SARS-CoV-2 vaccination in CLL: how often is enough?

In this issue of Blood, Shen et al¹ report a significant increase in seroconversion rates after repeated COVID-19 booster vaccinations in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL). Given that vaccine response in patients with hematologic malignancies, especially in patients with CLL, is often insufficient, further understanding of vaccine immune response is needed for this group of patients at high risk for severe COVID-19. Although the evolution of the pandemic is uncertain, it is likely to remain a serious threat to immunocompromised patients. The data discussed here support the benefits of boosters for these vulnerable patients.

Vaccination has seldom been as decisive as in 2020. Edward Jenner, the father of vaccinology, trusted his project of “sufficient moment to inspire the pleasing hope of it becoming essentially beneficial to mankind” in 1796 but certainly did not anticipate the indispensability of vaccines in the era of a pandemic. Ever since, vaccines have been a key element to prevent infection and to protect the most vulnerable patient groups, such as patients with CLL/MBL. Those patients have a severely impaired immune system due to cellular and humoral defects.² Most CLL-directed therapies further aggravate the underlying immunodeficiency, at least transiently, putting patients at an immense risk of a clinical course of severe COVID-19.³ 

Prospective studies investigating the immunogenicity of COVID-19 vaccines in patients with CLL indicate a significantly decreased immune response for both humoral and cellular paths compared with those of healthy individuals.^4,5 Although several studies assessed humoral response, only a few scrutinized the cellular response.⁴ Vaccine nonresponders remain unprotected unless they receive passive protection from monoclonal antibodies, such as tixagevimab copackaged with cilgavimab. A long-term prevention and mitigation strategy against COVID-19 is needed that will allow immunocompromised patients’ participation in social life without the permanent threat of severe COVID-19.

In their prospective noninterventional trial, Shen et al describe seroconversion rates as well as T-cell responses in patients with CLL and MBL after multiple (up to 8) COVID-19 vaccine doses. After 2 doses, patients showed a weak antibody response at best, but a significant increase in seroconversion rates was observed after 3 and more doses. Notably, individuals with detectable antispike antibodies achieved a higher antibody level with subsequent doses, the level incrementally increasing with each vaccine dose. The study confirms the beneficial effect of multiple vaccine doses in patients with CLL/MBL. This is a striking result in a population with severely impaired B-cell responses caused by a disease, treatment, or often both. Whether the repeated immune stimulus or a post-treatment recovering immune status is driving the response is unclear and needs more study. These data are reassuring, considering the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection waves expected in the forthcoming months.

The authors investigated antibodies against Omicron (BA.1) and Delta (B.1.617.2) as well as the wild-type control virus (B.1.319/D614G) from an early circulating 2020 clade (B.1). The level of protection from emerging variants remains to be determined in healthy as well as in vulnerable individuals. Especially, the cellular immune response has so far retained cross-reactivity in patients infected with variants of concern.⁶ The T-cellular response to the SARS-CoV-2 infection and vaccination may ensure protection even in the absence of either humoral or B-cellular response, as revealed by previous investigations among patients with hematologic malignancies and B-cell depletion.⁷ In contrast to prior data from a small CLL cohort that found an increased T-cell response after booster immunization,⁸ Shen et al found no correlation between the T-cell response and the number of vaccine doses. Likewise, previous studies found discordant immune responses in patients with CLL after COVID-19 vaccination; whereas here, there was a strong correlation between positive T-cell responses and high antispike levels. Future investigations should analyze T-cell responses in even greater detail. Systematic investigation of lymphocyte subsets will help examine these unresolved issues. It remains to be elucidated which patients develop a T-cell response while lacking antibody responses and how sequential boosters affect these lymphocyte subsets. Indeed, antibody production as the sole measure of protection offered by vaccines appears to be insufficient for immunocompromised patients.

The study investigated the immune response irrespective of the choice of vaccine. A subset of patients was analyzed in-depth, and the antibody increase in the heterologous cohort was 1.6 times higher than that in the homologous cohort but did not reach statistical significance. Although heterologous immunization seems to elicit stronger antibody and T-cell responses than homologous immunization,^9,10 the impact of the order of the vaccine type needs further study. The impact of different vaccine platforms on consecutive booster vaccinations would also be of great interest for future studies and may also have implications for the prevention of diseases other than COVID-19.

The best vaccination schedule for immunocompromised patients including those with CLL, needs yet to be determined, but the results presented by Shen et al give further guidance.¹ In patients who had received primary immunization and did not establish measurable antibody response, a third vaccine dose should likely be given after 4 weeks. The immune response of immunocompromised individuals to COVID-19 vaccines is currently difficult to predict, but protection needs to be established as soon as possible. This calls for repeating vaccination at 4-week intervals until the response is ultimately achieved. Because antibodies cannot be used as the sole correlate of protection, especially in patients with an impaired B-cell axis, determining the T-cell response may be an option, which is not yet broadly available. A current clinical trial for patients with lymphoma (NCT05160766) evaluates the feasibility and validity of serologic and cellular measures of protection during sequential booster vaccinations at 4-week intervals and may answer some of these pressing questions.

Although the pandemic has been a human catastrophe affecting clinical practice and global health, it has also urged tremendous innovation in vaccine development. In the future, this will likely prove an enormous benefit. Vaccination has been a neglected topic in the past, and we need to seize the moment to systematically understand vaccine immunology in immunocompromised hosts, such as patients with hematologic malignancies.

Conflict-of-interest disclosure: S.C.M. reports grants from University of Cologne (KoelnFortune), Dr Manfred Plempel Stipend, German Center for Infection Research (DZIF) clinical leave, and personal fees from Octapharma, outside the submitted work. O.A.C. reports grants and contracts from Amplyx, Basilea, the Federal Ministry of Education and Research, Cidara, DZIF, the Directorate-General for Research and Innovation (101037867), The Rare Fungal Disease Company, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, Mycoses Study Group Education & Research Consortium (MSG-ERC), Noxxon, Octapharma, Pardes, Pfizer, Scynexis, and Seres; honoraria for lectures from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, MSD, Mylan, Noscendo, Pfizer, and Shionogi; payment for expert testimony from Cidara; participation in a data safety monitoring board or an advisory board from Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, Pulmocide, Shionogi, and The Prime Meridian Group; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); stocks from CoRe Consulting; and other interests from the German Society for Haematology and Medical Oncology, Deutsche Gesellschaft für Infektiologie, the European Confederation of Medical Mycology, the International Society for Human and Animal Mycology, MSG-ERC, and Wiley, outside the submitted work.