COVID-19 vaccines for patients with haematological conditions.

Patients with haematological conditions have been disproportionately affected by the COVID-19 pandemic. A pooled meta-analysis of 3377 predominantly hospitalised patients with haematological malignancies and COVID-19 reported a mortality rate of 34% (95% CI 28–39). Advanced age (≥60 years) and non-White race were identified as risk factors for death. Mortality rate varied on the basis of the type of malignancy: 53% of patients with acquired bone marrow failure syndromes, 41% of patients with acute leukaemias, 32% of patients with lymphomas, 31% of patients with chronic lymphocytic leukaemia, and 34% of patients with myeloproliferative neoplasms. To place these data in perspective, the mean 30-day rate of mortality or referral to hospice was 11·8% (SD 2·5%) in a cohort study of 38 517 adults admitted to hospital with COVID-19 in the USA. The trajectory of COVID-19 in patients with benign haematological conditions such as haemoglobinopathy, haemophilia, pre-existing arterial or venous thromboembolism, and autoimmune cytopenia is relatively unknown, but as in the general population, is influenced by age and comorbidities.

Authorised COVID-19 vaccines are safe and effective in the general population. Given the high case fatality rate among patients with haematological conditions, prioritisation of COVID-19 vaccines for this group might appear straightforward. However, common to these vaccines is the exclusion of immunocompromised people from landmark phase 3 randomised controlled trials. Relevant exclusion criteria included the use of immunosuppressive or immunomodulatory agents, immunoglobulin or blood products, asplenia, and autoimmune conditions such as immune thrombocytopenic purpura. Most patients with haematological conditions, therefore, would have been ineligible for these trials. Until COVID-19 vaccines have been rigorously studied in this group, one must examine available data on the immune response to COVID-19 infection and non-COVID-19 vaccines to inform clinical practice and expectations.

Haematological conditions and their treatment are heterogeneous, and so the immune response to infection or vaccination is also expected to be variable. A case series reported 14 (67%) of 21 patients with chronic lymphocytic leukaemia developed IgG antibodies to SARS-CoV-2 nucleocapsid. Those who did not develop antibodies included both treatment-naive patients and patients receiving chronic lymphocytic leukaemia-directed therapy. The seroconversion rate among recipients of haematopoietic stem-cell transplantation and chimeric antigen receptor T-cell therapy was similar at 66% (25 of 38 patients). Intriguingly, B-cell lymphopenia in these patients did not preclude an antibody response to SARS-CoV-2. In acute leukaemia, antibodies against the external spike glycoprotein and internal nucleocapsid were detected in seven (88%) of eight patients. Besides a lower rate of antibody production, the humoral response in patients with haematological conditions is also slower than in the general population. SARS-CoV-2-specific cellular immunity in this group still needs to be characterised.

A 2011 Cochrane review of viral vaccines in patients with haematological malignancies concluded that, despite the low quality of evidence, the possibility of protection outweighed the minor risks of vaccination. Regrettably, there remains a lack of randomised studies to evaluate vaccine efficacy in patients with haematological conditions. One exception is a randomised placebo-controlled trial of adjuvanted recombinant zoster vaccine (RZV) in 569 patients with haematological malignancies. All patients were receiving or had received treatment for their haematological malignancy within 6 months before vaccination. RZV was well tolerated and induced a humoral response in 119 of 148 patients (80% [95% CI 73–86]). This per-protocol analysis excluded patients with non-Hodgkin B-cell lymphoma and chronic lymphocytic leukaemia, in whom the humoral response rate was between 20% and 50%. Herpes zoster occurred in two patients in the vaccine group who received proximate rituximab therapy. These observations confirm that B-cell depleting therapy, or perhaps B-cell malignancy, weakens the humoral vaccine response and overall vaccine efficacy.

Whether immunisation induces a primary or memory immune response could be an important consideration for specific haematological conditions or treatment. We investigated the de novo humoral immune response to recombinant hepatitis B vaccine and the recall response to RZV in patients with chronic lymphocytic leukaemia. Patients were treatment-naive (32 patients for hepatitis B vaccine and 22 patients for RZV) or receiving a BTK inhibitor for at least 6 months (26 patients for hepatitis B vaccine and 41 patients for RZV). Treatment-naive patients had an impaired humoral response to both vaccines, consistent with previous studies of other immunisations in this population. In patients on BTK inhibitor therapy, hepatitis B surface antibodies were negative in all but one patient at 3 months following vaccination. The rate of seroconversion with RZV was also numerically lower in patients treated with BTK inhibitors (41% [17 of 41]) than treatment-naive patients (59% [13 of 22]) but, in an interim analysis, did not meet statistical significance. It is worth noting that the absence of a humoral response does not inevitably preclude a cellular response to vaccination. Another study of RZV in patients treated with ibrutinib reported a T-cell response in 50% of patients (four of eight) who did not seroconvert. Treatment modification to improve vaccine response is not supported by current evidence, but deserves further study.

On the basis of existing knowledge about immune responses to COVID-19 infection and non-COVID-19 vaccines in patients with haematological conditions, one can anticipate an attenuated response to COVID-19 vaccines in this vulnerable population. Additional measures to mitigate the risk of COVID-19 are available. Household contacts of individuals at high risk of infectious complications have been recommended as a priority group for annual influenza vaccination and, following this logic, should receive COVID-19 vaccines. Passive immunisation via monoclonal antibodies or high-titre convalescent plasma has been shown to reduce viral load and reduce COVID-19 complications.

The prospect of benefit from COVID-19 vaccines must be weighed not only against their general tolerability, but also the substantial mortality from COVID-19 infection among patients with haematological conditions. Prospective cohort studies will provide information about the immunogenicity of these vaccines. Advocacy to include immunocompromised people in pivotal vaccine trials and an effort to systematically test strategies to boost vaccine response will help protect patients with haematological conditions against COVID-19 and future outbreaks.

CS received research funding from Genmab. AW received research support from Pharmacyclics, an AbbVie company; Acerta Pharma, a member of the AstraZeneca group; Merck; Nurix; Verastem; and Genmab. CP declares no competing interests. The authors are supported by the Intramural Program of the National Heart, Lung and Blood Institute, National Institutes of Health.