AstraZeneca/Oxford University have announced that their SARS-CoV-2 candidate vaccine AZD1222 showed efficacy in a first interim analysis of results from a Phase 3 clinical trial. This follows closely on the heels of recent reports from Pfizer/BioNTech and Moderna of the efficacy of their mRNA SARS-CoV-2 candidate vaccines in Phase 3 clinical trials.
Whilst the Pfizer/BioNTech and Moderna candidate vaccines are based on new RNA technology, the AstraZeneca/Oxford University candidate vaccine is a more conventional viral vectored vaccine. It contains a replication-deficient simian adenovirus vector (chimpanzee adenovirus Oxford 1 or ChAdOx1). This adenoviral vector has already been used in other vaccines, including influenza, TB, Zika and Middle East Respiratory Syndrome (MERS). To produce the AZD1222 candidate vaccine, the ChAdOx1 vector has been engineered to contain the gene that encodes the spike protein (S2) of SARS-CoV-2.When AZD1222 is administered to a patient, the S2 protein encoded by the gene in the adenoviral vector is expressed in the cells and elicits a host immune response against SARS-CoV-2.
The phase 3 clinical trial of AZD1222 has enrolled over 24000 participants from diverse racial groups in the UK, Brazil and South Africa, with each participant receiving either AZD1222 or a control vaccine. The trial tested 2 different dose regimes; either two full doses or a half dose followed by a full dose; the doses in both regimes being administered 28 days apart. AstraZeneca/Oxford University conducted the first interim analysis of the results when a predetermined threshold number of confirmed COVID-19 cases was reached among the trial participants (in this case 131). This interim analysis revealed that the majority of the confirmed COVID-19 cases in the trial had received the control vaccine, and there were no serious adverse effects. From this data, the overall efficacy of the AZD1222 was estimated to be about 70.4% This figure is significantly lower than the estimated efficacies recently reported for the Pfizer/BioNTech and Moderna candidate vaccines (90% to 95%), but it still is high enough for AZD1222 to be an effective vaccine.
Intriguingly, the efficacy of AZD1222 when administered as a half dose followed by a full dose was found to be 90%, whereas the efficacy dropped to 62% when administered as two full doses. The reasons for this disparity are unclear. It could be a statistical artefact of the trial size that disappears as more data is analysed. However, it has also been suggested that a lower initial dose may be more effective at stimulating T cells or may reduce immune responses to the ChAdOx1 vector itself. If further data confirms that the effect is real, then this would reduce the amount of vaccine needed to vaccinate each individual, which would reduce costs and allow vaccinations to be carried out with each batch of vaccine.
None of the confirmed COVID19 cases in participants who received AZD1222 were classified as “severe” or required hospitalisation. This suggests that the candidate vaccine reduces serious medical outcomes associated with COVID19. There were also indications in the trial that AZD1222 reduced the transmission of SARS-CoV-2 between individuals, as well as infection. Further trials in the United States, Kenya, Japan and India, which are expected to include over 60,000 participants will provide further information about the efficacy and safety of AZD1222. However, these interim results therefore show that AZD1222 displays great promise in tackling the SARS-CoV-2 pandemic.
Some questions still remain. For example, the relative effectiveness of any of AZD1222 in different age groups or ethnic groups or elderly patients has yet to be established. Similarly, the duration of the protective effect remains to be determined.
Because they have been researched and used extensively for decades, adenovirus vaccines, like AZD1222 offer some major benefits over the mRNA candidate vaccines of Pfizer/BioNTech and Moderna. Not only is AZD1222 cheaper, but it is also stable at higher temperatures. This allows AZD1222 to transported and stored at normal fridge temperature (2-8oC), rather than the freezer temperatures (-20oC or -70oC) required for the mRNA candidate vaccines. This is likely to make the roll out of AZD1222 much more straightforward, since suitable distribution networks are already in place. AZD1222 may therefore be an important player in large-scale vaccination programs, especially in low and middle income countries.
These results from AstraZeneca/Oxford University mean that there are now three candidate vaccines with demonstrated efficacy against SARS-CoV-2. Phase 3 trials of other candidate vaccines are ongoing and results of these trials are likely to be announced over the next few months, potentially adding to the armoury of effective vaccines. In the meantime, Pfizer/BioNTech, Moderna and AstraZeneca/Oxford University will all be submitting their data to regulators with a view to getting approval for their candidate vaccines under emergency provisions. Once the vaccines are approved by regulators, vaccination programs can begin around the world. Whilst major manufacturing and logistical challenges remain, the approval of these vaccines will be a major step that may bring the end of the global SARS-CoV-2 epidemic into sight.
