EU Nodes-AstraZeneca/ Oxford; AstraZeneca/SK BIO; Serum Institute of India COVID-19 vaccine

Extended version of the vaccine

EU Nodes-AstraZeneca/ Oxford; AstraZeneca/SK BIO; Serum Institute of India COVID-19 vaccine

Authorization

World Health Organization Emergency Use Listing Procedure

EU Nodes -AstraZeneca/Oxford COVID-19 vaccine
Listed for emergency use
Status of assessment: finalized April 15, 2021 [WHO, 2021 ]
SK BIO- AstraZeneca/Oxford COVID-19 vaccine
Listed for emergency use
Status of assessment: finalized February 15, 2021 [WHO, 2021 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Individuals aged 18 years and above [World Health Organization, 2021 ]
Serum Institute of India COVID-19 vaccine
Listed for emergency use
Status of assessment: finalized February 15, 2021 [WHO, 2021 ]
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Individuals aged 18 years and above [World Health Organization, 2021 ]

European Commission (based upon the recommendation of the European Medicines Agency)
Authorized for emergency use (Conditional Marketing Authorization)
29 January 2021
Conditional marketing authorization in individuals 18 years of age and older [EMA, 2021 ]

Regulatory Authorities of Regional Reference in the Americas

National Administration of Drugs, Foods and Medical Devices (ANMAT, Argentina)
Authorized for emergency use AstraZeneca-Oxford COVID-19 vaccine: 30 December, 2020 [Ministerio de Salud Argentina, 2020 ]
Authorized for emergency use Serum Institute of India COVID-19 vaccine: 2 February, 2021 [Ministerio de Salud Argentina, 2021 ]


Brazilian Health Regulatory Agency (ANVISA, Brazil)
Marketing Authorization: 12 March, 2021 (Fiocruz/Astrazeneca) [Agência Nacional de Vigilância Sanitária - Anvisa, 2021 ]

Health Canada
Authorized for emergency use: 26 February, 2021 [Government of Canada, 2021 ].

Public Health Institute (ISP, Chile)
Authorized for emergency use: 27 February, 2021 [Instituto de Salud Pública, 2021 ]

National Institute of Food and Drug Monitoring (INVIMA, Colombia)
Authorized for emergency use: 19 February, 2021 [Instituto Nacional de Vigilancia de Medicamentos y Alimentos de Colombia (INVIMA), 2021 ]

Center for the State Control of Drug Quality (CECMED, Cuba)
Not authorized

U.S. Food and Drug Administration (FDA)
Not authorized

Federal Commission for the Protection against Sanitary Risk (COFEPRIS, Mexico)
Authorized for emergency use: 4 February, 2021
[Comisión Federal para la Protección contra Riesgos Sanitarios de Mexico (COFEPRIS), 2021 ]

Authorization in other jurisdictions in the Americas
Costa Rica
Democratic Republic of the Congo
Denmark
Ecuador
El Salvador
Grenada
Guadeloupe
Guatemala
Guyana
Haiti
Honduras
Jamaica
Maldives
Montserrat
Nicaragua
Panama
Paraguay
Peru
Saint Kitts and Nevis
Saint Lucia
Saint Vincent and the Grenadines
San Martin
Sao Tome and Principe
Trinidad and Tobago
Virgin Islands

Authorization in other jurisdictions
Albania
Angola
Anguilla
Antigua and Barbuda
Armenia
Australia
Austria
Azerbaijan
Bahrain
Bangladesh
Belgium
Belize
Bhutan
Bosnia and Herzegovina
Botswana
Brunei
Bulgaria
Burkina Faso
Cambodia
Central African Republic
Congo
Côte d'Ivoire
Croatia
Cyprus
Czechia
Egypt
Estonia
Eswatini
Ethiopia
European Union
Fiji
Finland
France
Gambia
Georgia
Germany
Ghana
Greece
Guinea-Bissau
Hungary
Iceland
India
Indonesia
Iran
Iraq
Ireland
Italy
Japan
Jordan
Kenya
Kosovo
Kuwait
Latvia
Lebanon
Lesotho
Liberia
Libya
Liechtenstein
Lithuania
Luxembourg
Madagascar
Malawi
Malaysia
Mali
Malta
Mauritius
Moldova
Mongolia
Morocco
Myanmar
Namibia
Nauru
Nepal
Netherlands
Niger
Nigeria
North Macedonia
Oman
Pakistan
Palestine State
Papua New Guinea
Philippines
Poland
Portugal
Romania
Rwanda
Saudi Arabia
Senegal
Serbia
Seychelles
Sierra Leone
Slovakia
Slovenia
Somalia
South Africa
South Korea
South Sudan
Spain
Sri Lanka
Sudan
Suriname
Sweden
Taiwan
Thailand
Timor-Leste
Togo
Tunisia
Uganda
Ukraine
United Arab Emirates
Uzbekistan
Vanuatu
Vietnam
Yemen
Zambia

Manufacturing

EU Nodes-AstraZeneca-Oxford COVID-19 vaccine

Manufacturer
AstraZeneca-Research-Based BioPharmaceutical Company is a global pharmaceutical company based in Cambridge, UK. EU Nodes AstraZeneca/Oxford COVID‐19 Vaccine is manufactured by AstraZeneca.

Drug Substance
Henogen S.A.; Belgium. Manufacturing of the active substance [WHO, 2021 ].
Catalent Maryland, Inc.; United States. Signed a contract with AstraZeneca to produce the vaccine at Catalent´s gene therapy facility in Harmans, Maryland [Rick Mullin, 2020 ].
Oxford Biomedica (UK) Limited; United Kingdom. Manufacturing of the active substance [WHO, 2021 ].
SK Bioscience Co Ltd.; Republic of Korea. Manufacturing of the active substance [WHO, 2021 ].
Halix B.V. Netherlands [WHO, 2021 ].
WuXi Biologics. China [WHO, 2021 ].
JCR Pharma K.K. Murotani Plant. Japan [WHO, 2021 ].
CSL Behring Australia Pty Ltd. Australia [WHO, 2021 ].

Drug Product
Catalent Anagni; Italy. Development and production of the vaccine. The company will provide vial filling and packaging [WHO, 2021 ], [Pharmaceutical Technology, 2020 ].
CP Pharmaceuticals Ltda.; United Kingdom. Production of the vaccine [WHO, 2021 ].
IDT Biologika; Germany. Production of the vaccine [WHO, 2021 ].
SK Bioscience Co Ltd.; Republic of Korea. Production of the vaccine [WHO, 2021 ].
Universal Farma, S.L. (“Chemo”), Spain [WHO, 2021 ].
Daiichi Sankyo Biotech Co. Japan [WHO, 2021 ].
KM Biologics Co. Ltd. Japan [WHO, 2021 ].
Seqirus Pty Ltd. Australia [WHO, 2021 ].
CP Pharmaceuticals Limited. United Kingdom [WHO, 2021 ].

AstraZeneca-SK BIO COVID-19 vaccine

Manufacturer
SK Bioscience Co Ltd., it is a company that has specialized in vaccine development and manufacture, located in South Korea. Currently, it manufactures AstraZeneca-SK BIO COVID-19 vaccine.
Serum Institute of India COVID-19 vaccine

Manufacturer
Serum Institute of India Pvt. Ltd.,is a biotechnology company located in India. It is one of the manufacturers of the AstraZeneca/Oxford COVID-19 vaccine under its own brand, Serum Institute of India COVID-19 vaccine (Covishield). It has capacity to manufacture 50 million doses per month of Covishield and is planning to scale it up to 100 million doses. Vaccines manufactured by the Serum Institute of India are accredited by the World Health Organization

General characteristics

AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is composed of DNA encoding the SARS-CoV-2 protein S, which is contained in a chimpanzee adenovirus capsule. The adenovirus with the DNA that integrates it enters the cell through endocytosis. Once inside the cytoplasm, the DNA is released and migrates to the cell nucleus where it is transcribed creating mRNA that encodes protein S. Subsequently, this mRNA is translated into the rough endoplasmic reticulum where protein S is created in the cytoplasm, processed and finally, presented by immune and non-immune antigen-presenting cells [Joseph Angel De Soto, 2021 ].
AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is composed of a replication-deficient recombinant chimpanzee adenovirus (ChAdOx1-S) vector, encoding the SARS-CoV2 spike (S) glycoprotein. The spike protein in the vaccine is expressed in a trimeric pre-fusion conformation. Adenoviruses are unencapsulated icosahedral particles (virions) that contain a single copy of the double-stranded DNA genome [WHO, 2021 ].

Dosage form and ingredients
The pharmaceutical form is a solution for intramuscular injection that is provided in a multidose vial (vial : 2, 8 or 10 doses of 0.5 mL, total vial volume:1, 4 or 5 mL per vial).

The vaccine contains the following ingredients:
Active ingredient:
One dose (0.5 ml) contains: Chimpanzee Adenovirus encoding the SARS-CoV-2 Spike glycoprotein (ChAdOx1-S), not less than 2.5 × 10^8 infectious units.

Excipients:
L-Histidine
L-Histidine hydrochloride monohydrate
Magnesium chloride hexahydrate
Polysorbate 80 (E 433)
Ethanol
Sucrose
Sodium chloride
Disodium edetate (dihydrate)
Water for injections

Risk considerations

AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine uses a non-replicating and non-integrating platform. This means the vaccine component does not interact with the genome and does not carry a risk for infection [Antrobus RD, 2014 ].
Adenoviral vectors are frequently used for gene transfer because of their high cellular transduction efficiency in vitro and in vivo. Expression of viral proteins and the low capacity for foreign DNA limits the clinical application of first- and second-generation adenoviral vectors. Adenoviral vectors with all viral coding sequences offer the prospect of decreased host immune responses to viral proteins, decreased cellular toxicity of viral proteins and increased capacity to accommodate large regulatory DNA regions [Lundstrom K, 2021 ].
In most cases, third generation replication-deficient adenoviral vectors with deletions in genes E1 and E3 have been use for the expression of the SARS-CoV-2 spike (S) protein or their receptor binding domain (RBD) [Lundstrom K, 2021 ].
The ChAdY25/ChAdOx1 is a recombinant E1 E3-deleted vector developed a decade ago based on the chimpanzee adenovirus Y25. The vector was constructed in a bacterial artificial chromosome and demonstrated comparable immunogenicity to that of other species of chimpanzee adenovirus vectors. The prevalence of virus neutralizing antibodies against ChAdY25 in serum samples collected from human populations was particularly low compared to published data for other chimpanzee adenoviruses [Dicks MD, 2012 ].

Dosification and schedule

Effectiveness and observational studies of national vaccination programmes are limited to an inter-dose interval of not more than 12 weeks at this time. However, binding antibodies against the COVID-19 spike protein have only a slow decay over a period of 6 months. An immunological correlate of protection is yet to be established, but antibodies persist over at least 26 weeks after the first dose, albeit at a lower level compared with the peak antibody levels. Because ChAdOx1-S [recombinant] vaccines induce both a T cell and B cell response, it is likely that there is some degree of protection against clinical disease conferred by one dose beyond 12 weeks, in particular against severe disease, defined as requiring hospitalization or causing death. However, data to quantify this are not currently available. Both seroconversion rates and antibody titres are only slightly lower in older adults after administration of one dose, compared with younger adults [World Health Organization, 2021 ].

Dose-finding studies
COV001 was a phase 1 randomized trial that evaluated different doses and schedules of the vaccine (dose of 5 x 10^10 viral particles [vp] or half-dose; schedules based on single injection, prime and boost at week 4, 8, 16 or at 9 months, or a three dose schedule at 0, 4 weeks and 9 months)
[Barrett JR, 2020 ].
The details of the intervention groups compared are the following:
· Single dose of 5 x 10^10 vp
· Single dose of 5 x 10^10 vp at week 0 and a boost dose of 5 x 10^10 vp 9 months later
· Single dose of 5 x 10^10 vp
· Two doses of 5 x 10^10 vp at week 0 and week 8
· Single dose of 5 x 10^10 vp at week 0 and a boost dose of 2.5 x 10^10 vp at week 8
· Single dose of 5 x 10^10 vp at week 0 and a boost dose of 0.5 mL (3.5 to 6.5 x 10^10 vp) a minimum of 4 weeks later
· One dose of 5 x 10^10 vp at week 0 and one dose of 5 x 10^10 vp at week 4
· Single dose of 5 x 10^10 vp at week 0, a boost dose of 0.5 mL (3.5 to 6.5 x 10^10 vp) a minimum of 4 weeks later, and a third dose of 0.5 mL (3.5 to 6.5 x 10^10 vp) at 9 months
· Single dose of 5 x 10^10 vp
· Single dose of 5 x 10^10 vp at week 0 and a boost dose of 0.5 mL (3.5 to 6.5 x 10^10 vp) a minimum of 4 weeks later
· Two doses of 5 x 10^10 vp ≤ 16 weeks apart, and a third dose of 0.5 mL (3.5 too 6.5 x 10^10 vp) at 9 months.
The booster dose was safe and better tolerated than priming doses, elicited higher anti-spike neutralizing antibody titers, as well as substantially enhanced Fc-mediated functional antibody responses. Also, a booster dose 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 [Barrett JR, 2020 ].
Heterologous (mix-and-match) studies are ongoing with regard to the interchangeability of Pfizer-BioNTech COVID-19 vaccine with other COVID-19 vaccines. Preliminary results from a heterologous priming schedule where BNT162b2 was given as the second dose following the first dose of ChAdOx1- S [recombinant] vaccine showed a slightly increased but acceptable reactogenicity with superior or similar immunogenicity results, thus supporting the use of such a heterologous priming schedule in settings where the second dose for the ChAdOx1-S [recombinant] vaccine is not available due to vaccine supply constraints or other concerns [World Health Organization, 2021 ].

Elderly population
No dosage adjustment is required in elderly individuals ≥65 years of age [WHO, 2021 ].

Paediatric population
The safety and efficacy of COVID-19 Vaccine AstraZeneca in children and adolescents (aged <18 years old) have not yet been established. No data are available [WHO, 2021 ].

Indications and contraindications

Indications
AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is indicated in adult individuals 18 years and older [WHO, 2021 ].

Contraindications
AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is contraindicated in individuals with a known history of a severe allergic reaction to any component of the AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine [WHO, 2021 ].
The second dose of the vaccine should NOT BE GIVEN to those who have experienced anaphylaxis to the first dose of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine.
AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is contraindicated in individuals who have experienced major venous and/or arterial thrombosis in combination with thrombocytopenia following vaccination with any COVID-19 vaccine [WHO, 2021 ].

Precautions
Severe allergic reaction (e.g. anaphylaxis) to an injectable medication.
In general, persons with an immediate non-anaphylactic allergic reaction to the first dose should not receive additional doses, unless recommended after review by a health professional with specialist expertise.
A very rare and serious combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, has been observed following vaccination with AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine during post-authorization use. This includes cases presenting as venous thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia. Most of the events occurred within the first 14 days following vaccination and some events had a fatal outcome [WHO, 2021 ].
There should be a minimum interval of 14 days between the administration of this vaccine with any other vaccine in the immunization schedule, until data on co-administration with other vaccines are available [WHO, 2021 ].
The interaction of concomitant administration of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine with other vaccines has not been studied [EMA, 2021 ].
Vaccination may be offered regardless of a person‘s history of symptomatic or asymptomatic SARS-CoV-2 infection [WHO, 2021 ].
Although there are currently no medical contraindications on the vaccinating of a person with COVID-19, it is recommended to defer all vaccinations until complete recovery [PAHO, 2020 ].
Although there are currently no contraindications on the vaccinating of a person who has had contact with a COVID-19 case, it is recommended to defer vaccination until the quarantine has been completed (14 days after the last exposure) [PAHO, 2020 ].
Vaccination should be postponed in individuals suffering from acute severe febrile illness, or acute infection. However, the presence of a minor infection, such as cold, and/or low-grade fever should not delay vaccination [WHO, 2021 ].
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded [WHO, 2021 ].
As with other intramuscular injections, the vaccine should be given with caution in individuals with bleeding disorders or other conditions that increase the risk of bleeding, such as anticoagulant therapy, thrombocytopenia and hemophilia [WHO, 2021 ].
In individuals with risk factors for thromboembolism and/or thrombocytopenia the benefits and potential risks of vaccination should be considered.
Healthcare professionals should be alert to the signs and symptoms of thromboembolism and thrombocytopenia, as well as coagulopathies. Vaccinated individuals should be instructed to seek immediate medical attention if they develop symptoms such as a severe or persistent headaches, blurred vision, confusion, seizures, shortness of breath, chest pain, leg swelling, leg pain, persistent abdominal pain or unusual skin bruising or petechia a few days after vaccination [WHO, 2021 ].
Individuals who have previously had capillary leak syndrome must not be vaccinated with Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).
Healthcare professionals should be aware of the signs and symptoms of capillary leak syndrome and of its risk of recurrence in people who have previously been diagnosed with the condition.
Vaccinated individuals should be instructed to seek immediate medical attention if they experience rapid swelling of the arms and legs or sudden weight gain in the days following vaccination. These symptoms are often associated with feeling faint (due to low blood pressure) [EMA, 2021 ].
Very rare events of demyelinating disorders have been reported following vaccination with AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine. A causal relationship has not been established [WHO, 2021 ].
Vaccination is recommended for persons with comorbidities that have been identified as increasing the risk of severe COVID-19 [WHO, 2021 ].
Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with vaccination as a psychogenic response to the needle injection. It is important that precautions are in place to avoid injury from fainting.
Preliminary reproductive toxicity studies in mice have not shown harmful effects of the vaccine in pregnancy. ChAdOx1-S [recombinant] vaccine is a replication-defective vaccine. While available data on vaccination of pregnant women are insufficient to assess vaccine efficacy or vaccine-associated risks in pregnancy. WHO recommends the use of ChAdOx1-S [recombinant] vaccine in pregnant women only if the benefits of vaccination to the pregnant woman outweigh the potential risks. To help pregnant women make this assessment, they should be provided with information about the risks of COVID-19 in pregnancy (including, for example, that some pregnant women are at increased risk of infection, or have comorbidities that add to their risk of severe disease), the likely benefits of vaccination in the current epidemiological context, and the current limitations of the safety data in pregnant women. WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination. [WHO, 2021 ].
As the ChAdOx1-S [recombinant] vaccine is not a live virus vaccine, it is biologically and clinically unlikely to pose a risk to the breastfeeding child. On the basis of these considerations, a lactating woman who is part of a group recommended for vaccination according to the WHO Prioritization Roadmap, e.g. health workers, should be offered vaccination on an equivalent basis. WHO does not recommend discontinuing breastfeeding after vaccination [WHO, 2021 ].
The available data on AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine of children are insufficient to assess vaccine efficacy since no clinical trial evaluating vaccines to prevent COVID-19 has included children.
Data on administration of the vaccine are currently insufficient to allow assessment of vaccine efficacy or safety for persons living with HIV. It is possible that the immune response to the vaccine may be reduced, which may lower its clinical effectiveness. In the interim, given that the vaccine is nonreplicating, persons living with HIV who are part of a group recommended for vaccination may be vaccinated. Information and, where possible, counselling should be provided to inform individual benefit-risk assessment. It is not necessary to test for HIV infection prior to vaccine administration [WHO, 2021 ].
Immunocompromised persons: Available data are currently insufficient to assess vaccine efficacy. In the interim, given that the vaccine is nonreplicating, immunocompromised persons who are part of a group recommended for vaccination may be vaccinated. Information and, where possible, counselling about vaccine safety and efficacy profiles in immunocompromised persons should be provided to inform individual benefit-risk assessment[WHO, 2021 ].
Persons with autoimmune conditions: No data are currently available on the safety and efficacy of persons with autoimmune conditions. Persons with autoimmune conditions who are part of a group recommended for vaccination may be vaccinated [WHO, 2021 ].
Persons who previously received passive antibody therapy for COVID-19: Currently there are no data on the safety or efficacy of vaccination in persons who received monoclonal antibodies or convalescent plasma as part of COVID-19 treatment. Hence, as a precautionary measure, WHO recommends that vaccination should be deferred for at least 90 days to avoid interference of the antibody treatment with vaccine-induced immune responses [WHO, 2021 ].
Experience of overdose is limited. There is no specific treatment for an overdose with AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine. In the event of an overdose, the individual should be monitored and provided with symptomatic treatment as appropriate [WHO, 2021 ].
AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine has no influence on the ability to drive and use machines. However, some of the adverse reactions may temporarily affect the ability to do it [EMA, 2021 ].

Close observation for at least 30 minutes is recommended following vaccination.

Storage and logistics

Storage
AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is provided as a refrigerated solution for intramuscular injection stored at 5°C (41°F) (between 2°C to 8°C [36°F to 46°F]).
Unopened vaccine vials can be stored refrigerated between 2°C to 8°C (36°F to 46°F) for up to 6 month prior to first use [WHO, 2021 ].
The shelf-life of vaccine produced by the Serum Institute of India Pvt. Ltd of up to 9 months stored between 2 ° C and 8 ° C (36 ° F to 46 ° F) [WHO, 2021 ].
Do not freeze.
Store in the original carton to protect from light.
Open vials should be use as soon as possible and within 6 hours. The vaccine should be stored between 2°C and 8°C (36°F to 46°F) during the in-use period [WHO, 2021 ].

Logistic at the time of administration
The vaccine should be inspected visually prior to administration. The vaccine is a colorless to slightly brown, clear to slightly opaque solution. Discard the vial if the solution is discolored or visible particles are observed. Do not shake the vial [WHO, 2021 ].
Each vaccine dose of 0.5 mL is withdrawn into a syringe for injection to be administered intramuscularly. Use a separate sterile needle and syringe for each individual.
Vial 10 doses: When low dead volume syringes and/or needles are used, the amount remaining in the vial may be sufficient for an additional dose. Where a full 0.5 mL dose cannot be extracted, the remaining volume should be discarded. Do not pool excess vaccine from multiple vials [WHO, 2021 ].

Storage after first puncture

After first dose withdrawal, use the vial as soon as practically possible and within 6 hours, stored at 2°C to 8°C (36°F to 46°F). Discard any unused vaccine [WHO, 2021 ].

To facilitate the traceability of the vaccine, the name and the batch number of the administered product should be clearly recorded for each recipient [WHO, 2021 ].

Administration
1.Using aseptic technique, clean the vial stopper with a single-use antiseptic swab.
2. Use a 3 ml reuse prevention syringe (RUP) or a 5 ml RUP syringe, and a 21G or narrower needle.
3. Gently invert the vial to mix, and withdraw the 0.5 ml dose. If the amount of vaccine remaining in the vial cannot provide a full 0.5 ml dose, discard the vial and the remaining volume.
4. Administer the vaccine intramuscularly, preferably into the deltoid muscle. Do not administer the vaccine intravascularly, subcutaneously, or intradermally.
Discard the unused vaccine within 6 hours of opening the vial. COVID-19 Vaccine AstraZeneca contains genetically modified organisms, spills should be disinfected with an appropriate antiviral disinfectant.

Disposal
Due to the high risk that discarded vials of COVID-19 vaccines may be recovered, it is essential that they are guaranteed to be safely disposed of at the site of use; or study the possibility of applying reverse logistics, if the safe treatment and disposal of vaccine residues cannot be guaranteed, so that they are transferred to the place established for that purpose. Otherwise, consider the possibility that the discarded vaccine vials are shredded, if there is a safe way to do so [WHO, 2021 ].

AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine contains genetically modified organisms (GMOs). Any unused vaccine or waste material should be disposed of in compliance with the local guidance for genetically modified organisms or biohazardous waste. Spills should be disinfected using agents with activity against adenovirus.

Clinical studies - general characteristics

Randomized trials
COV001 is a phase 1/2 randomized trial sponsored by the University of Oxford and conducted in the United Kingdom. It was started in March 2020 and it is expected that will be completed by November 2021. It was registered with the numbers ISRCTN15281137 [University of Oxford, 2020 ], NCT04324606 [University of Oxford, 2020 ] and 2020-001072-15 [University of Oxford, 2020 ].
The trial will include 1112 healthy adults aged 18-55 years randomly assigned in a 1:1 ratio to receive the vaccine or meningococcal vaccine MenACWY (licensed control vaccine).
The results of this trial until December 2020 have been reported as part of a pooled analysis of 4 randomized trials evaluating this vaccine [Voysey M, 2021 ].

COV002 is a phase 2/3 trial sponsored by the University of Oxford and conducted in the United Kingdom that started in 28 May 2020. It was registered with the numbers ISRCTN90906759 [University of Oxford, 2020 ], 2020-001228-32 [CTRG, 2020 ] and NCT04400838 [University of Oxford, 2020 ]. It includes healthy adults aged 18 years and older. The expected sample size is 12390. Until now, data on 560 participants in the phase 2 component have been released.

COV003 is a phase 3 randomized trial sponsored by the University of Oxford and conducted in Brazil. It is registered with the numbers ISRCTN89951424 [University of Oxford, 2020 ], NCT04536051 [University of Oxford, 2020 ] and 2020-005226-28 [AstraZeneca AB, 2020 ].
The trial is including health professionals and adults with high potential for exposure to SARS-CoV-2, aged 18 years or older.
The expected sample size is 10300.
Participants are randomly assigned in a 1:1 ratio to receive ChAdOx1 nCoV-19 (5x10^10 viral particles) or 0.5 ml of meningococcal vaccine MenACWY (licensed control vaccine), 4-12 weeks apart, given intramuscularly.

COV005 was a phase 1/2, randomized trial sponsored by the University of Oxford and conducted in South Africa from 24 June 2020 to 9 November 2020. It was registered with the numbers NCT04444674 [University of Witwatersrand, South Africa, 2020 ] and PACTR202006922165132 [University of Oxford, 2020 ].
The trial included HIV-uninfected people between 18 to <65 years.
The sample size was 2021. The median age of the participants was 30 years and the proportion of females was 44%.
Participants were randomly assigned in a 1:1 ratio to receive two standard doses of ChAdOx1-nCoV19 vaccine (containing 5 x 10^10 viral particles) or saline (0.9% NaCl) placebo 21-35 days apart [University of Witwatersrand, South Africa, 2020 ].
Com-COV was a multi-centre single-blind phase II randomized parallel study sponsored by University of Oxford and conducted United Kingdom between October 2020 to November 2022. It was registered with ISRCTN69254139.
The trial included participants are 50 years and older with no or mild-to-moderate, well controlled comorbidity.
The sample size was 830. The mean age of the participants was 57·8 years and the proportion of women was 46%.
Participants were randomly assigned in a 1:1 ratio to receive ChAd/ChAd, ChAd/BNT, BNT/BNT or BNT/ChAd, administered at 28- or 84-day intervals. The intervention was administered as a intramuscular injection of 0.5 ml dose of ChAdOx1 nCOV-19 or 0.3 ml dose of BNT162b2 to the following arms:

1. Immunology cohort (receiving their booster vaccine dose after 28 days)
1. Prime ChAdOx1 nCOV-19, Boost ChAdOx1 nCOV-19
2. Prime ChAdOx1 nCOV-19, Boost BNT162b2
3. Prime BNT162b2, Boost BNT162b2
4. Prime BNT162b2, Boost ChAdOx1 nCOV-19

2. General cohort:
1. Prime ChAdOx1 nCOV-19, Boost ChAdOx1 nCOV-19 (28 day boost)
2. Prime ChAdOx1 nCOV-19, Boost BNT162b2 (28 day boost)
3. Prime BNT162b2, Boost BNT162b2 (28 day boost)
4. Prime BNT162b2, Boost ChAdOx1 nCOV-19 (28 day boost)
5. Prime ChAdOx1 nCOV-19, Boost ChAdOx1 nCOV-19 (84 day boost)
6. Prime ChAdOx1 nCOV-19, Boost BNT162b2 (84 day boost)
7. Prime BNT162b2, Boost BNT162b2 (84 day boost)
8. Prime BNT162b2, Boost ChAdOx1 nCOV-19 (84 day boost) [Liu X, 2021 ]
CombiVacS was a phase 2, open-label, randomized, controlled trial sponsored by Spanish Clinical Research Network - SCReN and conducted in Spain between April 2021- April 2022. It was registered with NCT04860739. The trial included healthy, or clinically stable adults aged 18-60 years who had received a prime ChAdOx1-S vaccination between 8 weeks and 12 weeks before the screening visit. The sample size was 676. The mean age of the participants was 43.98 years and the proportion of women was 57%. Participants were randomly assigned in a 2:1 ratio to receive BNT162b2 or observation. The intervention was administered as one intramuscular injection of BNT162b2 (0.3 mL) or maintain observation [Borobia AM, 2021 ]
ICMR/SII-COVISHIELD (phase 2/3) was a phase 2/3, observer-blind, randomised, controlled study sponsored by Serum Institute of India Private Limited and conducted 44105 between August 2020 to . It was registered with CTRI/2020/08/027170.
The trial included healthy adults aged more than or equal to 18 years.
The sample size was 1601. The mean age of the participants was 46 years in the immunogenicity/reactogenicity cohort, and 40 years in the safety cohort. The proportion of women of the immunogenicity/reactogenicity cohort ranged from 20 to 24%, and the proportion of women among safety cohort participants ranged from 22 to 27%.
Participants were randomly assigned in a 3:1 ratio to receive SII-ChAdOx1 nCoV-19, AZD1222, or placebo. The intervention was administered as two doses of vaccine (5 × 10¹⁰ viral particles) or placebo administered at 4-week intervals (+2-week window) [Prasad S. Kulkarni, 2021 ]

Ongoing randomized trials
COV008 is an ongoing phase 1 randomized trial (registered with the number NCT04816019 [University of Oxford, 2021 ]) sponsored by the University of Oxford that is being conducted in the United Kingdom. It was first registered in 25 March 2021 and plans to enroll 30 healthy adult participants that will receive different doses of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine delivered intranasally. It is expected to run through October 2021.

CV03872091 is an ongoing phase 1/2 randomized trial (registered with the number NCT04760730 [R-Pharm, 2021 ]) sponsored by R-Pharm that is being conducted in the Russian Federation. It was first registered in 18 February 2021 and plans to enroll 100 healthy adults ≥ 18 years of age that will receive heterologous prime boost use of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine and rAd26-S, to be administered one after the other interchangeably. It is expected to run through December 2021.

COV006 is an ongoing phase 2 randomized trial (registered with the number ISRCTN15638344 [University of Oxford, 2021 ]) sponsored by the University of Oxford that is being conducted in the United Kingdom. It was first registered in March 2020 and plans to enroll 300 healthy children and adolescents (aged 6-17 years) that will receive AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine (5.0 x 10^10 viral particles) given as a homologous prime boost schedules (28 and 84 days interval post prime). It is expected to run through September 2022.

D8110C00001 is an ongoing phase 3 randomized trial (registered with the number NCT04516746 [AstraZeneca, 2020 ] and PER-059-20 [AstraZeneca AB,, 2020 ]) sponsored by AstraZeneca that is being conducted in Argentina, United States, France, Colombia, Peru and Chile. It was first registered in August 2020 and plans to enroll 32459 adults ≥18 years of age that will receive AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine compared to saline placebo. It is expected to run through February 2023.

D8111C00002 is an ongoing phase 1/2 randomized trial (registered with the number NCT04568031 [AstraZeneca, 2020 ]) sponsored by AstraZeneca that is being conducted in Japan. It was first registered in August 2020 and plans to enroll 256 participants 18 years and older that will receive AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine compared to saline placebo. It is expected to run through November 2021.

D8111C00003 is an ongoing phase 1/2 randomized trial (registered with the number NCT04684446 [AstraZeneca, 2021 ]) sponsored by AstraZeneca that is being conducted in the Russian Federation and Belarus. It was first registered in December 2020 and plans to enroll 100 adults ≥ 18 years of age that will receive AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine given in combination with (either before or after) rAd26-S. It is expected to run through October 2021.

ECEHeVac is an ongoing randomized, open, multicenter, collaborative and adaptive non-inferiority trial (registered with the number NCT04988048 [Ministry of Public Health, Argentina, 2021 ]) sponsored by Ministry of Public Health, Argentina that is being conducted in Argentina. It was first registered in August 2021 and plans to enroll 1760 adults 18 years of age or older to evaluate the immunogenicity and reactogenicity of the heterologous vaccination schedules made up of the combination of vaccines available in Argentina (Sputnik-V, AstraZeneca, Sinopharm and Moderna). It is expected to run until February 2022.

Boost-TX is an ongoing phase 2, randomized, single-blinded study (registered with the number 2021-002927-39 [Medical University of Vienna, 2021 ]) sponsored by Medical University of Vienna that is being conducted in Austria. It was first registered in May 2021 and plans to enroll 200 kidney transplant recipients that will receive BNT162b2 or mRNA-1273 (mRNA) vaccines. End of study: Date not available.
GBP510_003 is an ongoing phase 3, randomized, controlled, observer-blind, parallel-group, multi-center study (registered with the number NCT05007951 [SK Bioscience Co., Ltd., 2021 ]) sponsored by SK Bioscience Co., Ltd.. It was first registered in August 2021 and plans to enroll 3990 adults aged 18 years and older that will receive GBP510 adjuvanted with AS03 to ChAdOx1-S . It is expected to run until September 2022.
HeVacc is an ongoing phase 2, randomized trial (registered with the number NCT04907331 [Medical University Innsbruck, 2021 ]) sponsored by Medical University Innsbruck that is being conducted in Austria. It was first registered in May 2021 and plans to enroll 3000 participants aged ≥ 18 and ≤ 65 years that will receive Vaxzevria or BNT162b2 as a boost. It is expected to run until December 2021.
MOSAIC is an ongoing phase 2, randomized trial (registered with the number NCT04894435) sponsored by Canadian Immunization Research Network that is being conducted in Canada [Canadian Immunization Research Network, 2021 ]. It was first registered in May 2021 and plans to enroll 1200 healthy adults or with mild or moderate stable comorbidities 18 years of age and older. Participants will receive two different vaccines (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) for first and second doses as well as for differing intervals between the first and second dose of two-dose vaccines. It is expected to run until March 2023.
COV-COMPARE is an ongoing phase 3, randomized trial (registered with the number NCT04864561 [Valneva Austria GmbH, 2021 ]) sponsored by Valneva Austria GmbH that is being conducted in United Kingdom. It was first registered in April 2021 and plans to enroll 4019 participants aged 18-29 years that will receive 2 intramuscular recommended doses of either VLA2001 or AZD1222. It is expected to run until June 2022.
AYUSH-AG-VAC-01 is an ongoing phase 3, randomized, parallel-group, placebo-controlled trial (registered with the number CTRI/2021/06/034496 [Arvind Chopra, 2021 ]) sponsored by CCRAS Ministry Of Ayush that is being conducted in India. It was first registered in June 2021 and plans to enroll 1200 healthy adults aged 18-45 years that will receive Ashwagandha and COVISHIELD Vaccine or Placebo and COVISHIELD Vaccine. End of study: Date not available.
CT-COV-31 is an ongoing phase 3, parallel-group, randomized, double-blind, controlled study (registered with the number NCT05011526 [Medigen Vaccine Biologics Corp., 2021 ]) sponsored by Medigen Vaccine Biologics Corp. It was first registered in August 2021 and plans to enroll 1020 adults of 18 years and above that will receive MVC-COV1901 or AZD1222. It is expected to run until June 2022.

Other studies providing efficacy or safety data
Lopez Bernal et al conducted a case control design study in the United Kingdom [Jamie Lopez Bernal, 2021 ] evaluating all adults aged 70 years and older (over 7.5 million) from December 2020 to February 2021 vaccinated with either BNT162b2 or AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine.

Vasileiou et al conducted a prospective cohort study in Scotland [Eleftheria Vasileiou, 2021 ] evaluating the effectiveness of the first dose of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine in preventing hospital admissions using the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) database which contains records for 5.4 million people (~99% of population).

Other ongoing registered studies
AssiutU21 is an ongoing prospective cohort (registered with the number NCT04706143 [Assiut University, 2021 ]) sponsored by the Assiut University that is being conducted in Egypt. It was first registered in January 2021 and plans to enroll 100 healthy adults aged 25-65 years old receiving COVID-19 different available vaccines. It is expected to run through August 2021.

AZD1222 - rAd26-S is an ongoing observational, single group assignment study (registered with the number NCT04686773 [R-Pharm, 2021 ]) sponsored by R-Pharm that is being conducted in Azerbaijan. It was first registered in December 2020 and plans to enroll 100 adults ≥ 18 years of age to evaluate the safety and tolerability of one intramuscular dose of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine followed by one intramuscular dose of rAd26-S. It is expected to run through September 2021.

COVA is an ongoing non-randomized study (registered with the number NCT04800133 [The University of Hong Kong, 2021 ]) sponsored by The University of Hong Kong that is being conducted in China. It was first registered in March, 2021 and plans to enroll 900 healthy individuals between 11-16 years old that will receive one of the 3 following COVID-19 vaccines: Sinovac, Pfizer-BioNTech or AstraZeneca COVID-19 vaccine. It is expected to run through March, 2025.

D8111C00001 is an ongoing observational, single group assignment study (registered with the number NCT04540393 [AstraZeneca, 2020 ]) sponsored by AstraZeneca that is being conducted in the Russian Federation and Belarus. It was first registered in September 2020 and plans to enroll 100 adults ≥ 18 years of age to evaluate the safety and immunogenicity of 2 doses of AZD1222. It was expected to run through May 2021 but it was suspended due to the occurrence of suspected unexpected serious adverse reaction at University of Oxford sponsored Phase 2/3 study.
COVATRANS is an ongoing cohort study (registered with the number NCT04828460 [University Hospital, Strasbourg, France, 2021 ]) sponsored by University Hospital, Strasbourg that is being conducted in France. It was first registered in April 2021 and plans to enroll 3500 kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna, and Astra-Zeneca vaccines. It is expected to run until February 2023.
HHCTC_COVID-19_VACCINE_Ab is an ongoing phase 4, non-randomized study (registered with the number NCT04775069 [Humanity & Health Medical Group Limited, 2021 ]) sponsored by Humanity & Health Medical Group Limited that is being conducted in Hong Kong, China. It was first registered in March 2021 and plans to enroll 900 adults with chronic liver disease or Underlying CLD, aged 18 years and older that will receive Pfizer-Biontech, Sinovac, or Astrazeneca-Oxford vaccine. It is expected to run until March 2022.
ILBS-COVID-05 is an ongoing non-randomized study (registered with the number NCT04794946 [Institute of Liver and Biliary Sciences, India, 2021 ]) sponsored by Institute of Liver and Biliary Sciences, India that is being conducted in India. It was first registered in March 2021 and plans to enroll 2200 adults ≥ 18 years of age that will receive 2 IM doses (0.5 mL) of AZD1222(Covishield) at Day 0 and after 6-8 weeks of the first dose (Day 42-56 days) in liver cirrhosis and non-liver cirrhosis groups. It is expected to run until March 2022.
COVAC-IC is an ongoing non-randomized study (registered with the number NCT04805216 [University Hospitals of North Midlands NHS Trust, 2021 ]) sponsored by University Hospitals of North Midlands NHS Trust that is being conducted in United Kingdom. It was first registered in March 2021 and plans to enroll 80 immunocompromised and immunocompetent haematology patients aged 18 years and older that will receive blood tests at baseline, 15 - 30 days after 2nd dose of BNT162b2, ChAdOx1-S, or mRNA-1273 vaccines. It is expected to run until November 2021.
Friis-Hansen L et al is an ongoing non-randomized study (registered with the number NCT04842305 [Lenanrt Friis-Hansen, 2021 ]) sponsored by Lenanrt Friis-Hansen that is being conducted in Denmark. It was first registered in April 2021 and plans to enroll 500 SARS-COV-2 Naïve persons, COVID-19 convalescents, and vaccinated with Pfizer-BioNTech BNT162b2, Moderna mRNA-1273, or AstraZeneca ChAdOx1-S vaccine. It is expected to run until March 2024.
D8111R00003 is an ongoing phase 4 real-world, observational, non-interventional, prospective cohort study (registered with the number NCT04877743 [AstraZeneca, 2021 ]) sponsored by AstraZeneca that is being conducted in France, Germany, Spain, Sweden. It was first registered in May 2021 and plans to enroll 15000 adults vaccinated with AZD1222. It is expected to run until March 2024.
Eswatini Implementation & VE is an ongoing open-label, single-arm implementation study (registered with the number NCT04914832 [Shabir Madhi, 2021 ]) sponsored by Shabir Madhi that is being conducted in Eswatini. It was first registered in June 2021 and plans to enroll 600 18 years and older that will receive an intramuscular injection of AZ1222, a second dose will be given 10 weeks after the first injection. It is expected to run until May 2022.
COVEMUZ-3 is an ongoing non-randomized study (registered with the number NCT04939402 [Universitair Ziekenhuis Brussel, 2021 ]) sponsored by Universitair Ziekenhuis Brussel that is being conducted in Belgium. It was first registered in June 2021 and plans to enroll 200 employees of the UZ Brussel who has been vaccinated with ChAdOx1. It is expected to run until June 2022.
ImmunoHaema-COVID-VAX-21 is an ongoing prospective, cohort, non-interventional, single-center clinical study (registered with the number NCT04878822 [Ospedale di Circolo - Fondazione Macchi, 2021 ]) sponsored by Ospedale di Circolo - Fondazione Macchi that is being conducted in Italy. It was first registered in May 2021 and plans to enroll 300 patients with haematological malignancies 18 years of age and older that will receive BNT162b2 vaccine, ChAdOx1 nCoV-19 vaccine, or Ad26.COV2.S vaccine. It is expected to run until April 2023.
AssiutU21 is an ongoing prospective cohort (registered with the number NCT04706143 [Assiut University, 2021 ]) sponsored by Assiut University that is being conducted in Egypt. It was first registered in January 2021 and plans to enroll 100 healthy adults aged from 25-65 years old non immune-compromised or immune suppressed that received different available vaccines. It is expected to run until August 2021.
Bauernfeind S et al is an ongoing phase 4, non-randomized study (registered with the number DRKS00025271 [Uniklinik Regensburg Abteilung für Hygiene und Infektiologie, 2021 ]) sponsored by Uniklinik Regensburg Abteilung für Hygiene und Infektiologie that is being conducted in Germany. It was first registered in May 2021 and plans to enroll 154 Universitätsklinikum Regensburg staff aged 18-60 years vaccinated with ChAdOx1-S that will receive a second dose with BNT162b2 vaccine. End of study: date not available.
EC 022/2564 is an ongoing phase 2, non-randomized study (registered with the number Chulabhorn Royal Academy [Chulabhorn Royal Academy, 2021 ]) sponsored by TCTR20210517006 that is being conducted in Thailand. It was first registered in May 2021 and plans to enroll 3000 healthy adults 18 years of age and older that will receive Gam-COVID-Vac, CoronaVac, or ChAdOx1. It is expected to run until July 2022.
COVACC2 is an ongoing non-randomized study (registered with the number NCT04996238 [University Hospital, Ghent, 2021 ]) sponsored by University Hospital, Ghent that is being conducted in Belgium. It was first registered in August 2021 and plans to enroll 300 adults (18-100 years) to gain more insight in the immunological characteristics and immune response of healthy people vaccinated with BNT162b2 and ChAdOx1 vaccines. It is expected to run until January 2022.
COVAXAER01 is an ongoing phase 1, open-label non-randomised dose-escalation study (registered with the number NCT05007275 [Imperial College London, 2021 ]) sponsored by Imperial College London that is being conducted in United Kingdom. It was first registered in August 2021 and plans to enroll 15 healthy adult volunteers aged 30-55 years that will receive AZD1222 (booster) administered by inhalation via vibrating mesh nebulize. It is expected to run until September 2022.
NL73618.100.20 is an ongoing phase 4, non-randomized study (registered with the number 2021-001202-30 [Diakonessenhuis, 2021 ]) sponsored by Diakonessenhuis that is being conducted in Netherlands. It was first registered in April 2021 and plans to enroll 400 healthy volunteers aged 18 years and older that will receive Pfizer, Moderna, Janssen, or AstraZeneca COVID-19 vaccine. End of study: date not available.
CVG01 is an ongoing non-randomized study (registered with the number 2021-001769-19 [GUVAX (Gothenburg University Vaccine Research Institute), 2021 ]) sponsored by GUVAX that is being conducted in Sweden. It was first registered in March 2021 and plans to enroll 1200 adults aged 18 years and older to evaluate the humoral immune response after vaccination against Covid-19 between immune competent subjects and patients with primary or secondary immune deficiency. End of study: date not available.
Poovorawan Y et al is an ongoing non-randomized study (registered with the number TCTR20210520004 [The National Research Council of Thailand, 2021 ]) sponsored by The National Research Council of Thailand that is being conducted in Thailand. It was first registered in May 2021 and plans to enroll 120 healthy adults who had been previously infected with COVID-19, above 18 years of age. Participants will receive virus vector ChAdOx-1 nCoV-19 and inactivated vaccine CoronaVac . It is expected to run until June 2022.

Methods used to assess efficacy and effectiveness

Primary efficacy endpoint in phase 3 trials
COV002 trial [University of Oxford, 2020 ]
Efficacy of the vaccine against COVID-19 in adults aged 18 years and older measured by virologically confirmed (PCR or other nucleic acid amplification test) symptomatic cases of COVID-19.
COV003 trial [University of Oxford, 2020 ]
Virologically confirmed symptomatic cases of COVID-19 over the course of 12 months.

Methods used to assess safety

Primary safety endpoints in phase 3 trials
COV002 trial [University of Oxford, 2020 ]
Safety of the vaccine in adults and children measured by recording the occurrence of serious adverse events throughout the study duration.
COV003 trial [University of Oxford, 2020 ]
Occurrence of solicited local and systemic reactogenicity signs and symptoms for 7 days following vaccination; occurrence of serious adverse events over the course of 12 months.

Efficacy and effectiveness of the vaccine

Efficacy of the vaccine in preclinical studies

Van Doremalen et al [van Doremalen N, 2020 ] conducted a study in mice and rhesus macaques. The vaccine elicited a robust humoral and cell-mediated response in mice, predominantly Th1. In rhesus macaques, vaccination induced a balanced Th1/Th2 humoral and cellular immune response. Vaccinated animals challenged with SARS-CoV-2 did not develop pneumonia and presented a reduced viral load in bronchoalveolar lavage fluid and lower respiratory tract tissue compared with control animals. There was no difference in nasal shedding between vaccinated and control animals.

Lambe et al [Lambe T, 2021 ] conducted a study using rhesus macaque and ferret challenge models. In rhesus macaques, the lung pathology caused by SARS-CoV-2 mediated pneumonia was reduced by prior vaccination which induced neutralizing antibody responses after a single intramuscular administration. In ferrets, the vaccine reduced both virus shedding and lung pathology. Antibody titers were boosted by a second dose.

Silva-Cayetano et al [Silva-Cayetano A, 2020 ] demonstrated that the vaccine induced both cellular and humoral immunity in adult and aged mice using in-depth immunophenotyping to characterize the innate and adaptive immune response induced upon intramuscular administration of the vaccine in mice. A single dose generated spike-specific Th1 cells, Th1-like Foxp3+ regulatory T cells, polyfunctional spike-specific CD8+ T cells and granzyme-B-producing CD8 effectors. A second dose enhanced the immune response in aged mice.

Graham et al [Graham S.P., 2020 ] compared the immunogenicity of one or two doses of the vaccine in both mice and pigs. A single dose induced antigen-specific antibody and T cells responses. A booster immunization enhanced antibody responses with a significant increase in SARS-CoV-2 neutralizing titers.

Van Doremalen et al [Neeltje van Doremalen, 2021 ] conducted a study in Syrian hamsters and rhesus macaques. Intranasally vaccinated hamsters exposed to SARS-CoV-2 virus with the D614G mutation in the spike protein, significantly decreased viral load in comparison to controls. No viral RNA or infectious virus was found in lung tissue, both in a direct challenge and a transmission model.

Efficacy of the vaccine in clinical trials

Main Immunogenicity outcomes

The combined results of 17,178 participants analyzed in the COV001, COV002, COV003 and COV005 trials (8597 receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine and 8581 receiving control vaccine) [Voysey M, 2021 ] showed antibody levels were maintained by day 90 (geometric mean ratio [GMR] 0.66 [95% CI 0.59 to 0.74]). In the participants who received two standard doses the binding antibody response after an interval of 12 or more weeks in those who were aged 18-55 years was GMR 2.32 [2.01 to 2.68]).

Key messages

AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduces the risk of contracting COVID-19

Main efficacy outcomes of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine

Contracting COVID-19 (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received control vaccine was 0.46 (95% CI 0.39 to 0.56). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting COVID-19 in 54%, compared with control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19. Comparison: AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus control vaccine

In the available trials, 346 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 8581 presented this outcome (40 per 1000) versus 161 out of 8597 in the group that did receive it (19 per 1000). In other words, 21 per 1000 people did not develop the outcome because of the intervention. This is the same as saying that the intervention led to an absolute risk reduction of 2.1%, or that the intervention reduced the risk of contracting covid-19 by 2.1 percentage points. Another way of presenting the same information about the absolute effects is the number needed to treat for an additional beneficial/harmful outcome (NNTB/H), the number of participants who need to receive the intervention for one of them to experience the outcome. In this case, the NNTB is 9.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as high certainty evidence.

Contracting severe COVID-19 (measured at least 14 days after the second injection)

There was only 1 event out of 11724 in the control group of the trials and no events in the intervention group (12021 participants).

The relative risk of contracting severe COVID-19 in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received control vaccine was 0.33 (95% CI 0.01 to 7.98). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting severe COVID-19 in 67%, compared with the control vaccine. However, the certainty of the evidence for this estimate is low because of imprecision.




Summary of findings (iSoF)

Efficacy and effectiveness of the vaccine on subgroups

Sex

Randomized trials
The proportion of females in the combined analysis of COV002 and COV003 was 60.5% (7045 out of 11636 participants) [Voysey, Merryn, 2021 ].
The magnitude of the effect was similar between the subgroups, and there was no statistical evidence of a subgroup effect by sex

Age

Randomized trials
The proportion of patients >55 years of age in the efficacy population of the combined analysis of COV002 and COV003 was 12.2% (1418 out of 11636 participants) [Voysey, Merryn, 2021 ].
The efficacy in the 18-55 years group in the different trials, doses and administration schedule ranged from 59.3% to 65.6%. These results were no statistically different from the efficacy of the vaccine in the overall group [Voysey, Merryn, 2021 ].
Efficacy estimates for different age have not been yet reported. The researchers plan to present them in future analyses when a larger dataset is available [Voysey, Merryn, 2021 ].

Other studies
Lopez Bernal et al conducted a case control design study in the United Kingdom [Jamie Lopez Bernal, 2021 ] evaluating all adults aged 70 years and older (over 7.5 million) from December 2020 to February 2021. Vaccination with a single dose of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine was associated with a significant reduction in symptomatic SARS-CoV2 positive cases in older adults with even greater protection against severe disease. The vaccine effects were seen from 14-20 days after vaccination reaching an effectiveness of 60% (95%CI 41-73%) from 28-34 days and further increasing to 73% (95%CI 27-90%) from day 35 onwards.

Vasileiou et al [Eleftheria Vasileiou, 2021 ] found that the effect of a single dose of the AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine would prevent hospitalization related to COVID-19, when restricting the analysis to those aged ≥80 years (81%; 95% CI 65 to 90 at 28-34 days post-vaccination).

Children and adolescents

Randomized trials
Children were excluded from the COV001, COV002, COV003 and COV0005 trials, so no data are available for this subgroup [Voysey, Merryn, 2021 ].
COV006 is an ongoing randomized trial [University of Oxford, 2021 ] evaluating the efficacy in children 6-17 years old.
Comparative studies
COVA is an ongoing non-randomized study [The University of Hong Kong, 2021 ] evaluating the efficacy in children 11-16 years old.

Pregnancy

Randomized trials
Pregnant females have been excluded from the COV001, COV002, COV003 y COV005 trials, so no data are available for this subgroup [Voysey, Merryn, 2021 ].

Breast-feeding

Randomized trials
Breastfeeding females were excluded from the COV001, COV002, COV003 and COV005 trials, so no data are available for this subgroup [Voysey, Merryn, 2021 ].

Immunocompromised people

Randomized trials
The phase 2, randomized, single-blinded study Boost-TX is currently evaluating the efficacy/safety of the vaccine in kidney transplant recipients [Medical University of Vienna, 2021 ].
Comparative studies
The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and older who receive Pfizer, Moderna and Astra-Zeneca vaccines [University Hospital, Strasbourg, France, 2021 ].
The non-randomized study COVAC-IC is currently evaluating the effectiveness/safety of the vaccine in immunocompromised and immunocompetent haematology patients aged 18 years and older [University Hospitals of North Midlands NHS Trust, 2021 ].

The prospective, cohort, non-interventional, single-center clinical study ImmunoHaema-COVID-VAX-21 is currently evaluating the effectiveness/safety of the vaccine in patients with haematological malignancies 18 years of age and older [Ospedale di Circolo - Fondazione Macchi, 2021 ].

Persons living with HIV

Randomized trials
COV005 trial [Madhi S, 2021 ] did a secondary analysis of comparing a group of patients living with HIV and a group of patients without HIV who were part of the study trial in Africa. The study showed comparable safety and immunogenicity of the vaccine between persons living with HIV
and HIV-negative individuals.

Chronic lung disease

Randomized trials
Available data are currently insufficient to assess efficacy in persons with chronic lung disease.

Cardiac disease

Randomized trials
Available data are currently insufficient to assess efficacy in persons with cardiac disease

Diabetes

Randomized trials
Available data are currently insufficient to assess efficacy in persons with diabetes

Liver disease

Randomized trials
Available data are currently insufficient to assess efficacy in persons with liver disease
Comparative studies
The non-randomized study ILBS-COVID-05 is currently evaluating the effectiveness/safety of the vaccine in liver cirrhosis and non liver cirrhosis groups [Institute of Liver and Biliary Sciences, India, 2021 ].
Persons with recent COVID-19

Randomized trials
Available data are currently insufficient to assess efficacy in persons with recent COVID-1

Other data from vaccine efficacy and effectiveness

Duration of protection

Randomized trials
The duration of protection afforded by the vaccine is unknown as it is still being determined by ongoing clinical trials.
Limitations of vaccine effectiveness

Randomized trials
Protection starts from approximately 3 weeks after the first dose of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine. Individuals may not be fully protected until 15 days after the second dose is administered. As with all vaccines, vaccination with AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine may not protect all vaccine recipients.
SARS-CoV-2 variants

Randomized trials
An analysis of the COV001 and COV002 trials explored the efficacy of the vaccine against SARS-CoV-2 variant of concern B.1.1.7, first identified in the United Kingdom. The efficacy analysis was based on the incidence of symptomatic COVID-19 14 days after a second dose of vaccine in 8534 participants. Clinical vaccine efficacy against symptomatic infection was 70.4% (95% CI 43.6 to 84.5) for B.1.1.7 and 81.5% (67.9 to 89.4) for non-B.1.1.7 lineages.
Laboratory virus neutralization activity by vaccine-induced antibodies was lower against the B.1.1.7 variant [Emary KRW, 2021 ].

An analysis of the COV005 trial [Madhi SA, 2021 ] explored the efficacy of the vaccines against emerging SARS-CoV-2 variants of concern, including the B.1.351 (501Y.V2) variant first identified in South Africa. The efficacy analysis was based on the incidence of laboratory-confirmed symptomatic COVID-19 more than 14 days after the second dose in 2026 participants. COVID-19 developed in 3.2% vs 2.5% of the vaccinated versus non-vaccinated participants (efficacy of 21.9%; 95% CI -49.9 to 59.8). The B.1.351 variant was present in 92.9% (vaccine efficacy against this variant was 10.4%; 95% CI -76.8 to 54.8).

Preliminary analyses have shown a slightly reduced vaccine effectiveness of ChAdOx1-S [recombinant] vaccine against B1.1.1.7 in the V002 trial in the United Kingdom which is associated with only a limited reduction in neutralizing antibodies. Preliminary analyses from the phase 1/2a trial (COV005) in South Africa indicate a marked reduction in vaccine effectiveness against mild and moderate disease due to B 1.351 based on small sample size and substantial loss of neutralizing antibody activity. This study was designed to assess efficacy against the disease of any severity, but the small sample size did not allow a specific assessment of vaccine efficacy against severe COVID-19. Indirect evidence is compatible with protection against severe COVID-19; however, this remains to be demonstrated in ongoing clinical trials and post-implementation evaluations
[WHO, 2021 ].

Safety of the vaccine

Safety of the vaccine in preclinical studies

Risk of DNA modification or infection
The viral vector platform is by definition a non-integrating platform. So, there is no potential risk of insertional mutagenesis [Morris SJ, 2016 ].
The vector is a chimpanzee adenovirus modified to avoid its replication [Dicks MD, 2012 ].
The widespread seroprevalence of neutralizing antibodies to common human adenovirus limits the use of human adenoviruses as vaccine vectors, so simian adenoviruses constitute an alternative [Morris SJ, 2016 ].

Safety of the vaccine in clinical trials

Key messages

In the randomized trials, AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine did not increase the risk of adverse events.

In the randomized trials, AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine did not increase the risk of serious adverse events.

Main safety outcomes of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine

Any adverse event (mean follow up: 3.4 months)

In the available trials [Voysey, Merryn, 2021 ] 126 people receiving control vaccine out of 11724 presented this outcome (11 per 1000) versus 95 out of 12021 in the group that did receive the vaccine (8 per 1000).

The relative risk of any adverse event in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received control vaccine was 0.74 (95% CI 0.56 to 0.96). This means that the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine within the trial reported 26% less adverse events than the group that received the control vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: any adverse event. Comparison: AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus control vaccine

Applying the GRADE approach, we assessed the certainty of the evidence for this outcome as high.

Serious adverse events (mean follow up: 4.1 months)

Based on the information provided in the available trials [Voysey, Merryn, 2021 ], 127 people receiving control vaccine out of 11962 presented this outcome (11 per 1000) versus 108 out of 12282 in the group that did receive the vaccine (9 per 1000).

The relative risk of serious adverse event in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received control vaccine was 0.83 (95% CI 0.64 to 1.07). This means that the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine within the trial reported 17% less adverse events than the group that received the control vaccine.

Applying the GRADE approach, we assessed the certainty of the evidence for this outcome as low because the precision of the estimate does not exclude the possibility of serious adverse events.

Summary of findings (iSoF)

Safety of the vaccine in subgroups

Sex

Randomized trials
The proportion of females in the combined analysis of COV002 and COV003 was 60.5% (7045 out of 11636 participants) [Voysey, Merryn, 2021 ].
The subgroup effect in safety outcomes has not been reported in the trials.
Age

Randomized trials
The proportion of patients >55 years of age in the combined analysis of COV002 and COV003 was 12.2% (1418 out of 11636 participants) [Voysey, Merryn, 2021 ].
Combined safety estimates for different age have not been yet reported. The researchers plan to present them in future analyses when a larger dataset is available [Voysey, Merryn, 2021 ]. However, in individual trials it has been reported that the vaccine seems to be better tolerated in older adults than in younger adults [Ramasamy, Maheshi N, 2021 ]
Children and adolescents

Randomized trials
Children were excluded from the COV001, COV002, COV003 and COV0005 trials, so no data are available for this subgroup [Voysey, Merryn, 2021 ].
COV006 is an ongoing randomized trial [University of Oxford, 2021 ] evaluating the safety in children 6-17 years old.
Other studies
COVA is an ongoing non-randomized study [The University of Hong Kong, 2021 ] evaluating the safety in children 11-16 years old.
Pregnancy

Randomized trials
Pregnant females have been excluded from the COV001, COV002, COV003 y COV005 trials, so no data are available for this subgroup [Voysey, Merryn, 2021 ].
Breast-feeding

Randomized trials
Breastfeeding females were excluded from the COV001, COV002, COV003 and COV005 trials, so no data are available for this subgroup [Voysey, Merryn, 2021 ].
Persons/ individuals with comorbidities

Randomized trials
Available data are currently insufficient to assess safety in individuals with comorbidities.
Comparative studies
The non-randomized study ILBS-COVID-05 is currently evaluating the effectiveness/safety of the vaccine in liver cirrhosis and non liver cirrhosis groups [Institute of Liver and Biliary Sciences, India, 2021 ].
Immunocompromised persons

Randomized trials
Available data are currently insufficient to assess safety in individuals with comorbidities.
Comparative studies

Safety of the vaccine post-authorization

Post-authorization studies

Comparative post-authorization studies
There are no comparative studies addressing post-authorization safety of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine.

Non-comparative post-authorization studies
Menni et al conducted a phase 4 study from a real world setting investigating self-reported systemic and local effects within eight days of vaccination in 387,471 individuals from the COVID Symptom Study app in the United Kingdom who received one dose of the vaccine (n=178,220) between December 2020 and February 2021. Systemic side effects were reported in 29.4% after the vaccine dose and were more prevalent among individuals with pre-existing COVID-19 infection (51.6%) and among younger people (<55 years 45.3% vs >55 years 26.9%) [Cristina Menni, 2021 ].

Spontaneous report data
Disclaimer: Reporting suspected adverse reactions after authorization of the medicinal product is important because it allows continuous monitoring of the benefit/risk balance of the vaccines. However, they do not indicate a causal association between the vaccine and the observed effects. Furthermore, this information should not be used to estimate the frequency of adverse events in people receiving the vaccine or to make comparisons between different vaccines. The information emerging about possible adverse effects needs to be carefully evaluated in order to first establish if the adverse effect might have been caused by the vaccine.

In a news release distributed via the European Medicines Agency website in April 07, 2021, EMA‘s safety committee addressed the possible link of AstraZeneca‘s COVID-19 vaccine to very rare cases of unusual blood clots with low blood platelets. The committee took into consideration the advice from an expert group and a review of 62 cases of cerebral venous sinus thrombosis and 24 cases of splanchnic vein thrombosis reported in the EU drug safety database (EudraVigilance) as of 22 March 2021, 18 of which were fatal. The cases came mainly from spontaneous reporting systems including information from around 25 million people that had received the vaccine [EMA, 2021 ].

Monitoring

The following post-authorization monitoring activities have been recommended by WHO
• Safety surveillance and monitoring:
− Serious adverse events such as cerebral venous sinus thrombosis, thrombotic events with thrombocytopenia, anaphylaxis and other serious allergic reactions, Bell‘s palsy, and transverse myelitis
− Cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death;
− Background rates of AESIs (including thromboembolic events, cerebral venous sinus thrombosis, and TTS), maternal and neonatal outcomes, and mortality in groups prioritized for vaccination; − incidence by WHO region, age, and sex, and pathomechanism of TTS.
· Vaccine effectiveness over time.
· Ongoing collection of safety data in vaccine recipients.
· Surveillance for COVID-19 among vaccinated individuals, looking for vaccine-induced enhanced disease (possibly as vaccine-induced antibody levels decline)
· Safety data from inadvertently vaccinated pregnant females during trials and post-authorization.
· Safety data from pregnant females who receive vaccine because they are members of prioritized groups, e.g. health workers.
· Prospective studies on the safety of the vaccine in pregnant females.
· Impact on infants of vaccination of breastfeeding mothers.
· Safety data on vaccination in immunocompromised persons, including persons living with HIV and persons with autoimmune disease.
· Impact of delayed second dose as currently implemented by certain countries.

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