New findings from a team of researchers at the University of Birmingham show that COVID-19 vaccines provide good levels of protection to people with chronic lymphocytic leukaemia although 20% still produce no antibodies to fight the virus after four vaccine doses.
Chronic lymphocytic leukaemia is the most common type of adult leukaemia. It profoundly affects people’s immune system and those with the condition have been found to be at increased risk of severe illness and death from COVID-19. Low levels of vaccine-induced antibodies are particularly common in people on certain types of treatment for the illness.
In this new study, published in the journal Cancer Cell, researchers set out to investigate the effectiveness of third and fourth doses of vaccine for this group, as well as levels of protection against the Omicron variant, and rates of breakthrough infection.
Blood samples were taken from 404 people with chronic lymphocytic leukaemia following their third dose, and from 186 people following their fourth vaccine dose. Anyone who had previously had COVID-19 was not included in the study.
The team had previously found that only two thirds of people with chronic lymphocytic leukaemia generate antibodies after their first two vaccine doses, compared with 100% of people without the disease. The new findings showed that this rate increased to 80% of people following a third vaccine dose. It did not appear to make a difference if they had the same vaccine or a different one as their booster.
In contrast, a fourth dose did not appear to improve the rate further, indicating that the proportion of people who develop an antibody response levels out after the third dose.
Three people from the study who had no post-vaccination antibodies went on to catch COVID-19 and this infection also did not result in antibodies being generated.
The following factors were found to be independently associated with a weak antibody response to vaccination:
- low levels of immunoglobulin
- ongoing treatment with Bruton tyrosine kinase inhibitors, a drug used to treat leukaemia
- treatment immediately after vaccination
These factors reduced the probability of generating an antibody response by 80%, 90% and 96% respectively.
In those people with chronic lymphocytic leukaemia who did generate antibodies after vaccination, levels of these increased 4.5-fold after the third vaccine dose, becoming comparable to levels seen in the control group after two doses of vaccine.
The researchers also looked at people’s T cell response to vaccination. T cells (immune memory cells) are known to play a key role in fighting infection. Levels of T cells in the study participants were found to be comparable to those seen in the control group after two doses of vaccine, and were substantially higher following third dose in people who had received the AstraZeneca vaccine as their primary course. In line with findings from other studies, this suggests that adenoviral-based vaccines may be particularly effective in generating T cell immunity in people whose immune systems are suppressed.
The researchers went on to look at how effective these immune responses were against the Omicron variant of the virus, now the dominant strain worldwide. They found that the antibodies generated after three doses of vaccine were poor at recognising Omicron compared to the original strain of the virus, but this reduction was similar in people who don’t have chronic lymphocytic leukaemia. However, T cells generated by the study cohort were equally able to recognise both the original and Omicron COVID-19 strains, suggesting that vaccine-induced T cell responses may give people with chronic lymphocytic leukaemia strong protection against the Omicron variant.
In order to get a better sense of the actual protection these immune responses may give, the researchers then looked at data on breakthrough infections among the study participants. 14% were found to have caught COVID-19 within 14 months of their first vaccine dose. Of these, 7.6% occurred when the Alpha variant was dominant, 33% were during the Delta wave, and 59% happened during the Omicron wave.
The proportion of people needing hospital treatment during these three phases was 20%, 32% and 7.7% respectively. Monoclonal antibody therapy became available in the community in December 2021 and may have contributed to the reduced rate of hospitalisation during the Omicron wave, though only 36% of those infected during this period received therapy. There were no COVID-19-related deaths in the study cohort.
Somewhat unexpectedly, people who generated antibodies after a second dose of vaccine showed a 79% increase in infection rate, most likely due to differences in social behaviour (this sub-group was generally younger than those that didn’t generate antibodies). This observation highlights the difficulty of defining immune protection and indicates a need for caution in predicting individual infection risk on the basis of antibody levels alone.
In general, being younger and having low levels of immunoglobulin were also found to be associated with a higher rate of infection.
The researchers concluded that vaccines are currently providing robust clinical protection for people with chronic lymphocytic leukaemia. In particular, vaccine-induced T cell responses are comparable with those seen in the general population, and may be vitally important in preventing severe disease. Nevertheless, 20% of this group still do not generate any detectable antibody response after vaccination, highlighting the importance of alternative approaches for immune protection, such as treatment with monoclonal antibodies in this group.
This work was supported by National Core Studies Immunity Programme and the UK Coronavirus Immunology Consortium (UK-CIC), funded by the National Institute for Health Research and UK Research and Innovation.