A University of Birmingham-led study has shown that a third of patients with the most common type of leukaemia fail to generate any measurable antibody response following two doses of COVID-19 vaccination.
Furthermore, the research showed that in the two thirds of patients who do develop antibodies, levels are much lower than compared to healthy people and also have a profoundly reduced ability to ‘neutralise’ the globally dominant Delta variant.
The largest study of its kind, the research identified a number of important new findings which researchers say will be crucial to shaping future management and public health policy for patients with this type of blood cancer, who are immunosuppressed and at an increased clinical risk from SARS-CoV-2 infection.
Key new findings are:
- Only 67% of the leukaemia patients generated any measurable antibody response to double COVID-19 vaccination, compared to 100% of the age-matched healthy population.
- In those patients with leukaemia who did have an antibody response, antibody levels were 3.7 times lower than that seen in the healthy control group.
- Antibody levels declined by 33% at four months after leukaemia patients’ second vaccine.
- No difference in antibody responses were observed between those participants receiving the Oxford/AstraZeneca vaccine and those receiving the Pfizer/BioNTech vaccine.
- Antibody responses showed weak ability to neutralise the spike protein from the now globally dominant SARS-CoV-2 Delta variant compared to healthy controls.
500 patients with chronic lymphocytic leukaemia - the most common leukaemia in adults - were recruited to the study. 41% had received two doses of the Pfizer/BioNTech vaccine, whilst 59% had received two doses of the Oxford/AstraZeneca vaccine. The average age of participants was 67 and 53% of the cohort was male. Their antibody response to double COVID-19 vaccination was compared to that of 94 age-matched healthy ‘controls’. Blood samples were obtained from all study participants between two to three weeks following their second vaccination, and again up to 30 weeks later.
Antibody responses were seen in 67% (336) of the leukaemia patients, compared to 100% (93) of age-matched controls. In those with leukaemia who did generate an antibody response, the average antibody level was 3.7 times lower in magnitude and only just over a quarter (27%) of that seen in the healthy controls.
Using blood samples of 94 of the leukaemia patients, and 94 healthy controls, the team also analysed their ability to 'neutralise' live SARS-CoV-2 infection in the laboratory using the original Wuhan virus and the Delta variant. In the healthy cohort, average neutralisation of live Wuhan and Delta virus was 96% and 84% respectively. However, in the leukaemia patients, neutralisation of Wuhan virus was only 62% and even lower at 14% in the Delta variant. Neutralisation assays in the lab give us the closest indication as to how patients are likely to handle the virus should they be exposed to it in the community. Therefore the data suggests that leukaemia patients are still at ongoing risk and susceptibility to catching the virus, despite having had two doses of the COVID-19 vaccination.
It is concerning that 33% of patients in our study did not generate any measurable antibody response to two doses of COVID-19 vaccination, and particularly concerning that in those who did generate an antibody response, there was a profound loss in ability to neutralise live Delta variant. The Delta variant is now globally dominant and more than twice as contagious as the Wuhan virus. Current COVID-19 vaccines are based on the spike protein sequence from the original Wuhan virus, whereas the Delta variant contains additional mutations.Dr Helen Parry, a National Institute for Health Research (NIHR) academic clinical lecturer at the University of Birmingham.
Meanwhile, antibody titers in leukaemia patients who had previously been infected with COVID-19 were 21-times higher than those seen in patients without previous infection - revealing strong immunological ‘priming’ after natural infection.
The leukaemia patients without previous COVID-19 infection had equal antibody responses, no matter which of the two vaccines types they had been given.
Dr Graham McIlroy, clinical research fellow at the University of Birmingham, says: “This provides evidence that both mRNA and adenovirus-based vaccines provide equal efficacy in leukaemia patients, and it is important we assess this further by analysing the antibody response to other COVID-19 vaccines currently being used around the world.”
The researchers also found that those with leukaemia most likely to fail to respond to COVID-19 vaccination are men (with a 46% reduction in the probability of developing an antibody response); patients being treated with a treatment called Bruton tyrosine kinase inhibitor (BTKi) therapy (80% reduction); those with a history of infection who require regular antibiotics (72% reduction); and those with low serum levels of two types of immunoglobulin known as IgA and IgM (72% and 57% reduction respectively).
The scientists also analysed how antibody responses differed depending on the stage and treatment of the disease. Those who have never been treated but are under active monitoring had the highest antibody response rates, with 79% showing a positive response. The antibody response rate was lowest in patients who were actively being treated (43%), while markedly higher rates of antibody response (56%) were seen in patients who had completed anti-CD20 therapy – a widely used treatment - more than 12 months prior to their second vaccine, compared to rates of 24% in those whose CD20 therapy ended less than 12 months prior to double vaccination.
“This finding suggests that vaccination should be encouraged in patients who are in remission at least one year after anti-CD20 therapy,” Dr McIlroy said.
Paul Moss, Professor of Haematology at the University of Birmingham and Principal Investigator of the UK Coronavirus Immunology Consortium (UK-CIC), concluded: “The rapid development of vaccines for COVID-19 has been a major step forward in the battle against this global pandemic, however, our findings argue strongly that further protection for this vulnerable cohort is needed. A third vaccine dose is likely to boost antibody responses in some patients, but there are additional complications in leukaemia patients and additional medical interventions may be required.
"What is encouraging is that we found that in those who did generate an antibody response this increased 294-fold between their first and second vaccines, which may bode well for the use of an additional third booster vaccine. We will now continue to assess antibody responses prospectively and following third booster vaccination. 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 research, published as a pre-print and therefore yet to be peer reviewed, was funded by the National Core Studies Immunity programme which is funded by the UK Research and Innovation (UKRI). It was also partially supported by UK-CIC which is jointly funded by UKRI and the National Institute for Health Research (NIHR).
Dr Jonathan Pearce, Director of the COVID-19 Response at the Medical Research Council (MRC), which is part of UKRI and co-funded the study, said: “This study increases our understanding of how people with leukaemia respond to the COVID-19 vaccine, helping us to identify key at-risk patient groups who don’t develop a strong immune response. For at-risk people, it highlights the importance of additional protection measures, including third doses – currently the MRC and Vaccines Taskforce funded OCTAVE DUO* study is investigating third vaccine doses in people with weakened immune systems.”