Additional mRNA-COVID vaccine doses could rescue antibody responses in blood cancer patients

To date, the coronavirus disease 2019 (COVID-19) has claimed nearly 6.6 million lives while disrupting healthcare systems, social interactions and economic activity worldwide.

Since the emergence of the causative Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the development of COVID-19 vaccines has been a top priority, eventually leading to the introduction of multiple types of vaccines. However, some patient populations have consistently failed to respond to these vaccines, including patients with blood cancers.

To learn: Third-party primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with hematologic malignancies. Credit: Hospital Man /

A new nature communication Journal studies report that changing the vaccine protocol to include a third primary dose in this patient subset could enhance their antibody responses to SARS-CoV-2. Regardless, however, some are unresponsive and may require additional doses of vaccine or other protective measures, such as B. monoclonal antibodies (mAbs) that neutralize the virus.


At the beginning of the pandemic, due to rapidly increasing case and mortality rates, several high-risk patient groups were quickly identified, including patients of advanced age and patients with various diseases.

Some of the medical conditions that increased patients’ susceptibility to COVID-19 were cardiovascular risk factors or diseases, immunocompromised condition and cancer. For example, hematologic malignancy has been thought to significantly increase the patient’s risk. Given the high mortality rates of 20-40% in this subgroup during the first wave of the pandemic, quarantine was recommended for these patients.

Several SARS-CoV-2 variants (VOCs) of concern have been identified, most of which were isolated in 2022. The most recent VOC is the Omicron variant, which is associated with higher transmissibility than previous VOCs but lower severity in terms of hospitalization and mortality rates.

Aside from the lower virulence, the mild nature of Omicron variant infection may be due to pre-existing community-level immunity as a result of widespread infection and vaccination. In addition, many patients received early treatment with neutralizing mAbs and did not clinically deteriorate.

Most COVID-19 vaccines produce antibodies against the viral spike protein, the immunodominant neutralizing epitope. These neutralizing antibodies prevent infection by inhibiting the binding between the receptor-binding motif (RBM) of the viral spike protein and the host cell’s angiotensin-converting enzyme 2 receptor (ACE2).

Various commercial serological assays are available to measure the concentration of vaccine-induced anti-spike antibodies. Importantly, there is no consensus as to what levels of specific immunoglobulin G (IgG) antibodies against spike protein correlate with adequate neutralizing activity.

The RECOVERY study showed that patients who did not show an antibody response were more likely to die from COVID-19. Conversely, the mAb cocktail of casirivimab and imedevimab was associated with a 20% relative risk of death before the omicron variant became the dominant circulating strain.

This cocktail was then made available among immunocompromised patients with anti-spike antibody titers below the 10th percentile range of detection by serological assays, given these patients’ increased susceptibility to COVID-19. However, the Omicron variant’s broad resistance to most neutralizing mAbs (nMAbs) has led to limitations in the use of this cocktail unless the delta variant is identified.

In response, scientists have attempted to develop other broadly neutralizing nMAbs to protect vaccine recipients who fail to mount an effective immune response and those who are unable to take the vaccine for various reasons.

Several studies have reported a variety of vaccine reactions in cancer patients. While some have responded well in remission from their cancer, most do not produce anti-spike antibodies after two doses of the vaccine.

A third COVID-19 vaccine dose was added to this regimen for blood cancer patients in the UK, with the third messenger ribonucleic acid (mRNA) vaccine dose to be given eight or more weeks after the second dose. A booster dose was then recommended, to be given eight weeks after the first two or three doses of vaccine.

In the UK, a national program has been initiated to offer outpatient nMAb treatment or antiviral medicines to people at increased risk of severe COVID-19, including blood cancer. This program mainly offers antiviral drugs, regardless of previous vaccination status or antibody response.

About the study

The current study used real-world data on antibody responses in blood cancer patients from the Monitoring Adaptive Responses to COVID-19 Vaccines in Hematology (MARCH) study.

The MARCH study is observational and retrospective in nature and aimed to identify the nature and strength of adaptive immune responses to COVID-19 vaccines in 381 patients with blood disorders. All patients were at least 18 years old and had a history of blood cancer with one or more serological tests for SARS-CoV-2 antibodies.

Patients with chronic myeloid leukemia were excluded from the study because these patients were shown to have an almost normal response to vaccination. In addition, none of the patients included in the current study had a history of SARS-CoV-2 infection.

Almost all patients had received two doses of AstraZeneca-ChAdOx1-S/nCoV-19 or Pfizer-BioNTech-BNT162b2 vaccine in a 40:60 ratio. The median gap between the first two doses was 75 days. The third dose was almost always the Pfizer vaccine and was given a median of 187 days after the second vaccine dose.

Serological testing was performed in 171 patients after the first dose, 327 patients after the second dose, and 162 patients after the third dose. These tests were performed at a median interval of 57 days after the first dose and approximately 50 days after the second and third doses. Control data for serological testing are available approximately 50 days after the first dose and 21 and 90 days after the second dose.

What did the study show?

Blood cancer patients had detectable antibody responses in less than 50% of patients after the first dose; however, after two doses, this increased to nearly 75%. After the third dose, over 86% of the patients had antibodies.

Categorized by cancer type, only half of patients with chronic lymphocytic leukemia (CLL) and just over 60% with B-cell lymphoma responded with detectable levels of antibodies.

The type of cancer treatment the patients are currently undergoing also affected the antibody response. For example, 55% of patients who received anti-CD50 mAbs such as rituximab at any time in the previous 6 months had a serological response, while 50% who received the immunotherapy drug venetoclax had an antibody response.

In contrast, patients on other drugs that inhibit immune responses, such as the JAK/STAT pathway inhibitors, responded poorly to two doses of vaccine at 57%; however, this response rate increased to over 90% in this patient subgroup after receiving the third dose.

In addition to the weak numerical response, the quantitative response was consistently and significantly lower in those who showed detectable antibody production after vaccination compared to healthy controls. Specifically, mean anti-spike antibody titers were 214 BAU/mL in blood cancer patients compared to 603 BAU/mL in healthy controls after the second dose.

A third vaccine dose saved the cancer cohort, with the mean titer rising to 1,026 BAU/mL. However, the 10th percentile of detectable antibody titers remained at approximately 570 BAU/mL. It was seen in less than 20% of blood cancer patients after two doses of vaccine, compared with over 55% of healthy controls at that time.

However, an increasing number of responders among patients without CLL or B-cell lymphoma or plasma cell dyscrasia continued to demonstrate poor response. Non-response was also more common among those treated with certain medications.

Administration of an mRNA vaccine is critical to increase the percentage of responders and serological responses, regardless of whether recipients had previously received ChAdOx1-S/nCoV-19 or BNT162b2. However, the immune responses after two doses of ChAdOx1-S/nCoV-19 were significantly different from the higher titers achieved with two doses of BNT162b2.

What are the effects?

A significant proportion of patients with hematologic malignancies show no detectable serological response, and many of those who do have only low titers with an unknown degree of protection.”

However, a significant increase in the percentage of responders and the strength of the immune response was achieved with a third dose of mRNA vaccine in this cohort.

Many patients with hematologic malignancies remain at increased risk for COVID-19 due to the nature of their disease and/or current treatments. Therefore, these patients would likely derive the greatest benefit from prophylactic nMAb therapy rather than the current recommendation of oral antiviral drugs if they develop SARS-CoV-2 infection.

This treatment approach is already practiced in the UK in patients with a history of solid organ transplantation and should be extended to patients who are unlikely to respond to three or more doses of vaccine.

Magazine reference:

  • Cook LB O’Dell G Vourvou E et al. (2022). Third-party primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with hematologic malignancies. nature communication. doi:10.1038/s41467-022-34657-z.

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