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 on 15 April 2021 [WHO, 2021 ].

SK BIO- AstraZeneca/Oxford COVID-19 vaccine
Listed for emergency use on 15 February 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency use in individuals 18 years of age and older [WHO, 2022 ].

Serum Institute of India COVID-19 vaccine
Listed for emergency use on 15 February 2021 [WHO, 2021 ].
EUL/WHO Authorization: Authorized for emergency use in individuals 18 years of age and older [WHO, 2021 ].
SAGE/WHO Recommendation: Authorized for emergency use in individuals 18 years of age and older [WHO, 2022 ].

European Commission (based upon the recommendation of the European Medicines Agency)
Authorized for emergency use (Conditional Marketing Authorization)
29 January 2021: For individuals of 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)
EU Nodes-AstraZeneca/Oxford COVID-19 vaccine: Authorized for emergency use on 30 December 2020 [Ministerio de Salud Argentina, 2020 ].
Serum Institute of India COVID-19 vaccine: Authorized for emergency use on 2 February 2021 [Ministerio de Salud Argentina, 2021 ].

Brazilian Health Regulatory Agency (ANVISA, Brazil)
Authorized for emergency use on 12 March 2021 (Fiocruz/Astrazeneca) [Agência Nacional de Vigilância Sanitária - Anvisa, 2021 ].

Health Canada
Authorized for emergency use on 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 on 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 on 4 February 2021 [Comisión Federal para la Protección contra Riesgos Sanitarios de Mexico (COFEPRIS), 2021 ].

Authorization in jurisdictions in Latin America and the Caribbean
Anguilla
Antigua and Barbuda
Bahamas
Barbados
Belize
Bermuda
Bolivia
Costa Rica
Dominica
Dominican Republic
Ecuador
El Salvador
Grenada
Guadeloupe
Guatemala
Guyana
Haiti
Honduras
Jamaica
Montserrat
Nicaragua
Panama
Paraguay
Peru
Saint Kitts and Nevis
Saint Lucia
Saint Vincent and the Grenadines
San Martin
Suriname
Trinidad and Tobago
Uruguay
Virgin Islands

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

The Emergency Use Authorization does not constitute marketing authorization in the country.

Manufacturing

EU Nodes-AstraZeneca-Oxford COVID-19 vaccine


Manufacturer
Manufactured by AstraZeneca AB in Sweden.

Other manufacturers

Drug Substance [WHO, 2021 ].
Henogen S.A., Belgium. Manufacturing of the active substance [WHO, 2021 ].
Catalent Maryland, Inc. Maryland, United States.
Oxford Biomedica (UK) Limited; United Kingdom. Manufacturing of the active substance [WHO, 2021 ].
Halix B.V., Netherlands.
WuXi Biologics, China.
JCR Pharma K.K. Murotani Plant, Japan.
CSL Behring Australia Pty Ltd., Australia.
mAbxience SAU, Argentina.
Siam Bioscience Co., Ltd, Thailand.

Drug Product
Amylin, the United States. Manufacturing of drug product [WHO, 2021 ].
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 ].
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 ].
Nipro Pharma Corporation Ise Plant 647-240., Japan, [WHO, 2021 ].
Siam Bioscience Co., Ltd, Thailand, [WHO, 2021 ].
Liomont, S.A., Mexico.

AstraZeneca-SK BIO COVID-19 vaccine


Manufacturer
Manufactured by SK Bioscience Co Ltd. in South Korea [WHO, 2021 ].

Serum Institute of India COVID-19 vaccine


Manufacturer
Manufactured by Serum Institute of India Pvt. Ltd. under the commercial name of Covishield [WHO, 2021 ].

General characteristics

The 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 ].

The 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 ].

 

Ingredients
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 × 108 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

The 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 ].

Dosing and schedule

Dose-finding studies

COV001 was a phase 1 randomized trial that evaluated different doses and schedules of the vaccine (dose of 5 x 10¹⁰ viral particles 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 10¹⁰ viral particles • Single dose of 5 x 10¹⁰ viral particles at week 0 and a boost dose of 5 x 10¹⁰ viral particles 9 months later • Single dose of 5 x 10¹⁰ viral particles • Two doses of 5 x 10¹⁰ viral particles at week 0 and week 8 • Single dose of 5 x 10¹⁰ viral particles at week 0 and a boost dose of 2.5 x 10¹⁰ viral particles at week 8 • Single dose of 5 x 10¹⁰ viral particles at week 0 and a boost dose of 0.5 mL (3.5 to 6.5 x 10¹⁰ viral particles) a minimum of 4 weeks later • One dose of 5 x 10¹⁰ viral particles at week 0 and one dose of 5 x 10¹⁰ viral particles at week 4 • Single dose of 5 x 10¹⁰ viral particles at week 0, a boost dose of 0.5 mL (3.5 to 6.5 x 10¹⁰ viral particles) a minimum of 4 weeks later, and a third dose of 0.5 mL (3.5 to 6.5 x 10¹⁰ viral particles) at 9 months • Single dose of 5 x 10¹⁰ viral particles • Single dose of 5 x 10¹⁰ viral particles at week 0 and a boost dose of 0.5 mL (3.5 to 6.5 x 10¹⁰ viral particles) a minimum of 4 weeks later • Two doses of 5 x 10¹⁰ viral particles ≤ 16 weeks apart, and a third dose of 0.5 mL (3.5 too 6.5 x 10¹⁰ viral particles) at 9 months.

The booster dose was safer and better tolerated than primary 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 ].

Preliminary results from a heterologous primary schedule study 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 primary schedule in settings where the second dose for the ChAdOx1-S [recombinant] vaccine is not available due to vaccine supply constraints or other concerns [WHO, 2022 ].

Children and adolescents

The safety and efficacy of ChAdOx1-S [recombinant] vaccine in children and adolescents (below 18 years of age) have not yet been established. There are limited data to recommend vaccination for persons of this age range [WHO, 2021 ].

Indications and contraindications

Indications

The AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is indicated for individuals 18 years and over [WHO, 2022 ].

Contraindications

The 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, 2022 ]. (See the list of ingredients under 'General characteristics' in the extended version).

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.

People who have had thrombosis with thrombocytopenia syndrome (TTS) following the first dose of the AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine should not receive a second dose of the same vaccine [WHO, 2022 ].

Precautions
Allergic reactions
Persons with a history of anaphylaxis to any other vaccine or injectable therapy should be observed for 30 minutes after vaccination in health care settings where anaphylaxis can be immediately treated.

In general, persons with an immediate non-anaphylactic allergic reaction to the first dose (such as urticaria, angioedema or respiratory symptoms, that occur within 4 hours of administration) should not receive additional doses, unless recommended after review by a health professional with specialist expertise.

Thrombosis with thrombocytopenia syndrome
A very rare syndrome of blood clotting combined with low platelet counts, which is described as thrombosis with thrombocytopenia syndrome (TTS) has been reported around 3 to 21 days following vaccination with the ChAdOx1-S vaccine. A causal relationship between the vaccine and TTS is considered plausible although the biological mechanism for this syndrome is still being investigated.

There is a considerable geographical variation regarding the reported incidence since most of these cases were notified from the United Kingdom and the European Union (EU) and very few from non-European countries, despite the extensive use of the ChAdOx1-S vaccine in these countries [WHO, 2022 ].

Evidence suggest that the risk of TTS is lower following the second dose of ChAdOx1-S vaccine than after the first dose. It is currently unknown whether there is a risk of TTS following a third dose.

The benefit–risk ratio is greatest in older age groups as the risk of severe COVID-19 disease outcomes including COVID-19 related thromboembolic events increases with age.

Current evidence does not suggest that pregnant women are at any greater risk of TTS than nonpregnant women. However, pregnancy is associated with higher rates of thrombosis, thrombocytopenia, and hemorrhage [WHO, 2022 ].

In countries with ongoing SARS-CoV-2 transmission, the benefit of vaccination in protecting against COVID-19 far outweighs the risks. However, benefit–risk assessments may differ from country to country. As data from additional studies become available, enabling a better understanding of the pathophysiology of TTS and its relationship to the vaccine, recommendations on vaccination will be updated. [WHO, 2022 ].

Neurological events
Guillain-Barré syndrome (GBS) has been reported very rarely following vaccination with ChAdOx1-S [recombinant] vaccine. However, a causal relationship with the vaccine has neither been confirmed nor ruled out and more rigorous studies are needed to fully assess the significance of these events. Based on the available data, the potential benefits of the ChAdOx1-S [recombinant] vaccine continue to outweigh any potential risk of GBS, particularly given the increase in the more transmissible variants. Health workers should be alert to possible signs and symptoms of GBS to ensure timely and accurate diagnosis (or to rule out other causes) and management of potential cases [WHO, 2022 ].

Pregnancy
Available data on vaccination of pregnant women are insufficient to assess vaccine efficacy or vaccine-associated risks in pregnancy.
WHO recommends the use of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine in pregnant women only if the benefits of vaccination 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, the likely benefits of vaccination in the local epidemiologic context, and the current limitations of the safety data in pregnant women [WHO, 2022 ].
WHO does not recommend pregnancy testing prior to vaccination. WHO does not recommend delaying pregnancy or terminating pregnancy because of vaccination [WHO, 2022 ].

Breastfeeding
Vaccine effectiveness is expected to be similar in breastfeeding women as in other adults. AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine is not a live virus vaccine and it is biologically and clinically unlikely to pose a risk to the breastfeeding child. Based on this considerations, WHO recommends the use of the AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine in breastfeeding women as in other adults [WHO, 2022 ].
WHO does not recommend discontinuing breastfeeding because of vaccination [WHO, 2022 ].

Persons living with HIV
Persons living with HIV who are well controlled on highly active antiretroviral therapy should be vaccinated. It is not necessary to test for HIV infection before administration of the vaccine [WHO, 2022 ].

Persons with previous SARS-CoV-2 infection
Vaccination may be offered regardless of a person’s history of symptomatic or asymptomatic SARS-CoV-2 infection [WHO, 2022 ].
The optimal time interval between a natural infection and vaccination is not yet known. An interval of 3 months could be considered [WHO, 2022 ].

Persons with current acute COVID-19
Persons with acute PCR-confirmed COVID-19, including between doses, should not be vaccinated until after they have recovered from acute illness and the criteria for discontinuation of isolation have been met [WHO, 2022 ].

Other precautions
EMA recommends that 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 ].

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 ].

Vaccination should be postponed in individuals with an acute febrile illness (body temperature over 38.5ºC) until they are afebrile [WHO, 2022 ].


Co-administration with other vaccines
For adults, COVID-19 vaccines may be administered concomitantly or at any time before or after other adult vaccines, including: live attenuated vaccines, inactivated, adjuvanted, or non-adjuvanted vaccines [WHO, 2022 ].
When administered concomitantly, the vaccines should be injected at separate sites, preferably different extremities [WHO, 2022 ].

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 to 8°C (36°F to 46°F) [WHO, 2021 ].
Do not freeze.
Keep vials in outer carton to protect from light.

Administration logistics

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.

Ten-dose vial: 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 taking the first dose from the multidose vial, the vial should be used within a maximum of 6 hours (stored at 2°C to 8°C [36°F to 46°F]) or discarded at the end of the immunization session, whichever comes first [WHO, 2022 ].

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.

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 accordance with local requirements. Spills should be disinfected using an appropriate antiviral disinfectant [WHO, 2021 ].

Clinical studies - general characteristics

Randomized trials 

D8110C00001 is a 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 enrolled 32459 adults ≥18 years of age that will receive the AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine compared to saline placebo. It is expected to run through February 2023. Data from the study was published on 29 September 2021 [Falsey AR, 2021 ].

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 1 112 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 over. The expected sample size is 12 390. 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 and over. The expected sample size is 10 300. Participants are randomly assigned in a 1:1 ratio to receive ChAdOx1 nCoV-19 (5.0 x 1010 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 5.0 x 1010 viral particles) or saline (0.9% NaCl) placebo 21-35 days apart [University of Witwatersrand, South Africa, 2020 ].

Com-COV was a phase 2 randomized trial sponsored by University of Oxford and conducted United Kingdom between October 2020 to November 2022. It was registered with ISRCTN69254139. The trial included participants aged 50 years and over. 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 randomized 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 randomised trial sponsored by Serum Institute of India Private Limited and conducted in 44 105 individuals since August 2020. It was registered with CTRI/2020/08/027170. The trial included healthy adults aged 18 years and over. The sample size was 1 601. 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 (5.0 × 1010 viral particles) or placebo administered at 4-week intervals (+2-week window) [Prasad S. Kulkarni, 2021 ].

ComFluCOV was a multicentre, randomized, controlled, phase 4 trial sponsored by University Hospitals Bristol NHS Foundation Trust and conducted United Kingdom between March 2021- August 2021. It was registered with ISRCTN14391248. The trial included adults in receipt of a single dose of AstraZeneca or Pfizer COVID-19 vaccine. The sample size was 679. The median age of participants by influenza vaccine type was 51 years for those receiving the cellular quadrivalent vaccine, 52 years for those receiving the recombinant quadrivalent vaccine, and 69 years for those receiving the MF59C adjuvanted, trivalent vaccine. The proportion of women was 58%. Participants were randomly assigned in a 1:1 ratio to receive concomitant administration of either an influenza vaccine or placebo alongside their second dose of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India or Pfizer COVID-19 vaccine. The intervention was administered as an age-appropriate influenza vaccine or a placebo injection in addition to alongside their second dose of a COVID-19 vaccine homologous to their first dose (AstraZeneca or Pfizer COVID-19 vaccine). At the second visit between 21 and 28 days later, those who received an influenza vaccine at day 0 received a placebo injection and vice versa [Lazarus R, 2021 ].

COV-BOOST was a blinded, multicentre, randomized, controlled, phase 2 trial sponsored by University Hospital Southampton NHS Foundation Trust and conducted in United Kingdom between May 2021 - August 2022. It was registered with ISRCTN73765130. The trial included adults aged 30 years or older, in good physical health (mild to moderate well-controlled comorbidities were permitted), who had received two doses of either Pfizer or AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine. The sample size was 2883. The median age of ChAd/ChAd-primed group was 53 years in the younger age group and 76 years in the older age group. In the BNT/BNT-primed group, the median age was 51 years in the younger age group and 78 years in the older age group. The proportion of females was 46.7% in the ChAd/ChAD-primed and 53.6% in BNT/BNT-primed group. Participants were randomly assigned in a 1:1:1:1 ratio in group A, 1:1:1:1:1 in group B, and 1:1:1:1 in Group C to receive an experimental vaccine or control. The intervention was administered as:

  1. Group A received NVX-CoV2373( Novavax), a half dose of NVX, AstraZeneca, or control quadrivalent meningococcal conjugate vaccine (MenACWY).
  2. Group B received Pfizer, VLA2001 (Valneva), a half dose of VLA, Ad26.COV2.S (Janssen) or MenACWY.
  3. Group C received mRNA1273 (Moderna), CVnCov (CureVac), a half dose of BNT, or MenACWY [Munro, Alasdair P S, 2021 ].

COV006 was a phase 1/2 participant-blinded, randomised controlled trial sponsored by University of Oxford and conducted England, United Kingdom between March 2020 to September 2022. It was registered with ISRCTN15638344.The trial included children aged 6-17 years. A preliminary report included children aged 12-17 years with a sample size of 150. The median age of the participants was 15 years and the proportion of women was 49%. Participants were randomly assigned in a 4:1:4:1 ratio to receive two doses of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine or control. The intervention was administered as a two-dose series of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine or capsular group B meningococcal with a 28 days interval (short-interval), or a two-dose series of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine or capsular group B meningococcal second doses with an 84 days interval (long-interval) [Grace Li, 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 the 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 the 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 the AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine (5.0 x 1010 viral particles) given as a homologous prime boost schedules (28 and 84 days interval post prime). It is expected to run through September 2022.

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 aged 18 years and over that will receive the 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 the 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 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 aged 18 years and over 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 trial (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 trial (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 over 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, aged 18 years and over. 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 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 randomized trial (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 1 020 adults aged 18 years and over that will receive MVC-COV1901 or AZD1222. It is expected to run until June 2022.

CT-COV-24 is an ongoing phase II, prospective, randomized, observer-blinded, multi-Center (registered with the number NCT05197153 [Medigen Vaccine Biologics Corp., 2022 ]) sponsored by Medigen Vaccine Biologics Corp. that is being conducted in Taiwan. It was first registered in January 2022 and plans to enroll 960 participants aged between 18 years to 80 years that received that will receive a heterologous booster dose With AstraZeneca, Moderna, or MVC-COV1901 COVID-19 vaccine. It is expected to run until December 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 over (over 7.5 million) from December 2020 to February 2021 vaccinated with either BNT162b2 or the 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 the 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).

Suntronwong N et al. was a comparative cohort study conducted in Thailand [Nungruthai Suntronwong, 2022 ], evaluating immunogenicity results from adult individuals who had received two doses of Sinovac COVID-19 vaccine and a booster dose of AstraZeneca COVID-19 vaccine.

Spensley K et al. was a cohort study conducted in United Kingdom [Katrina Spensley, 2022 ], evaluating vaccine effectiveness against the Omicron (B.1.1.529) variant in patients receiving haemodialysis.

The VIVALDI study was a cohort study conducted in United Kingdom [Oliver Stirrup, 2022 ], evaluating immunogenicity results from older adults residents of long-term care facilities who received two-dose of AstraZeneca or Pfizer COVID-19 vaccine.

Lytras T et al. was a comparative cohort study conducted in Greece [Theodore Lytras, 2022 ], evaluating vaccine effectiveness from individuals aged 15 years and over who had received two doses of Pfizer, Moderna, AstraZeneca COVID-19 vaccine or a single-dose of Janssen COVID-19 vaccine.

7 vaccines against COVID 19 is an ongoing prospective Cohort study (registered with the number NCT05228912 [Hospital Clinica Nova, 2021 ]) sponsored by Hospital Clinica Nova that is being conducted in Mexico. It was first registered in February 2022 and plans to enroll 1870 Children, Adult and Older Adult that will receive Pfizer-BioNTech, Moderna, Gamaleya, Cansino, Sinovac, Astrazeneca and Janssen COVID-19 vaccines. It is expected to run until October 2024.

Ranzani OT et al. was a Case-control study (test-negative) conducted in Brazil [Ranzani OT, 2022 ], evaluating vaccine effectiveness from individuals in a socially vulnerable community after the first and second dose of AstraZeneca COVID-19 vaccine when Gamma and Delta were the predominant variants circulating.

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 trial (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-Oxford/SK Bioscience/Serum Institute of India 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 over 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 trial (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 over 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 trial (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 2 200 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 trial (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 over 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 trial (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 15 000 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 individuals aged 18 years and over 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 trial (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, aged 18 years and over 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 trial (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 trial (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 aged 18 years and over that will receive Gam-COVID-Vac, CoronaVac, or ChAdOx1. It is expected to run until July 2022.

COVACC2 is an ongoing non-randomized trial (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  non-randomised trial (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 trial (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 over that will receive Pfizer, Moderna, Janssen, or AstraZeneca COVID-19 vaccine. End of study: date not available.

CVG01 is an ongoing non-randomized trial (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 over 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 trial (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, aged 18 years and over. Participants will receive virus vector ChAdOx-1 nCoV-19 and inactivated vaccine CoronaVac. It is expected to run until June 2022.

Stupica D et al. is an ongoing observational study (registered with the number NCT05198453) sponsored by University Medical Centre Ljubljana that is being conducted in Slovenia [University Medical Centre Ljubljana, 2021 ]. It was first registered in January 2022 and plans to enroll 529 participants 18 years and over that received Pfizer, Moderna, AstraZeneca, or Janssen COVID-19 vaccine. It is expected to run for until January 2022.

STOPCoV is an ongoing cohort study (registered with the number NCT05208983 [University Health Network, Toronto, 2021 ]) sponsored by University Health Network, Toronto that is being conducted in Canada. It was first registered in January 2022 and plans to enroll 1286 individuals aged 30-50 years and individuals aged 70 years and over that will receive Pfizer, Moderna, Janssen, or AstraZeneca COVID-19 vaccines. It is expected to run until March 2024.

As-Vac-CoV is an ongoing non-randomized study (registered with the number EudraCT 2021-006832-24 [Ziekenhuis Oost-Limburg A.V., 2021 ]) sponsored by Ziekenhuis Oost-Limburg A.V. that is being conducted in Belgium. It was first registered in December 2021 and plans to enroll 2600 individuals aged 18 years and older that will receive a second dose or booster dose of AstraZeneca, Moderna, or Pfizer COVID-19 vaccine. End of study: date not available.

Methods used to assess efficacy

Primary efficacy endpoint in phase 3 trials 

D8110C00001 trial [Falsey AR, 2021 ] efficacy of the vaccine against COVID-19 in adults aged 18 years and over measured by virologically confirmed (PCR or other nucleic acid amplification test) symptomatic cases of COVID-19.

COV002 trial [University of Oxford, 2020 ] efficacy of the vaccine against COVID-19 in adults aged 18 years and over 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.

Safety evaluation methods

Primary safety endpoints in phase 3 trials 

D8110C00001 trial [Falsey AR, 2021 ] unsolicited adverse events recorded for all participants for 28 days after each dose and serious adverse events recorded until day 730.

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.

Vaccine efficacy and effectiveness

Efficacy of preclinical studies on the vaccine

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]).

The D8110C00001 [Falsey AR, 2021 ], was a phase 3 randomized trial, that included 34,117 participants who received the AstraZeneca / Oxford COVID-19 vaccine or placebo. Participants that were seronegative at baseline showed a large vaccine-induced serum IgG response to spike protein. Neutralizing antibody levels were higher than baseline at different measurement points in the vaccine group, increasing further after the second dose. However, they remained low throughout the trial in the placebo vaccine group.

ICMR / IBS-COVISHIELD was a phase 2/3 randomized trial, which included 1601 participants who received the AstraZeneca/Oxford COVID-19 vaccine or the Serum Institute of India (ISS) COVID-19 vaccine. The trial included the immune response of the participants. Results showed that in the immunogenicity/reactogenicity cohort (n = 401) baseline anti-S IgG antibody titers were <100 (AU)/ml in the SII and AstraZeneca/Oxford COVID-19 vaccine groups. One month after the first dose (day 29), the GMTs were >6600 AU/ml in both groups, and one month after the second dose, the GMTs were >28500 AU/ml in both groups, this means that there was a 325-fold increase in antibody titers in both groups compared to baseline. In both vaccine groups, >91% of participants demonstrated seroconversion after the first dose and ≥98% demonstrated seroconversion after the second dose. These means that ISS COVID-19 vaccine showed a non-inferior immune response compared to the AstraZeneca/Oxford COVID-19 vaccine [Prasad S. Kulkarni, 2021 ].

Key messages

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

AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine probably reduces the risk of contracting severe 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 placebo vaccine was 0.36 (95% CI 0.21 to 0.61). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting COVID-19 in 64%, compared with placebo 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 placebo vaccine

In the trial identified in this review, 476 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 17131 presented this outcome (28 per 1000) versus 234 out of 26259 in the group that did receive it (10 per 1000). In other words, 18 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.8%, or that the intervention reduced the risk of contracting COVID-19 by 1.8 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 56. Which means that 56 people need to receive the vaccine for one of them to not contract COVID-19.

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)

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 placebo vaccine was 0.09 (95% CI 0.01 to 0.93). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting severe COVID-19 in 91%, compared with placebo vaccine.

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

In the trial identified in this review, 9 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 20274 presented this outcome (4 per 10000) versus 0 out of 29683 in the group that did receive it (0 per 10000). In other words, 4 less people per 10000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.04%, or that the intervention reduced the risk of contracting severe COVID-19 by 0.04 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 2500. Which means that 2500 people need to receive the vaccine for one of them to not contract severe COVID-19.

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

Mortality

The existing evidence does not allow to assess the impact of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine on the risk of death attributable to COVID-19. The information provided by randomized trials was not adequately powered to estimate a difference in this outcome. Deaths can occur in the intervention and control group for reasons unrelated to COVID-19 or the vaccine. Establishing that there is a reduction (or increase) in the risk of death attributable to Moderna COVID-19 vaccine would require trials with a higher statistical power.

Efficacy of the vaccine in subgroups

Contracting COVID-19 (>65y) (measured at least 14 days after the second injection)

The relative risk of contracting COVID-19 in > 65-year-old participants in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received placebo vaccine was 0.18 (95% CI 0.06 to 0.49). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting COVID-19 in > 65-year-old participants in 82%, compared with placebo vaccine.

Figure - Forest plot of risk ratio meta-analysis. Outcome: contracting COVID-19 in >65 year old participants. Comparison: AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus placebo vaccine

In the trial identified in this review, 14 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 1812 presented this outcome (8 per 1000) versus 5 out of 3696 in the group that did receive it (1 per 1000). In other words, 7 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.7%, or that the intervention reduced the risk of contracting COVID-19 in >65 year old participants by 0.7 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 143. Which means that 143 people need to receive the vaccine for one of them to not contract severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

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

The relative risk of contracting COVID-19 in the female subgroup in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received placebo vaccine was 0.33 (95% CI 0.21 to 0.52). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting COVID-19 in the female subgroup by 67%, compared with the placebo.

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

In the trial identified in this review, 46 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 3721 presented this outcome (12 per 1000) versus 32 out of 7740 in the group that did receive it (4 per 1000). In other words, 8 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 0.8%, or that the intervention reduced the risk of contracting COVID-19 in female subgroup by 0.8 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 125. Which means that 125 people need to receive the vaccine for one of them to not contract severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

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

The relative risk of contracting COVID-19 in the male subgroup in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received placebo vaccine was 0.24 (95% CI 0.16 to 0.34). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine reduced the risk of contracting COVID-19 in male subgroup in 76%, compared with placebo vaccine.

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

In the trial identified in this review, 84 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 4829 presented this outcome (17 per 1000) versus 41 out of 9922 in the group that did receive it (4 per 1000). In other words, 13 less people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk reduction of 1.3%, or that the intervention reduced the risk of contracting COVID-19 in male subgroup by 1.3 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 77. Which means that 77 people need to receive the vaccine for one of them to not contract severe COVID-19.

Applying the GRADE approach [The GRADE Working Group, 2013 ], we assessed the certainty of the evidence for this outcome as low. The certainty of the evidence is based in the following judgments: Risk of bias: no concerns; Inconsistency: no concerns; Indirectness: the information available is based on a short term follow-up; Imprecision: the information provides from a small sample; Publication bias: no concerns.

Summary of findings (iSoF)

Efficacy and effectiveness of the vaccine in subgroups

Sex

Randomized trials

The proportion of females in the combined analysis of COV002 and COV003 was 60.5% (7,045 out of 11,636 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% (1 418 out of 11 636 participants) [Voysey, Merryn, 2021 ].

The efficacy in the 18-55 years group in the different trials, doses and administration schedules ranged from 59.3% to 65.6%. These results were not statistically different from the efficacy of the vaccine in the overall group [Voysey, Merryn, 2021 ].

Efficacy estimates for different ages 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 the 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 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).

The VIVALDI study included 1317 samples from 402 residents and 632 staff fully vaccinated (AstraZeneca=593; Pfizer=534). Data were collected 21 days after the second dose. The study showed that two-dose of AstraZeneca or Pfizer COVID-19 vaccine elicits robust and stable antibody responses in older Long-Term Care Facility residents, consistent with overall levels of vaccine-induced immunity [Oliver Stirrup, 2022 ].

 

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 randomized study">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 ].

Other 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 AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccines [University Hospital, Strasbourg, France, 2021 ].

The randomized study">non-randomized study COVAC-IC is currently evaluating the effectiveness/safety of the vaccine in immunocompromised and immunocompetent hematology 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 ].

The randomized study">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 ].

 Spensley K et al. included 1121 patients on hemodialysis. All patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between December 1, 2021, and January 16, 2022. The study showed that partial vaccination did not provide protection against infection. Vaccine effectiveness against Omicron infection in patients who had received a booster vaccine was 58%. Analysing vaccine effectiveness in the 747 patients who had been boosted, significant effectiveness was seen in both patients who received AstraZeneca COVID-19 vaccine (47%)and Pfizer COVID-19 vaccine (66%) [Katrina Spensley, 2022 ].


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.

Other data on vaccine efficacy and effectiveness

Main effectiveness outcomes of AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine (Other studies)

Contracting COVID-19

Ghosh S et al. was a comparative cohort study conducted in India. The study enrolled 1,595,630 participants (1,312,938 Vaccine group; 282,692 Control group). Based on data from the existing surveillance system among Health Care Workers and Frontline Workers of the Indian Armed Forces from January 16 until May 30, 2021. The cohort transitioned from unvaccinated to fully vaccinated, serving as its own internal comparison. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 94.9% (95% CI 92.5 to 96.6) [Ghosh S, 2021 ].

Pritchard E et al. was a cohort study conducted in United Kingdom. The study enrolled 373,402 participants (99,267 Vaccine group; 274,135 Control group). Based on data from the existing surveillance system among Health Care Workers and Frontline Workers of the Indian Armed Forces from January 16 until May 30, 2021. The cohort transitioned from Unvaccinated to Fully Vaccinated, serving as its own internal comparison. The outcome was measured from 21 days after the second dose. The result of the study found vaccine effectiveness of 79% (95% CI 65 to 88).[Pritchard E et al., 2021 ].

Lopez Bernal J et al. was a case-control study conducted in the United Kingdom. The study enrolled 156,930 participants (76,385 received AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine). Based on a test-negative design including individuals aged 70 years and over in England from 6 October 2020 to 21 February 2021. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 73% (95% CI 27 to 90). [Lopez Bernal J, 2021 ].

Hitchings M et al. was a case-control study conducted in Brazil. The study enrolled 61,164 participants (30,680 Vaccine group; 30,680 Control group). Based on test negative control design using individual-level information from adults ≥60 years of age who had a residential address in São Paulo State on 9 July 2021 from the SES-SP laboratory testing registry, the national surveillance databases for acute respiratory illness (ARI) and severe ARI, and the SES-SP vaccination registry. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 77.9% (95%CI 69.2 to 84.2). [Matt Hitchings, 2021 ].

Pramod S et al. was a case-control study conducted in India. The study enrolled 720 participants (360 Vaccine group; 360 Control group). Based on test negative control design using individual-level information from healthcare workers in Puducherry, India. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 54% (95% CI 27 to 71). [Stuti Pramod, 2021 ].

Alireza Mirahmadizadeh et al. was a cohort study conducted in Iran. The study enrolled 1,882,148 participants: 881,638 vaccine group; 1,000,510 control group. Based on data derived from administrative repositories during mass-vaccination campaigns or programs between February 09, 2021 and the end of follow-up in October 22, 2021; the study results showed a vaccine effectiveness of 84.4% (95%CI 83.5 to 85.3%) against infection, 81.5% (95%CI 79.5 to 83.4%) against hospitalization and 91.8% (95%CI 88.2 to 95.4%) against death [Alireza Mirahmadizadeh, 2022 ].

Chadeau-Hyam M et al. was a cohort study conducted in United Kingdom. The study enrolled 172,862 participants: 76,291 vaccine group; 96,571 control group. Based on data from a series of random cross-sectional surveys in the general population of England aged 5 years and older, between May 2020 and September 2021, the study results showed a vaccine effectiveness of 44.8% (95%CI 22.5 to 60.7) against infection in vaccinated individuals [Chadeau-Hyam M, 2022 ].

Ranzani OT et al. was a case-control study (test-negative) conducted in Brazil. The study included 10,077 RT-qPCR tests : 6,394 symptomatic group; 3,683 asymptomatic group. Based on a community-program testing database with the vaccination campaign database, between January 2021 and November 2021. The study results showed adjusted vaccine effectiveness against symptomatic COVID-19 was 31.6% (95% CI 12.0 to 46.8) after 21 days of first dose and 65.1% (95% CI 40.9 to 79.4) after 14 days of second dose. In addition, adjusted vaccine effectiveness against COVID-19 infection was 31.0% (95% CI 12.7 to 45.5) after 21 days of first dose and 59.0% (95% CI 33.1to 74.8) after 14 days of second dose [Ranzani OT, 2022 ].

Sritipsukho P et al. was a case-control study conducted in Thailand. The study enrolled 3,353 participants. Based on a test negative design of consecutive individuals (age ≥18 years) at-risk for COVID-19 who presented for nasopharyngeal real-time polymerase chain reaction (RT-PCR) testing between 5 July 2021 and 23 October 2021 that were prospectively enrolled and followed up for disease development, the study results showed a vaccine effectiveness of 83% (95% CI, 70–90%) [Sritipsukho P, 2022 ].

Rearte A et al. was a case control study conducted in Argentina. The study included 358,431 individuals in the analysis of ChAdOx1 nCoV-19 vaccine: 126,531 in the case group and 231,900 in the control group. The study assessed the effectiveness of three vaccines (rAd26-rAd5, ChAdOx1 nCoV-19, and BBIBP-CorV) on SARS-CoV-2 infection and risk of death in people with RT-PCR confirmed COVID-19, using data from the National Surveillance System (SNVS 2.0). All individuals aged 60 years or older reported to SNVS 2.0 as being suspected to have COVID-19 who had disease status confirmed with RT-PCR were included in the study. The odds ratio of the ChAdOx1 nCoV-19 vaccine on the risk of SARS-CoV-2 infection in individuals with only one dose was OR 0.6 (95% CI 0.59 to 0.61). After the second dose was OR 0.32 (95% CI 0.31 to 0.33) [Rearte A, 2022 ].

Fano V et al. was a comparative cohort study conducted in Italy. The study included 371,423 participants: 221,000 received Pfizer vaccine and 150,423 received AstraZeneca vaccine. The study estimated the effectiveness of Pfizer and AstraZeneca vaccines since 27/12/2020, and followed until diagnosis of SARS-CoV-2 infection or 25/4/2021, whichever came first. Adjusted hazard ratios of SARS-CoV-2 infection at weekly intervals since the first dose were estimated through a Cox regression model using 0-13 days as reference time-interval. Adjusted AstraZeneca vaccine effectiveness between 49 and 55 days was 63.2% ( 95%CI 24.8 to 82) [Fano V, 2022 ].

 

Marra AR et al was a retrospective cohort study conducted in Brazil. The study included 13,813 health care workers (aged ≥18 years) working in a private healthcare system in Brazil between January 1, 2021 and August 3, 2021, to assess vaccine effectiveness. In total, 13,813 HCWs met the inclusion criteria for this analysis. Among them, 6,385 (46.2%) received the CoronaVac vaccine, 5,916 (42.8%) received the ChAdOx1 vaccine, and 1,512 (11.0%) were not vaccinated. Vaccine effectiveness against COVID-19 infection was 87.9% (95% CI 82.6 to 91.6). [Marra AR, 2022 ]


Contracting severe COVID-19

Lopez Bernal J et al. was a case-control study conducted in the United Kingdom. The study enrolled 156,930 participants (76,385 received the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine). Based on a test-negative design including individuals aged 70 years and over in England from 6 October 2020 to 21 February 2021. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 37% (95% CI 13 to 59) [Lopez Bernal J, 2021 ].

Alencar CH et al. was a comparative cohort study conducted in Brazil. The study enrolled 313,328 participants: 159,970 Vaccine group (27,193 received the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine) and 40 941 Control group. Based on a retrospective data analysis from people aged 75 years and over from the National Mortality System (SIM) and from the Immunization Program (SIPNI), between 17 January and 11 May 2021. The outcome was measured from 21 days after vaccination. The result of the study found vaccine effectiveness of 99.8 (95% CI 99.6 to 99.9) [Alencar CH, 2021 ].

Ghosh S et al. was a comparative cohort study conducted in India. The study enrolled 1,595,630 participants (1,312,938 Vaccine group; 282,692 Control group). Based on data from the existing surveillance system among Health Care Workers and Frontline Workers of the Indian Armed Forces from January 16 until May 30, 2021. The cohort transitioned from unvaccinated to fully vaccinated, serving as its own internal comparison. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 98.53% (95% CI: 0.00 to 99.9). [Ghosh S, 2021 ].

Hitchings M et al. was a case-control study conducted in Brazil. The study enrolled 61,164 participants (30,680 Vaccine group; 30,680 Control group). Based on test negative control design using individual-level information from adults ≥60 years of age who had a residential address in São Paulo State on 9 July 2021 from the SES-SP laboratory testing registry, the national surveillance databases for acute respiratory illness (ARI) and severe ARI, and the SES-SP vaccination registry. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 87.6% (95% CI 78.2 to 92.9). [Matt Hitchings, 2021 ].

Pramod S et al. was a case-control study conducted in India. The study enrolled 720 participants (360 Vaccine group; 360 Control group). Based on test negative control design using individual-level information from healthcare workers in Puducherry, India. The outcome was measured from 14 days after vaccination. The result of the study found vaccine effectiveness of 95% (95% CI 44 to 100). [Stuti Pramod, 2021 ].

Sheikh A 2021, was a cohort study conducted in Scotland. This study used data from a national surveillance database to estimate vaccine effectiveness against death from delta variant infection between April 1 and August 16, 2021, among adult participants who were followed up to September 27, 2021. Mortality analysis was based on 114,706 adults who tested positive for SARS-CoV-2 and a total of 201 deaths were reported. Among participants between 40 and 59 years of age, vaccine effectiveness against death from COVID-19 was 88% (95% CI, 76 to 93) for ChAdOx1 nCoV-19 and 95% (95% CI, 79 to 99) for BNT162b2. Among participants aged 60 years or older vaccine effectiveness was 90% (95% CI, 84 to 94) and 87% (95% CI, 77 to 93), respectively. Overall, vaccine effectiveness against death from the delta variant 14 or more days after the second vaccine dose was 90% (95% CI, 83 to 94) for BNT162b2 and 91% (95% CI, 86 to 94) for ChAdOx1 nCoV-19. [Sheikh A, 2021 ]

Suah JL et al. was a cohort study conducted in Malaysia. The study enrolled 1,239,445 participants: 489,921 Vaccine group; 749,524 Control group and was based on data from four secondary data sets constructed from national COVID-19 surveillance: (1) the COVID-19 cases line listing, (2) the ICU admissions register, (3) the COVID-19 deaths line listing, and (4)the COVID-19 vaccine recipients line listing, linked deterministically with the case and personal identification numbers, between 1 April 2021 and 15 September 2021. The outcome was measured starting 14 days after the second dose. The study results showed vaccine effectiveness of 95.6% (95%CI 88.3 to 98.4) for ICU admission and 95.3% (95%CI 91.3 to 97.4) for Death in vaccinated individuals. [Suah JL, 2021 ]

Alireza Mirahmadizadeh et al. was a cohort study conducted in Iran. The study enrolled 1,882,148 participants: 881,638 vaccine group; 1,000,510 control group. Based on data derived from administrative repositories during mass-vaccination campaigns or programs between February 09, 2021 and the end of follow-up in October 22, 2021; the study results showed a vaccine effectiveness of 84.4% (95%CI 83.5 to 85.3%) against infection, 81.5% (95%CI 79.5 to 83.4%) against hospitalization and 91.8% (95%CI 88.2 to 95.4%) against death [Alireza Mirahmadizadeh, 2022 ] 

Lytras T et al. included a total of 14,676,605 vaccine administered doses ( Pfizer= 11,427,784; Moderna=1,161,905; AstraZeneca=1,505,334; Janssen= 581,582). Data were collected between 11 January 2020 and 8 December 2021. The study showed that two doses of Pfizer, Moderna, or AstraZeneca COVID-19 vaccines offered vaccine effectiveness >90% against both intubation and death across all age groups. The effectiveness of the Janssen COVID-19 vaccine was ranged between 61-81%. There was some waning over time but vaccine effectiveness remained >80% at six months, and three doses increased vaccine effectiveness again to near 100%. Vaccination prevented an estimated 19,691 COVID-19 deaths (95% CI 18,890 to 20,788) over the study period [Theodore Lytras, 2022 ].

Taherian Z et al. conducted a cohort study in Iran which included 583,434 vaccinated individuals and 2,551,140 unvaccinated persons.Based on data of all vaccinated individuals from March 2020 to August 2021. Data of unvaccinated individuals were collected from the census for this period. Vaccine effectiveness as risk reduction rate for infection was 99, for hospitalization was 99.4 and for death it was 100 [Taherian Z, 2022 ].

Arregocés-Castillo et al. was a retrospective cohort study conducted in Colombia. The study included 2,828,294 participants: 1,414,147 fully vaccinated (any vaccine) and 1,414,147 unvaccinated. The study evaluated the effectiveness of vaccines against COVID-19-related hospitalization and death in people aged 60 years and older. Participant follow-up was done between March 11, 2021, and Oct 26, 2021.It was estimated the overall effectiveness of being fully vaccinated, as well as effectiveness for each vaccine. The aim results showed that vaccine effectiveness against hospitalization without death was 90.8% (95% CI 85.5 to 94.2) in adults > 60 years. Effectiveness against death after hospitalization was 97.5% (95% CI 95.8 to 98.5) and against death without hospitalization was 93.9% (95% CI 89.3 to 96.6) in adults > 60 years [Arregocés-Castillo L, 2022 ].

 

Elsie MF Horne et al. was a comparative cohort  study conducted in England. The study included data from the OpenSAFELY-TPP database. The study included 1,773,970 individuals with BNT162b2 vaccine,  2,961,011 individuals with ChAdOx1 vaccine and 2,433,988 unvaccinated individuals. The study compared individuals who had received two doses of BNT162b2 or ChAdOx1 with unvaccinated individuals during six 4-week comparison periods, separately by age subgroups. The Hazard Ratio versus unvaccinated for COVID-19 hospitalization ranged from (≥ 65 years) 1.16 (95% IC 0.98 to 1.37) to 1.20 (95% IC 1.14 to 1.27) for ChAdOx1 vaccine. Rates of COVID-19 hospitalization and COVID-19 death at week 26 showed HRs <0.26 (>74% vaccine effectiveness) for ChAdOx1 [Elsie MF Horne, 2022 ].


Transmission

No studies reported or assessed this outcome.


SARS-CoV-2 variants

Immunogenicity outcomes

Emary KRW et al. was a randomized trial conducted in the UK (COV002 phase 2/3). The study included 8,534 participants ≥ 18 years old (4,244 in the vaccinated group and 4,290 in the control group). The study measured neutralizing antibody responses using a live virus microneutralization assay against lineage B.1.1.7 and a non-canonical lineage B.1.1.7 (Victoria). The neutralization activity of the laboratory virus by the antibodies induced by the vaccine was lower against variant B.1.1.7 than against the Victoria lineage (Geometric mean ratio 8.9 (95% CI: 7.2–11.0 )) [Emary KRW, 2021 ].

Suntronwong N et al. included 458 fully vaccinated participants (2 doses Sinovac=248; 2 doses Sinovac plus AstraZeneca booster=210). Data were collected 34 days after infection. The study showed that binding antibody levels in sera from patients with breakthrough infection were significantly higher than those in individuals who had received AstraZeneca as a booster dose. However, neutralizing activities against wild-type and variants including alpha, beta, and delta were similar between patients with breakthrough infections and those who received a booster vaccination with AstraZeneca. Omicron was neutralized less effectively by serum from breakthrough infection patients, with a 6.3-fold reduction compared to delta variants [Nungruthai Suntronwong, 2022 ].

Madhi SA et al. was a randomized trial conducted in South Africa (COV005 phase 1/2). The study included 2,021 participants ages 18 to 65 (1,011 in the vaccine group and 1,010 in the placebo group). The study measured neutralizing antibody titers and anti-SARS-CoV-2 spike-binding antibody (bAb) levels 28 days after two standard doses (5.0 × 1010 viral particles). Vaccination recipients had greater resistance to variant B.1.351 than placebo recipients. They showed an antibody response after the first dose with a mean titer 131.57 (95% CI 20 to 403.72) and after the second dose, a mean titer 276.61 (95% CI 123.96 a 525.46) The geometric mean titers fell from 297 against the parent virus to 85 against the RBD only mutant and 74 against the B.1.351 variant [Madhi SA, 2021 ].

Angkasekwinai N et al. was a cohort study conducted Thailand . Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that for both the Sinovac-prime and AstraZeneca-prime groups, the PRNT50 GMT against the Delta and Beta variant was significantly higher among those who received a booster dose of Pfizer (30µg or 15µg) compared to those who received AstraZeneca or Sinopharm/ BIBP. In addition, there was no statistical difference in PRNT50 between boosting with 30µg and 15µg- Pfizer regardless of the primary series vaccine and the type of variants. However, the PRNT50 against the Beta variant was in general around 1.5-fold lower than the Delta variants for both CoronaVac-prime and ChAdOx1-prime groups. The GMRs of the PRNT50 between post-boost and post-primary series were highest among the participants who received Pfizer boosting vaccination in bothSinovac-prime and AstraZeneca-prime groups. The SARS-CoV-2 RBD IgG levels and the neutralizing titers against Delta variant or Beta variant were strongly correlated.[ ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as second dose had significantly higher neutralizing titers against Delta and Beta than the groups that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and were 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against both the Delta and Omicron variants were significantly lower among groups who received Sinovac as a second dose compared to the other groups. Seropositivity rate for the Omicron variant was: 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].


Efficacy outcomes

Emary KRW et al. was a randomized trial conducted in the United Kingdom (COV002 phase 2/3). The study included 8 534 participants ≥18 years (4,244 in the vaccinated group and 4,290 in the control group). The study measured neutralizing antibody responses using a live virus microneutralization assay against lineage B.1.1.7 and a non-canonical lineage B.1.1.7 (Victoria). The results measured at least after 14 days after applying the second dose showed an efficacy of 70.4% (95% CI: 43.6 to 84.5) against primary symptomatic COVID-19 and an efficacy of 28.9% (95% CI −77.1 to 71.4) against asymptomatic or unknown infection [Emary KRW, 2021 ].

Madhi SA et al. was a randomized trial conducted in South Africa (COV005 phase 1/2). The study included 2 021 participants ages 18 to 65 (1,011 in the vaccine group and 1,010 in the placebo group). The study measured neutralizing antibody titers and anti-SARS-CoV-2 spike-binding antibody (bAb) levels 28 days after two standard doses (5.0 × 1010 viral particles). The results measured at least after 14 days after applying the second dose showed that among the 42 participants with COVID-19, 39 cases (92.9%) were caused by variant B.1.351, obtaining an efficacy of the vaccine of 10.4% (95% CI, −76.8 to 54.8) IR 73.1 (94,881) [Madhi SA, 2021 ].


Effectiveness outcomes 

López Bernal J. et al. carried out a case-control study (test-negative) in England, which included 19,109 COVID-19 cases (the alpha variant was detected in 14,837 samples). The study sought to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) during the period when the delta variant began a circular. The results showed an Effectiveness of vaccination against symptomatic disease of 74.5% (95% CI, 68.4 to 79.4) [Lopez Bernal J, 2021 ]. 

López Bernal J. et al. carried out a case-control study (test-negative) in England, which included 19,109 COVID-19 cases (the delta variant was detected in 4,272 samples). The study sought to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) during the period when the delta variant began to circulate. The results showed an effectiveness of vaccination against symptomatic disease of 67.0% (95% CI, 61.3 to 71.8) [Lopez Bernal J, 2021 ].

Spensley K et al. included 1121 patients on hemodialysis. All patients underwent weekly screening for SARS-CoV-2 infection via RT-PCR testing between December 1, 2021 and January 16, 2022. The study showed that partial vaccination did not provide protection against infection. Vaccine effectiveness against Omicron infection in patients who had received a booster vaccine was 58%. Analysing vaccine effectiveness in the 747 patients who had been boosted, significant effectiveness was seen in both patients who received AstraZeneca COVID-19 vaccine (47%)and Pfizer COVID-19 vaccine (66%) [Katrina Spensley, 2022 ]. 

Kislaya I et al. was a case-control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech or Moderna. Based on dat from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against Delta variant was44.1% (95% CI: 41.9  to 46.1) for the primary scheme, and 93.1% (95% CI: 91.7 to 94.3) for the booster. [Irina Kislaya, 2022 ]

McKeigue PM et al. was a case-control study conducted in Scotland, the study registered 5,645 severe cases and 50,096 controls, based on data from a subset of patients from   REACT-SCOTpresenting from Dec 1, 2020, to Sept 8, 2021, ensuring follow-up for at least 14 days after the presentation date. Effectiveness against developing severe COVID-19 during the Delta variant predominant period for AstraZeneca vaccine was 61% (95%CI: 53 to 68) for one dose and 89% (95%CI: 82 to 85) for two doses. [3ce44c0c897c319be33285d193cee9c4125ff6d5]

Kislaya I et al. was a case-control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech or Moderna. Based on data from RT-PCR SARS-CoV-2 positive cases were notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal from December 6 to 26, 2021. The effectiveness against Omicron variant was-7.1% (95% CI: -31.0 to 11.9) for the primary scheme, and 64.2% (95% CI: 36.8 to 79.4)  for the booster [Irina Kislaya, 2022 ].

Andrews N et al. was a case-control study conducted in England. The study enrolled 2,663,549 vaccinated participants: 204,154 cases for Delta variant, 886,774 cases for Omicron variant and 1,572, 621 test-negative controls. The study analyzed information from national databases, Pillar 1, Pillar 2, NIMS and NHS regarding Covid-19 vaccination, testing, and variants from November 25, 2021, through January 12, 2022. AstraZeneca effectiveness against Delta variant for symptomatic infection was 42.9% (95% CI 39.8 to 45.9) 4 weeks after the first dose, 43.5% (95% CI 42.4 to 44.5) 25 weeks after the second dose, 88.1% (95% CI 86.7 to 89.3) 10 weeks after a Pfizer-BioNTech booster, 94.9% (95% CI 93.8 to 95.9) 5-9 weeks after a Moderna booster and 83.3% (95% CI 69.7 to 90.8) 5-9 after AstraZeneca booster [Andrews N, 2022 ].

  

Booster dose

Immunogenicity outcomes

COV002 is a phase 2/3 randomized trial sponsored by the University of Oxford and conducted in the United Kingdom that started on 28 May 2020. The study included 552 healthy adults aged 18 years and over: 206 in the low-dose group (2.2 × 1010 viral particles); 208 in the standard-dose group (3.5 – 6.5 × 1010 virus particles). Anti-SARS-CoV-2-spike binding antibody (bAb) levels 28 days following the booster dose were measured. Result showed neutralizing antibody titres after a boost dose were similar across all age groups [Ramasamy, Maheshi N, 2021 ].

COV001 phase 1/2 randomized trial was conducted in the United Kingdom. The study included 52 healthy adults 18 to 55 years: 20 in the low-dose group (2.2 × 1010 viral particles); 32 in the standard-dose group (5.0 × 1010 viral particles). The result showed total antigen-specific T cell responses peaked 28 days after a second 5.0 × 1010 viral particles dose of ChAdOx1 nCoV-19. There was no significant difference in the magnitude of spike-specific T cell responses at 28 days following boost vaccination between the 28 or 56 days interval groups [Barrett JR, 2020 ].

Andrews N et al. was a case-control study (Test-negative) conducted in the United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against the symptomatic disease, hospitalization, and death in adults in England. The study results showed that PRNT50 at 2 weeks after booster dose were: 69.1 ( 95% CI 50.14 to 95.14) against Delta variant and 28.1 (95% CI 18.08 to 43.53) against Beta variant
[Andrews N, 2022 ].

Vargas L et al. was a comparative study conducted in Chile. The study included blood samples from different individuals; healthcare personnel volunteers from Hospital La Florida, and adult healthy volunteers aged 18 years and over. This study describes the production of IgG antibodies directed against the ancestral SARS-CoV-2 S protein induced by the two-dose scheme of the Coronavac vaccine in a Health Service of the Hospital La Florida, Santiago. In addition, The study analyzed the impact of the booster doses of Sinovac, Pfizer, or AstraZeneca COVID-19 vaccines, administered to individuals vaccinated with the two-dose scheme with CoronaVac six months earlier. Study results showed that two doses of Sinovac induce antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the Pfizer vaccine. However, the response induced by Sinovac can be greatly potentiated with a heterologous booster scheme with Pfizer or AstraZeneca vaccines. Furthermore, the heterologous booster regimes induce a durable antibody response that does not show signs of decay 3 months after the booster dose [Leonardo Vargas, 2022 ].

 

Heterologous vaccine regimens

Immunogenicity outcomes

Com-COV was a phase 2 randomized trial. The trial included 830 healthy adults aged 50 years and over: 115 Pfizer/ AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine; 114 ​​AstraZeneca/ Pfizer vaccine group; 234 Control group (Two doses of the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine or Pfizer COVID-19 vaccine). Immunogenicity was measured anti-SARS-CoV-2-spike binding antibody (bAb) levels 28 days following the second dose. Results showed SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher versus homologous vaccine schedule [Liu X, 2021 ].

CombiVacS was a phase 2 randomized trial. The trial included 676 adults aged 18-60 years: 450 in the intervention group (ChAd/BNT ); 226 in the control group. Immunogenicity was measured 14 days following the second dose. BNT162b2 given as a second dose in individuals prime vaccinated with ChAdOx1-S induced a robust immune response [Borobia AM, 2021 ].

ComFluCOV was a phase 4, randomized controlled trial. The trial included 679 volunteers aged ≥ 18 years: 129 AstraZeneca /QIVc group; 146 AstraZeneca /aTIV group; 128 AstraZeneca /QIVr group; 139 Pfizer /QIVc group; 79 Pfizer/ aTIV group; 58 Pfizer/ QIVr group. Immunogenicity was measured 21 days after receiving Astrazeneca. Results showed concomitant vaccination with AstraZeneca COVID-19 vaccine plus an age-appropriate influenza vaccine raises preserves antibody responses [Lazarus R, 2021 ].

Macchia et al. was a non-inferiority randomized clinical trial conducted in Argentina. The study compared the immune response generated by homologous Sputnik V regimen to the heterologous regimens of Sputnik V vaccine with either Moderna, Sinopharm BIBP or AstraZeneca vaccines [Macchia A, 2022 ].

Macchia et al. recruited 540 individuals with no history of COVID-19 infection who had received a first dose of the Sputnik V vaccine (component rAd26) at least 30 days prior. Participants were randomized to receive a second dose of either Sputnik V (component rAd26 or rAd5), AstraZeneca, Moderna or Sinopharm BIBP vaccines. The study showed all but the Moderna regimen were statistically inferior to the standard Sputnik V regimen (rAd26/rAd5). The Moderna regimen showed a 3.53 fold increase in antibody concentrations compared to the standard Sputnik V regimen [Macchia A, 2022 ].

Hollstein et al. was a prospective cohort study conducted in Germany. The study assessed the immune response elicited by the use of heterologous and homologous vaccine schedules of Pfizer and AstraZeneca vaccines. Hollstein et al, included 382 participants 18 to 65 years old who received either 2 doses of Pfizer COVID-19 vaccine or 2 doses of AstraZeneca Covid-19 vaccine or 1 dose of each one. The study measured the neutralizing antibody levels and T-cell responses from blood samples taken up to 2 weeks prior to the second dose and 2 weeks to 3 months after the second dose. Results showed an increase on neutralizing antibodies titers that was higher in the participants who received the Pfizer vaccine. After the first dose all groups had similar T-cell responses, however, the Pfizer vaccine as a second dose yielded a significant increase in T cell responses while the AstraZeneca vaccine generated no booster effect [Hollstein MM, 2022 ].

Nickel et al. was a prospective cohort study conducted in Germany. The study measured the antibody response to the wildtype, Beta and Delta variants generated by two doses of the Pfizer-BioNTech vaccine plus an homologous booster dose or a heterologous regimen consisting of AstraZeneca and Pfizer-BioNTech vaccines. [Olaf Nickel, 2022 ] Nickel et al. recruited 172 participants who received an homologous Pfizer-BioNTech primary vaccination regimen plus a Pfizer-BioNTech booster or received an heterologous regimen consisting of AstraZeneca and Pfizer-BioNTech vaccines or had recovered from COVID-19. The study found the AstraZeneca/Pfizer-BioNTech regimen induced higher levels of neutralizing antibodies (4 fold increase) against the wildtype virus than the homologous regimen. All groups had decreased antibody levels to the Beta and Delta variants. The Pfizer-BioNTech booster dose greatly increased neutralizing titers against the wildtype, Beta and Delta variants [Olaf Nickel, 2022 ].

Niyomnaitham et al. was a comparative study conducted in Thailand. The study recruited 210 participants equally divided (n=30) to receive Sinovac, AstraZeneca and Pfizer-BioNTech vaccines either as a first or second dose. Participants who received only Sinovac or AstraZeneca first and second doses also received a booster dose with Pfizer-BioNTech. The study found antibody levels were highest among the groups that received Pfizer-BioNTech as a second dose, levels were similar between homologous and heterologous regimens. These levels were significantly higher compared with the groups who received AstraZeneca or Sinovac as a second dose.  The groups who were given Pfizer-BioNTech as second dose had significantly higher neutralizing titers against Delta and Beta than the groups that received AstraZeneca or Sinovac as the second dose. Neutralizing titers against the Beta variant were reduced by 2 to 5-fold compared to the Delta variant. Overall, neutralization against Omicron was low across the groups and were 28- to 229-fold lower than Delta, depending on the vaccine schedules. Neutralization against both the Delta and Omicron variants were significantly lower among groups who received Sinovac as a second dose compared to the other groups. Seropositivity rate for the Omicron variant was : 80% (45/56), 50% (30/60) and 21% (21/58) for the groups that received  Pfizer-BioNTech, AstraZeneca and: Sinovac as a second dose respectively [Suvimol Niyomnaitham, 2022 ].

García-Pérez et al. was a secondary analysis of the CombiVac study. It was a phase 2 randomized controlled trial conducted in Spain. The study included 676 adults: 441 in the interventional group and 223 in the control group. Subjects primed with ChAdOx1-S were randomized to receive BNT162b2 as second dose or no vaccine. Subjects from control group received BNT162b2 as second dose and also on day 28, as planned based on favorable results on day 14. At day 28 post-vaccine, geometric mean titres (GMT) of RBD antibodies were 5616.91 BAU/mL (95% CI 5296.49–5956.71) in the IG and 7298.22 BAU/mL (6739.41–7903.37) in the CG (p < 0.0001). RBD antibodies titres decreased at day 180 (1142.0 BAU/mL [1048.69–1243.62] and 1836.4 BAU/mL [1621.62–2079.62] in the IG and CG, respectively; p < 0.0001). Neutralizing antibodies also waned from day 28 to day 180 in both the IG (1429.01 [1220.37–1673.33] and 198.72 [161.54–244.47], respectively) and the CG (1503.28 [1210.71–1866.54] and 295.57 [209.84–416.33], respectively). The lowest variant-specific response was observed against Omicron-and Beta variants, with low proportion of individuals exhibiting specific neutralizing antibody titres (NT50) >1:100 at day 180 (19% and 22%, respectively) [José Alcamí Pertejo, 2022 ].

 

Heterologous-booster regimens

Immunogenicity outcomes  

Tobudic S et al. was a clinical trial that evaluated the efficacy and safety of a booster dose in patients in whom seroconversion did not occur after the second dose. The additional booster dose was delivered with the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India or mRNA vaccines against COVID-19. Efficacy was measured by the difference in the SARS-CoV-2 antibody seroconversion rate between patients vaccinated with the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine (heterologous) and the mRNA vaccines (homologous) at the fourth week. The results demonstrated that seroconversion rates at week four were comparable between patients who received the AstraZeneca vaccine (6/27 patients, 22%) versus the mRNA vaccines (9/28, 32%) (p = 0,6). Overall, 27% of the patients seroconverted; furthermore, no serious adverse events related to immunization were observed [Michael Bonelli, 2021 ].

COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralizing responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

Suntronwong N et al. included 458 fully vaccinated participants (2 doses Sinovac=248; 2 doses Sinovac plus AstraZeneca booster=210). Data were collected 34 days after infection. The study showed that binding antibody levels in sera from patients with breakthrough infection were significantly higher than those in individuals who had received AstraZeneca as a booster dose. However, neutralizing activities against wild-type and variants including alpha, beta, and delta were similar between patients with breakthrough infections and those who received a booster vaccination with AstraZeneca. Omicron was neutralized less effectively by serum from breakthrough infection patients, with a 6.3-fold reduction compared to delta variants [Nungruthai Suntronwong, 2022 ]. 

Angkasekwinai N et al. was a cohort study conducted Thailand. Based on data from a single-center, tertiary care university-based hospital in Bangkok, between July to September 2021. Results showed that heterologous boosting vaccination with Pfizer following Sinovac or AstraZeneca primary series is the most immunogenic against SARS-CoV-2 variants. A lower dose Pfizer may be used as a booster in settings with limited vaccine supply.[ ].

Vargas L et al. was a comparative study conducted in Chile. The study included blood samples from different individuals; healthcare personnel volunteers from Hospital La Florida, and adult healthy volunteers aged 18 years and over. This study describes the production of IgG antibodies directed against the ancestral SARS-CoV-2 S protein induced by the two-dose scheme of the Coronavac vaccine in a Health Service of the Hospital La Florida, Santiago. In addition, The study analyzed the impact of the booster doses of Sinovac, Pfizer, or AstraZeneca COVID-19 vaccines, administered to individuals vaccinated with the two-dose scheme with CoronaVac six months earlier. Study results showed that two doses of Sinovac induce antibody titers against the SARS-CoV-2 ancestral strain which are lower in magnitude than those induced by the Pfizer vaccine. However, the response induced by Sinovac can be greatly potentiated with a heterologous booster scheme with Pfizer or AstraZeneca vaccines. Furthermore, the heterologous booster regimes induce a durable antibody response that does not show signs of decay 3 months after the booster dose [Leonardo Vargas, 2022 ].

Yavlinksy et al. was a prospective community cohort study conducted in England and Wales. The study evaluated the immune response generated by a booster dose of the Pfizer COVID-19 vaccine on Pfizer or AstraZeneca primary vaccination recipients. Yavlinsky et al. included 8680 adults aged 18 or older who received a Pfizer vaccine booster after either Pfizer or AstraZeneca primary vaccination. The study found the Pfizer booster dose increased peak antibody levels compared to after primary vaccination regardless of the primary regimen. For the Pfizer primary vaccination group anti S antibody levels increased from 2,386 U/mL (95%CI: 9,801-15,653) to 22,185 U/mL (95%CI: 21,406-22,990) after the booster dose. In the AstraZeneca group antibody levels increased from 1,192 U/mL (95%CI: 818-1735) to 19,203 U/mL (95%CI: 18,094-20,377) after the booster dose [Alexei Yavlinsky, 2022 ].


Effectiveness outcomes

COV-BOOST et al. was a clinical trial that evaluated the immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNTech, hereafter referred to as BNT). Efficacy was measured by neutralizing antibody titers at 28 days post-boost dose. The results demonstrated that all study vaccines boosted antibody and neutralizing responses after AstraZeneca/AstraZeneca initial course and all except one after Pfizer/Pfizer, with no safety concerns [Munro, Alasdair P S, 2021 ].

Andrews N et al. was a case-control study (Test-negative) conducted in the United Kingdom. The study included 893,845 eligible tests in those aged 18 years and over. The objective was to estimate the effectiveness of the Pfizer and Moderna booster vaccines against symptomatic disease, hospitalization, and death in adults in England. The study results showed that the booster dose was associated with an absolute vaccine efficacy from 14-34 days after a Pfizer booster of 94.4% (95% CI 94.1 to 94.7) following either an AstraZeneca or Pfizer primary scheme in individuals 50 years and older. With a Moderna booster, absolute vaccine effectiveness was 97.0 (95% CI 96.0 to 97.8) after an AstraZeneca primary scheme and 94.8% (95% CI 92.7 to 96.3%) Pfizer primary scheme [Andrews N, 2022 ].

Kislaya I et al. was a case-control study conducted in Portugal, the study enrolled 15,001 participants, 3.737 were eligible for a booster dose of Pfizer-BioNTech. Based on data from RT-PCR SARS-CoV-2 positive cases notified in the mandatory National Epidemiological Surveillance Information System (SINAVE) in Portugal. The booster effectiveness against Delta variant was 94% (95% CI: 93.4 to 94.6) and for Omicron variant the booster effectiveness was 68.8% (95% CI: 46.4 to 81.7) [Irina Kislaya, 2022 ].

RHH-001 was a phase 4 randomized study, conducted in Brazil and El Salvador, that analyzed the immune response generated by homologous and heterologous booster vaccines based on a primary vaccination regimen with the Sinovac vaccine. The study recruited 1240 participants randomly assigned to receive a booster dose with Janssen (n=306), Pfizer-BioNTech (n=340), AstraZeneca (n=304), and Sinovac (n=290) vaccines at least 6 months after the second dose. Results found all booster doses substantially increased binding and neutralizing antibody levels, the geometric fold-rise at day 28 post booster was 77 (67–88) for Janssen, 152 (134–173) for Pfizer-BioNTech, 90 (95% CI 77–104) for AstraZeneca, and 12 (11–14) for Sinovac. Heterologous booster regimens were superior to the homologous regimen with GMRs of 8.7 (5.9–12.9) for Janssen, 21.5 (14.5–31.9) for Pfizer-BioNTech, and 10.6 (7.2–15.6) for AstraZeneca. Neutralizing antibody titres were above the lower limit of detection in 75 (94%) of 80 participants tested at day 28 for the delta variant and in 61 (76%) of 80 participants for the omicron variant [Costa Clemens SA, 2022 ].

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

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

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 (1 to 3.4 months)

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 placebo vaccine was 1.02 (95% CI 0.55 to 1.87). This means AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine increased the risk of any adverse event in 2%, compared with placebo 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

In the trial identified in this review, 3327 people not receiving AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine out of 22516 presented this outcome (148 per 1000) versus 8866 out of 33608 in the group that did receive it (151 per 1000). In other words, 3 more people per 1000 did not develop the outcome because of the vaccine. This is the same as saying that the intervention led to an absolute risk increase of 0.3%, or that the intervention increased the risk of any adverse event by 0.3 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 NNTH is 333. Which means that 333 people need to receive the vaccine for one of them to experienced any adverse events.

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

Serious adverse events (1 to 3.4 months)

The relative risk of serious adverse events in the group that received AstraZeneca-Oxford/SK Bioscience/Serum Institute of India COVID-19 vaccine versus the group that received placebo vaccine was 0.87 (95% CI 0.71 to 1.07). No statistically significant differences between groups were found for serious adverse events.


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

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% (7,045 out of 11,636 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% (1,418 out of 11,636 participants) [Voysey, Merryn, 2021 ].

Combined safety estimates for different ages 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 was a phase 1/2 participant-blinded, randomised controlled trial evaluating the safety in children 6-17 years old. A preliminary report included children aged 12-17 years. The median age of the participants was 15 years Participants were randomly assigned in a 4:1:4:1 ratio to receive two doses of AstraZeneca COVID-19 vaccine or control. Pain and tenderness were the most common local solicited adverse events for all the Astrazeneca COVID-19 vaccine and capsular group B meningococcal arms following both first and second doses. For systemic solicited adverse events, fatigue and headache were the most commonly reported with higher proportions reported in the Astrazeneca COVID-19 vaccine arms compared with capsular group B meningococcal arms. The increase in systemic reactogenicity was less obvious after 48 hours post-immunisation. For participants receiving Astrazeneca COVID-19 vaccine, there were fewer reported solicited adverse events after the second dose than the first dose [Grace Li, 2021 ].

 

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 ].

 

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

The cohort study COVATRANS is currently evaluating the effectiveness/safety of the vaccine in kidney transplant recipients aged 15 years and over 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 hematology patients aged 18 years and over [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 hematological malignancies 18 years of age and over [Ospedale di Circolo - Fondazione Macchi, 2021 ].

Available data are currently insufficient to assess safety in individuals with comorbidities.

 

Persons living with HIV

Randomized trials

Available data are currently insufficient to assess safety in individuals with comorbidities.

Safety of the vaccine post-authorization

Post-authorization studies

Comparative post-authorization studies

Pottegård A et al. was a comparative cohort study conducted in Denmark and Norway. The study enrolled 281,264 participants that received the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India COVID-19 vaccine. Based on data from a Nationwide healthcare registers in Denmark and Norway between 9 February 2021 to 11 March 2021. The authors compared the rates of cardiovascular and haemostatic events in the first 28 days after vaccination versus control group. Results of the study showed that the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India groups had more venous thromboembolism (97% 95% CI 50% to 154%), thrombocytopenia/coagulation disorders (52% 95% CI -3% to 125%), bleeding events (23% 95% CI -13% to 55%), and less arterial events (-3% 95% CI -23% to 20%) and deaths (-66% 95% CI -81% to -43%) [Pottegård A, 2021 ].

Trogstad L et al. was a comparative cohort study conducted in Norway. The study enrolled 8,728 participants (3,416 ARN vaccine(Pfizer or Moderna); 5,132 AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine) healthy participants that received At least one dose of vaccination with the AstraZeneca, Moderna or Pfizer vaccines. The study compared the prevalence of skin, nose and gingival bleedings after receipt of adeno-vectored (AstraZeneca vaccine) or mRNA-vaccines (Pfizer or Moderna vaccines) against COVID-19. The results of the study showed that the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India group had more skin bleeding (OR 13.9 95 % CI 6.5 to 29.7), Nose bleeding (OR 7.0 95% CI 3.5 to 13.9) and gingival bleeding (OR 8.1 95% CI 3.7 to 17.6) than mRNA-vaccines group [Trogstad L, 2021 ].

Arnold DT et al. was a comparative cohort study conducted in United Kingdom. The study enrolled 66 participants who received the Pfizer-BioNTech or the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India COVID-19 vaccine. Based on data from the participants selected between January to February 2021. The study assessed the change in quality of life and symptoms after vaccination amongst a well characterized prospective cohort of patients originally hospitalised with COVID-19 with a significant proportion of persistent symptoms. The results showed that there was no significant worsening in quality-of-life or mental wellbeing metrics pre versus post-vaccination [David T Arnold, 2021 ].

Hippisley-Cox J et al. is a comparative study conducted in England. The study enrolled 29 121,633 patients with first dose of the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India, Pfizer vaccines or with a positive test of SARS-CoV-2. Based on data from electronic health records, the Office for National Statistics and the United Kingdom's health service (NHS) between 1 December 2020 and 24 April 2021. The authors compared the incidence rate ratio (IRR) pre-post vaccination. The results of the study showed that the AstraZeneca vaccine had an increased risk of thrombocytopenia (IRR 1.26 95% CI 1.13 to 1.42), and had no difference in venous thromboembolism (IRR 0.97 95% CI 0.89 to 1.06) and arterial thromboembolism (IRR 1,02 95% CI 0.98 to 1.06) [Hippisley-Cox J, 2021 ].

Magnus MC et al. was a case-control study conducted in Norway. The study enrolled 13,956 participants, with 60 participants receiving AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine. Based on data from Norwegian registries on first-trimester pregnancies, COVID-19 vaccination, background characteristics, and underlying health conditions of all women who were registered between February 15 and August 15, 2021, the study results reorted an Adjusted Odds Ratio of 0.84 (95%CI 0.48 to 1.48) for miscarriage [Magnus MC, 2021 ].

Patone M et al. was a case-control study conducted in United Kingdom. The study enrolled 32,552,534 participants, with 20,417,752 receiving AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine. Based on The English National Immunisation (NIMS) Database of COVID-19 vaccination, authors linked individual patient data to national data for mortality, hospital admissions and SARS-CoV-2 infection data between 1 December 2020 and 31 May 2021 with the objective of assessing the associations between the first dose of AstraZeneca or Pfizer vaccines and neurological complications. The study results showed an incidence rate ratio (IRR) of 0.97 (95%CI 0.78 to 1.22) for Acute CNS demyelinating events, of 1.07 (95%CI 0.87 to 1.31) for encephalitis, meningitis and myelitis, of 2.04 (95%CI 1.60 to 2.60) for Guillain–Barré syndrome, of 1.07 (95%CI 0.94 to 1.21) for Bell’s palsy, of 1.23 (95%CI 0.94 to 1.62) for myasthenic disorder, of 0.91 (95%CI 0.88 to 0.94) for Hemorrhagic stroke and of 1.01 (95%CI 0.86 to 1.18) for subarachnoid haemorrhage in vaccinated individuals [Patone M, 2021 ]

Hillson K et al. was a cohort study conducted in the United Kingdom, Brazil, and South Africa. The study enrolled 121 pregnant participants (among 9,755 participants) with 50 receiving AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccine. Based on data from analyzed pregnancies that have occurred in four ongoing phase 1, phase 2, and phase 3 clinical trials of AstraZeneca 7 in three countries, the study results showed a Fertility Rate Ratio of 1.14 (95%CI 0.76 to 1.71) and a miscarriage Risk Ratio (RR) of 0.86 (0.50 to 1.49) in vaccinated individuals [Hillson K, 2021 ].

Joshi PC et al. was a cohort study conducted in India. The study included 3,235 participants, of whom 828 were vaccinated and 2,407 were in the control group. Based on the findings of high-resolution CT scans, the study evaluated the CT severity score in vaccinated and unvaccinated subjects diagnosed with or suspected of having COVID pneumonia. The difference in median CT Severity score between unvaccinated cases (7.0), cases with a history of 1 dose (5.0), and fully vaccinated cases (3.0). By age groups, unvaccinated cases, cases with a history of 1 dose, and fully vaccinated cases, respectively: 18-44-year-old group; 9.0, 7.0 and 7.0. Group 45-59 years and 9.0, 8.0 6.0 Group >60 years [Joshi PC, 2021 ].

Hviid A et al. was a cohort study conducted in Denmark. The study enrolled 355,209 participants: 222,364 vaccine group; 130,640 control group and was based on data from Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates, between 27 December 2020 to 13 April 2021. The study results showed a risk difference (RD) of 1.68 (95%CI −0.64 to 4.00) for cerebral venous thrombosis, of 0.84 (95%CI -0.80 to 2.48) for splenic vein thrombosis, of 0.93 (95%CI -2.35 to 4.21) for pulmonary embolism, of 8.35 (95% CI 0.21 to 16.49) for deep vain thrombosis and 2.39 (95%CI −1.09 to 5.87) for thrombocytopenia in vaccinated individuals [Hviid A, 2022 ].

Joshi PC et al was a cohort study conducted in India. The study enrolled 3,235 participants: 828 vaccine group; 2,407 control group and assessed CT-Severity Score in vaccinated and non-vaccinated subjects who were diagnosed with COVID-pneumonia or were COVID suspects, based on findings in high-resolution CT scans. The study results showed a CT Severity score median difference amongst non-vaccinated cases, cases with a history of 1 dose and fully vaccinated cases of 7.0, 5.0, and 3.0 respectively in the 18-44 years group; 9.0, 7.0, and 7.0 respectively in the 45-59 years group and 9.0, 8.0 and 6.0 respectively in the >60 years group [Joshi PC, 2021 ].


Non-comparative post-authorization studies

Schulz, J. B et al. was a non-comparative study carried out in Germany, which included 7,126,424 first doses (Pfizer-BioNTech, Moderna, AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccines) and sought to estimate the incidence of cerebral venous thrombosis (CVT) within a month after administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as an underlying mechanism after vaccination. Given an incidence of 0.22-1.75 per 100 000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after AstraZeneca vaccination, especially for women [Schulz, J. B., 2021 ].

David Presby et al. is a retrospective cohort conducted in United States. The study enrolled 50,977 (AstraZeneca-Oxford/SK bioscience/ Serum Institute of India (AZ, n=2,093), Janssen/Johnson & Johnson (J&J&J, n=3,888), Moderna (n=23,776; M1, 14,553 first dose; M2, 9,223 second dose), or Pfizer/BioNTech (n=35,929; P&B1, 22,387 first dose; P&B2, 13,542 second dose) participants. Based on data from subscribers to the WHOOP platform using data collected through April 14, 2021 [David Presby, 2021 ].

Maria Abbattista et al. conducted a non-comparative study in Europe, which included 748,248 reports of adverse drug reactions (Pfizer-BioNTech, Janssen, Moderna and AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccines). The notification rate of cerebral venous thrombosis (CVT) per 1 million vaccinated persons-days was 1.92 (95% CI, 1.71-2.12) for Tozinameran, 5.63 (95% CI, 4, 74-6.64) for CX-024414, 21.60 (95% CI, 20.16-23.11)) for AstraZeneca-Oxford/SK bioscience/ Serum Institute of India and 11.48 (95% CI, 9.57-13.67) for Janssen. CVT occurred in conjunction with thrombocytopenia for all four vaccines. The observed-to-expected (OE) analysis ratio was greater than one for all four vaccines, both with the lowest and highest background incidence of CVT [Abbattista M, 2021 ].

ACP et al. was a retrospective cohort study conducted in the United Kingdom. The study recruited 373 participants who received the Pfizer-BioNTech, Moderna, and AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccines. Based on data from the London Cancer Center from December 8, 2020 to February 28, 2021. Of the patients, 88.5% were receiving cancer treatment (36.2% parenteral chemotherapy and 15.3% immunotherapy), 76.1% developed some degree of vaccine-related adverse events (VRAE's) of which 2.1% were grade 3. No grades 4/5 or anaphylaxis were observed. The most common VRAE within 7 days after vaccination were arm pain (61.7%), fatigue (18.2%), and headaches (12.1%). The most common grade 3 VRAE's was fatigue (1.1%). Our results demonstrate that COVID-19 vaccines in cancer patients have mild reactogenicity [So ACP, 2021 ].

Català A et al. Was a non-comparative study carried out in Spain, which included 405 skin reactions to the Pfizer-BioNTech, Moderna and AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccines. The most reported reactions in each vaccine group were COVID-ARM (injection site; mRNA-1273, Moderna, 61.9%), varicella zoster virus reactivation (BNT162b2, Pfizer-BioNTech, 17.2%), and urticaria (AZD1222, AstraZeneca-Oxford/SK bioscience/ Serum Institute of India, 21.1%). Most reactions to the mRNA-1273 (Moderna) vaccine are described in women (90.5%). Eighty reactions (21%) were classified as serious / very serious and 81% required treatment [Català A, 2021 ]. Kaur RJ et al. was a non-comparative study that reported 4 863 cardiovascular adverse events. Common adverse events observed with the study vaccines were tachycardia (16.41%), flushing (12.17%), hypertension (5.82%), hypotension (3.60%), and peripheral coldness (2.41%). According to the disproportionality analysis (IC025 values), acute myocardial infarction, cardiac arrest, and circulatory collapse were associated with vaccines in the age group > 75 years. Hypertension, severe hypertension, supraventricular tachycardia, sinus tachycardia, and palpitations were associated in all age groups and in both sexes [Jeet Kaur R, 2021 ].

William Whiteley et al. it was a non-comparative study conducted in England. The study enrolled 46,162,942 (8,712,477 BNT162b2; 12,481,337 ChAdOx1-S) adults registered with a general NHS practice in England and alive on December 8, 2020 who received the first dose of vaccination with ChAdOx1-S and BNT162b2. Based on data from electronic questionnaires during weeks 11-13, 2021. Increases in intracranial venous thrombosis (ICVT) and thrombocytopenia after AstraZeneca-Oxford/SK bioscience/ Serum Institute of India vaccination in adults < 70 years are small compared to their effect on reduction in morbidity and mortality from COVID-19, although more precise estimates are needed for adults < 40 years. For people [≥] 70 years old, arterial or venous thrombotic event rates were generally lower after either vaccine [William Whiteley, 2021 ].

Upinder Kaur et al. took place in India. The study recruited 804 participants. Based on data from February 5, 2021 and expected to continue through May 2022 with at least one year of follow-up of all enrolled beneficiaries. Approximately half of those vaccinated developed adverse events at any time after vaccination, and the majority of reactions were mild to moderate in severity. Adverse events following inmunization (AEFI's) were seen in 40% of the participants at the first dose and around 16% of the participants after the second dose. Individually, fever, injection site pain, and headache were the commonly observed AEFI's. The rate of severe AEFI's in our study was only 0.1% (n = 1). It was observed that the rate of reactogenicity decreased with age and was higher in women [Upinder Kaur, 2021 ].

Pavord S et al. was a non-comparative study conducted in the United Kingdom, which included 294 participants with suspected vaccine-induced immune thrombocytopenia and thrombosis (VITT). 170 definitive and 50 probable cases of VITT were identified, all patients who received the first dose of the AstraZeneca vaccine and presented 5 to 48 days (median, 14) after vaccination. The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage (overall mortality 22%) [Pavord S, 2021 ].

Lacy J et al. was a non-comparative study conducted in England. The study enrolled 40 participants and assessed the risk of a second COVID-19 vaccine dose in patients with vaccine-induced immune thrombotic thrombocytopenia [Lacy J, 2021 ].

Menni C et al. was a non-comparative study conducted in the United Kingdom. The study enrolled 627,383 participants and examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the Pfizer vaccine or one dose of the AstraZeneca-Oxford/SK bioscience/ Serum Institute of India COVID-19 vaccine [Menni C, 2021 ].  

Houshmand B et al. was a cross-sectional study conducted in Iran. The study included 1,205 respondents of a multicenter electronic questionnaire via an online platform over a 1-week period among vaccinated dental staff and dental students inquiring whether they experienced vaccine-related side-effects after vaccine administration. The majority of respondents received AstraZeneca (51.1%) and Sputnik (37.6%). The symptoms most frequently reported after vaccination were fatigue (79%), local pain in the injection site (77.4%), malaise (73%), and body pain (71.1%). Enrollees reported more onset of reactions on 0–12 h (44.1%) and 12–24 h (29.0%) after vaccine administration [Houshmand B, 2022 ].

Kant et al. was a non-comparative study conducted in the Netherlands. The study included 27,554 participants and assessed systemic adverse events following immunization and adverse events of special interest following immunization for Pfizer-BioNTech, Moderna, Janssen and AstraZeneca vaccines [Kant A, 2022 ].

Rolfes L et al. was a cohort study conducted in the Netherlands. The study enrolled 22,184 participants and explored factors that were associated with reactogenicity in general and systemic after the first dose of COVID-19 vaccine through a web-based design using patient-reported outcomes between February 1st 2021 and May 9th 2021 [Rolfes L, 2022 ].

Lee K.M et al. was a non-comparative study conducted in the United States. The study enrolled 39,129 participants aged 18 to 80 years old and investigated unexpected menstrual bleeding after SARS-CoV-2 vaccination using an exploratory, mixed-methods survey instrument intended to capture a wide range of responses from current and formerly menstruating adults, between April 7, 2021 and June 29, 2021. The study reported that 42% of people with regular menstrual cycles bled more heavily than usual, while 44% reported no change after being vaccinated [Lee, K. M., 2022 ].

Kim JE et al. was a case series conducted in South Korea. The study enrolled 13 participants diagnosed with Guillain-Barré Syndrome and its variants following COVID-19 vaccination at four referral hospitals during the period of the mass vaccination program between February and October 2021. Eight cases were reported after AstraZeneca vaccine and 5 cases after Pfizer vaccine [Kim JE, 2021 ].

Keh RYS et al. was a cohort study conducted in the United Kingdom. The study enrolled 996 Guillain-Barré syndrome cases considered for immunoglobulin treatment in the National Immunoglobulin Database, between 8 December 2021 and 8 July 2021. The study results showed that 198 Guillain-Barré syndrome cases occurred within 6 weeks of the first dose of COVID-19 vaccination, with an incidence of 0.618 cases per 100,000 vaccinations. A total of 176 were seen after AstraZeneca COVID-19 vaccine, 21 after Pfizer COVID-19 vaccine and 1 after Moderna COVID-19 vaccine [Keh RYS, 2022 ].

Kanack AJ et al. was a non-comparative study conducted in the United States. The study included 9 participants that presented vaccine-induced immune thrombotic thrombocytopenia (VITT) [Kanack AJ, 2022 ].

Orfanoudaki E et al. was a cross-sectional study conducted in Greece. The study included 1,007 inflammatory bowel disease (IBD) patients and aimed to investigate the real-world use and adverse events (AEs) of COVID-19 vaccines. The study results showed that adverse events were reported by 81% after the first dose and 76% after the second dose. Systemic adverse events were more common after the second dose (51% vs. 44%). Very few patients reported new-onset abdominal symptoms, mainly abdominal pain in 4% after the first dose, 6% after the second dose and diarrhea in 5% after the first dose, 7% after second dose. There were no serious adverse events leading to emergency room visit or hospitalization [Orfanoudaki E, 2022 ].

Nasergivehchi S et al. was a cohort study conducted in Iran. The study enrolled 334 healthcare workers who had contracted COVID-19 of different intensities and were vaccinated with different types of COVID-19 vaccine (Astrazeneca 12.9%, Sinopharm 16.2%, Sputnik 62.3%, Bharat Covaxin 6.9%) at least one month following recovery from the virus, between April 2021 and September 2021. The study assessed the incidence of headache following injection, showing that 39.2% of participants reported post-vaccination headache, with the highest rates reported for AstraZeneca, followed by Sputnik V [Nasergivehchi S, 2022 ].

 

Monitoring

WHO recommends the following research and post-authorization monitoring activities:

Safety surveillance and monitoring
- Serious adverse events, anaphylaxis and other serious allergic reactions, Bell’s palsy, cases of multisystem inflammatory syndrome following vaccination, cases of COVID-19 following vaccination that result in hospitalization or death.

Vaccine effectiveness
− Vaccine effectiveness over time and whether protection can be prolonged by booster doses.
− Studies to investigate whether this vaccine reduces SARS-CoV-2 transmission and viral shedding.
− Assessment and reporting of vaccination failures and virus sequence information.

Subgroups
− Prospective studies on the safety of COVID-19 vaccine in pregnant and lactating females.
− Randomized controlled trials on efficacy and safety of vaccination in children below the age of 18 years.
− Safety data on vaccination in immunocompromised people, including patients living with HIV and autoimmune disease.

Vaccination logistics
− Immunogenicity and safety studies of co-administration with other vaccines, including influenza and pneumococcal vaccines, to adults and older persons.
− Safety, immunogenicity, and impact of a delayed second dose, as currently implemented by certain countries.
− Stability of the vaccine under alternative cold-chain distribution and storage conditions.
− Effectiveness of the proposed strategies for the prevention and management of anaphylactic reactions.
− Interchangeability studies within and across COVID-19 vaccine platforms.

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