Cancer patients who are immune suppressed remain at increased risk from COVID-19 and have recently been prioritised for additional booster bivalent vaccines. Despite this, previous studies have shown that humoral and cellular immune responses often fail to reach levels comparable to the general population following booster doses. The emergence of the omicron variant of SARS-CoV-2 has necessitated the deployment of modified bivalent mRNA vaccines that direct the synthesis of spike protein from Omicron in combination with ancestral spike. Bivalent booster vaccines have shown utility in general population studies [1,2,3] but there is little understanding of their relative immunogenicity in patients with immune suppression.
Chronic lymphocytic leukaemia (CLL) is the most common subtype of leukaemia and is associated with significant immune suppression. Indeed, mortality rates following SARS-CoV-2 infection approached 33% in the pre-vaccine era [4]. Here we studied SARS-CoV-2 immunity in a cohort of 84 patients with CLL who received an original/Omicron BA.1 bivalent vaccine during their booster vaccine regimen. This represented the 6th vaccine for 66% of recipients and the 5th vaccine for 34%, whilst the median time since the previous vaccine was 154 days (IQR 123–215). 57% received the Moderna Spikevax bivalent Original/Omicron BA.1 vaccine whilst 43% received the Pfizer Comirnaty Original/Omicron BA.1 vaccine. Blood samples were taken 10 days (3–28) prior to vaccine delivery (n = 50) and/or at 40 days following vaccination brackets (IQR 31–56.5) (n = 67).
Antibody responses against ancestral spike protein were initially measured using the Roche Elecsys platform which had been employed throughout this prospective cohort study [5] (methods available in Supplementary materials). Excluding participants with prior infection, 87% (58/67) of patients demonstrated a measurable antibody response compared to 100% within healthy donors. Encouragingly, antibody titres amongst responders were equivalent to those seen within healthy controls, a feature not seen following previous booster vaccines (Fig. 1a). Furthermore, titres were now seen to be equivalent in patients with or without clinical or serological evidence of prior natural SARS-CoV-2 infection and it was noteworthy that responses were also detectable in 91% (10/11) of patients with pan-hypogammaglobulinaemia. Nine patients remained seronegative, confirming prior evidence for a plateau of serological response in patients with CLL, and 6 of these were taking Bruton tyrosine kinase inhibitor medication, which is a highly effective treatment but suppresses humoral immunity. Two patients were untreated whilst one patient had received venetoclax and obinutuzumab therapy (Fig. 1b).
We next determined relative antibody generation against ancestral and Omicron spikes to assess the specificity of serological response following bivalent vaccination. The mean antibody titre against the ancestral spike was 2.8 fold higher than against Omicron and is likely to reflect the multiple vaccine exposures to ancestral spike immunogen. However, antibody levels against the ancestral spike increased by 1.9 fold (p = 0.14) following the bivalent vaccine compared to a 2.2-fold increase to the Omicron BA.1 variant (p = 0.07) (Fig. 1c). We next assessed antibody functional activity by neutralisation of ancestral or Omicron BA.1 spike protein-pseudotyped viruses. Again, although overall neutralising activity was superior against the ancestral variant, relative neutralisation following bivalent vaccination improved only 2.3-fold against the ancestral spike (p = 0.23) compared to 3.4-fold against the BA.1 protein (p = 0.05) (Fig. 1d). As such, a preferential increment in serological response against Omicron BA.1 was observed following bivalent vaccination. Despite this, the neutralisation of recent Omicron subvariants, including XBB, was limited (1e).
Cellular immunity against SARS-CoV-2 is believed to be important in controlling severe COVID-19 and may be particularly valuable in patients with humoral immune suppression. As such, we next assessed the cellular response against peptides from either ancestral or Omicron spike protein. Robust cellular immunity was observed with a 1.4-fold relative increase in ELISpot response following bivalent vaccination against ancestral spike peptides (p = 0.01) compared to 3.1-fold against Omicron peptides (p ≦ 0.0001) (Fig. 1f).
Limitations of this study include the small number of patients on BCL2 inhibitor therapy and the lack of neutralisation data against the more recent viral variant BA.2.86. However, our analysis of antibody binding, antibody neutralisation and cellular immunity against the ancestral and Omicron spike show relative enhancement against the Omicron variant following bivalent vaccination which augurs well for responses to future variant-specific vaccines. Despite this, we observed relatively poor neutralisation of Omicron subvariants which supports delivery of updated vaccines based on current circulating variants. A subset of patients with CLL that continue to lack antibody responses, due to ongoing treatment or underlying immune suppression, will also require additional protective approaches such as prophylactic antibody administration in order to minimise the risk of infection.
In conclusion, our data reveal the value of a regime of multiple booster vaccinations for patients with immune suppression and demonstrate encouraging immunogenicity of bivalent vaccines in this vulnerable population.
Data availability
All datasets used during the current study are available from the corresponding author upon reasonable request.
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Acknowledgements
We also thank Millie Manning, Danielle Sutherland, Tamsin Drury and Alex Bray for their help in recruitment.
Funding
This work was partially supported by the UK Coronavirus Immunology Consortium. (UK-CIC) funded by DHSC/UKRI and the National Core Studies Immunity. Programme, UKRI award MC_UU_00034/6P. This is independent research was partly carried out at the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the UK-CIC, UKRI, the NIHR or the Department of Health and Social Care. Sponsors had no role in the study design, collection, analysis, interpretation of the data or write up of the report.
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TR, HP, RB, PM designed the study. HP, RB, GM,SP, GP recruited participants. TR, GU, PS, NL, SS, ML, AE, SP, SM, KS, CS, CB, JZ, BW performed the experiements. PM, HP wrote the manuscript and HP, GM, SD, BW verified and analysed the data. All authors had full access to the data and approved submission of this report. PM and HP are joint last authors.
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Work performed under the CIA UPH IRAS approval (REC 20\NW\0240) from North-West and Preston ethics committee and conducted according to the Declaration of Helsinki. Informed consent was obtained by remote consultation and wet ink signed. All data presented are anonymised and non-identifiable.
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Roberts, T., Uwenedi, G., Bruton, R. et al. Enhancement of Omicron-specific immune responses following bivalent COVID-19 booster vaccination in patients with chronic lymphocytic leukaemia. Blood Cancer J. 14, 22 (2024). https://doi.org/10.1038/s41408-023-00940-5
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DOI: https://doi.org/10.1038/s41408-023-00940-5