COVID-19

COVID-19: safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2 (AstraZeneca/Oxford)

Examination of the study methodology and results according to the PICOT principle, SWOT analysis and real-world applicability

How is vaccine efficacy determined? - It is based on the ratio of confirmed COVID-19 infections in patients receiving a vaccine over those in the control arm.
How long is the protective period? – The duration of follow-up after vaccination is important for assessing both the longevity of the effect of a vaccine, as well as its long-term safety profile.
How is vaccine safety assessed? – It should be differentiated between a primary reaction to a vaccine, such as a skin reaction or post-vaccination fever (reactogenicity) and serious adverse events with potentially a lasting health impact.

An interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK

Clinical data and real-world demands of COVID-19 vaccines: ChAdOx1 nCoV-19 vaccine (AZD1222)

Published in the Lancet on December 8th, 2020 (https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext)

This study is unlike any other conducted before. Not only in terms of its potential importance for global health, but also in terms of its methodology, construct and reporting. In more normal times, no study would intend on bringing together data from different patient study groups, with different inclusion criteria (and even unintentional different dosing regimens) in order to fast-track publication and, ultimately, translate those findings rapidly into clinical practice. However, these are truly exceptional times - and the scientific community has responded accordingly. Given the unique (and complex) construct of this study, a systematic approach to appraising the results is essential.

Application of the Population - Intervention - Control - Outcomes – Time (PICOT) template helps in this endeavour.

Examination of the study methodology and results according to the PICOT principle

POPULATION:

At first glance this is very simple - participants aged 18 years and older (n=11 636 participants included in the interim primary efficacy analysis). However, behind this single headline inclusion criterion, this interim analysis of the efficacy and safety of the ChAdOx1 nCoV-19 vaccine includes data from four ongoing blinded, randomised, controlled trials done across three countries: COV001 (phase 1/2; UK), COV002 (phase 2/3; UK), COV003 (phase 3; Brazil), and COV005 (phase 1/2; South Africa). Furthermore, the phase 1 study (COV001) included an efficacy cohort and the phase 2 and 3 studies (COV002, COV003, and COV005) expanded enrolment to a wider population of participants with higher likelihood of exposure to the virus, such as health-care workers.Exclusion criteria were reduced for phase 3 trials, so that older adults and individuals with a range of comorbidities were also enrolled. Three of the studies are single blind and one is double blind (COV005).In summary, regarding the patients of interest, this study is different from many others in that the individual studies are somewhat heterogeneous. Yet, despite differences across the studies, there is sufficient consistency to justify the proposal for pooled analysis of data, to provide greater precision for both efficacy and safety outcomes. With more time and more data, a more focused analysis of subgroups of particular interest (e.g. the extreme of age, black and Asian minority (BAME) etc.) will be afforded. However, in the race against controlling the global pandemic, speed (and overall safety) of any proposed vaccine are the main priorities.

INTERVENTION:

The intervention of interest was the ChAdOx1 nCoV-19 vaccine: a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene.Note: Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial inadvertently received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort)

CONTROL:

The comparison of interest (control) group was the meningococcal group A, C, W, and Y conjugates vaccine (first dose) or saline (second dose). Study participants were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control.

OUTCOMES:

The primary efficacy outcome was virologically confirmed, symptomatic COVID-19, defined as a nucleic acid amplification test (NAAT)- positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia).In participants who received two standard doses (SD/SD cohort), vaccine efficacy was 62·1% (95% CI 41·0–75·7). That is, 27 patients infected [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs 71 [1·6%] of 4455 in the control group. In participants who received a low dose followed by a standard dose (LD/SD cohort), efficacy was 90·0% (67·4–97·0). That is, 3 infected patients [0·2%] of 1367 in the vaccine groups vs. 30 [2·2%] of 1374 in the control group, p =0·010. Overall vaccine efficacy across both interaction groups was 70·4% (95·8% CI 54·8–80·6), with 30 patients infected [0·5%] of 5807 in the vaccine group vs 101 [1·7%] of 5829 in the control group.With regards to safety, there were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group.In summary, with regards to the outcomes of interest, vaccine efficacy was 70·4% after two doses and protection of 64·1% after at least one standard dose, against symptomatic disease, with no apparent safety concerns.

TIME:

The time of interest is reported as 14 days after a second dose of vaccine, as this is considered as the start of the protective period. Median follow-up in patients who received 2 doses of the vaccine was 2 months, this meaning that overall safety (of 2 doses) and efficacy results are to be interpreted with this time constraint.

Strengths – Weaknesses – Opportunities – Threats (SWOT) analysis

The WHO has suggested that a minimum criteria for any vaccine against COVID-19 should be a “clear demonstration of efficacy with a ~ 50% point estimate”(1) which can be assessed by disease, severe disease or transmission endpoints. This analysis asseses the strengths and weaknesses and real-world applicability of the ChAdOx1 nCov-19 vaccine.

Strengths

The recruitment of participants in an age-escalation manner per study design, thus reflecting the hierarchical distribution of risk conferred by COVID-19 according to age.
Participants were randomly assigned to receive the ChAdOx1 nCoV-19 vaccine or the quadrivalent MenACWY protein-polysaccharide conjugate vaccine rather than a saline placebo alone, in order to maintain masking of participants who had local or systemic reactions. This resembles the concept of a sham-controlled trial.
Participants, clinical investigators, and the laboratory team remained masked to group allocation for the duration of the study.
As previously reported, side-effects in the immediate post-vaccination phase are fewer in number and intensity if a lower dose is used, in older patients and after the 2nd booster dose.
Most of the reported local and systemic adverse events were mild to moderate in severity.
Overall safety was reported to be satisfactory, without major, definitely vaccine-related serious adverse events.
Anonymised participant data of a randomized trial will be made available when the trial is complete, upon request directed to the corresponding author. Proposals are reviewed and approved by the sponsor, investigator, and collaborators on the basis of scientific merit. After approval of a proposal, data is shared through a secure online platform after signing a data access agreement.
All data will be made available for a minimum of 5 years from the end of the trial.

Weaknesses

Participants with severe or uncontrolled medical comorbidities were excluded: those patients represent higher risk in COVID infection registries.
Only 12% of the presently analysed patients were above 55 years of age.
The analysis of the vaccine efficacy was not performed in patients older than 55 at this time, due to only 5 events being reported in this subpopulation.
Two different batches of vaccine (low dose/standard dose and twice the standard dose) were used in this study.
The possible variation of severity of local reactions due to the difference in injection volumes between different batches of vaccine in the low-dose group.
The selection of participants aged 70 years and older might not be representative of the general older population, including those living in residential care settings or older than 80 years
Volunteers with substantial comorbidities or clinical frailty were excluded.
This is an interim analysis, and the final data set is expected to be larger.
Vaccine efficacy was estimated based on the rate of symptomatic COVID-19 cases, and the rate of asymptomatic cases was not systematically assessed across all 4 pooled randomized trials.
An endpoint of interest to both an individual patient and health care organizations would be the rate of prevented COVID-19 hospitalizations. With only 10 such hospitalization events available for the present analysis, no reliable assessment regarding this endpoint could be made.

Opportunities

The previously reported similar safety and immunogenicity of ChAdOx1 nCoV-19 in older adults compared with younger adults, which could support the use of this vaccine in this older age group (however, the full data set phase 3 trial is needed).
Also previously reported robust humoral and cellular immune responses obtained in the older adult population were encouraging given that a number of studies have shown that decreasing immune function with age leads to decreased immune responses to vaccines.
The lower dose of vaccine was less reactogenic than the standard dose of vaccine across all age groups.
These results are encouraging to conduct further analyses upon completion of the data collection to assess immunogenicity, safety, and efficacy also in older adults with a wider range of comorbidities.

Threats

To over-interpret the present results and apply them to propose this vaccine in older population with comorbidities including those living in residential care settings or older than 80 years.
Can homologous boosting with adenovirus-vectored vaccines be done without loss of immunogenicity to the pathogen-specific transgene?
Despite the overall conclusion by the authors that 2 cases of transverse myelitis in the ChAdOx1 group were not directly linked to the vaccination, this occurrence may still represent a clustering of similar adverse events in the vaccinated study population, which may warrant further caution.