29th January 2021, Dr Chee L Khoo
I know we have touched on this vaccine before when we discussed Covid-19 vaccine candidates. We briefly discussed the interim results then but since we are likely to get the AstraZeneca/Oxford (AZO) vaccine in the national vaccine roll-out in primary care, there will be many questions coming from our patients in the coming weeks. We better be very up to date with the data so that we can answer their questions confidently and competently. We probably need to know the full details of this vaccine since this is also the vaccine that we are getting ourselves. Until recently, I thought we were front line workers.
This vaccine is code named ChAdOx1 nCoV-19. This is a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein) gene. What that means is the Covid-19 spike protein genetic code is inserted into a chimpanzee adenovirus and the adenovirus is then injected into participants. Once in the body, the adenovirus then infects human cells and the RNA genetic code is released into the cytoplasm. The human cells then makes the spike protein. This is detected by the body’s immune system and neutralising antibodies are raised in preparation when exposed to Covid-19 virus.
The AZO vaccine trial was a pooled interim analysis of four ongoing randomised controlled trials in Brazil, South Africa and UK (two trials). Both COV001 (UK) and COV005 (South Africa) were Phase 1/2 trials, COV002 (UK) was a Phase 2/3 trial while COV003 (Brazil) was a Phase 3 trial. The efficacy was assessed from pooled data combining COV002 and COV003 and the safety analysis was assessed using data from all four studies. The studies only included participants who received two doses of the vaccine. The trials were all slightly different. Along the way, there were quite a few amendments to the original trial designs.
COV001 (phase 1/2; UK)
This was a single blind phase 1/2 trial that enrolled 1077 healthy volunteers aged 18–55 years. Participants were randomised to either a standard dose of the ChAdOx1 nCoV-19 vaccine or MenACWY vaccine. This study was originally planned as a single dose study but was later amended to a two-dose regime.
COV002 (phase 2/3; UK)
This was a continuing single blind Phase 2/3 trial targeting participants working in professions with high possible exposure to SARS-CoV-2, such as health and social care settings. 10 673 participants were recruited. There were two dosage groups – one group received a low dose as their first dose and a standard dose as a second dose (LD/SD), another group received standard dose for both doses (SD/SD). Initial participants in both groups were between 18-55 years old but participants between 56-69 years and > 70 years were enrolled into the SD/SD group later. MenACWY was used as the control in both doses.
COV003 (phase 3; Brazil)
This was also a continuing single-blind phase 3 study in Brazil also targeting participants older than 18 years at high risk of exposure to the virus, including health-care workers. 10 002 participants were recruited. MenACWY was used as control for the first dose and saline for the second dose.
COV005 (phase 1/2; South Africa)
This was a continuing double-blind phase 1/2 study in South Africa in healthy adults aged 18–65 years living without HIV. 2096 participants were recruited. The control used was saline.
Participants across all four trials were asked to contact the study site if they experienced specific symptoms associated with COVID-19 and received regular reminders to do so. Those who met symptomatic criteria had a clinical assessment, a swab taken for a Covid-19 test and blood samples taken for safety and immunogenicity. For most participants, if you don’t have symptoms, you are not swabbed.
In the COV002 trial, to test for asymptomatic infections, participants were asked to provide a weekly self-administered nose and throat swab for Covid-19 from 1 week after first vaccination. In Brazil, there was no testing plan for asymptomatic infections. In COV005 (South Africa), asymptomatic infections were detected from swabs obtained at study visits attended but the data was not included in the analysis. Data from asymptomatic infections were not included in the analysis as the numbers are low thus far.
The Primary Outcome
The primary outcome was virologically confirmed, symptomatic COVID-19, defined as a swab positive combined with at least one qualifying symptom (fever =37·8°C, cough, shortness of breath, or anosmia or ageusia). Those with Covid-19-positive swabs within 14 days after the second vaccination, or those who discontinued from the study before having met the primary efficacy endpoint with a follow-up time of less than 15 days after the second vaccination were excluded from the analysis.
They started recruiting in April 2020. 11 636 participants in COV002 and COV003 met the inclusion criteria for the primary analysis, 5807 of whom received two doses of ChAdOx1 nCoV-19 and 5829 of whom received two doses of control product. The 86·7% were aged 18–55 years in the UK and 89·9% in Brazil. Those aged >56 years were recruited later and contributed 12·2% of the total cohort in the analysis. 53·2% in COV002 in the LD/SD group received a second dose at least 12 weeks after the first and only 0·8% received a second dose within 8 weeks of the first.
The number of symptomatic infections amongst the 11 636 participants were actually pretty low. Overall, there were 131 cases of symptomatic Covid-19 – 30 (0.5%) in the vaccine arm and 101 (1.7%) in the control arm resulting in an overall efficacy of 70.4%. In participants who received SD/SD vaccines, the efficacy was 62.1% whereas in those who received the LD/SD vaccines, efficacy was higher at 90.0%. Efficacy was not affected by the time interval between the vaccine doses (<6 weeks vs >6 weeks).
10 participants were hospitalised due to Covid-19 with 2 classified as severe. All 10 were in the control arm. No one in the vaccine arm was hospitalised.
Despite vaccination in 11,636 participants, the number of reported serious adverse events were low and occurred pretty much as often in the vaccine group as in the control group. Serious adverse events occurred in 168 participants, 79 of whom received ChAdOx1 nCoV-19 and 89 of whom received MenACWY or saline control. There were 175 events (84 in the ChAdOx1 nCoV-19 group and 91 in the control group), three of which were considered possibly related to either the experimental or a control vaccine.
There was one case of haemolytic anaemia in the control group in the COV001 10 days after MenACWY vaccine was administered. A case of transverse myelitis was reported 14 days after ChAdOx1 nCoV-19 booster vaccination as being possibly related to vaccination, with the independent neurological committee considering the most likely diagnosis to be of an idiopathic, short segment, spinal cord demyelination.
There were two other cases of transverse myelitis – one occurred 10 days after a first vaccination with ChAdOx1 nCoV-19 but considered unlikely to be related by the site investigator when further investigation revealed pre-existing, but previously unrecognised, multiple sclerosis and the second case was reported 68 days after MenACWY vaccination.
In summary, overall, the two-dose regimen of ChAdOx1 nCoV-19 vaccine is efficacious against symptomatic Covid-19 with an acceptable safety profile. Vaccine efficacy across both groups with the SD/SD regime was 70.4%. In the LD/SD group, vaccine efficacy was higher at 90.0%.
Because the trials were designed primarily to evaluate the efficacy against symptomatic disease, the trial could not report on disease prevention or transmissibility. While data has been collected for asymptomatic infections, the data has not included in the analysis yet. Therefore, the effectiveness in reducing new cases of Covid-19 is unknown.
Thus, any claim of achieving herd immunity with mass vaccination would be baseless. If we are vaccinating our patients, do we need to inform them? After all, informed consent is not informed consent unless they are informed of what they are getting.
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