Today, researchers from the University of Oxford have published further data from the Phase I/II clinical trials of the ChAdOx1 nCoV-19 coronavirus vaccine, evidencing the decision to move to a two-dose regimen in ongoing phase III trials, and how ChAdOx1 nCov-19 induces broad antibody and T cell functions.
These findings are reported in two papers, both released in the peer-reviewed journal Nature Medicine.
Previous studies have shown that in order to develop any vaccine against SARS-CoV-2 coronavirus, two key elements of the immune system need to be activated: a neutralizing antibody against the coronavirus spike protein which is likely to be critically important in protecting against the disease, as well as robust T cell responses.
Professor Katie Ewer, a lead author of one of the papers, said: “This highly detailed analysis of the immune responses to ChAdOx1 nCoV-19 further underpins the potential of this vaccine to induce protection against COVID-19 disease and provides additional reassurance of the safety of this approach.
Using these advanced immunological techniques, we can better understand the different cellular and antibody-mediated mechanisms that contribute to the protection afforded by this vaccine, as demonstrated in the recent data from the subsequent Phase 3 trials.”
One of these papers outlines the early-stage planning involved in the design of Phase III trials to investigate two booster dose schedules, a standard dose followed by a second standard dose and a standard dose followed by a lower dose (investigated in order to determine if this could be a viable ‘dose sparing’ strategy).
Furthermore, the researchers show lower reactogenicity (eg sore arm) to either booster dose, and increased immune system responses; these data were used to support the change to a two-dose regimen in the ongoing Phase III trials.
In order to rapidly roll out any candidate vaccine, it is important that no screening is required of people who are about to receive a dose, and the authors add that that the reactogenicity does not appear to be affected by the presences of antibodies to coronavirus.
The booster doses of the vaccine are both shown to induce stronger antibody responses than a single dose, with the standard dose / standard dose inducing the best response – supporting the decision taking previously to move to a two-dose vaccine regimen in the Phase III clinical trials.
The paper also shows that many different antibody functions are triggered by the vaccine that may be important in protection from the disease.
In the second paper, the authors detail an extensive investigation of the T cell and antibody responses generated by ChAdOx1 nCoV-19.
They report that the proteins – known as cytokines – which allow T cells to generate ‘signals’ to the rest of our immune system produced by the body’s immune system in response to the ChAdOx1 nCoV-19 vaccine predominantly induce Th1 cytokines rather than Th2 cytokines.
The authors further report induction of a T cell subset, known to be particular effective at clearing virus-infected cells from the body during infection.
This type of T cell response in combination with the detailed antibody profile is highly favorable for an efficacious vaccine, and further support the profile of this vaccine as a safe vaccine.
The ChAdOx1 nCoV-19 vaccine (AZD1222) was developed at Oxford University and consists of a replication-deficient chimpanzee adenoviral vector ChAdOx1, containing the SARS-CoV-2 structural surface glycoprotein antigen (spike protein; nCoV-19) gene.
Following initiation of a phase 1 clinical trial in the UK (COV001) on April 23, 2020, three further randomised controlled trials of the candidate vaccine were initiated across the UK (COV002), Brazil (COV003), and South Africa (COV005).
A further phase 1/2 trial has recently been initiated in Kenya and is not reported here. The immunogenicity results from the phase 1/2 UK study, COV001, in 1077 healthy adults aged 18–55 years,5 and a phase 2 cohort in COV002 in older adults (≥56 years)6 have been published and show an acceptable safety profile for the vaccine with induction of binding and neutralising antibodies as well as generation of interferon-γ enzyme-linked immunospot responses, with higher antibody titres after a second dose of vaccine.5, 6, 7
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.
tuAll studies have completed enrolment of their respective efficacy cohorts and are in the follow-up phase. Paediatric studies have not yet been initiated.
Here, we present the combined interim analysis of efficacy and safety from randomised controlled trials of ChAdOx1 nCoV-19.
Study design and participants
COV001 is a continuing single-blind phase 1/2 clinical trial in five sites in the UK, which began on April 23, 2020, and enrolled 1077 healthy volunteers aged 18–55 years, as previously described.5 Briefly, healthy adult participants were enrolled after screening to exclude those with pre-existing health conditions. Participants were randomly assigned 1:1 to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles (standard dose), measured using spectrophotometry, or meningococcal group A, C, W, and Y conjugate vaccine (MenACWY) as control.
An open-label non-randomised subgroup of ten participants were given two doses of ChAdOx1 nCoV-19 28 days apart, as previously reported.5 This study was originally planned as a single-dose study and 88 participants in the phase 1 part of the study remain recipients of a single dose. However, the protocol was modified to a two-dose regime, following an amendment on July 30, 2020 (version 9.0; appendix 2 pp 180–181), for the remaining phase 2 cohorts as a result of robust booster responses identified in the evaluation of the early immunogenicity cohorts, with the booster dose given at the earliest possible time.5
COV002 is a continuing single-blind phase 2/3 study in the UK that began on May 28, 2020, and enrolled participants in 19 study sites in England, Wales, and Scotland. Enrolment particularly targeted individuals working in professions with high possible exposure to SARS-CoV-2, such as health and social care settings.
Two dosage groups were included in COV002: participants who received a low dose of the vaccine (2·2 × 1010 viral particles) as their first dose and were boosted with a standard dose (in the LD/SD group), and subsequent cohorts who were vaccinated with two standard-dose vaccines (SD/SD group). Initial dosing in COV002 was with a batch manufactured at a contract manufacturing organisation using chromatographic purification.
During quality control of this second batch, differences were observed between the quantification methods (spectrophotometry and quantitative PCR [qPCR]) prioritised by different manufacturing sites. In consultation with the national regulator (Medicines and Healthcare products Regulatory Agency), we selected a dose of 5 × 1010 viral particles by spectrophotometer (2·2 × 1010 viral particles by qPCR), in order to be consistent with the use of spectrophotometry in the phase 1 study (COV001),5 and to ensure the dose was within a safe and immunogenic range according to measurements by both methods.
A lower-than-anticipated reactogenicity profile was noted in the trial, and unexpected interference of an excipient with the spectrophotometry assay was identified. After review and approval by the regulator, it was concluded that the qPCR (low-dose) reading was more accurate and further doses were adjusted to the standard dose (5 × 1010 viral particles) using a qPCR assay. The protocol was amended on June 5, 2020, resulting in enrolment of two distinct groups with different dosing regimens with no pause in enrolment (version 6.0; appendix 2 p 330). A suite of assays has now been developed for characterisation of concentration (which confirmed the low and standard dosing), and future batches are all released with a specification dose of 3·5–6·5 × 1010 viral particles, and this was used for the booster doses in the efficacy analysis presented here.
The LD/SD cohort (aged 18–55 years) was enrolled over 11 days between May 31 and June 10, 2020. The SD/SD cohort (aged 18–55 years) was enrolled from June 9 to July 20, 2020. Subsequently, enrolment of older age cohorts began (from Aug 8, 2020, for participants aged 56–69 years and from Aug 13, 2020, for participants aged ≥70 years), all of whom were assigned to two standard doses (SD/SD cohort).
Each site implemented the protocol amendment before changing from low-dose administration to standard-dose administration, and therefore there was no overlap in enrolment of participants in these cohorts.
The 18–55-year-old cohorts were originally planned as single-dose efficacy cohorts. However, the protocol was modified on July 20, 2020, to offer a second dose to the participants in these cohorts as a result of robust booster responses identified in the evaluation of the early immunogenicity cohorts (version 9.0; appendix 2 pp 331–332).5 Boosting began on Aug 3, 2020, resulting in a longer gap between prime and booster vaccines in these cohorts than for those aged 55–69 years and those aged 70 years or older, as these participants were enrolled into two-dose groups from the start.
Results for participants enrolled into immunogenicity subgroups have been previously published, including a small subset who received a low-dose boost.6 Full details are available in the study protocol (appendix 2 pp 184–342) and the procedures have been previously described.6
COV003 is a continuing single-blind phase 3 study in Brazil that began on June 23, 2020. The focus of recruitment was targeted at those at high risk of exposure to the virus, including health-care workers at six sites across Brazil. Participants were aged 18 years or older, and this trial included individuals with stable pre-existing health conditions. All participants were offered two doses of the vaccine at a dose of 3·5–6·5 × 1010 viral particles with administration up to 12 weeks apart (target 4 weeks), following a protocol amendment on July 28, 2020, to include booster groups (version 4.0; appendix 2 pp 438–439). Full details are available in the study protocol (appendix 2 pp 343–441).
COV005 (South Africa)
COV005 is a continuing double-blind phase 1/2 study in South Africa in healthy adults aged 18–65 years living without HIV that began on June 28, 2020. An additional immunogenicity cohort of those living with HIV was also enrolled but are not included in this interim analysis. All participants were offered two doses of the vaccine at a dose of 3·5–6·5 × 1010 viral particles, with doses administered 4 weeks apart. A small subgroup of 44 participants received a half-dose vaccine (21 as their first dose and 23 as their second dose) as a result of variability in the release assay, before the adoption of new methods for characterisation of concentration. Adjustment in dose was discussed with and approved by the national regulator. Full details are available in the study protocol (appendix 2 pp 442–559).
A combined independent data safety monitoring board reviews safety data from all four trials on a regular basis.
reference link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext
More information: undefined undefined et al. T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial, Nature Medicine (2020). DOI: 10.1038/s41591-020-01194-5
undefined undefined et al. Phase 1/2 trial of SARS-CoV-2 vaccine ChAdOx1 nCoV-19 with a booster dose induces multifunctional antibody responses, Nature Medicine (2020). DOI: 10.1038/s41591-020-01179-4