Blunted humoral response after mRNA vaccine in patients with haematological malignancies

Patients with haematological malignancies are at a higher risk for severe COVID-19 outcomes than healthy individuals.¹ These patients can also have long-term direct and indirect clinical consequences of SARS-CoV-2 infection, including stalled cancer care. Therefore, to reduce the impact of COVID-19 on this clinically vulnerable population, optimal vaccine protection is paramount. The COVID-19 mRNA vaccines produce a robust adaptive immune response in healthy individuals and have been a tremendous success in real-world conditions. However, the pivotal mRNA vaccine trials excluded patients with cancer who were on active treatment.² As such, little information is available about vaccine efficacy in patients with haematological malignancies.

Among patients with haematological malignancies, vaccine-induced immunity is generally subdued and depends on the type of cancer and its treatment, as well as the immunogenicity of the specific vaccine. Responses to traditional influenza and pneumococcal immunisation are inadequate, especially in haematopoietic stem-cell transplantation (HSCT) recipients or after B-cell depleting therapies such as Bruton's tyrosine kinase inhibitors (BTKIs) or anti-CD20 antibodies.³

Nevertheless, advancements in vaccine technologies hold immense promise. Newer recombinant, adjuvanted vaccines have improved clinical protection in immunocompromised patients. For example, randomised controlled trials of the recombinant zoster vaccine early after autologous HSCT show a 68% (95% CI 55·6–77·5) vaccine efficacy⁴ compared with an efficacy of 91% (86·8–94·5) in adults aged 70 years or older. Additionally, the recombinant zoster vaccine elicits humoral and cellular immune responses in the majority of patients with haematological malignancies, with an estimated 87% effectiveness in preventing herpes zoster.⁵

Vaccine responses with newer B-cell depleting therapies also have been studied. A report comparing antibody response to recombinant hepatitis vaccine (CpG-adjuvanted hepatitis B vaccine) and shingles vaccine (recombinant zoster vaccine) among recipients of BTKIs showed an overall low response rate to the hepatitis B vaccine. However, for the recombinant herpes zoster vaccine, humoral immune responses were slightly lower, but not significantly different, than those in treatment-naive individuals, suggesting that BTKIs might not impair recall responses as much as a response to novel viral antigens.⁶

In The Lancet Haematology, Kazimieras Maneikis and colleagues⁷ present findings from their prospective national study in Lithuania in which they measured post-vaccination SARS-CoV-2 antibody responses in 857 SARS-CoV-2 seronegative patients with haematological malignancies. The authors measured anti-S1 IgG antibody concentrations before first immunisation with BNT162b2 (Comirnaty; Pfizer-BioNTech), on the day of the second immunisation, and 7–21 days after the second immunisation. Compared with 68 healthy 18–60-year-olds, patients with haematological malignancies also aged 18–60 years had significantly lower antibody concentrations after the second vaccine dose (median 6961 AU/mL [IQR 1292–20 672] vs 21 395 AU/mL [14 831–33 553]; p<0·0001). The comparison of untreated and treated patients with haematological malignancies showed lower antibody concentrations in treated individuals, especially in those treated with BTKIs (n=44) and anti-CD20 therapies (n=87) within the past 12 months. A small number of evaluated patients on venetoclax (n=10) and ruxolitinib (n=16) also responded poorly. As expected, responses improved if the vaccines were administered 6 months after HSCT or the last therapy, except for rituximab, where humoral responses were largely absent for the first 12 months after treatment. Additionally, the finding that the second BNT162b2 dose did not augment antibody concentrations in most patients who responded poorly to the first dose might provide practical insight to the commonly posed question of whether a third homologous vaccine dose might boost clinical protection. Overall, nine vaccine breakthrough infections occurred in patients who had received both doses of the vaccine.

The main limitation of the study is that the authors did not evaluate T-cell response to the BNT162b2 vaccine. SARS-CoV-2 infected patients with haematological malignancies without demonstrable seroconversion (humoral response) might have preserved T-cell responses that corelate with improved survival, suggesting that cellular immunity will have an essential role in vaccine-mediated protection.⁸ Additionally, study participants represented a diverse group of patients with haematological malignancies with a small sample size to measure the effect of specific treatments. Despite the limitations, the study results further our understanding of vaccine elicited humoral immunity in a highly heterogeneous population in which many factors can influence vaccine response (eg, age, cancer, current and past treatments, comorbidities, duration of cancer).

Enhancing SARS-CoV-2 vaccine responses to reach better clinical protection in immunocompromised patients is an area of active research—an early analysis has been done of a third homologous or heterologous vaccine dose with mRNA or Ad26.COV2.S (Janssen) vaccine in recipients of solid organ transplants who responded poorly to the two-dose vaccine series.⁹ The third vaccine dose was administered a median of 67 days (IQR 54–81) after the second dose, and was safe but produced a boost in antibody titres in only 25% of patients without an initial response—a single case of post-vaccine antibody-mediated organ rejection occurred in a patient who had received a heart transplant. No studies on third doses of the same or different vaccine have been reported in patients with haematological malignancies.

Until further data become available, the study by Maneikis and colleagues will help inform crucial clinical decisions. In places where community SARS-CoV-2 prevalence is declining, the primary SARS-CoV-2 immunisation should be timed to treatment to ensure the best possible immune protection. In addition, the study provides the evidence base for counselling patients on the importance of adherence to non-pharmacological interventions against SARS-CoV-2 until better vaccination or prophylactic immune therapeutics are available; this is especially important as less restrictive public health measures are adopted. Finally, the study underscores the crucial need for research to improve SARS-CoV-2 immunisation strategies in individuals who are less protected by current approaches.

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I declare no competing interests.