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), COVID-19 vaccine development has been a top priority and ultimately led to the rollout of several types of vaccines. However, some patient populations have shown a consistent lack of response to these vaccines, including those with blood cancers.
Study: Third primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with haematological malignancies. Image Credit: Hospital Man / Shutterstock.com
A new Nature Communications journal study reports that modifying the vaccine protocol to include a third primary dose in this patient subgroup could enhance their antibody responses against SARS-CoV-2. However, irrespective of this, some remain unresponsive and may require additional vaccine doses or other protective measures, such as monoclonal antibodies (mAbs) that neutralize the virus.
At the start of the pandemic, several high-risk patient groups were quickly identified due to rapidly rising case and mortality rates, some of whom included those of advanced age and those with a variety of medical conditions.
Some of the medical conditions that increased patients’ susceptibility to COVID-19 included cardiovascular risk factors or disease, immunocompromised state, and cancers. Hematological malignancy, for example, was considered to increase the patient’s risk significantly. Given the high mortality rates of 20-40% in this subgroup during the first wave of the pandemic, these patients were advised to quarantine.
Several SARS-CoV-2 variants of concern (VOCs) have been identified, most of which were isolated in 2022. The most recent VOC is the Omicron variant, associated with greater transmissibility than previous VOCs but reduced severity in terms of hospitalizations and mortality rates.
Aside from lower virulence, the mild nature of infection with the Omicron variant may be due to pre-existing immunity at the community level as a result of widespread infections and vaccinations. Moreover, many patients received early treatment with neutralizing mAbs and did not deteriorate clinically.
Most COVID-19 vaccines produce antibodies against the viral spike protein, the immunodominant neutralizing epitope. These neutralizing antibodies prevent infection by inhibiting engagement between the receptor binding motif (RBM) of the viral spike protein and the host cell angiotensin-converting enzyme 2 (ACE2) receptor.
Various commercial serological assays are available to measure the concentration of vaccine-induced anti-spike antibodies. Importantly, there is no agreement on what levels of specific immunoglobulin G (IgG) antibodies to the spike protein correlate with adequate neutralizing activity.
The RECOVERY trial showed that patients who failed to mount 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 tenth percentile range of detection of serologic assays, considering the increased vulnerability of these patients to COVID-19. However, the broad resistance of the Omicron variant to most neutralizing mAbs (nMAbs) led to restrictions placed on the use of this cocktail unless the Delta variant is identified.
In response, scientists have sought to develop other broadly-neutralizing nMAbs to protect vaccine recipients who fail to develop an effective immune response and those who cannot take the vaccine for various reasons.
Several studies have reported a variety of vaccine responses among patients with cancer. However, while some in remission from their cancer have responded well, most fail to produce anti-spike antibodies following two vaccine doses.
A third COVID-19 vaccine dose was added to this regimen for patients with blood cancers in the United Kingdom, with the third messenger ribonucleic acid (mRNA) vaccine dose to be given eight or more weeks after the second dose. Subsequently, a booster dose was recommended to be administered eight weeks after the primary two or three vaccine doses.
In the U.K., a national program was initiated to offer outpatient nMAb treatment or antivirals to individuals at an increased risk of severe COVID-19, including those with blood cancer. This program primarily offers antivirals, irrespective of prior vaccination status or antibody response.
About the study
The current study utilized real-world data on antibody responses in blood cancer patients from the Monitoring Adaptive Responses to COVID-19 vaccines in Haematology (MARCH) study.
The MARCH study is observational and retrospective in design and aimed to identify the type 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 blood cancer history with one or more serological tests for SARS-CoV-2 antibodies.
Patients with chronic myeloid leukemia were excluded from the study, as these patients have been shown to respond almost normally to vaccination. In addition, no patients included in the current study had a prior history of SARS-CoV-2 infection.
Almost all patients had received two doses of either the AstraZeneca-ChAdOx1-S/nCoV-19 or Pfizer-BioNTech-BNT162b2 vaccines in a proportion of 40:60. The median gap between the first two doses was 75 days. The third dose was almost invariably the Pfizer vaccine and was administered after a median of 187 days from the second vaccine dose.
Serological testing was carried out after the first dose in 171 patients, the second dose in 327 patients, and the third dose in 162 patients. These tests were conducted at a median interval of 57 days after the first dose and about 50 days after the second and third doses. Control data is available for serological testing at about 50 days from the first dose and 21 and 90 days from the second dose.
What did the study show?
Patients with blood cancers exhibited detectable antibody responses in less than 50% of patients after the first dose; however, this rose to almost 75% after two doses. After the third dose, over 86% of patients exhibited antibodies.
When categorized by cancer type, only half of the patients with chronic lymphoid leukemia (CLL) and just over 60% with B-cell lymphoma responded with detectable antibody levels.
The type of cancer treatment that patients were currently undergoing also impacted the antibody response. For example, 55% of patients receiving anti-CD50 mAbs like rituximab any time during the previous six months showed a serologic response, whereas 50% receiving the immunotherapeutic drug venetoclax exhibited an antibody response.
In contrast, patients on other drugs that inhibited immune reactions, such as the JAK/STAT pathway inhibitors, responded poorly to two vaccine doses at 57%; however, this response rate rose to over 90% in this patient subgroup after receiving the third dose.
In addition to the poor numerical response, the quantitative response in those exhibiting detectable antibody production after vaccination was consistently and significantly lower compared to healthy controls. More specifically, median 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 rescued the cancer cohort, with the median titer rising to 1,026 BAU/mL. However, the tenth percentile of detectable antibody titers remained at about 570 BAU/mL. It was observed in less than 20% of blood cancer patients after two vaccine doses as compared to over 55% of healthy controls at this time point.
Nevertheless, a rising number of responders among patients without CLL or B-cell lymphoma, or plasma cell dyscrasias continued to show a poor response. A failure to respond was also more common among those treated with certain drugs.
The administration of an mRNA vaccine is crucial to boosting the percentage of responders and serological responses, irrespective of whether the recipients had previously received ChAdOx1-S/nCoV-19 or BNT162b2. However, immune responses after two doses of ChAdOx1-S/nCoV-19 varied significantly from the higher titers achieved with two BNT162b2 doses.
What are the implications?
A substantial proportion of patients with hematological malignancies fail to mount any detectable serological response, and many of those who do, have only low-level titres with unknown degree of protection.“
Nevertheless, a significant increase in the percentage of responders and in the strength of the immune response was achieved with a third mRNA vaccine dose in this cohort.
Many patients with hematological malignancies remain at an increased risk for COVID-19 due to the nature of their illness and/or current treatments. Thus, these patients would likely gain the most significant benefit from prophylactic nMAb therapy, rather than the current recommendation of oral antivirals, if they develop SARS-CoV-2 infection.
This treatment approach is already in practice for patients with a history of solid organ transplant in the U.K. and should be extended to those likely to fail to respond to three or more vaccine doses.
- Cook, L. B., O’Dell, G., Vourvou, E., et al. (2022). Third primary SARS-CoV-2 mRNA vaccines enhance antibody responses in most patients with haematological malignancies. Nature Communications. doi:10.1038/s41467-022-34657-z.