated SARS CoV-2). The challenge was done on two separate
days giving a cohort (a) that were all dosed on one day and cohort (b) that were all dosed on a
different day. Overall, COVID-19 Vaccine AstraZeneca appeared to offer protection in this
challenge model. Dosing was well tolerated and induced neutralising antibodies with booster
dosing increasing neutralising antibody titres significantly although this enhancement did not
appear to be sustained for much longer than a week. There was a good correlation between
neutralising antibody titre with antibody binding to spike protein, suggesting that binding to
spike protein is contributing to the neutralising activity of serum from vaccines. After viral
challenge, vaccinated ferrets showed reduced challenge viral RNA in the upper respiratory
tract and this was cleared earlier compared to controls. These results were mirrored by tissue
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PCR results, which showed that in the upper respiratory tissues there was less detectable viral
RNA in vaccinated ferrets. Lung histopathology in vaccinated ferrets appeared to be reduced,
one-week post-challenge compared to controls but a deterioration was seen in vaccinated
ferrets and the difference in lung histopathology between groups at two weeks post-challenge
was negligible. The vaccine appeared to delay the appearance of lung pathology.
A post-vaccination SARS-CoV-2 challenge in rhesus macaques was conducted to evaluate
protection and the potential for vaccine-associated enhanced respiratory disease (ERD) (van
Doremalen
et al 2020). This study showed that COVID-19 Vaccine AstraZeneca reduced
clinical disease score in monkeys and prevented damage to the lungs upon challenge to the
upper and lower respiratory tract with SARS-CoV-2 virus; a prime-boost regimen induced
humoral immune responses. COVID-19 Vaccine AstraZeneca reduced viral load in the lungs,
reducing virus replication in the lower respiratory tract. Despite this, there was no reduction
in viral shedding from the nose with either prime-only or prime-boost regimens. These data
support an interpretation that COVID-19 Vaccine AstraZeneca may not prevent infection nor
transmission of SARS-CoV-2, but it may reduce illness. The immune responses were not
skewed towards a Th2-type and there was no suggestion of disease aggravation following
COVID-19 Vaccine AstraZeneca.
Study 6284 was done to test potential activity of COVID-19 Vaccine AstraZeneca to protect
rhesus monkeys from a challenge with SARS-CoV-2 virus. In this study 3 male and 3 female
monkeys were vaccinated once with COVID-19 Vaccine AstraZeneca and 3 male and 3
female monkeys with phosphate buffered saline, by intramuscular injection. Monkeys were
challenged with SARS-CoV-2 virus four weeks later and killed on days 7 or 13 or 14 after
viral challenge. COVID-19 Vaccine AstraZeneca induced neutralising antibodies and had an
effect to reduce the magnitude of weight loss or temperature increase caused by SARS CoV-
2 challenge. The vaccine appears to prime the immune system to release activated monocytes
and T helper cells within the early days following SARS CoV-2 challenge and vaccinated
monkeys appeared to have increased antigen-specific T cells following challenge.
Vaccination offered some protection against disease as shown on a CT scan 5 days after
challenge, this had abated by day 12. Lung lesion severity appeared to be reduced in most
vaccinated monkeys at 1 or 2 weeks after the viral challenge and there was a reduction in
viral RNA in the lung and bronchoalveolar lavage fluid in most vaccinated monkeys. There
was, however, little evidence of reduction in viral RNA in the upper respiratory tract and at
day 7 post-challenge, there appeared to be an increase in viral RNA in the large intestine of
vaccinated monkeys. In summary, COVID-19 Vaccine AstraZeneca did offer a level of
protection in this challenge experiment and did not appear to cause vaccine-enhanced
disease.
Study 617078 was a safety pharmacology study designed to assess the potential effects of
COVID-19 Vaccine AstraZeneca on the vital systems (cardiovascular, respiratory) in male
mice given a single intramuscular dose of COVID-19 Vaccine AstraZeneca. Administration
of COVID-19 Vaccine AstraZeneca resulted in a statistically significant decrease in
respiratory rate and increase in inspiration and expiration time throughout the whole 4-hour
recording period. These statistically significant differences were considered to be a
consequence of the variability in pre-dose data and that the profile of these respiratory
parameters appeared similar across all recording days and therefore these respiratory changes
were considered not to be associated with COVID-19 Vaccine AstraZeneca. Dosing with
COVID-19 Vaccine AstraZeneca did not result in changes in any of the other parameters
monitored in this study: there were no changes in arterial blood pressure, heart rate, body
temperature or respiratory parameters.
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In summary, neither ferrets nor monkeys developed clinically evident disease after SARS
CoV-2 and this places limitations on the ability to show that vaccination reduced disease.
However, small group sizes contribute to the difficulty.
In the studies in ferrets and monkeys, evaluations were made of the safety profile of the
vaccine. These evaluations confirmed changes at injection sites in the injected muscle and
reactions consistent with a minor local inflammatory effect. These changes attributed to
COVID-19 Vaccine AstraZeneca suggest that it is likely to be tolerable as an intramuscular
injection and to have effects consistent with an immunogen.
There was, however, a finding of hepatitis in ferrets. In the literature, vaccination against
SARS (not SARS CoV-2 note) was reported to enhance hepatitis in ferrets (Weingartl H
et al 2004 J Virol 78(22) 12672-12676) but the vaccine used in that study was a modified vaccinia
virus Ankara based vaccine, containing the gene for the SARS viral spike protein: neither of
these characteristics offer insight as to whether COVID-19 Vaccine AstraZeneca might
induce hepatitis. General toxicity studies are reported from mice as reviewed in this
assessment report below. Further comment and a conclusion on potential liver toxicity is
given there.
There is a theoretical concern of vaccine-associated disease enhancement, where use of
COVID-19 Vaccine AstraZeneca might put vaccinated individuals at risk of worse disease if
they later encounter SARS CoV-2. The study in rhesus monkeys, however, did not identify
evidence of concern of this effect following vaccination with COVID-19 Vaccine
AstraZeneca.
The safety pharmacology investigations did not identify a concern for use of COVID-19
Vaccine AstraZeneca. Although there was an apparent effect of the vaccine, examination of
the trace above shows that at baseline, the respiratory rate was already lower in those mice
who later were dosed with COVID-19 Vaccine AstraZeneca: all the groups showed a
reduction and that in those given COVID-19 Vaccine AstraZeneca seemed no greater than in
the other groups.
III.3 Pharmacokinetics
The vaccine is intended to be given as an intramuscular injection. Two biodistribution studies
were performed which suggest that, after injection, the virus does not replicate, or persist and
it is not detectable except at the injection site.
Absorption
No absorption studies were performed with COVID-19 Vaccine AstraZeneca since the route
of administration is intramuscular (IM).
Distribution
COVID-19 Vaccine AstraZeneca has been manufactured so that it is unable to replicate in
cells. Therefore, after infecting a cell, there is expected to be no further spread of the virus.
Study uno0009/MAB-001 was a biodistribution study performed in compliance with Good
Laboratory Practice, in which mice were injected with AdCh63METRAP virus. The study
was carried out to determine the distribution of infectious adenovirus particles in mouse
organs one week after a single intradermal dose in the ear. Two mice were also analysed
immediately after injection. The results suggest that the virus is lost from the injection site
over time and a lack of replication in tested mouse tissues. AdCh63METRAP was only
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detected at the injection site, and not in any other organs. These results are consistent with the
injection of a non-replicating virus. However, of note when interpreting these data, the study
report notes that immediately after injection, AdCh63METRAP will begin to enter cells and
is no longer available to infect the HEK 293 cells used in the assay.
Study uno0014/RMBBioDIST-001 evaluated tissue distribution following a single IM dose
in mice each of different viruses, AdCh63 MSP-1 and MVA MSP-1. Results for the virus
MVA MSP-1, an attenuated pox virus, are not described here as they are not relevant for
what is expected with COVID-19 Vaccine AstraZeneca. Results showed AdCh63-MSP1 was
detected at the injection sites on the day of dosing but not at 24 hours or 7 days later. No
AdCh63-MSP1 was detected in any internal organ. Comparing between these two studies
into distribution, the report comments that the route of administration appears to affect the
persistence of infectious virus at the injection site as by the intramuscular route, virus was
only detectable at the injection site immediately after injection. These results are consistent
with the injection of a replication deficient virus for AdCh63-MSP1.
Study 0841mv38-001 was a biodistribution and shedding study using the ChAdOx1 vector
with a hepatitis B virus (HBV) insert after IM injection on days 1 and 28 in mice.
Distribution to some samples of all tissues was noted on day 2 and day 29. The highest levels
(copies/mg sample) were noted at the site of administration (skeletal muscle), ranging from 3
x 108 to 9.97 x 109 copies/mg sample. In the majority of samples of other tissues taken on day
56, the levels were below the level of quantification, indicating elimination. Low levels were
noted in 1 sample (of 6) for each of heart and liver, 1 of 3 for ovary and testes, and 3 of 6
lymph node samples at this timepoint. This study does not contain assessment of CNS,
relevant peripheral nerves or bone marrow and it does not include analysis at shorter time
points compared to the already available studies and no description of the validation of
method analysis. This platform study will be superseded by Study 514559, designed to
explore the distribution of COVID-19 Vaccine AstraZeneca after a single intramuscular
injection in male and female mice. A draft report is expected February 2021.
Metabolism
No metabolism studies were performed.
Excretion
No excretion studies were performed.
In summary, COVID-19 Vaccine AstraZeneca is an unadjuvanted vaccine containing a
replication-incompetent virus. As such, the virus should not spread at all far from the site of
its administration and this profile was confirmed for the viruses tested where it was identified
at the injection site and its draining lymph node. These results are considered suitable to
stand in place of a dedicated study with COVID-19 Vaccine AstraZeneca as the same results
would be expected. It is agreed that it is reasonable to omit an
in vivo study in mice, as
animal use for this purpose is not expected to provide any additional useful information on
COVID-19 Vaccine AstraZeneca.
The active principle is not the immunogen but is the induced immune response. The time
course of immune response induced is of interest: this has been characterised to a sufficient
extent in the pharmacodynamic studies described above.
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Absorption, metabolism and excretion studies are not required for vaccines: this position is in
line with relevant regulatory guidance (WHO guidelines on nonclinical evaluation of
vaccines, 2005).
The pharmacokinetic data presented are acceptable.
III.4 Toxicology
Single dose toxicity
No single dose toxicity studies have been performed with COVID-19 Vaccine AstraZeneca.
This is acceptable and in line with relevant guidelines (WHO 2005; WHO 2014).
Repeat dose toxicity
Study 513351 was a 6-week intermittent dosing intramuscular vaccine toxicity study in the
mouse with a 4-week recovery. The objective of this study was to determine the potential
toxicity of COVID-19 Vaccine AstraZeneca (total viral particle dose of 3.7x1010) when given
by IM injection intermittently (on days 1, 22 and 43) to mice, with a 28 day recovery period
to evaluate the potential reversibility of any findings. In addition, the immunogenicity was
evaluated. Scheduled necropsies were conducted either at the end of the 6-week treatment
period (day 45) or at the end of the 28 day recovery period.
Administration of COVID-19 Vaccine AstraZeneca to CD-1 mice (total viral particle dose of
3.7 x 1010) by intramuscular injection on 3 occasions (once every 3 weeks) over a 43 day
period was well tolerated, with a transiently higher body temperature in males, decreases in
monocytes in males and females (consistent with the expected pharmacology of COVID-19
Vaccine AstraZeneca) and increase in globulin and decrease in albumin and albumin/globulin
ratio, consistent with an acute phase response, observed. In all animals dosed with COVID-
19 Vaccine AstraZeneca, antibodies against the S-glycoprotein were raised and maintained
throughout the dosing and recovery periods in all animals. In COVID-19 Vaccine
AstraZeneca animals, higher spleen weights were observed but with no correlating
macroscopic or microscopic changes. Non adverse, mixed and/or mononuclear cell
inflammation was observed in the subcutaneous tissues and skeletal muscle of the
administration sites and adjacent sciatic nerve of animals dosed with COVID-19 Vaccine
AstraZeneca which were consistent with the anticipated findings after intra-muscular
injection of an immunogenic vaccine.
Study QS18dl was performed to investigate the potential toxicity of ChAdOx1 Chik or
ChAdOx1 MERS in inbred (Balb/c) mice, aged 8 weeks old and weighing ~20g, when given
as an IM injection on two occasions, 14 days apart. Following a 13 day observation period
the mice were killed and subject to post mortem examinations. The doses of ChAdOx-1 Chik
and of ChAdOx-1 MERS were each 1 x 1010 viral particles, in 25 or 35 μl per injection. Each
mouse was injected twice on each dosing day, in the left and the right hindlimb. These
vaccines were in development to prevent chikungunya (a viral infection spread by mosquito
bites) and middle eastern respiratory syndrome (MERS, camel flu; a coronavirus that causes
a respiratory illness) and can be considered to be similar to COVID-19 Vaccine AstraZeneca.
Results showed that each of these vaccines were well tolerated and was not associated with
any adverse effects. All the effects described are expected as responses to injection of a
vaccine, reflecting immune stimulation and/or the response to introduction of the injecting
needle into muscle tissue. The changes in the lumbar lymph node reflect that this is the
lymph node local to the injection site in the hindlimb. The slight increases in glucose,
potassium and phosphorus and decreases in triglycerides and liver weight may not be direct
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effects of vaccination and there was a reduction in body weight gain, but the magnitude of
these effects was small, and these changes were not considered adverse.
Study un0013 evaluated the potential toxicity of AdCh63 MSP-1 and MVA MSP-1 or a
combination of AdCh63 ME-TRAP and MVA ME-TRAP in inbred (Balb/c) mice when
given as an IM injection on two occasions, 14 days apart, followed by a 13 day observation
period, when mice were killed and subject to post mortem examinations. These vaccines
were developed to prevent malaria. Results showed that there were no signs of toxicity in
response to these vaccines: the changes noted are consistent with effects of an immune
response to a vaccine, including a mild inflammatory reaction at intramuscular injection sites.
Study xmm0003 was performed with vaccine containing the ChAdOx1 construct but with a
gene insert other than from SARS-CoV-2. Ten male and 10 female BALB/c mice were given
one IM injection with vaccine ChAdOx1 NP+M1 then 14 days later were given a booster
dose with a different vaccine, MVA NP+M1. Control mice were given saline on days 1 and
15. Mice were followed to day 13 after their second dose and then killed for post mortem
analyses. The antigen in this vaccine was derived from influenza. The results demonstrated
changes considered to be consistent with an immune response to vaccination, reflecting in the
lymph nodes, likely, B cell proliferation, and of increased white blood cells with some local
inflammation at the injection site.
Genotoxicity
No genotoxicity studies were performed.
Carcinogenicity
No carcinogenicity studies were performed. Carcinogenicity testing is generally not
considered necessary to support the development and licensure of vaccine products for
infectious diseases (WHO, 2005).
Reproductive and developmental toxicity
An evaluation of the impact of COVID-19 Vaccine AstraZeneca on embryo-fetal
development was completed in a dose-range study (Study 490838). The main GLP embryo-
fetal development study, Study 490843, is ongoing with an audited draft report due at the end
of January 2021.
Prenatal and postnatal development
In Study 490838, control (group 1) or COVID-19 Vaccine AstraZeneca (group 3) was
administered via the IM route to groups of outbred (CD-1) female mice on day 1 (13 days
prior to pairing for mating to a non-dosed male) and again on gestation day (GD) 6 at 2.59 x
1010 per occasion (embryofetal development phase). In further mice, control (group 2) or
COVID-19 Vaccine AstraZeneca (group 4) was administered via the IM route on GD 6 and
GD 15 at 2.59 x 1010 per occasion (littering phase). Mice were killed either on day 17 (groups
1 and 3) or followed to day 14 post birth (groups 2 and 4). The dose used was either 0
(controls) or 2.59 x 1010 viral particles per dose, considered as a maximum feasible dose. For
a 40g mouse, the dose represents an excess over humans of ~906.5 fold. A dose of 1.7x1010
virus particles in mice has been previously shown to induce an appropriate immune response.
Results showed that anti-S glycoprotein antibody responses were raised in dams following
administration of COVID-19 Vaccine AstraZeneca and these were maintained through the
gestational and lactation periods. Seropositivity of fetuses and pups was confirmed and was
indicative of placental and lactational anti-S glycoprotein antibody transfer, respectively.
There were no COVID-19 Vaccine AstraZeneca -related effects seen for dams in-life
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including at the injection site, for female reproduction, fetal or pup survival and no abnormal
gross pathology findings in pups or in dams in either phase. There were no COVID-19
Vaccine AstraZeneca -related fetal visceral or skeletal findings.
Prenatal and postnatal development, including maternal function
See above.
Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
See above: no studies have been done in which juvenile animals were dosed directly.
Local tolerance
No such studies have been done. This was evaluated in general toxicity studies which is
preferred to the conduct of separate studies to evaluate local tolerance.
Other toxicity studies
No such studies have been done.
Toxicity conclusions
The vaccine is to be provided as two doses (each 0.5 mL) given intramuscularly. One dose
(0.5 mL) contains COVID-19 Vaccine (ChAdOx1-S* recombinant) 5 x 1010 viral particles
(vp). * Recombinant, replication-deficient chimpanzee adenovirus vector encoding the
SARS-CoV-2 Spike (S) glycoprotein.
Adenoviruses are double-stranded DNA viruses naturally present in the environment: some
can cause mild illness. They have the capacity to infect mammalian cells independent of the
cell cycle stage and so can infect post-mitotic cells and they can produce large amounts of
progeny. However, removal of genes responsible for adenoviral replication eliminates this
and the degree of pathogenicity should be reduced.
Mice were used in all toxicity studies and were selected as they show a reliable immune
response to ChAdOx-1 vaccines and this was confirmed for COVID-19 Vaccine
AstraZeneca. The choice of mouse for safety studies is accepted. A single species is
acceptable; both males and females were evaluated.
The nature of toxicity was similar across these different studies: there were minor
inflammatory reactions at the injection site and lymphoid organs showed an expected
response to vaccination. Of note, the usual study design is to give one more dose to animals
than is intended in humans. The general toxicity study with COVID-19 Vaccine AstraZeneca
met this expectation. Given that the toxicity seen was minimal and the dose of vaccine used
was in large excess of that to be used in humans, the general toxicity data presented suffice to
support human use.
There was no indication of liver toxicity in mice and at necropsy livers appeared normal. It is
possible that mice recovered from liver changes before the assessments of liver function and
post mortem evaluations were made but this seems unlikely. Based on the biodistribution
data presented, COVID-19 Vaccine AstraZeneca is not expected to reach the liver. Although
identified in ferrets this was not seen in monkeys: overall, the vaccine seems to pose no
special risk of liver toxicity.
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The study reports did not indicate any changes of relevance to the brain and peripheral
nervous system and there are no statements to the effect of any adverse or unusual behaviour
in vaccinated mice.
Concerning the potential for induction of antibody-dependent disease enhancement, whereby
use of the vaccine might put vaccinees at risk of worse disease, this risk is not well
characterised. It is not clear at present even if this can be assessed appropriately in studies in
animals. The general toxicity studies do not give any insights on this as the study designs do
not include exposure to virus.
The mouse may not be the best choice of species for the evaluation of potential reproductive
toxicity as the exposure to the organs of the fetus during their development to antibody
induced by the vaccine probably did not occur. Nevertheless, international guidelines
indicate that mice are an acceptable species for testing potential reproductive toxicity and no
indication of harm was identified. Further information from the company will be supplied.
Considering potential use in women who are breastfeeding, the preliminary study does not
give sufficient evidence of lack of risk and therefore a final recommendation on use in
pregnant or lactating women cannot be made at this time. The ongoing GLP-compliant study
should provide more information once it is completed. The information provided to
healthcare professionals states that COVID-19 Vaccine AstraZeneca should only be
considered in pregnancy when the potential benefits outweigh any potential risks for the
mother and fetus.
The conclusion of this assessment is that COVID-19 Vaccine AstraZeneca could be
supported for use in humans to prevent COVID-19. Further information is awaited to define
the recommendation on use in women who are or may be pregnant or who are breastfeeding.
III.5 Ecotoxicity/Environmental Risk Assessment
It is agreed that, in accordance with CHMP guidance EMEA/CHMP/SWP/4447100 entitled,
"Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use"
published 01 June 2006, due to their nature, vaccines are unlikely to result in a significant
risk to the environment. Therefore, an environmental risk assessment is not provided in this
application. This is acceptable. This vaccine contains a genetically modified organism
(GMO). However, consequences of release and persistence of the GMO in the environment
are regarded as negligible.
III.6 Discussion on the non-clinical aspects
The non-clinical data currently available for COVID-19 Vaccine AstraZeneca can be
accepted as sufficient with specific mitigations in place. There are no scientific objections
arising from this review to the authorisation for temporary supply for this product under
Regulation 174.
IV
CLINICAL ASPECTS
IV.1 Introduction
The immunogenicity, efficacy and safety data supporting this authorisation for temporary
supply have been generated by four studies, presented below. COVID-19 Vaccine
AstraZeneca is referred to as AZD1222 in this clinical review.
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Table 1: Overview of AZD1222 studies
COV001
COV002
COV003
COV005
Abbreviated Title
A phase I/II study to
A phase 2/3 study to
A Randomized, Controlled,
An adaptive phase I/II
determine efficacy,
determine efficacy,
Phase III Study to
randomized placebo-
safety and
safety and
Determine Safety, Efficacy,
controlled trial to
immunogenicity in
immunogenicity; safety
and Immunogenicity
determine safety,
healthy adult volunteers
and immune-genicity
immunogenicity and
sub-studies:
efficacy in subjects
• healthy children aged 5
without HIV; and safety
to 12 years, inclusive
and immunogenicity in
• HIV+ adults aged 18 -
subjects with HIV.
55 years
Region
United Kingdom
United Kingdom
Brazil
South Africa
Control
MenACWY (D1&2)
MenACWY (D1&2)
D1 MenACWY
D1&2:Placebo: Normal
D2 Placebo (0.9% saline
saline (0.9% NaCl)
solution)
Age (years)
18-55
≥ 18
≥ 18
≥ 18-65
Paracetamol use
Prophylactic for a
Prophylactic for a portion
Prophylactic for all
As clinically needed
portion of participants
of participants
Primary endpoint
Virologically-
Virologically-confirmed
Virologically-confirmed
PCT+ COVID-19 cases >
confirmed (PCR+)
(PCR+) symptomatic
(PCR+) symptomatic cases
14 days after booster dose
symptomatic cases of
cases of COVID-19
of COVID-19
in participants COVID-19
COVID-19
naïve at the time of
randomization and who
received 2 doses of test
product
No subjects
Planned/completed
1122/1077
12390
10300
2070
In the safety set
1067
10663
10002
2013
All studies have completed enrolment of their respective efficacy cohorts and are in the
follow-up phase, with the exception of the paediatric group in COV002.
All studies were originally planned to investigate a single dose regimen but were amended in
July 2020 to investigate a two-dose regimen in view of early immunogenicity results. The
booster was planned to be given at the earliest possible time (in principle, 28 days after the
prime dose), but due to logistical constraints, this interval was very variable.
All studies were conducted in line with current Good Clinical Practice (GCP).
IV. 2 Pharmacokinetics
No pharmacokinetic data have been submitted for this application and none were required.
IV.3 Clinical immunogenicity
Bioanalytical assays
The qualification or validation reports for each bioanalytical assay have been provided. These
include the neutralising assays (pseudoneutralisation and live neutralisation), binding anti-
spike and anti-RBD antibody assays, ELISpot assay, and intracellular cytokine staining
assay. Overall, the methods were considered acceptable and fit for purpose.
Study COV001
Initial data described hereafter were published in Lancet 2020; 396: 467–78 (Folegatti PM et
al); Nat Med. 2020 (Ewer K et al). Overall, 88 healthy adults aged 18–55 years were
randomly assigned to receive ChAdOx1 nCoV-19 (AZD1222) at a dose of 5 × 10¹⁰ viral
particles or MenACWY as a single intramuscular injection. Blood samples were drawn at
days 3, 7, 14, 28, and 56 after vaccination. Ten participants assigned to a non-randomised
group received a two-dose regimen, with the booster vaccine administered 28 days after the
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first dose.
A single dose elicited both humoral and cellular responses against SARS-CoV-2, with a
booster immunisation augmenting neutralising antibody titres. After the booster dose, the
levels of binding and neutralising antibodies were comparable to those of a panel of
convalescent serum samples.
Anti-spike IgG responses at the peak of the response after vaccination (day 28) showed a
polarized IgG1 response, consistent with naturally acquired antibodies against SARS-CoV-2,
as well as an IgG3 response in most vaccinees. A mixed IgG1 and IgG3 response, with low
levels of IgG2 and little detectable IgG4 is consistent with induction of Th1-type human IgG
subclasses (IgG1 and IgG3).
Flow cytometry with intracellular cytokine staining (ICS) of peripheral blood mononuclear
cells (PBMCs) stimulated with peptides spanning the S1 and S2 subunits of SARS-CoV-2
spike protein demonstrated antigen-specific cytokine secretion from CD4+, and to a slightly
lesser extent CD8+, peaking 14 days after the vaccine dose. CD4+ responses were heavily
biased toward secretion of Th1 cytokines (IFN-γ and IL-2) rather than Th2 (IL-5 and IL-13).
Based on this finding, it was decided to further investigate a prime-boost regimen of two
doses of 5 × 10¹⁰ viral particles (20 subjects) or one dose of 5 × 10¹⁰ viral particles followed
by one half dose (2.5 × 10¹⁰ viral particles) administered 8 weeks apart. These data were
published in Nat Med 2020 (Barrett et al).
They confirmed that a second vaccine dose enhances both the titre and the functionality of
the antibody response measured 28 days after the booster dose. Fc-mediated anti-spike
antibody effector functions, which may have a role in the protection against COVID-19, were
in the same range or higher than those measured in sera from convalescent patients. A
booster dose of vaccine induced stronger antibody responses than a dose-sparing half dose
boost, although the magnitude of T cell responses did not increase with either boost dose.
Study COV002 – Phase II part
These data were published in Lancet 2020 Nov 18:S0140-6736(20)32466-1 (Ramasamy MN
et al). The study aimed at evaluating the impact of age on antibody and T cell responses to
the vaccine. Three different age groups of subjects, 18-55, 56-69, and ≥ 70 years,
respectively, received two doses of vaccine, 4-6 weeks apart. After a change in manufacturer,
it was found that the first dose received by these subjects contained about half the intended
number of viral particles; for the second dose, it was decided to administer the same lower
dose and to recruit three other similar age groups that would receive two doses of the
intended amount (5 × 10¹⁰) of viral particles.
The median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar
across the three age cohorts, and likewise, the neutralising antibody titres. The antibody
response was generally comparable after the first dose and at its peak, 14 days after the
booster dose, but tended to be slightly lower with the lower dose regimen compared to the
standard dose regimen at day 56. T-cell responses peaked at day 14 after a single standard
dose and did not increase significantly after the boost vaccination, with no trend according to
dose or age.
In this study, the antibody response to the viral vector was also investigated. Anti-ChAdOx1
neutralising titres increased in all groups to similar levels but were not increased further after
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a boost dose of vaccine at day 28. A weak negative correlation was found between anti-
ChAdOx1 levels before the booster dose and the anti-spike IgG response to the booster dose.
Pooled analysis (COV001, -002, -003, -005)
The immune response to vaccination was assessed 28 days after the first and second doses in
a subset of the trial subjects. Subgroup analyses were conducted by baseline serostatus
(positive/negative), by age (18-64/ ≥ 65 years), by country (UK/Brazil/South Africa), and
comorbidity (yes/no). A proportion of vaccines received a lower priming dose and the
standard booster dose (LDSD) while the majority received two standard doses (SDSD). The
results were presented overall (SDSD + LDSD) and in the two subsets (LDSD and SDSD).
The rate of seroconversion (≥4-fold increase from baseline) by S-binding antibodies was
≥ 98% at 28 days after the first dose and > 99% at 28 days after the second dose for
seronegative participants at baseline. The rate of seroconversion with a live neutralisation
assay was high (> 80%) at 28 days after the first dose and > 99% at 28 days after the second
dose for seronegative participants.
For seronegative participants at baseline, an increase in S-binding antibodies was observed at
28 days after the first dose with a notable further increase at 28 days following the second
dose. Of note, baseline seropositive participants also had increased S-binding responses after
the first dose, but in contrast to the baseline seronegative group, antibody levels were not
further increased by the second dose, which is consistent with an ‘immune plateau’ noted
with other vaccines.
Geometric mean titres (GMT) for S-binding antibodies in the SDSD subgroup were
numerically higher after the first dose compared with the GMT for the LDSD subgroup.
Following the second dose, GMT further increased for both regimens, with an apparent
higher GMT for the LDSD regimen. Similar results were observed for the other antibody
assays.
Table 2: SARS-CoV-2 S-binding antibody levels by serostatus at baseline
SDSD + LDSD
SDSD
LDSD
Subgroup
Timepoint Statistic
AZD1222
Control
AZD1222
AZD1222
SEROSTATUS
N
1655
1197
1356
299
Seronegative
Post Dose 1 n / Nsub
885 / 1617
704 / 1166
817 / 1320
68 / 297
GMT
8156.07
56.85
8386.46
5836.18
(95% CI)
(7563.3, 8795.3)
(51.6, 62.6)
(7758.6, 9065.1)
(4340.4, 7847.4)
Post Dose 2 n / Nsub
886 / 1617
705 / 1166
819 / 1320
67 / 297
GMT
30206.20
62.70
29034.74
48986.76
(95% CI)
(28271.0, 32273.9)
(56.3, 69.8)
(27118.2, 31086.7)
(38483.3, 62357.0)
Seropositive
Post Dose 1 n / Nsub
29 / 38
28 / 31
28 / 36
1 / 2
GMT
178522.42
7303.99
175120.84
305936.00
(95% CI)
(123872.3, 257283.1) (3307.9, 16127.4) (120096.9, 255354.8)
(NE, NE)
Post Dose 2 n / Nsub
29 / 38
25 / 31
28 / 36
1 / 2
GMT
114488.67
8296.39
112978.13
166062.00
(95% CI)
(74664.2, 175554.8) (4233.6, 16258.1) (72553.8, 175925.4)
(NE, NE)
In the SDSD group, after starting from similar immune responses to the first dose there is a
clear trend that longer dose intervals are associated with higher responses induced by the
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second dose. The same pattern is reflected in the nAb responses. When comparing SDSD and
LDSD groups with the same dose interval, the immune response after the second dose is
similar. Given that the median dose interval in the LDSD group was 12 weeks compared with
5 weeks in the SDSD group in Brazil and 10 weeks in the SDSD group in the UK, these data
suggest that the higher levels of immunogenicity engendered in the LDSD group are
influenced more by interval than by dose level.
Table 3: SARS-CoV-2 S-binding antibody levels by dose level and interval (seronegative at
baseline)
SDSD
LDSD
AZD1222
AZD1222
< 6 wks
6-8 wks
9-11 wks
≥ 12 wks
< 6 wks
6-8
9-11 wks
≥ 12 wks
wks
Visit
Window
Statistic
N=677
N=239
N=169
N=235
N=3
-
N=126
N=168
Baseline
N
481
137
110
154
3
NA
30
35
GMT
60.51
58.02
48.79
52.98
50.92
NA
64.09
52.42
95% CI
(54.1,
(46.3,
(39.6,
(44.4,
(3.9,
NA
(40.4,
(37.7,
for GMT
67.7)
72.6)
60.1)
63.2)
669.2)
101.6)
72.9)
Min,
16.5,
16.5,
16.5,
16.5,
16.5,
NA
16.5,
16.5,
Max
71694.0
7228.0
4497.0
827.0
127.0
565.0
304.0
Day 28
N
479
99
87
152
3
NA
30
35
post the
GMT
8734.08
7295.54
7492.98
8618.17
7496.44
NA
4803.21
6750.27
first dose
95% CI
(7883.1,
(5857.4,
(5885.1,
(7195.4,
(1461.4,
NA
(3255.7,
(4184.6,
for GMT
9676.9)
9086.7)
9540.2)
10322.3)
38454.7)
7086.4)
10889.0)
Min,
16.5,
426.0,
46.0,
93.0,
3922.0,
NA
268.0,
51.0,
Max
126108.0
84533.0
82133.0
263135.0
14622.0
35010.0
85889.0
Day 28
N
443
116
106
154
3
NA
29
35
post the
GMT
22222.73
24363.10
34754.10
63181.59
22121.36
NA
36928.89
66274.91
second
dose
95% CI
(20360.5,
(20088.5,
(30287.2,
(55180.1,
(8547.7,
NA
(24509.6,
(49546.6,
for GMT
24255.3)
29547.3)
39879.8)
72343.4)
57250.2)
55641.2)
88651.1)
Min,
101.0,
40.0,
3590.0,
4612.0,
14411.0,
NA
3713.0,
6456.0,
Max
178580.0
276501.0
579194.0
767654.0
30100.0
559449.0
481664.0
High seroconversion rates by S-binding antibodies were observed in older adults (≥65 years)
after the first SD (97.8% [N=136, 95% CI: 93.7; 99.5]) and the second SD (100.0% [N=111,
95% CI: 96.7; NE]). The GMT for S-binding antibodies were lower in adults ≥ 65 years of
age than in younger adults after both the first dose and second dose. Similarly, nAb
(pseudoneutralisation) GMTs were lower in the older adults. These data differ from those of
Phase II in that the sample size is larger and draws from a broader population that includes
older adults with comorbidities. Furthermore, the majority of participants ≥ 65 years old had
a dose interval of <6 weeks, which may have contributed to the lower titres observed after the
second dose.
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Table 4: SARS-CoV-2 nAbs Levels (by Pseudoneutralisation Assay) by Age (seronegative
at baseline)
LDSD + SDSD
SDSD
LDSD
Subgroup
Timepoint
Statistic
AZD1222
Control
AZD1222
AZD1222
Age 18-64
Post Dose 1
n / Nsub
645 / 1373
522 / 994
500 / 1104
145 / 269
GMT
58.124
20.374
59.026
55.120
(95% CI)
(52.69, 64.12)
(19.99, 20.76)
(52.87, 65.90)
(44.35, 68.51)
Post Dose 2
n / Nsub
651 / 1373
501 / 994
497 / 1104
154 / 269
GMT
181.790
21.487
173.708
210.528
(95% CI)
(166.36, 198.66) (20.67, 22.33) (156.52, 192.78) (178.31, 248.57)
Age ≥65
Post Dose 1
n / Nsub
75 / 244
77 / 172
75 / 216
-
GMT
37.103
21.105
37.103
-
(95% CI)
(29.26, 47.05)
(18.96, 23.49)
(29.26, 47.05)
-
Post Dose 2
n / Nsub
52 / 244
54 / 172
52 / 216
-
GMT
109.212
21.066
109.212
-
(95% CI)
(77.58, 153.73)
(18.98, 23.38)
(77.58, 153.73)
-
IV.4 Clinical efficacy
A pooled efficacy analysis, justified by the similar design of the four COV studies, has been
conducted to support the use of AZD1222 to immunise adult subjects against COVID-19.
Methods
Study participants
Healthy adults, with no history of laboratory confirmed COVID-19 were enrolled in the
studies. The main other exclusion criteria were subjects with immunodeficiencies or on
chronic immunosuppressant therapy; subjects with history of angioedema or anaphylaxis;
subjects with severe and/or uncontrolled cardiovascular disease, respiratory disease,
gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological
illness (mild/moderate well controlled comorbidities are allowed); pregnancy, lactation or
intention to become pregnant during the study (continuous effective contraception was
required during the course of the study). Seasonal influenza and pneumococcal vaccinations
were allowed with an interval of least 7 days before/after the study vaccine in some studies
(otherwise 30 days).
Statistical analysis
The primary endpoint was the incidence of SARS-CoV-2 virologically-confirmed COVID-19
occurring ≥ 15 days after the second vaccine dose. COVID-19 cases were PCR-confirmed
with at least one of the following symptoms: objective fever (defined as ≥ 37.8 °C), cough,
shortness of breath, anosmia, or ageusia, and confirmed by an adjudication committee.
The statistical analysis of vaccine efficacy (VE) used a Poisson regression model with robust
variance to estimate the relative risk (RR) of the incidence of cases in the AZD1222 and
control groups. The model contained the terms of study code, treatment group, and age group
at randomisation (18-55 years, 56-69 years, and ≥ 70 years). The logarithm of the period at
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risk for primary endpoint was used as an offset variable in the model to adjust for participants
having different follow-up times during which the events occur.
VE, which is the incidence of infection in the vaccine group relative to the incidence of
infection in the control group expressed as a percentage, was calculated as VE = 1- relative
risk. The VE, and its corresponding 2-sided (1-α) % confidence interval (CI), was estimated
from the model.
One interim analysis and a primary analysis were planned. For an individual study to be
included in the pooled analysis of efficacy, a minimum of 5 primary endpoint defined cases
had to be accrued. The analyses were to be triggered based on counts of COVID-19 cases
that occurred ≥ 15 days after the second dose in participants who were randomised between
SDSD and control. The interim analysis was triggered when at least 53 COVID-19 cases
fulfilling the criteria above had occurred. The primary analysis would have been triggered
when 105 COVID-19 cases had occurred. While the analyses were triggered by the number
of cases in participants who received SDSD, cases in participants who received LDSD were
also to be included for the analysis of the primary endpoint. This was estimated to provide an
additional 10 and 20 cases at the interim and primary analysis respectively. A gamma alpha-
spending function was used to control the overall Type 1 error at 5%.
The combined analysis was to be considered positive if the alpha adjusted confidence interval
at either analysis had a lower bound > 20%. With assumptions of a true VE of 60% a total of
125 cases provides 96% power to achieve the pre-specified success criterion. Under the same
assumption this number of events gives 83% power to achieve a confidence interval lower
bound > 30%.
The main secondary endpoints included severe COVID-19, defined as ≥ grade 6 in the WHO
clinical progression scale, hospitalisation, and asymptomatic SARS-CoV-2 infection, defined
as PCR-confirmed SARS-CoV-2 infection and no symptom record.
The primary analysis was based on the SDSD + LDSD Seronegative for Efficacy Analysis
Set, i.e., randomised participants who had received LDSD or SDSD, were seronegative at
baseline, and had follow up data ≥ 15 days after the second dose.
Results
An interim analysis was conducted with a data cut-off date of 04 November 2020. Studies
COV001 and COV005 were excluded as they had fewer than 5 cases eligible for the primary
endpoint: 1 case and 2 cases, respectively. All 3 of the cases were in the control group.
Due to the rapid accumulation of cases prior to database cut-off, 98 cases from participants
randomised between SDSD and control were included in the interim analysis. The alpha level
for the interim analysis calculated from the gamma (-2.5) alpha-spending function was 4.16%
based the actual number of SDSD cases at the interim, meaning inferences on the primary
endpoint were made using 95.84% confidence intervals. Whilst alpha was determined based
on the 98 cases from participants who received SDSD, the primary analysis was prespecified
to include participants who received either LDSD or SDSD (131 cases).
Study population
The efficacy population included a total of 11,636 individuals, 5807 in the test group and
5829 in the control group.
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The disposition of the participants for the efficacy analysis is summarised below.
The dosing schedule and baseline characteristics of the primary analysis set are summarised
hereafter.
Table 5: Dosing intervals (SDSD + LDSD Seronegative for Efficacy Analysis Set)
AZD1222
Control
Parameter
(N = 5807)
(N = 5829)
Dose schedule n(%)
< 6 weeks
1702 (29.3)
1698 (29.1)
6-8 weeks
568 (9.8)
527 (9.0)
9-11 weeks
1444 (24.9)
1488 (25.5)
12+ weeks
2093 (36.0)
2116 (36.3)
Table 6: Demographics (SDSD + LDSD Seronegative for Efficacy Analysis Set)
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Table 7: Baseline characteristics (SDSD + LDSD Seronegative for Efficacy Analysis Set)
The age in the primary analysis population ranged from 18 to 88 years, with a median of 40
years; 88% of the population were adults between 18 and 55 years of age, 8% between 55
and 69 years, and 4% ≥ 70 years. The population included a majority of female subjects
(61%) and a vast majority of White subjects (83%) with 4% of Asian and 4% of Black
people. The proportion of subjects with comorbidities was substantial (36%): obesity (20%);
cardiovascular disease (11%), mainly hypertension (5%); respiratory disease (12%), mainly
asthma (8%); and diabetes (2%).
Primary efficacy endpoint
Out of the 131 COVID-19 cases, 30 were reported in the vaccine group and 101 in the
placebo group. The point estimate for VE was 70.4% with a 95.84% confidence interval
ranging from 54.8 to 80.6%. The pre-specified criterion for study success was met; the lower
bound of the 95.84% confidence interval was above 20%. The point estimate was above 50%
and the confidence interval lower bound above 30%, so efficacy was also shown in line with
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the target profile outlined by WHO for COVID-19 vaccines.
Table 8: Vaccine efficacy for incidence of first SARS-CoV-2 virologically-confirmed
COVID-19 occurring ≥ 15 days post second vaccine dose in participants seronegative at
baseline
Participants with events
AZD1222
Control
VE
95.84% CI
N
n (%)
N
n (%)
(%)
(%)
Primary endpoint
5807
30 (0.52)
5829
101 (1.73)
70.42
(54.84, 80.63)
Efficacy was also shown if only the subgroup of participants randomised between SDSD and
control were considered (VE=62.10%, 95.84% CI [39.96, 76.08]). In the subgroup
randomised between LDSD and control, VE was 90.05%, 95.84% CI (65.84, 97.10).
The results were consistent in the subgroup of participants with a comorbidity at baseline,
where a comorbidity is defined as BMI ≥ 30 kg/m2, cardiovascular disorder, respiratory
disease or diabetes (VE=73.4%, 95% CI [48.5, 86.3]), and in the UK alone (VE=73.5%, 95%
CI [55.5, 84.2]).
There is limited information available on efficacy in participants aged 65 or over, although
there is nothing to suggest lack of protection. In this subpopulation, there were only two
COVID-19 cases in the primary analysis. When considering all cases from dose 1, there were
2 cases on AZD1222 compared to 8 on control (VE=76%), although this result was
associated with a wide confidence interval.
Only one COVID-19 case (in the control group) was reported in participants seropositive at
baseline.
Severe cases and hospitalisations
There was only 1 severe COVID-19 case in the primary efficacy analysis (from 15 days after
dose 2) in the control group. Even considering all cases from dose 1 there were only 2 severe
cases, both in the control group.
There were 5 hospitalisations in the primary efficacy analysis, all on control. Considering all
cases from dose 1, there were 2 hospitalisations in the AZD1222 group and 16 in the control
group providing some evidence of an effect of the vaccine on COVID-19-related
hospitalisations with a CI lower bound above 30% (VE=87.59%; 95% CI 46.03, 97.15). Both
hospitalisations in the AZD1222 group were before 22 days after dose 1, as were 7 of the 16
in the control group. The two cases of hospitalisation in the AZD1222 group occurred on
days 1 and 10 post vaccination.
Asymptomatic cases
Participants in the COV002 study had weekly self-swabs using the central NHS Pillar 2
testing mechanism. Analyses including asymptomatic cases demonstrated that the overall
incidence of infections was decreased, not just the incidence of symptomatic COVID-19,
thereby suggesting an effect on transmission as well.
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Table 9: Vaccine efficacy for incidence of first SARS-CoV-2 symptomatic or symptomatic
infection occurring ≥ 15 Days post second vaccine dose in participants seronegative at
baseline
Participants with events
AZD1222 (N=3744)
Control (N=3804)
VE
95.84% CI
n (%)
n (%)
(%)
(%)
Symptomatic
18 (0.48)
68 (1.79)
73.52
(55.50, 84.24)
Asymptomatic
29 (0.77)
40 (1.05)
Total
47 (1.26)
108 (2.84)
56.46
(38.74, 69.05)
Onset of protection
The early onset of protection is illustrated in the figure below, which displays cumulative
incidence for the first COVID-19 occurrence after Dose 1 among all vaccinated participants.
Disease incidence is similar in the vaccine and placebo arms until approximately 21 days
after Dose 1, at which point the curves diverge, with cases accumulating at a faster rate in the
control group compared to the AZD1222 group.
Figure 1: Cumulative incidence plot for time to first SARS-CoV-2 virologically-confirmed
COVID-19 occurring post first vaccine dose
Protection after the first vaccine dose
Exploratory analyses were conducted to investigate whether protective immunity was
induced by the first dose and what the duration of protection was. The follow-up time began
at 22 days after the first dose and was censored at the time of the second dose. Results
indicated that the first dose provided protective immunity at least until 12 weeks.
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Table 10: Vaccine efficacy for incidence of first SARS-CoV-2 virologically-confirmed
COVID-19 occurring post first dose + 22 Days and before second dose of vaccine
Participants with events
AZD1222
Control
VE
95% CI
N
n (%)
N
n (%)
(%)
Cases to Week 12
7998
12 (0.15)
7982
44 (0.55)
73.00
(48.79, 85.76)
Effect of dose interval on VE ≥ 15 days after dose 2
The dataset in which efficacy of a two-dose regimen had been demonstrated contained data
over a wide range of dose intervals (4 to 26 weeks): 29.3% were < 6 weeks, 34.7% were 6-
11 weeks, and 36.0% were ≥ 12 weeks.
Subgroup analyses were conducted of vaccine efficacy by dosing interval. In line with
immunogenicity data where increases in the binding and neutralising antibody responses
were observed with increased dosing interval, efficacy was demonstrated with more certainty
for dose intervals from 8-12 weeks. For the subgroup with dosing interval 8-11 weeks, VE
was 72.85%, 95% CI (43.45, 86.97), for the subgroup with dosing interval > 11 weeks, it was
81.90%, 95% CI (59.93, 91.90). Exploratory subgroup analyses showed vaccine efficacy
around 80% for longer dosing intervals, but data were limited and estimates were associated
with wide confidence intervals.
Efficacy of using an initial half dose
A proportion of participants received a half dose of vaccine for their first administration.
Participants were not randomised between receiving a half dose (LD) or the standard dose
(SD) for the first dose, and because of other confounding factors, it is not possible to
confidently compare results from the two different dosing regimens. Such factors include
differences in the dosing interval (generally longer for LD), population studied (younger
population for LD), country (UK only for LD) and stage of pandemic (participants receiving
LD were initially dosed at a time when the incidence of cases in the UK was low). There is
not persuasive evidence of a real difference in VE between SD and LD, and the apparent
difference is considered more likely to be the result of confounding factors, especially the
dosing interval. Conclusions on vaccine efficacy were primarily based on the pre-planned
primary analysis including both SD and LD participants, and not on subgroups.
IV.5 Clinical safety
Safety population and exposure
The any dose safety analysis set comprises 23,745 subjects, pooled from the 4 multicentre
trials, that received at least one dose of study intervention up to the data cut-off 04 November
2020. Of these, 12021 received at least one dose of AZD1222; 8266 received 2 doses of
which 6568 were SDSD. Approximately one third of subjects each had a dose schedule in the
range of < 6 weeks, 6 to 11 weeks, or ≥ 12 weeks.
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Table 11: Study drug exposure (any dose safety analysis set)
Parameter
AZD1222
Control
(N = 12021)
(N = 11724)
Dose levela n (%)
LDSD
1516 (12.6)
1472 (12.6)
LDLD
127 (1.1)
69 (0.6)
SDSD
6568 (54.6)
6472 (55.2)
SDLD
55 (0.5)
36 (0.3)
LD
305 (2.5)
281 (2.4)
SD
3450 (28.7)
3394 (28.9)
Total
12021
11724
Number of doses
1
3755 (31.2)
3675 (31.3)
n (%)
2
8266 (68.8)
8049 (68.7)
Total
12021
11724
Dose schedule n (%)
< 6 weeks
3412 (41.3)
3234 (40.2)
6-8 weeks
680 (8.2)
604 (7.5)
9-11 weeks
1558 (18.8)
1550 (19.3)
12+ weeks
2616 (31.6)
2661 (33.1)
Total
8266
8049
SD = Standard dose; LD = Low dose
a Dose level of control group is decided by the dose level of the corresponding vaccine group
Total row includes the number of participants with non-missing data for the corresponding characteristic and was used as the
denominator for calculating percentages for all categories
The median duration of follow-up in the AZD1222 group was 105 days post-dose 1, and 62
days post-dose 2.
The baseline demographics and characteristics of the safety population are presented below
in Table 12. Overall these were balanced between the 2 study groups.
Table 12: Baseline demographics and characteristic (any dose safety analysis set)
Characteristic
Statistics
AZD1222
Control
Total
(N = 12021)
(N = 11724)
(N = 23745)
Age group at
18 to 64 years
10852 (90.3)
10783 (92.0)
21635 (91.1)
screening, n (%)
≥ 65 years
1169 (9.7)
940 (8.0)
2109 (8.9)
18 to 55 years
9802 (81.5)
9788 (83.5)
19590 (82.5)
56 to 69 years
1398 (11.6)
1296 (11.1)
2694 (11.3)
≥ 70 years
821 (6.8)
639 (5.5)
1460 (6.1)
Sex, n (%)
Female
6711 (55.8)
6550 (55.9)
13261 (55.8)
Male
5310 (44.2)
5171 (44.1)
10481 (44.1)
Transgender
0
1 (<0.1)
1 (<0.1)
Missing
0
2 (<0.1)
2 (<0.1)
Racea, n (%)
White
9081 (75.5)
8887 (75.8)
17968 (75.7)
Asian
425 (3.5)
371 (3.2)
796 (3.4)
Black
1211 (10.1)
1210 (10.3)
2421 (10.2)
Other
798 (6.6)
752 (6.4)
1550 (6.5)
Mixed
489 (4.1)
483 (4.1)
972 (4.1)
Unknown
16 (0.1)
17 (0.1)
33 (0.1)
Missing
1 (<0.1)
4 (<0.1)
5 (<0.1)
BMI category n
<30 kg/m2
9305 (77.4)
8998 (76.7)
18303 (77.1)
(%)
≥30 kg/m2
2308 (19.2)
2318 (19.8)
4626 (19.5)
Missing
408 (3.4)
408 (3.5)
816 (3.4)
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Serostatus at Day 0
Negative
11445 (95.2)
11139 (95.0)
22584 (95.1)
n (%)
Positive
345 (2.9)
373 (3.2)
718 (3.0)
Missing
231 (1.9)
212 (1.8)
443 (1.9)
Cardiovascular
Yes
1540 (12.8)
1435 (12.2)
2975 (12.5)
disorder n (%)
No
10477 (87.2)
10287 (87.7)
20764 (87.4)
Missing
4 (<0.1)
2 (<0.1)
6 (<0.1)
Respiratory disease
Yes
1253 (10.4)
1229 (10.5)
2482 (10.5)
n (%)
No
10764 (89.5)
10493 (89.5)
21257 (89.5)
Missing
4 (<0.1)
2 (<0.1)
6 (<0.1)
Diabetes n (%)
Yes
39 (2.8)
290 (2.5)
629 (2.6)
No
11142 (92.7)
10898 (93.0)
22040 (92.8)
Not collectedb
534 (4.4)
533 (4.5)
1067 (4.5)
Missing
6 (<0.1)
3 (<0.1)
9 (<0.1)
Comorbidity at
Yes
4293 (35.7)
4217 (36.0)
8510 (35.8)
baselinec n (%)
No
6977 (58.0)
6764 (57.7)
13741 (57.9)
Missing
751 (6.2)
743 (6.3)
1494 (6.3)
Current smoker n
Yes
991 (8.2)
1034 (8.8)
2025 (8.5)
(%)
No
11026 (91.7)
10682 (91.1)
21708 (91.4)
Missing
4 (<0.1)
8 (0.1)
12 (0.1)
aEach race category counts participants who selected that category. Arab is counted under white
b COV001 does not collect this information; participants are counted in category ‘Not collected’
cCormorbidy at baseline = Yes if any comorbidity at baseline (BMI ≥30 kg/m2, cardiovascular disorder, respiratory disease
or diabetes) is yes.
There were more females (56%) than males. Twenty-four percent of subjects were from
ethnic minority backgrounds. The majority of subjects in the safety population were in the
younger age group 18-55 years (83%). Of the 1169 (9%) subjects in the AZD1222 group that
were ≥65 years of age, 668 received 2 doses, of which 586 were SDSD. Overall three percent
of subjects were seropositive at baseline, the percentage was highest in South Africa (14.8%)
and much lower in Brazil (2.3%) and the UK (1.6%). Just over one third of subjects had at
least one comorbidity at baseline. The most common comorbidities were obesity,
hypertension and asthma.
Local and systemic reactogenicity
Solicited adverse events (AEs) were collected via a diary card for 7 days following each
vaccination in a subset of 6,137 subjects, mainly from the UK and South Africa. Of these,
5145 were in the Dose 1 SD subset (Table 13). There were some differences in how
reactogenicity data was collected in the South African trial, in particular, solicited AEs were
collected until Day 6 instead of day 7, there was no grade 4 severity option and fewer AE
terms were solicited.
Table 13: Reactogenicity population by subgroup (Dose 1 SD reactogenicity subset)
Subpopulation
Number of Participants evaluated for solicited AEs
AZD1222 (N=2648)
Control (N=2497)
Country
UK
1636
1497
Brazil
100
99
South Africa
912
901
Comorbidity
Yes
822
775
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No
1393
1308
Serostatus at baseline
Positive
160
179
Negative
2387
2224
Age
18-64 years
2245
2172
≥ 65 years
403
325
In the AZD1222 Dose 1 SD group, 2580 subjects were evaluated for solicited AEs after
vaccination 1 and 1662 subjects after vaccination 2, of which 400 and 266 respectively were
≥65 years of age. A slightly higher percentage of subjects were seropositive at baseline
compared with the overall safety population, which likely reflects the higher number of
subjects that were seropositive at baseline in South Africa.
An overall summary of solicited AEs in the dose 1 SD safety analysis set is provided in table
14 below.
Table 14: Overall summary of solicited AEs (Dose 1 SD safety analysis set)
Days 0 to 7 After Any
Days 0 to 7 After First
Days 0 to 7 After
Dose
Dose
Second Dose
Participants*
AZD1222
Control
AZD1222
Control
AZD1222
Control
(N=10069) (N=9902) (N=10069) (N=9902) (N=10069) (N=9902)
Evaluated for solicited AEs, n
2648
2497
2580
2425
1662
1526
Any solicited AE, n (%)
2277
1791
2161
1637
1026
722
(86.0)
(71.7)
(83.8)
(67.5)
(61.7)
(47.3)
Any solicited local AE, n (%)
1979
1258
1839
1117
778
456
(74.7)
(50.4)
(71.3)
(46.1)
(46.8)
(29.9)
Any ≥ Grade 3 severity solicited
252 (9.5)
138 (5.5)
210 (8.1)
112 (4.6)
70 (4.2)
38 (2.5)
local AE, n (%)
Any solicited systemic AE, n
1932
1488
1817
1320
741
545
(%)
(73.0)
(59.6)
(70.4)
(54.4)
(44.6)
(35.7)
Any ≥ Grade 3 severity solicited
221 (8.3)
63 (2.5)
192 (7.4)
41 (1.7)
37 (2.2)
27 (1.8)
systemic AE, n (%)
*Participants with multiple events in the same category are counted once in that category. Participants with
events in more than 1 category are counted once in each of those categories. Denominators used in the
percentage calculations are the number of participants “Evaluated for solicited AEs”.
Solicited AEs were assessed daily after vaccination from Day 0 to Day 6 for COV0005 and to Day 7 for rest of
studies via e-diary or diary card.
No grade 4 severity option for events collected in COV005. Pain and warmth, malaise, nausea and vomiting
were not assessed for COV005. Induration, feverishness and chills did not include COV005 since no severity
grading collected. For redness, swelling and fever severity grading was derived based on reported value.
Bruising only collected for COV005.
Overall, 86% of subjects in the AZD1222 group (Days 0-7 after any vaccination) experienced
at least one solicited AE compared to 72% in the control group. The majority of solicited
AEs were mild or moderate. Ten percent of subjects in the AZD1222 group experienced at
least one grade ≥3 local solicited AE and 8% at least one grade ≥3 systemic solicited event
compared with 6% and 3% in the control group, respectively. Solicited AEs were milder and
reported less frequently after the second dose compared with the first.
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Table 15: Summary of Local Solicited Adverse Events (Dose 1 SD safety analysis set) –
Days 0-7 after any vaccination
Local solicited Adverse Events/
AZD1222
Control
Severity
(N = 10069)
(N = 9902)
Participants with any local solicited AE
1979 (74.7)
1258 (50.4)
1: Mild
1382 (52.2)
967 (38.7)
2: Moderate
345 (13.0)
153 (6.1)
3: Severe
252 (9.5)
138 (5.5)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2497
Pain
941 (54.2)
586 (36.7)
1: Mild
776 (44.7)
522 (32.7)
2: Moderate
156 (9.0)
61 (3.8)
3: Severe
9 (0.5)
3 (0.2)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
Tenderness
1688 (63.7)
987 (39.5)
1: Mild
1398 (52.8)
902 (36.1)
2: Moderate
258 (9.7)
78 (3.1)
3: Severe
32 (1.2)
7 (0.3)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2497
Redness
368 (14.0)
218 (8.8)
1: 2.5-5 cm
176 (6.7)
123 (5.0)
2: 5.1-10 cm
67 (2.6)
36 (1.5)
3: >10 cm
125 (4.8)
59 (2.4)
4: Necrosis or ED
0 (0.0)
0 (0.0)
Total participants evaluated
2626
2480
Warmth
308 (17.7)
232 (14.5)
1: Mild
301 (17.3)
223 (14.0)
2: Moderate
7 (0.4)
9 (0.6)
3: Severe
0 (0.0)
0 (0.0)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
Itch
335 (12.7)
187 (7.5)
1: Mild
272 (10.3)
156 (6.2)
2: Moderate
53 (2.0)
26 (1.0)
3: Severe
10 (0.4)
5 (0.2)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2497
Swelling
262 (10.0)
145 (5.8)
1: 2.5-5 cm and no IwA
96 (3.7)
52 (2.1)
2: 5.1-10 cm or IwA
28 (1.1)
26 (1.0)
3: >10 cm or PDA
138 (5.3)
67 (2.7)
4: Necrosis
0 (0.0)
0 (0.0)
Total participants evaluated
2626
2481
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Local solicited Adverse Events/
AZD1222
Control
Severity
(N = 10069)
(N = 9902)
Induration
164 (9.4)
136 (8.5)
1: 2.5-5 cm and no IwA
66 (3.8)
52 (3.3)
2: 5.1-10 cm or IwA
27 (1.6)
27 (1.7)
3: >10 cm or PDA
71 (4.1)
57 (3.6)
4: Necrosis
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
Bruising
158 (17.3)
60 (6.7)
1: <10 mm
123 (13.5)
48 (5.3)
2: 10-25 mm
28 (3.1)
8 (0.9)
3: >25 mm
7 (0.8)
4 (0.4)
Total participants evaluated
912
901
Abbreviations: AE = Adverse Event, ED = Exfoliative dermatitis; ER=Emergency department; IwA = Interfere with activity; PDA =
Prevent daily activity.
Total participants evaluated was used as denominator in the percentage calculations.
If a participant reported more than one occurrence of the same event, the event of greatest intensity was included in the analysis.
Solicited AEs were assessed daily after vaccination from Day 0 to Day 6 for COV005 and to Day 7 for rest of studies via e-diary or diary
card.
No grade 4 severity option for events collected in COV005. Pain and warmth were not assessed for COV005. Induration did not include
COV005 as grading scale was not compatible.
For redness and swelling, severity grading was derived based on reported value. Bruising only collected for COV005.
The most frequently reported local solicited AEs in the AZD1222 Dose 1 SD group after any
vaccination were tenderness (64%) and pain (54%). The most comment events of Grade ≥3
were swelling (5%) and redness (5%). No grade 4 AEs were reported.
Table 16: Summary of Systemic Solicited Adverse Events (Dose 1 SD safety analysis set) –
Days 0-7 after any vaccination
Systemic Solicited Adverse Events/
AZD1222
Control
Severity
(N = 10069)
(N = 9902)
Participants with any systemic solicited AE
1932 (73.0)
1488 (59.6)
1: Mild
973 (36.7)
1022 (40.9)
2: Moderate
738 (27.9)
403 (16.1)
3: Severe
220 (8.3)
63 (2.5)
4: ER or hospitalization
1 (0.0)
0 (0.0)
Total participants evaluated
2648
2497
Fever
208 (7.9)
31 (1.2)
1: 38.0 - 38.4°C
122 (4.6)
18 (0.7)
2: 38.5 - 38.9°C
67 (2.5)
6 (0.2)
3: 39.0 - 40°C
18 (0.7)
7 (0.3)
4: >40°C
1 (0.0)
0 (0.0)
Total participants evaluated
2644
2493
Feverishness
583 (33.6)
171 (10.7)
1: Mild
270 (15.6)
153 (9.6)
2: Moderate
252 (14.5)
16 (1.0)
3: Severe
61 (3.5)
2 (0.1)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
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Systemic Solicited Adverse Events/
AZD1222
Control
Severity
(N = 10069)
(N = 9902)
Chills
554 (31.9)
132 (8.3)
1: Mild
278 (16.0)
115 (7.2)
2: Moderate
216 (12.4)
17 (1.1)
3: Severe
60 (3.5)
0 (0.0)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
Joint pain
698 (26.4)
310 (12.4)
1: Mild
492 (18.6)
250 (10.0)
2: Moderate
176 (6.6)
48 (1.9)
3: Severe
30 (1.1)
12 (0.5)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2496
Muscle pain
1164 (44.0)
540 (21.6)
1: Mild
797 (30.1)
452 (18.1)
2: Moderate
317 (12.0)
79 (3.2)
3: Severe
50 (1.9)
9 (0.4)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2496
Fatigue
1407 (53.1)
955 (38.2)
1: Mild
856 (32.3)
704 (28.2)
2: Moderate
466 (17.6)
224 (9.0)
3: Severe
85 (3.2)
27 (1.1)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2497
Headache
1394 (52.6)
975 (39.0)
1: Mild
901 (34.0)
743 (29.8)
2: Moderate
422 (15.9)
209 (8.4)
3: Severe
71 (2.7)
23 (0.9)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
2648
2497
Malaise
768 (44.2)
323 (20.2)
1: Mild
417 (24.0)
252 (15.8)
2: Moderate
285 (16.4)
64 (4.0)
3: Severe
66 (3.8)
7 (0.4)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
Nausea
380 (21.9)
209 (13.1)
1: Mild
291 (16.8)
173 (10.8)
2: Moderate
74 (4.3)
34 (2.1)
3: Severe
15 (0.9)
2 (0.1)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
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Systemic Solicited Adverse Events/
AZD1222
Control
Severity
(N = 10069)
(N = 9902)
Vomiting
29 (1.7)
14 (0.9)
1: Mild
14 (0.8)
8 (0.5)
2: Moderate
9 (0.5)
4 (0.3)
3: Severe
6 (0.3)
2 (0.1)
4: ER or hospitalization
0 (0.0)
0 (0.0)
Total participants evaluated
1736
1596
Abbreviations: AE = Adverse Event, ER=Emergency department.
Total participants evaluated was used as denominator in the percentage calculations.
If a participant reports more than one occurrence of the same event, then the event of greatest intensity is included in the analysis.
Solicited AEs were assessed daily after vaccination from Day 0 to Day 6 for COV005 and to Day 7 for rest of studies via e-diary or diary
card.
No grade 4 severity option for events collected in COV005. Malaise, Nausea and Vomiting were not assessed for COV005. Feverish and
Chills did not include COV005 since no severity grading collected.
For Fever, severity grading was derived based on reported value.
The most frequently reported systemic solicited AEs in the AZD1222 Dose 1 SD group after
any vaccination were fatigue (53%) and headache (53%). The most comment events of Grade
≥3 were malaise (4%) and chills (4%). One grade 4 event of fever >40° was reported after
vaccination 1.
All of the local and systemic solicited events were reported more commonly in the AZD1222
Dose 1 SD group compared with the control, including in the UK where active control was
used for both doses, and are considered ADRs for AZD1222. This is reflected in the
Information for Healthcare Professionals and the Information for UK recipients.
The incidence of subjects with at least one local or systemic solicited event after any
vaccination was highest on day 1 following vaccination, decreasing to 4% and 13 %,
respectively, by day 7. The most common systemic solicited AEs at day 7 were fatigue,
headache and malaise. Only 0.7% and 0.2% of subjects had a local or systemic solicited AE
grade ≥3 at day 7 respectively.
Data on solicited AEs by dosing interval were provided. However, this is difficult to
interpret. Whilst post dose 2 the incidence of solicited AEs appeared lower in subjects with a
dosing window <6 weeks, this pattern was also seen post dose 1 and may reflect potential
differences in the population. No increase in the incidence of local or systemic solicited AEs
≥ grade 3 was observed after vaccination 2 between subjects that had a dosing interval less or
more than 6 weeks.
The number of subjects in the reactogenicity subset that were seropositive at baseline is small
limiting any firm conclusions that can be drawn. Except for a higher rate of subjects with any
≥ grade 3 local solicited AE (15% vs 9%), the incidence of solicited AEs in the dose 1 SD
AZD1222 group was similar in the seropositive and seronegative subjects. No seropositive
subjects reported a grade 4 solicited AE, one grade 4 solicited AE (fever) was reported in the
seronegative group.
With regards to age, the number of subjects evaluated for solicited AEs in the ≥65 years
group are relatively small. Whilst a similar percentage of subjects in the 18-64 years and ≥65
years reported at least one solicited AE, fewer subjects in the ≥65 years reported a local or
systemic solicited AE, or any ≥ grade 3 solicited AE.
Currently there are insufficient data to support a recommendation for use of prophylactic
paracetamol. However, information is included in the Information for Healthcare
Professionals and the Information for UK recipients regarding symptomatic use of
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paracetamol-containing products.
Adverse events
Unsolicited AEs were collected through 28 days post each dose. The overall incidence after
any vaccination with any dose was higher in the AZD1222 group (38%) compared to the
control (28%). However, the overall incidence of unsolicited AEs reported >7 days after any
dose was similar between the 2 groups. Most of the unsolicited AEs were mild to moderate in
severity. The incidence of unsolicited AEs with severity ≥ Grade 3 reported within 28 days
after any dose was low (< 2%) and similar between the 2 groups.
The most frequently reported AEs, occurring in ≥2% of the AZD1222 group, were consistent
with AEs commonly observed following vaccination. These predominantly occurred ≤ 7 days
of any dose. There were no AEs with an incidence ≥ 2% reported > 7 days of any dose.
Adverse event data were evaluated at the preferred term level, and with reference to AE
listings which included information on onset, duration, severity, seriousness and relatedness.
AEs by System Organ Class (SOC) are summarised below:
Table 17: Unsolicited Adverse Events by System Organ Class (Any dose for safety analysis
set)
Number (%) of Participantsa
System Organ Class
AZD1222
Control
(N= 12021)
(N = 11724)
Participants with any unsolicited AE
4539 (37.8)
3266 (27.9)
System Organ Class uncoded
85 (0.7)
78 (0.7)
Infections and infestations
348 (2.9)
364 (3.1)
Neoplasms benign, malignant and unspecified (incl
5 (<0.1)
11 (<0.1)
cysts and polyps)
Blood and lymphatic system disorders
40 (0.3)
46 (0.4)
Immune system disorders
14 (0.1)
16 (0.1)
Metabolism and nutrition disorders
41 (0.3)
34 (0.3)
Psychiatric disorders
66 (0.5)
45 (0.4)
Nervous system disorders
1408 (11.7)
918 (7.8)
Eye disorders
68 (0.6)
49 (0.4)
Ear and labyrinth disorders
42 (0.3)
42 (0.4)
Cardiac disorders
30 (0.2)
21 (0.2)
Vascular disorders
61 (0.5)
59 (0.5)
Respiratory, thoracic and mediastinal disorders
401 (3.3)
422 (3.6)
Gastrointestinal disorders
577 (4.8)
414 (3.5)
Hepatobiliary disorders
1 (<0.1)
3 (<0.1)
Skin and subcutaneous tissue disorders
180 (1.5)
140 (1.2)
Musculoskeletal and connective tissue disorders
1261 (10.5)
627 (5.3)
Renal and urinary disorders
26 (0.2)
25 (0.2)
Pregnancy, puerperium and perinatal conditions
1 (<0.1)
0
Reproductive system and breast disorders
44 (0.4)
35 (0.3)
Congenital, familial and genetic disorders
1 (<0.1)
1 (<0.1)
General disorders and administration site conditions
3049 (25.4)
1759 (15.0)
Investigations
205 (1.7)
115 (1.0)
Injury, poisoning and procedural complications
87 (0.7)
90 (0.8)
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Social circumstances
2 (<0.1)
1 (<0.1)
a Number (%) of participants with AEs, sorted on international order for system organ class. Participants with multiple
events in the same preferred term are counted only once in each of those preferred term. Participants with events in more
than 1 preferred term are counted once in each of those preferred term. Unsolicited AEs summarized from the start of each
dose until Day 28. Unevaluable event is an event with pending query at the time of the interim analysis database lock.
The imbalance in the SOC of
Nervous system disorders was mainly driven by ‘headache’
events, reported by 9.3% subjects after AZD1222 vs 6.1% after control. There were also
imbalances in events of ‘lethargy’ (0.4% vs 0.2%) and ‘somnolence’ (0.3% vs 0.2%) which
are captured by the adverse drug reaction (ADR) ‘fatigue’ (see ‘
General disorders and
administration site conditions below). A slight imbalance was seen in events of ‘dizziness’
(0.6% vs 0.5%) and it is noted that this is a known ADR for the control MenACWY vaccines.
‘Headache’ and ‘dizziness’ are included as ADRs in the Information for Healthcare
Professionals and the Information for UK recipients
In addition, a detailed review of neurological AEs was undertaken which identified the
following neurological cases of interest:
• A new diagnosis of multiple sclerosis in the AZD1222 group. Symptom onset was
10 days after first AZD1222 dose. MRI of the brain and spinal cord demonstrated
multiple lesions. All but one of these lesions were not gadolinium-enhancing
suggesting that most lesions pre-dated the AZD1222 dose.
• A likely case of ‘short segment inflammatory myelitis’ in the AZD1222 group,
although the diagnosis is not certain. Symptom onset was 14 days after second
AZD1222 dose.
Based on the available data, the presence or the absence of a causative association
between the AZD1222 vaccine and these two cases cannot be concluded with
certainty.
• A case of ‘transverse myelitis’ in the control group. Symptom onset was 54 days
after first control dose.
• Six cases of facial paralysis, three in each study group. The three cases in the
AZD1222 group were all one-sided ‘facial nerve palsies’, two of which had features
suggesting they were not related to AZD1222 vaccination (one case is considered
related to chronic suppurative otitis media / mastoiditis, the other occurred 80 days
after vaccination).
• Two cases of trigeminal neuralgia (both in the control group).
These cases and other potential neurological events are covered by the list of adverse events
of special interest (AESIs) previously defined by the MHRA for inclusion as part of the RMP
for any potential COVID-19 vaccine and will be subject to routine and additional
pharmacovigilance measures. In addition, ‘Neuroinflammatory disorders’ is included in the
RMP as an ‘Important potential risk’. Section 4.8 of the HCP information reflects that “
Very
rare events of neuroinflammatory disorders have been reported following vaccination with
COVID-19 Vaccine AstraZeneca. A causal relationship has not been established.’
The imbalance in the SOC of
Gastrointestinal disorders was mainly driven by events of
‘diarrhoea’ (1.3% vs 1.0%), ‘nausea’ (1.9% vs 1.2%) and ‘vomiting’ (0.7% vs 0.4%). In
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addition, an imbalance in events of abdominal pain (0.4% vs 0.3%) and upper abdominal
pain (0.2% vs 0.1%) was seen, particularly ≤7 days post any vaccination. Given the other
ADRs in the gastrointestinal SOC, a relationship with AZD1222 is considered plausible.
‘Diarrhoea’, ‘nausea’, ‘vomiting’ and ‘abdominal pain’ are considered ADRs and are
included in the Information for Healthcare Professionals and the Information for UK
recipients.
The imbalance in the SOC of
Musculoskeletal and connective tissue disorders was mainly
driven by events of ‘arthralgia’ (1.4% vs 0.8%) and myalgia (7.6% vs 3.1%). These are
considered ADRs and are included in the Information for Healthcare Professionals and the
Information for UK recipients
The imbalance in the SOC of
General disorders and administration site conditions was
mainly driven by events of asthenia (2.2% vs 1.1%), chills (3.4% vs 0.9%), fatigue (4.8% vs
2.8%), malaise (2.3% vs 1.3%), pyrexia (7.5% vs 1.9%) and vaccination site pain (10.4% vs
6.5%). With the exception of ‘asthenia’, based on the local and systemic reactogenicity data
these are all considered ADRs and are included in the Information for Healthcare
Professionals and the Information for UK recipients. In view of the similarity of the terms
‘asthenia’ and ‘fatigue’, and given that ‘fatigue’ is included as an ADR with a frequency
designation of ‘very common’, it is acceptable that ’asthenia’ is not included as an ADR. In
addition, an imbalance in cases of ‘influenza-like illness’ (1.0% vs 0.6%) was noted and this
has also been included as an ADR.
The small imbalance in the SOC of
Investigations was mainly driven by events of ‘body
temperature increased’ (0.7% vs 0.1%) which is captured by the listed ADR ‘pyrexia’
(frequency ‘very common’).
Within the SOC
Skin and subcutaneous tissue disorders, 0.4% of subjects in the AZD1222
group reported the event ‘hyperhidrosis’ compared with 0.2% in the control group. The
majority of cases occurred ≤ 7 days post any dosing. The event ‘pruritus’ was reported by
0.2% of cases in both treatment groups. The majority of cases, particularly in the AZD1222
group, occurred ≤ 7 days post any dosing. Pruritus is a listed event for one of the 2 control
MenACWY vaccines used. The event ‘rash’ was reported by 0.2% of cases in both treatment
groups. Rash is a listed event for both of the control MenACWY vaccines used.
‘Hyperhidrosis’, ‘pruritus’ and ‘rash’ have been included as ADRs in the Information for
Healthcare Professionals and the Information for UK recipients
Within the SOC
Blood and lymphatic system disorders, 0.3% of subjects in both treatment
groups reported the event ‘lymphadenopathy’. Lymphadenopathy is known to be associated
with vaccines and is related to the immune response. Lymphadenopathy is a listed event for
one of the 2 control MenACWY vaccines used. Lymphadenopathy has been included as an
ADR in the Information for Healthcare Professionals and the Information for UK recipients.
Within the SOC
Metabolism and nutrition disorders the event ‘decreased appetite’ was
reported by 0.2% subjects in the AZD1222 group and 0.1% in the control group. The
majority of these events occurred ≤ 7 days post any dosing. Decreased appetite is a listed
event for at least one of the 2 control MenACWY vaccines used. Decreased appetite has been
included as an ADR in the Information for Healthcare Professionals and the Information for
UK recipients.
No serious cases of
drug hypersensitivity have been reported with AZD1222 up to the data
cut-off. One case of anaphylaxis was reported, this occurred 63 days after vaccination and
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was considered related to antibiotics. In addition, one event of angioedema was reported 8
days after vaccination and occurred after crab ingestion. One grade 1 AE of drug
hypersensitivity was reported 11 days post vaccination. On the same day the subject reported
a number of local grade 1 reactions and all AEs had a duration of 10 days. A MedDRA SMQ
search of ‘narrow hypersensitivity’ revealed no imbalance in the percentage of subjects with
at least one hypersensitivity AE. This remained the case if events including the listed ADR
‘rash’
were excluded. Hypersensitivity is not considered an ADR at present; however, reports
of hypersensitivity will be kept under review.
A single case of erythema multiforme was reported 4 days post dose 2 in the AZD1222
group. This was grade 2 in severity, considered unlikely related to study medication by the
investigator and was ongoing. However, in view of the proximity to dose 2, erythema
multiforme will also be kept under review.
Subgroup data for unsolicited adverse events were provided by country, age, serostatus and
comorbidity. In both the AZD1222 and control groups, the incidence of unsolicited AEs was
higher in Brazil than in the UK or South Africa. This may in part reflect the fact that only 2%
of the subjects in Brazil had solicited events collected, therefore more subjects may have
reported typical reactogenicity AEs as unsolicited events. There is no indication of a worse
safety profile in subjects aged ≥ 65 years, subjects who were seropositive at baseline or in
subjects with at least one comorbidity.
Serious adverse events
Two deaths were reported in subjects that received AZD1222; one subject died 64 days after
vaccination from
Pneumocystis jirovecii pneumonia, they also had an AE of HIV test
positive, and one subject died 86 days after their second dose of vaccine from metastatic
ovarian cancer. Four deaths occurred in the control group (COVID-19 pneumonia,
craniocerebral injury, injury, and homicide). None of the deaths were considered vaccine-
related by the investigator.
Fewer than 1% of subjects reported a serious adverse event (SAE) and the reporting rate was
balanced between the two study groups (0.7% AZD1222, 0.8% control). There were no clear
imbalances by SOC. The most frequently reported SAEs by SOC were ‘Infections and
Infestations’ (0.1% vs 0.2%) and ‘Injury, poisoning and procedural complications’ (<0.1% vs
0.1%).
Only 5 SAEs were considered related by the investigator, of which 3 were in the AZD1222
group (pyrexia, C-reactive protein increased and transverse myelitis) and 2 were in the
control group (autoimmune haemolytic anaemia, and myelitis). After the data cut-off,
causality for the SAE of CRP increased was updated by the investigator to not treatment
related. The case of pyrexia (40.5°) occurred 2 days after dose 1 of AZD1222. It was
associated with increased sweating, shortness of breath, weakness, and loss of sense of smell
and taste. The event was treated with paracetamol and resolved the same day. The case of
transverse myelitis in the AZD1222 group and of myelitis in the control group are discussed
in the ‘Adverse events’ section above. Overall within the SOC
Nervous system disorders’,
there were 7 SAEs in the AZD1222 group and 4 in the control group.
There were no clinically meaningful imbalances in SAE incidence for any subgroup (country,
age, serostatus or comorbidity).
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Adverse events of special interest
AESI were based on the Brighton Collaborative case definitions (SPEAC 2020), clinical
experience and scientific interest. AESI were grouped under neurological, vascular,
haematological and immunological (including anaphylaxis and vaccine associated enhanced
disease). The incidence of AESI was low and balanced between the two treatment groups.
Table 18: AESI by special interest category (any dose safety analysis set)
Special Interest Category
Number (%) of participantsa
AZD1222
Control
(N = 12021)
(N = 11724)
Participants with any AESI
95 (0.8)
126 (1.1)
Anaphylaxis
1 (<0.1)
0
Generalized convulsion
1 (<0.1)
1 (<0.1)
Neurologic events-other
64 (0.5)
79 (0.7)
Potential immune mediated conditions –
1 (<0.1)
3 (<0.1)
Gastrointestinal disorders
Potential immune mediated conditions –
1 (<0.1)
1 (<0.1)
Musculoskeletal disorders
Potential immune mediated conditions -
5 (<0.1)
4 (<0.1)
Neuroinflammatory
Potential immune mediated conditions –
3 (<0.1)
4 (<0.1)
Skin disorders
Potential immune mediated conditions –
0
1 (<0.1)
Vasculitides
Potential immune mediated conditions –
3 (<0.1)
3 (<0.1)
Other
Thrombotic, thromboembolic, and
4 (<0.1)
8 (<0.1)
neurovascular events
VAERD
12 (0.1)
23 (0.2)
aNumber (%) of participants with AEs, sorted in alphabetical order for special interest category. Participants with multiple
events in the same preferred term are counted only once in each of those PTs. Participants with events in more than 1 PT are
counted once in each of those PTs.
The non-serious event of anaphylaxis is discussed in the ‘Adverse events’ section above.
Vaccine associated enhanced disease (VAED), including vaccine associated enhanced
respiratory disease (VAERD) is a theoretical risk, which is relevant to all COVID-19
vaccines. Currently, there are only 2 cases of severe COVID-19 that have been reported in
the any dose efficacy set, both in the control group, limiting any conclusions that can be
drawn. However, the type of immune response triggered by the vaccine (Th1 skewed) and the
number of COVID-19 hospitalisations in the any dose efficacy set (2 vs 16) provides
reassurance. It is recognised that VAERD may not become apparent until efficacy of the
vaccine starts to wane. This is an important potential risk in the RMP and will be monitored
via routine and additional pharmacovigilance activities.
There were no clinically meaningful imbalances in AESI incidence for any subgroup
(country, age, serostatus or comorbidity).
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Laboratory findings
Laboratory testing was only conducted in a subgroup of subjects up to 28 days after each
dose. The incidence of decreases in white blood cells, neutrophils, and platelets was slightly
higher in the AZD1222 group compared with control. However, there were very few
unsolicited haematology or biochemistry adverse events reported and these were balanced
between the 2 study groups.
Safety in special populations
Pregnancy and breastfeeding
Women who were pregnant or breastfeeding were excluded from the clinical trials.
Pregnancy was reported for 21 subjects; 12 in the AZD1222 group and 9 in the control group.
Of these pregnancies, 5 ended in spontaneous abortion – 2 in the AZD1222 group and 3 in
the control group. Due to the limited duration of follow-up, the outcome of the remaining
pregnancies is awaited. The results of preliminary studies in animals do not indicate direct or
indirect harmful effects with respect to pregnancy, embryofetal development, parturition or
post-natal development; definitive animal studies have not been completed yet. The full
relevance of animal studies to human risk with vaccines for COVID-19 remains to be
established. Therefore, administration of COVID-19 Vaccine AstraZeneca in pregnancy
should only be considered when the potential benefits outweigh any potential risks for the
mother and fetus. It is unknown whether AZD1222 is excreted in breast milk
Information for Healthcare Professionals and the Information for UK recipients reflect these
recommendations. Use in pregnancy and lactation is included in the RMP as missing
information.
Paediatric population
In-line with the proposed indication, no data have been provided in subjects less than 18
years of age.
Immunosuppression
No data are currently available in immunocompromised subjects or in subjects taking
immunosuppressants. Safety data is awaited in a subgroup of HIV positive subjects that were
included in studies COV002 and COV005. This will be followed up in the RMP.
Safety related to interactions
No data are available on use with concomitant vaccines, including influenza vaccines.
Receipt of any vaccine, other than the study intervention within 30 days before and after each
study vaccination, was an exclusion criterion in the clinical trials. In studies COV001 and
COV002 there was an exception for licensed seasonal influenza and pneumococcal
vaccinations. These were permitted at least 7 days before or after their study vaccine.
Discontinuations due to adverse events
No data were collected on adverse events leading to treatment or study withdrawal. However,
the number of subjects who declined to receive a second dose of vaccine or withdrew early
was balanced between the AZD1222 and control groups.
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IV.6 Risk Management Plan (RMP)
Every new medicine that is authorised has a Risk Management Plan (RMP) in place to ensure
the medicine is used as safely as possible. An RMP details important risks for the medicine
and how more information can be obtained about these. This includes important identified
risks which have been demonstrated to be associated with the medicine and require additional
measures as part of the authorisation to minimise any potential risk to users. Important
potential risks are those where there is a potential association with the product but the
association has not been confirmed and further information needs to be collected to establish
whether this risk exists. Missing information topics are typically those which have not been
fully evaluated in the clinical trials, are relevant to the use of the product and require further
information to be gathered.
The following section describes the RMP that has been agreed for the safe use of COVID-19
Vaccine AstraZeneca.
In addition to routine pharmacovigilance and risk minimisation measures, the MHRA has
requested that all COVID-19 vaccines carry out further ad hoc pharmacovigilance activities
specific to the pandemic situation. This includes more frequent safety signal detection
activities with additional epidemiological analysis of potential safety signals and targeted
safety events, frequent pharmacovigilance meetings with the MHRA, monthly
pharmacovigilance safety update reports and batch specific surveillance.
The important identified risks, important potentials risks and missing information for the
COVID-19 vaccine AstraZeneca are as follows:
Important Identified risk None
Important potential risk Neuroinflammatory disorders
Vaccine-associated enhanced disease (VAED)
Missing information
Use of COVID-19 Vaccine AstraZeneca in pregnant and breastfeeding
women
Use of COVID-19 Vaccine AstraZeneca in subjects with severe
immunodeficiency
Use of COVID-19 Vaccine AstraZeneca in subjects with severe and/ or
uncontrolled underlying disease
Use of COVID-19 Vaccine AstraZeneca with other vaccines
Long-term Effectiveness
There are no important identified risks for COVID-19 Vaccine AstraZeneca.
Neuroinflammatory disorders has been included as an important potential risk. Very rare
events of neuroinflammatory disorders were reported in clinical trials following vaccination
with COVID-19 Vaccine AstraZeneca. A causal relationship has not been established. The
pharmacovigilance plan will further investigate whether there is a link between the vaccine
and neuroinflammatory disorders.
Vaccine associated enhanced disease (VAED) has been included as a potential risk. This is a
theoretical risk which is relevant to all COVID-19 vaccines based on VAED having been
seen in animal models for vaccines developed for SARS-CoV-1 (a similar but not identical
virus to SARS-CoV-2, the virus responsible for COVID-19). VAED has also been seen in
association with use of another respiratory virus vaccine, the Respiratory syncytial virus
(RSV) vaccine. There is currently no evidence from non-clinical or clinical data of an
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association of VAED with COVID-19 Vaccine AstraZeneca; this potential risk will be
further investigated as part of the pharmacovigilance plan for this vaccine.
Use in pregnant and breastfeeding women is included as missing information because this
group was excluded from the clinical trials and further data need to be collected on the safety
and efficacy of this use.
Use of COVID-19 Vaccine AstraZeneca in subjects with severe immunodeficiency is
included as missing information as this group was excluded from the clinical trials and
further data need to be collected on the safety and efficacy of this use.
Use of COVID-19 Vaccine AstraZeneca in subjects with severe and/ or uncontrolled
underlying disease is included as missing information as this group was excluded from the
clinical trials and further data need to be collected on the safety and efficacy of this use.
Use of COVID-19 Vaccine AstraZeneca with other vaccines when co-administered with
other vaccines (either interchangeably with alternative licensed COVID-19 vaccines, or
concurrently with seasonal illness vaccines) has not been evaluated. Further data need to be
collected on the safety and efficacy of this use.
Vaccine efficacy for COVID-19 Vaccine AstraZeneca has been clearly demonstrated in
clinical trials. Vaccine effectiveness relates to how well a vaccine works in the “real world”
setting outside of clinical trials and being used in a wider variety of people. Therefore, long-
term real-world data on vaccine effectiveness need to be collected and this has been included
as a missing information topic.
The following studies have been proposed to gather more information on these topics:
Study
Summary of activity objectives
Safety concerns addressed
Status
• D8111R00003
Primary Objectives:
• Immune-mediated
Planned
• D8111R00004
• To assess the safety and tolerability of at least neurological conditions
• DSRU study (study
1 dose of the AZD1222 in adults ≥ 18 years of
• Vaccine-associated
code to be confirmed) age for a predefined period (eg, 3 months) after
enhanced disease
vaccination with first dose of AZD1222.
• Use of AZD1222 in
Enhanced active
pregnant and breastfeeding
surveillance A Phase
Secondary Objectives:
women
IV Enhanced Active
• To assess the longer-term safety and
• Use of AZD1222 in
Surveillance Study of
tolerability of at least 1 IM dose of AZD1222 in
subjects with severe
People Vaccinated
adults ≥ 18 years of age for 12 months after
immunodeficiency
with AZD1222
vaccination with first dose of AZD1222
• Use of AZD1222 in
subjects with severe and/or
Secondary Objectives (pregnancy sub-study):
uncontrolled underlying
• To estimate the frequency of selected adverse
disease
pregnancy outcomes in women receiving the
• Use of AZD1222 with
AZD1222 vaccine during pregnancy or up to a
other vaccines
predefined period (eg, 60 days) before estimated
date of conception
• To estimate the frequency of selected adverse
fetal/neonatal outcomes at birth and up to 6
months of life in infants from pregnancies in
which the mothers received the AZD1222
vaccine during pregnancy or up to a predefined
period (eg, 60 days) before estimated date of
conception.
AZD1222 Pregnancy
Primary Objectives:
• Use of AZD1222 in
Planned
Registry
• To estimate the frequency of selected adverse
pregnant and breastfeeding
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pregnancy outcomes (ie, spontaneous abortions,
women
Pregnancy Registry
stillbirths, and preterm births) in women
of Women Exposed
receiving at least 1 dose of the AZD1222
to AZD1222
vaccine during pregnancy or up to a predefined
Immediately Before
period (eg, 60 days) before estimated date of
or During Pregnancy
conception
• To estimate the frequency of selected adverse
fetal/neonatal outcomes (ie, major congenital
malformations and small for gestational age) at
birth and up to at least the 6 months of life (to
account for diagnosis of major congenital
malformations that might be delayed) in infants
from pregnancies in which the mothers received
the AZD1222 vaccine during pregnancy or up to
a predefined period (eg, 60 days) before
estimated date of conception.
Post-marketing safety
Primary Objectives:
• Immune-mediated
Planned
study
• To estimate the incidence of safety concerns
neurological conditions
and AESIs in recipients and non-recipients of
• Vaccine-associated
A post-
AZD1222, among all populations targeted for
enhanced disease
authorisation/post-
vaccination and in the specific populations
• Use of AZD1222 in
marketing
considered as missing information
pregnant and breastfeeding
observational study
• To estimate the relative risk (comparing
women
using existing
exposed and unexposed person time) of safety
• Use of AZD1222 in
secondary health data
concerns including AESIs among all
subjects with severe
sources to evaluate
populations targeted for vaccination and in the
immunodeficiency
the association
specific populations considered as missing
• Use of AZD1222 in
between exposure to
information
subjects with severe and/or
AZD1222 and safety
• To characterise the use of AZD1222 among
uncontrolled underlying
concerns.
all populations targeted for vaccination and in
disease
the specific populations considered as missing
• Use of AZD1222 with
information
other vaccines
• D8111R00005
Primary Objective:
Vaccine effectiveness
Planned
• To estimate brand specific vaccine
Post-marketing
effectiveness against laboratory-confirmed
effectiveness study
SARS-CoV-2 in hospitalized patients, overall
and by age group (< 18, 18-64 and ≥ 65 years
Post-authorisation/
old), after adjusting for potential confounders.
Post-marketing
retrospective cohort
study to evaluate the
effectiveness of the
AZD1222 vaccine to
prevent serious
COVID-19 infection
in conditions of usual
care through public-
private partnership
with COVIDRIVE
utilizing primary data
collected
prospectively through
the COVIDRIVE
platform
The company is also planning an additional study to look at safety of COVID-19 Vaccine
AstraZeneca in patients taking immunosuppressant medicines and with primary
immunodeficiency.
The following ongoing pivotal clinical studies will also provide further safety data:
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Study name and description
Summary of objectives
Status
Study COV001
Primary Objectives:
A Phase I/II Study to Determine
• To assess efficacy of AZD1222 against COVID-19
Efficacy, Safety, and
• To assess the safety of AZD1222
Immunogenicity of the Candidate
Coronavirus Disease (COVID-19)
Key secondary Objectives:
Vaccine ChAdOx1 nCoV-19 in UK
• To assess the reactogenicity profile of AZD1222
Healthy Adult Volunteers
To assess cellular and humoral immunogenicity of AZD1222.
•
Status: Ongoing
Study COV002
Primary Objectives:
A Phase II/III Study to Determine the
• To assess efficacy and safety of AZD1222 against COVID-19
Efficacy, Safety, and
in adults aged 18 years and older in the UK
Immunogenicity of the Candidate
Coronavirus Disease (COVID-19)
Secondary Objectives:
Vaccine ChAdOx1 nCoV-19
• To assess the reactogenicity profile of AZD1222
• To assess efficacy of AZD1222 against severe and non-severe
•
Status: Ongoing
COVID-19
• To assess humoral immunogenicity of AZD1222
• To assess cellular immunity of AZD1222 in older adults
• To assess the safety and immunogenicity of a booster dose of
AZD1222 in older adults aged 56 years or older (two-dose
schedule).
Study COV003
Primary Objective:
A Randomised, Controlled, Phase III
• To evaluate the efficacy of AZD1222 vaccine against
Study to Determine the Safety,
COVID-19 disease confirmed with PCR
Efficacy, and Immunogenicity of the
Non-Replicating ChAdOx1 nCoV-19
Secondary Objectives:
Vaccine
• To evaluate the safety, tolerability and reactogenicity profile
of AZD1222
•
Status: Ongoing
• To evaluate the efficacy of AZD1222 against severe and non-
severe COVID-19 disease
• To evaluate the humoral immunogenicity of AZD1222
• To assess the cellular immunogenicity of AZD1222.
Study COV005
Primary Objective:
An Adaptive Phase I/II Randomised
• To assess the safety of AZD1222 in healthy HIV-uninfected
Placebo-controlled Trial to
adults
Determine Safety, Immunogenicity
•
and Efficacy of Non-Replicating
To assess efficacy of AZD1222 against COVID-19
ChAdOx1 SARS-CoV-2 Vaccine in
• To assess the safety of the candidate vaccine AZD1222 in
South African Adults Living Without
adults living with HIV
HIV; and Safety and Immunogenicity
in Adults Living with HIV
• To evaluate the immunogenicity of AZD1222 after first and
second doses of vaccine in adults living with HIV
•
Status: Ongoing
Secondary Objectives:
To assess the immunogenicity of AZD1222 in healthy HIV-
uninfected adults.
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IV.7 Discussion on the clinical aspects
Clinical immunogenicity
Although there are no defined immune correlates of protection against COVID-19, it is
generally accepted that high-titre neutralising antibodies with a robust cytotoxic CD8+ T cell
response and Th1-biased CD4+ effector response will be optimal for protective immunity
after SARS-CoV-2 exposure.
AZD1222 elicits the rapid development of binding and neutralising antibodies after a priming
dose, which are further increased with a booster dose to levels comparable to those measured
in serum samples from convalescent patients.
The importance of the dosing interval is emphasised in the Phase III results. These seem to
suggest that higher levels of antibodies are generated after a lower prime dose compared to
the standard dose; however, this finding is confounded by the observation that the dose
interval for the majority of participants in the standard dose group was shorter (< 6 weeks)
than in the lower dose group (≥ 12 weeks). Antibody levels tend to increase as the interval
between the prime and booster doses increases, so that, when considering antibody levels
between lower and standard dose at the same intervals, there is no difference between the
lower and standard dose.
There is a general concern about immunosenescence, and therefore, immunogenicity data in
the older subgroups are critical. High seroconversion rates but lower GMTs were observed in
the elderly (≥ 65 years) compared to younger adults, although the differences in the dosing
interval may have partly confounded the results after the booster dose. Furthermore, the level
of T cell responses was comparable in the elderly and younger age groups.
T cell responses are rapidly induced after the first dose of vaccine and are well maintained up
to 28 days following the booster dose. The responses are heavily biased toward secretion of
Th1 cytokines (IFN-γ, IL-2 and/or TNFα) while no response is found for cells secreting Th2
cytokines (IL-4, IL5, IL-13). IgG serotypes, predominantly IgG1 and IgG3, are also
consistent with a Th1-polarised response, which is the profile targeted for COVID-19 vaccine
in order to avoid potential disease enhancement.
Finally, although AZD1222 elicits the development of neutralising antibodies against the
viral vector, they do not seem to interfere significantly with the magnitude of the anti-spike
response.
Clinical efficacy
Based on the description of the study population presented with the interim analysis, the
study results are considered to support vaccine efficacy in a population at risk of severe
COVID-19 based on comorbidities. There is some uncertainty about the effects of the
vaccine in subjects over 65 years of age as this population is currently not well represented.
As good efficacy has been demonstrated in subjects with comorbidities and immunogenicity
results in the elderly population are broadly comparable to those of younger adults, there is
currently no indication of a significant loss of efficacy in this population.
Overall, the current data show a high level of short-term efficacy. The median duration of
follow-up after the second vaccine dose is slightly longer than 2 months, which is considered
the shortest follow-up period required to achieve some confidence that any protection is
likely to be more than very short-lived.
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However, the data do not address the following aspects.
• Data are currently limited for dose intervals < 2 months. However, more data on 4 to 6
week-intervals will be submitted with further analyses of the ongoing trials. Therefore, a
pragmatic approach allowing for some degree of flexibility in dosing intervals is currently
considered appropriate within the context.
• Data on severe disease are insufficient to draw any definite conclusion although no case
has been reported in the AZD1222 group and the vaccine efficacy has been shown on
hospitalisations occurring after the first dose.
• Although data in individuals above 65 year of age are currently limited, more information
is expected in the near future, with the submission of further analyses of the ongoing
trials.
• Regarding COVID-19 cases, no viral genomic sequencing data of the isolated strains and
no immunogenicity data in these vaccine failures are currently available. This will be
addressed at a broader level by the COVID-19 Genomics UK (COG-UK) Consortium and
in the immunogenicity follow-up.
• There are no data in pregnant women and immunosuppressed patients as these subjects
are excluded from the trial. These aspects are addressed in the Risk Management Plan.
• Data on vaccine protection after 2 doses are currently lacking beyond 2-3 months and this
will be addressed with longer follow-up in the ongoing clinical trials and effectiveness
studies in accordance with the Risk Management Plan.
• There are currently no data in adolescents (12 to 17 years old). Enrolment in a safety and
immunogenicity sub-study is due to start and these data will be submitted when available.
Clinical Safety
As of the 04 November 2020 data cut-off, safety data were available for 23,745 subjects. Of
these subjects, 12021 subjects received at least one dose of AZD1222 of which 8266 received
2 doses of AZD1222. The median duration of follow-up post dose 2 was 62 days in the
AZD1222 and control groups, which is acceptable in the context of this Regulation 174
procedure.
The safety profile is characterised by local and systemic reactogenicity, which is likely to
affect most recipients to a mild or moderate degree for a few days after vaccination. By day 7
the incidence of subjects with at least one local or systemic reaction was 4% and 13%,
respectively. No major safety concerns are raised. Based on the solicited local and systemic
reactogenicity data, and the adverse event data, the following adverse drug reactions have
been included in the Information for Healthcare Professionals and the Information for UK
recipients:
• Very common (≥ 10%): headache, nausea, myalgia, arthralgia, Injection site
tenderness, injection site pain, injection site warmth, injection site erythema, injection
site pruritus, injection site swelling, injection site bruising (including injection site
haematoma – uncommon), fatigue, malaise, pyrexia (including feverishness – very
common, and fever ≥ 38° - common), chills
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• Common (≥ 1% to < 10%): vomiting, injection site induration, influenza-like illness
• Uncommon (≥ 0.1% to < 1%): lymphadenopathy, decreased appetite, dizziness,
abdominal pain, hyperhidrosis, pruritus, rash
A very small number of neuroinflammatory events have been reported following vaccination
with AZD1222 but a causal relationship with AZD1222 has not been established.
‘Neuroinflammatory conditions’ is included in the RMP as an important potential risk and
will be closely monitored by routine and additional pharmacovigilance activities.
Analyses of safety data by age, comorbidity (yes/no), baseline SARS-CoV-2 status and
country have been provided. These analyses do not raise any specific concerns.
In the AZD1222 group, only 18% of subjects were >55 years of age and about 10% were
≥ 65 years of age. Whilst data are therefore limited in older subjects, particularly those ≥ 65
years, it is of reassurance that the frequency and severity of solicited adverse events was
lower in subjects ≥ 65 years, and the incidence of serious adverse events and adverse events
of special interest was similar between subjects less than and ≥ 65 years. In addition, no
clinically relevant difference was seen in the larger population of subjects that had at least
one comorbidity. Therefore, it is considered that the available evidence supports a broad
indication.
Whilst the number of subjects with severe COVID-19 is too low to assess the potential for
vaccine-associated enhanced disease, the type of immune response triggered by the vaccine
(Th1 skewed) and a review of the number of COVID-19 hospitalisations in the 2 treatment
groups provides reassurance (2 vs 16) regarding this theoretical risk. As VAED may not
become apparent until efficacy of the vaccine starts to wane this is included as an important
potential risk in the RMP with both routine and additional pharmacovigilance activities
planned.
There are no data in pregnant or breastfeeding women or immunosuppressed subjects. These
populations are identified as missing information in the RMP with both routine and
additional pharmacovigilance activities planned.
The safety population, exposure and length of follow-up are acceptable for authorisation for
temporary supply under Regulation 174. Safety data corresponding to longer follow-up will
be submitted as laid out in the RMP.
Conclusion on the clinical aspects The short-term data for COVID-19 Vaccine AstraZeneca are supportive of a favourable
benefit/risk. From a clinical perspective, based on the reviewed information, there is no
objection to the temporary supply of COVID-19 Vaccine AstraZeneca under a Regulation
174.
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V
USER CONSULTATION
Evaluation of the patient information for readability via a user consultation study is currently
deferred in the context of emergency supply under a Regulation 174.
VI
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
The quality of the product is acceptable in the context of batch specific release under
Regulation 174. The non-clinical and clinical data submitted have shown the positive
benefit/risk of this product for active immunisation to prevent COVID-19 caused by SARS-
CoV-2 virus, in individuals 18 years of age and older.
The use of COVID-19 Vaccine AstraZeneca should be in accordance with official guidance.
The
Information for Healthcare Professionals on COVID-19 Vaccine AstraZeneca and the
Information for UK recipients on COVID-19 Vaccine AstraZeneca are satisfactory.
The
Information for Healthcare Professionals on COVID-19 Vaccine AstraZeneca and the
Information for UK recipients on COVID-19 Vaccine AstraZeneca for this product are
available on the MHRA website.
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TABLE OF CONTENT OF THE PAR UPDATE
Steps taken after the initial procedure with an influence on the Public Assessment Report
(non-safety variations of clinical significance).
Please note that only non-safety variations of clinical significance are recorded below and in
the annexes to this PAR. The assessment of safety variations where significant changes are
made are recorded on the MHRA website
Application
Scope
Product
Date of grant
Outcome
Assessment
type
information
report
affected
attached
Y/N
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