School of Infection & Immunity

COVID-19 vaccines have been shown to work well in protecting healthy people against severe COVID-19 infection.

However, initial data from the ongoing OCTAVE trial led by Institute scientists and clinicians shows that a significant proportion of clinically at-risk patients with certain immunocompromised conditions or immunosuppressant therapies mount a lower or undetectable immune response after two doses of the same vaccine.

Funded by the Medical Research Council, OCTAVE is a multi-centre, UK-wide trial led by the University of Glasgow and co-ordinated by the University of Birmingham’s Cancer Research UK Clinical Trials Unit in collaboration with the universities of Oxford, Imperial College London and Leeds Teaching Hospitals NHS Trust.

The study is evaluating the immune responses following COVID-19 vaccination in patients with a range of important immune-mediated inflammatory diseases such as cancer, inflammatory arthritis, severe vasculitis treated with rituximab, diseases of the kidney or liver, or patients who are having a stem cell transplant. All patients with rheumatic conditions were recruited in Glasgow.

Using state-of-the-art immune tests performed on blood samples taken before and/or after COVID-19 vaccination in the first 600 people recruited across the UK, OCTAVE’s early data, which was recently published as a pre-print in The Lancet, show that up to 40 per cent of people in the patient groups studied mounted a low coronavirus anti-spike antibody immune response after two COVID-19 vaccines.

The initial data also shows that while most patients had detectable antibodies four weeks after two vaccines, approximately 11 per cent of these immunocompromised patients failed to generate any antibodies.

The failure to generate antibodies was found at higher proportion in some specific patient sub-groups. In particular, in patients with ANCA-Associated Vasculitis who have received Rituximab treatment, which blocks the B cells that make antibodies.

In-depth analysis of patient vaccine response within each of the disease subgroups included in the study found that a significant proportion of patients studied in OCTAVE generate lower levels of antibodies when compared with healthy subjects after two COVID-19 vaccines.

Importantly, however, the significance of these findings in terms of what they can tell us about protection from severe COVID-19 infection is not currently known, as it is unclear what level of antibody is needed for this protection

The same team led by the University of Glasgow have also started a follow-on study, OCTAVE-DUO, which is investigating the immune response after a further booster - third - dose of vaccine in the OCTAVE participants who were low responders after their standard two COVID-19 vaccines.

Professor Iain McInnes, lead of the OCTAVE and OCTAVE-DUO trials and Head of the College of MVLS, said: “The roll-out of the vaccine programme was extremely important for these vulnerable groups of patients.

"However, due to their underlying medical conditions and treatments, which can weaken their immune systems, we were concerned that people with these medical conditions may not receive optimal protection. So it was, and remains, extremely important to investigate this unanswered question. 

“While 40 per cent of these clinically at-risk patent groups were found to have a low or undetectable immune response after a double dose of the vaccine, we are encouraged that this figure isn’t higher.

"However, it is possible even partial protection may be clinically beneficial, and this is something we will closely monitor.

“There are also imminent plans in place to investigate the effects of administrating an alternate vaccine dose to the group with an undetectable or low vaccine immune response, and we hope these findings will support the role out of an immunological screening programme for vulnerable patients to identify those who will benefit from a subsequent vaccine boost.

“We would continue to encourage all people and especially those patients within these clinically at-risk groups to make sure they receive their vaccine doses if they haven’t done so already.”

The Institute's Professor Stefan Siebert, who is a lead investigator in the OCTAVE study, said “My patients have been asking me for a long time: 'Will these vaccines work as well in people like me who are immunosuppressed?' Until now we have not known the answer to this question.

"These preliminary OCTAVE data indicate a mixed picture, with most showing some antibody response but not all, and in about 40 per cent this response is lower than that seen in healthy people after two vaccines.

"This is not the same for all of the groups we studied, so we are doing more work to identify those conditions or treatments that have the biggest impact on the response to vaccines so that we can find better strategies to protect all our patients from severe COVID-19 infection.”

Professor Pam Kearns, Director of the University of Birmingham’s Cancer Research UK Clinical Trials Unit, said: “A significant number of people in the UK were advised to shield because they have conditions or long term illnesses which place them at greater risk of severe illness and death from COVID-19.

“The rapid development of vaccines for COVID-19 has been a major step forward in the battle against this global pandemic, and the most clinically-at-risk people were among the first in the UK to be offered one. However, while we know COVID-19 vaccines are highly effective in healthy individuals, questions have remained as to how effective they are in protecting the chronically ill.

“These preliminary results of OCTAVE and the results of our continuing and forthcoming research will be instrumental in helping inform how best to vaccinate patients with chronic conditions and protect them from COVID-19 infection in the future.”

Dr Rob Buckle, Chief Scientist of the Medical Research Council, part of UKRI, which co-funded the trial, said: “Today’s results will be of concern for the subset of people within those who are immunosuppressed for whom the vaccine didn’t trigger a large protective response.

"We’re funding an extension to the OCTAVE study to give third jabs to this group, which we hope will deliver a much-needed immunity boost, or identify those who could benefit from other interventions.

"One of the real strengths of the UK’s scientific response to the pandemic has been the way that we’ve assembled teams of experts to lead cutting-edge and responsive studies like this, to inform our vaccine roll-out and government decision-making in real time.”

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Examining the immunological effects of COVID-19 vaccination in patients with conditions potentially leading to diminished immune response capacity – the OCTAVE Trial

• Pamela Kearns, Stefan Siebert, Michelle Willicombe, Charlotte Gaskell, Amanda Kirkham, Sarah Pirrie, Sarah Bowden, Sophia Magwaro, Ana Hughes, Zixiang Lim, Stavros Dimitriadis, Sam M. Murray, Thomas Marjot, Zay Win, Sophie L. Irwin, Georgina Meacham, PITCH Study Group, OCTAVE Study Group, Alex G. Ritcher, Peter Kelleher, Jack Satsangi, Paul Miller, Daniel Rea, Gordon Cook, Lance Turtle, Paul Klenerman, Susanna J. Dunachie, Neil Basu, Thushan I. de Silva, David Thomas, Eleanor Barnes, Carl S. Goodyear, Iain McInnes.
•  SSRN: https://ssrn.com/abstract=3910058 or http://dx.doi.org/10.2139/ssrn.3910058

The OCTAVE (Observational Cohort Trial-T-cells Antibodies and Vaccine Efficacy in SARS-CoV-2) study looks at those with immune mediated inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, ANCA-Associated Vasculitis, inflammatory bowel disease, as well as hepatic disease and renal failure.

So far, more than 2,500 patients have been recruited to the trial, making it one of the largest global studies in which detailed immune response is being assessed post-SARS-CoV-2 vaccination.

The data reported in this pre-print includes the post-vaccine immune response results from the first 600 patients recruited four weeks post second dose.

As the study progresses, around 3,000 people will be recruited. Participants in the study have all received either COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) or ChAdOx1 Vaccine (AstraZeneca) as part of the National COVID19 vaccination programme.

Image legend: Figure 1. Anti-spike (S) responses at pre-vaccine, pre-second dose and 4 weeks post-second dose across disease groups in OCTAVE and PITCH Healthy controls. Anti-S titre at baseline (pre-vaccine), following first-dose (pre-boost) and 4 weeks post second-dose vaccine (Post-Boost) in (A) Healthy Controls (HS), ANCA-associated vasculitis (AAV), Inflammatory arthritis (IA; rheumatoid arthritis and psoriatic arthritis), Haemodialysis (HD), and Haemodialysis on Immunosuppression (HD-IS), (B) Healthy Controls (HS), Hepatic disease (HepD), inflammatory bowel disease (IBD), solid cancer (SC; Breast and Lung) and haematological malignancies (HM; Acute Myeloid Leukaemia and Multiple Myeloma), and Haemopoietic Stem Cell Transplant (HSCT) patients. For visualisation data was placed on a log scale and groups were split across two graphs with the same HC on both. Bars represent median/IQR.

Enquiries: ali.howard@glasgow.ac.uk or elizabeth.mcmeekin@glasgow.ac.uk / 0141 330 6557 or 0141 330 4831

First published: 26 August 2021