A virus engineered to transport a gene. The vector of a viral vector vaccine is a non-pathogenic or mildly pathogenic virus. The genome of the vector is engineered to contain a gene encoding the viral protein against which an immune response is to be mounted. Once injected, the viral vector enters the vaccinees cells, which then synthesise the proteins encoded by the modified viral genome, including the protein against which an immune response is sought (1,2).

Adenoviruses are deoxyribonucleic acid (DNA) viruses that naturally infect human and primate cells. They can be used as viral vectors, preferably choosing an adenovirus rarely encountered by humans, to reduce the risk of vaccinees having already developed immunity to the vector. Pre-existing immunity hinders the viral vector’s ability to enter cells, reducing the efficacy of the viral vector vaccine.

The viral vector selected for the ChAdOx1 nCoV-19 vaccine is a chimpanzee adenovirus that has been genetically modified to greatly reduce its ability to replicate. This vector is called ChAdOx1. Its use in humans is limited to a few clinical trials (1,3,4). In the ChAdOx1 nCoV-19 vaccine, the gene for the spike protein on the surface of the virus Sars-CoV-2 has been inserted into the genome of the ChAdOx1 viral vector (4). The mRNA vaccines tozinameran and mRNA1273 Sars-CoV-2 also cause the vaccinee’s cells to produce the Sars-CoV-2 spike protein, to trigger an immune response (5,6).

About 21 000 trial participants, but weak data. The evaluation data available as of late January 2021 on the efficacy of the ChAdOx1 nCoV-19 vaccine are mainly from a pooled analysis of two comparative randomised trials in a total of about 21 000 adults aged 18 years or older, with no known history of covid-19 (4,7). The control groups were supposed to receive a meningococcal vaccine. The control groups received a different vaccine rather than a placebo in order to reduce the risk of participants guessing which product they had received, based on the adverse effects they experienced.

The protocols of these trials initially intended participants to receive a single injection. The preliminary data on immunogenicity led to the addition in mid-2020 of a second injection, 28 days after the first. But in reality, the interval between the two injections exceeded 6 weeks in most cases, and often 12 weeks (4). Furthermore, in one trial, the control group received normal saline instead of meningococcal vaccine for their second injection (4).

These trials were conducted in single-blind fashion: the participants did not know which product they had received, but the investigators did. The fact that the investigators knew which vaccine had been administered reduces the strength of the evidence provided by the trial (7). The trials were conducted in the United Kingdom and Brazil, before the identification of certain Sars-CoV-2 variants isolated in these countries in particular from December 2020 onwards (7).

Data from only about half (11 600) of the trial participants were taken into account in the published analysis of the vaccine’s efficacy. The other participants were excluded from this analysis for a variety of reasons, including: positive covid-19 serology at baseline; no second injection; less than 15 days of follow-up after the second injection; diagnosed with covid-19 within 14 days after the second injection. Some participants received the meningococcal vaccine as their first injection then the ChAdOx1 nCoV-19 vaccine as their second injection: they too were excluded from the analysis (4). The exclusion of about half of the participants from the efficacy analysis greatly weakens the quality of its results.

Great uncertainty over the extent of its preventive effect. The average age of the 11 600 participants taken into account in the efficacy analysis was 41.5 years. 12% were older than 55 years of age, and only about 6% (660 participants) were aged 65 or older. 36% had at least one risk factor for developing severe covid-19 other than their age, usually obesity (20%), asthma or hypertension (4). 78% of the participants were healthcare or social care workers (7).

Efficacy was evaluated by recording the number of cases of symptomatic, laboratory-confirmed covid-19 that occurred from day 15 onwards after the second injection (4). By the time half of the patients had been followed up for at least two months after the second injection, 37 cases of covid-19 had occurred in the vaccine groups, versus 112 cases in the control groups, in other words the vaccine reduced the risk of developing covid-19 by 67%, with a 95% confidence interval (95CI) of 52% to 77% (7). The ChAdOx1 nCoV-19 vaccine appeared to have a preventive effect from about 3 weeks after the first injection (4). These results show that the level of efficacy of the ChAdOx1 nCoV-19 vaccine is more uncertain than that of the mRNA vaccines previously authorised (see > HERE and > HERE)..

Some patients in the ChAdOx1 nCoV-19 groups received only half a dose by mistake at their first injection. Although the vaccine appeared to have greater efficacy in these participants, this analysis is invalidated by a number of confounding factors. For example, the patients who received the half-dose were younger than those who received the full dose, and were at lower risk of contracting the disease because the virus was less prevalent in their environment (4,7).

Very little data on severe forms of covid-19. In the analysis that included 11 600 of the participants, no cases of severe covid-19 occurred in the vaccine groups, versus 2 cases in the control groups. Two participants in the vaccine groups were hospitalised for covid-19 (within 10 days of the first injection), versus 16 in the control groups (4). The number of cases of severe covid-19 was therefore too low to demonstrate the efficacy of the ChAdOx1 nCoV-19 vaccine in preventing severe disease, even though such an effect seems likely. The vaccine appeared to reduce the risk of developing covid-19 to a similar extent in patients with a risk factor for developing severe covid-19 as in other patients (4).

These trials were not designed to evaluate the efficacy of the ChAdOx1 nCoV-19 vaccine in adults aged 65 years or older, only 660 of whom were included in the efficacy analysis, and only two of whom developed covid-19 (4). A double-blind randomised placebo-controlled trial in about 30 000 adults is in progress as of late January 2021, with results due in March 2021 (8).

Caution in immunocompromised patients. The main foreseeable adverse effects of a viral vector vaccine are those common to vaccines in general, notably local reactions at the injection site and systemic reactions. The possibility of the vaccine worsening Sars-CoV-2 infection is a hypothesis that must be taken into account, in view of the findings of certain animal studies with a Sars-CoV-1 coronavirus vaccine (5). Among the 37 patients who developed covid-19 after receiving the ChAdOx1 nCoV-19 vaccine, two were hospitalised and none developed severe disease (4,7). The possibility of infection with the viral vector cannot be ruled out completely, but is less likely to occur when the virus has been modified to reduce its ability to replicate. Adenovirus infections are usually mild in an otherwise healthy human. Severe human adenovirus infections have been reported in immunocompromised patients (9).

Immunodeficiency and chronic use of immunosuppressive treatments were exclusion criteria for these trials (4).

Local and systemic adverse effects are common. When evaluating the adverse effects of the ChAdOx1 nCoV-19 vaccine, the British Medicines and Healthcare Products Regulatory Agency (MHRA) took into account data from four comparative trials, including the two trials described above, with about 24 000 participants in total (4). The fact that most of the controls in these trials received a meningococcal vaccine would tend to decrease any differences in the incidence of adverse effects common to all vaccines. In these trials, 75% of participants in the ChAdOx1 nCoV-19 vaccine groups had a local reaction during the 7 days following an injection, versus 50% in the control groups, including pain, swelling, redness and itching. Severe local reactions occurred in 10% of participants who received the ChAdOx1 nCoV-19 vaccine, versus 6% of controls (4). Systemic adverse events during the 7 days following an injection were reported by 73% of participants in the ChAdOx1 nCoV-19 vaccine group, versus 60% of controls, with severe reactions occurring in 8% versus 3%. The reported systemic reactions were fever, chills, joint pain, muscle pain, fatigue, headache, malaise and nausea (4). No serious allergies to the vaccine were reported during the trials (4). A history of angioedema or anaphylaxis were exclusion criteria (4). The vaccine’s excipients include polysorbate 80, but not polyethylene glycol (PEG) (10). Myelitis (inflammation of the spinal cord) was diagnosed in one participant in each group a few weeks after vaccination. Three cases of facial paralysis were reported in each group (4). The MHRA announced that it would pay particular attention to such adverse effects once the ChAdOx1 nCoV-19 vaccine was marketed in the United Kingdom (4). This has been the case since December 2020, but no pharmacovigilance data had been released as of mid-January 2021.

A multidose vial for storage between 2°C and 8°C. The ChAdOx1 nCoV-19 vaccine is marketed as a solution for injection in multidose vials, a format that can lead to errors, including the risk of administering multiple doses in a single injection (10).

This vaccine must be stored in a refrigerator, between 2°C and 8°C. The solution is ready to use, requiring no dilution. Once the first dose has been withdrawn, the contents of the vial must be used within 6 hours and must not be exposed to temperatures higher than 25°C (10).

In practice, as of late January 2021, more uncertainty with this vaccine than with the first two vaccines authorised in the European Union. As of late January 2021, while awaiting a thorough analysis and more data, the following points from the main clinical trials of the ChAdOx1 nCoV-19 vaccine will help inform patients who are offered vaccination:

• The quality of the evidence available is generally weak, partly due to the fact that the trials were not conducted as planned, and that the published efficacy data only pertain to about half of the trial participants.
• In trials, the risk of developing covid-19 was reduced by about 70% in the ChAdOx1 nCoV-19 vaccine groups, but the level of efficacy it provides is more uncertain than that of the two mRNA vaccines authorised previously. A reduction in the incidence of severe covid-19 is likely, but remains unproven.
• 36% of participants had at least one risk factor for developing severe covid-19 other than their age, but the level of efficacy of the ChAdOx1 nCoV-19 vaccine is even more uncertain in this population than in the total population. Only about 6% of the participants were aged 65 or older.
• The main known adverse effects of the ChAdOx1 nCoV-19 vaccine are local and systemic reactions, which occur very commonly. As with any product that has not been in use for long, many unanswered questions remain, in particular concerning the use of this viral vector in humans.

In summary, as of late January 2021, the uncertainties surrounding the ChAdOx1 nCoV-19 vaccine are greater than those surrounding the two mRNA vaccines that are already available in the European Union (see > HERE and > HERE). As a result, decisions concerning the use of the ChAdOx1 nCoV-19 vaccine will vary enormously, depending on the context and the person concerned. It remains important to provide patients with balanced information on the risks of covid-19 and on what is known and unknown about the efficacy and adverse effects of the available vaccines. It is also important to report any adverse events that occur following vaccination.

©Prescrire 29 January 2021

Translated from:

• "Vaccin covid-19 ChAdOx1 nCoV-19 (firme AstraZeneca) : beaucoup d'incertitudes autour de l'ampleur de son efficacité" Application Prescrire 29 January 2021

Sources:

1. HAS "Aspects immunologiques et virologiques de l’infection par le Sars-Cov-2. Variabilité génétique, réponses immunitaires, plateformes vaccinales et modèles animaux" 25 November 2020: 134 pages. 2
2. Dong Y et al. "A systematic review of Sars-CoV-2 vaccine candidates" Signal Transduct Target Ther 2020; 5 (237): 14 pages.
3. Guo J et al. "Development of novel vaccine vectors: chimpanzee adenoviral vectors" Hum Vaccin Immunother 2018; 14 (5): 1679-1685.
4. MHRA "Public assessment report for authorisation for temporary supply. Covid-19 vaccine AstraZeneca, solution for injection in multidose container covid-19 vaccine (ChAdOx1-S [recombinant])": 57 pages. 5
5. Prescrire Editorial Staff "The covid-19 messenger RNA vaccine tozinameran (Comirnaty°, from Pfizer and BioNTech) in elderly patients: limited data, many uncertainties” 23 December 2020.
6. Prescrire Editorial Staff "The covid-19 messenger RNA vaccine from Moderna: as with the tozinameran vaccine (Comirnaty°, Pfizer/BioNTech), limited data and unanswered questions" 6 January 2021. 7
7. Voysey M et al. "Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK" Lancet 2020: 13 pages. Published online at www.thelancet.com on 8 December 2020. 8
8. "Phase III double-blind, placebo-controlled study of AZD1222 for the prevention of covid-19 in adults. NCT04516746". clinicaltrials.gov accessed 13 January 2021: 5 pages. 9
9. Loustalot F et al. "Les adénovirus non-humains. Un risque zoonotique?" Médecine Sciences 2015; 31 (12): 1102-1108.
10. MHRA "Information for UK healthcare professionals-Covid-19 Vaccine AstraZeneca" 29 December 2020: 10 pages.
     

For more information:

• "Covid-19: Follow Prescrire's independent, evidence-based analysis of the pandemic" > HERE