|Year : 2021 | Volume
| Issue : 2 | Page : 59-65
COVID-19 vaccines and their potential use in patients with hematological malignancies
Ashraf Dada1, Ghadeer Al-Bishi2, Binyam Usman3
1 King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia
2 Department of Pathology and Laboratory Medicine
3 Department of Oncology and Hematology
|Date of Submission||15-Mar-2021|
|Date of Decision||10-May-2021|
|Date of Acceptance||16-May-2021|
|Date of Web Publication||06-Aug-2021|
Dr. Ashraf Dada
Department of Pathology, King Faisal Specialist Hospital & Research Center, Jeddah
Source of Support: None, Conflict of Interest: None
Many uncertainties exist regarding COVID-19 vaccination in patients undergoing treatment for hematological malignancies. We intend the illustrate the various types of COVID-19 vaccine currently in use and their mechanism of action. We have complied, recommendations for COVID-19 vaccination in patients suffering with specific hematological malignancies and those undergoing HCT and CAR-T cell therapy in this review. We have also discussed the available safety data for COVID-19 vaccination in the immunocompromised population.
Keywords: COVID-19, hematological malignancies, vaccines
|How to cite this article:|
Dada A, Al-Bishi G, Usman B. COVID-19 vaccines and their potential use in patients with hematological malignancies. J Appl Hematol 2021;12:59-65
| Introduction|| |
At the end of 2019, a novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global outbreak of the respiratory illness called coronavirus disease 2019 (COVID-19). Since the initial outbreak in Wuhan/China, COVID-19 has been labeled the first pandemic to be caused by a coronavirus by the World Health Organization. The majority of infected people develop only mild symptoms or no symptoms at all. Nevertheless, some of the sick people experience severe courses, especially those who are particularly at risk. Confirmed new cases and mortality continue to rise globally, as the SARS-CoV-2 is a highly contagious virus and spreads by different transmission ways, for example, by the breath of the respiratory contaminated aerosols and the direct contact to surfaces or from human to human. Thus, this SARS-CoV-2 pandemic presents an extraordinary and unprecedented challenge to global health. Physical distancing, masks, disinfection of the surfaces, and frequent handwashing are widely implemented measures to control the spreading of the pandemic. Nevertheless, there has been a very concerning increase in the number of infected cases, with a peak of >800 k cases per day. In an attempt to control this monumental increase of cases and to control the pandemic, numerous COVID19 vaccine candidates are in development, and according to the WHO, there are currently more than 200 COVID-19 vaccine candidates in various trial phases and some reaching the preapproval stage or being authorized for use. The goals of vaccination against COVID-19 are as follows: a) to reduce the severity of disease in the recipient, b) to reduce the number of deaths due to COVID-19, c) to reduce the negative psychological, social, economic and health related effects of the corona pandemic. The vaccines are based on different platforms including innovative messenger RNA (mRNA) technologies, DNA, viral vectored, subunit, inactivated, and live-attenuated vaccines. However, most COVID-19 candidate vaccines express the spike protein or parts of the spike protein to stimulate humoral and cellular immune response, so that the body can develop memory B-cells to produce antibodies and T-cells against the S-protein of SARS-CoV-2 virus. The development of immune memory cells by vaccines is what is expected to protect the person against subsequent COVID-19 infection. Each COVID-19 vaccine has distinct advantages and disadvantages, but the development of different COVID-19 vaccines provides some redundancy and overlap. To match the urgent need of vaccine in managing the global pandemic threat, the clinical trials for the vaccines were performed in a very fast manner. For this reason, the vaccines could not be tested in all risk groups, such as children, pregnant women, and breastfeeding women. There is also considerable uncertainty about vaccinating patients with malignancies. This review will briefly address the current existing different types of vaccines used against the pandemic and their principal mechanisms. Furthermore, it will discuss and emphasize the possibilities and limitations of COVID-19 vaccines in patients with hematological malignancies.
| Types of COVID-19 Vaccines|| |
In principle, there are two kinds of immunizations, namely active and passive immunizations. Passive immunization is usually used as a treatment for COVID-19 patients to avoid worsening of the disease and thus reduce the mortality rate. This kind of immunization is usually not used for vaccination as the half-shelf time of the passively administered IgG neutralization antibodies is limited to 20 days only. Active immunity can be induced by pharmaceutical vaccines that are produced by various gigantic manufactories that have the potential to immunize the global population. Only this kind of vaccine is expected to control the COVID-19 transmission, so that the world hopefully can start to recover from the pandemic [Figure 1].
|Figure 1: The passive immunization limited to selective or unselected antibodies administration by the transfusion of convalescent plasma. The active immunization is the desired immunization which can be massively produced by large pharmaceutical companies|
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| Messenger RNA Vaccines|| |
mRNA vaccines use a new technique to help our bodies build protection against the SARS-CoV-2 virus. These vaccines contain a blueprint for the viral antigen in the form of genetic material, mRNA. The nucleoside-modified mRNA is formulated in lipid nanoparticles (LNPs), which enable the delivery of the RNA into host cells to allow the expression of the SARS-CoV-2 S-antigen. The vaccine elicits both neutralizing antibody and cellular immune responses to the spike (S) antigen, which may contribute to protection against COVID-19 disease [Figure 2]. In the case of Pfizer's and Moderna's vaccines,, the mRNA provides the genetic information to synthesize the spike protein that the SARS-CoV-2 virus uses to attach to and infect human cells. Each type of vaccine is packaged in proprietary LNPs to protect the mRNA from rapid degradation, and the nanoparticles serve as an adjuvant to attract immune cells to the site of injection. Once administered, the RNA is taken up by host cells. The intracellular lipases degrade the LNP exposing the mRNA. The mRNA is then translated into the S-protein, and is on its cell surface, stimulating an antibody and T-cell response. It is important to mention that the mRNA molecule does not enter the cell nucleus and cannot be incorporated into the DNA of a cell. After production of the S-protein, the mRNA is broken down relatively quickly by the body. A change in the genome, i.e. an impairment of the germ cells (egg cells or sperm), cannot take place.
|Figure 2: With an messenger RNA vaccination, a selected part of the viral RNA genome which is the S-protein is administered to a person in the form of a messenger RNA and entered the cell through receptor-binding domain. As a result, S-proteins of the severe acute respiratory syndrome coronavirus 2 are built in the cytoplasm of human cells, which are harmless and cannot cause infection for the vaccinated person. After synthesis of S-protein by the ribosomes in the cytoplasm, messenger RNA is then rapidly broken down into harmless pieces that are eliminated by the body. After presenting the S-protein in the cell surface by the major histocompatibility complex, the body forms humoral and cellular immune response against the severe acute respiratory syndrome coronavirus 2 virus initiating neutralization antibodies and T-cells activation, respectively. With this technology, the human body is instructed to produce its own vaccine|
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| DNA Vaccines|| |
DNA vaccines are made up of small strands of DNA, a gene, encoding the antigen of interest (in this case spike protein or S-protein, of the COVID-19). The gene is attached to a plasmid for delivery into the body. The plasmid is used so that the body does not degrade the foreign gene before it can provoke an immune response. Once administered, the DNA is taken up by host cells which produce the S-protein, and show the antigen (S-Protein) on its cell surface, thus stimulating an antibody and T-cell response.
| Live-Attenuated Vaccines|| |
These vaccines contain a live but less infective form of the pathogen. These vaccines have all the components of the original pathogen, but they possess mutations that reduce their ability to replicate inside the body, so they will not reproduce natural infection. It is a proven vaccine technology used to vaccinate people against many infections such as polio, tuberculosis, and chickenpox. As of the beginning of September 2020, however, only three COVID-19 vaccines are live-attenuated vaccines, with none entering clinical trials in the U.S. One of these is being developed at Griffith University, where parts of the SARS-CoV-2 genome are mutated to reduce but not abolish the ability of the SARS-CoV-2 virus to replicate in human cells. Because they still have a live virus, these types of vaccines may not be safe for people who are people who have impaired immune systems, either from taking certain medications or because they have certain medical conditions. They also need careful storage to stay viable.
| Inactivated Vaccines|| |
Evolving from live-attenuated vaccines that are able to slowly replicate in the body, inactivated vaccines contain a whole pathogen that is killed or inactivated by chemical, heat, or radiation. This eliminates the possibility of physiological and fast replicating of the pathogen and their possibility to cause infection. The inactivated vaccines have all the components of the original pathogen to induce a memory response. Various inactivated vaccines are available to vaccinate people against infections such as cholera and hepatitis A. Following in these footsteps is the COVID-19 vaccine CoronaVac, produced by Sinovac, containing the inactivated SARS CoV 2 virus. However, vaccines using inactivated viruses usually require multiple doses. They may also not provoke quite as strong a response as a live vaccine, and they may require repeat booster doses over time. Nonetheless, they are safer and more stable to work with than with live virus vaccines.
| Vector Vaccines|| |
Viral vector vaccines are similar to live-attenuated vaccines in that they use a harmless virus or an attenuated virus known as a vector. However, the attenuated virus carries a foreign gene in their genome representing the antigen of interest (e.g., the spike protein in SARS-CoV-2). When the virus infects a cell, they administer this foreign gene into the cell. The cell then transcribes and translates the gene to produce the antigen, and displays the antigen on the cell surface to stimulate an immune response. The infected cell may also slowly reproduce the virus which allows more cells to become infected and display the antigen on its surface. There are different vector vaccines that became the approval for use in humans against the COVID-19 pandemic, among them AstraZeneca, Gomaila, and Johnson and Johnson. The last-mentioned two companies use a human adenovirus as a vector, while AstraZeneca works with animal adenovirus (chimpanzee).
| Subunit Vaccines|| |
These vaccines take parts of the pathogen (antigens) that simulate an immune response and inject them into the body. Most subunit vaccines consist of proteins from the pathogen (such as the SARS-CoV-2 S-protein), but they can also be fragments of bacterial toxins (toxoids) or pathogenic components such as the cell wall. At least two of the COVID-19 vaccine candidates are subunit vaccines: NVX-CoV2373 developed by Novavax and SCB-2019 developed by Clover Biopharma. Both vaccines contain the whole S-protein of the SARS-CoV-2 virus combined with an adjuvant, a chemical that enhances the immune response to the vaccine. Subunit vaccines produce strong antibody responses as the antigens are collected, processed, and presented to B-cells to stimulate antibody production. However, subunit vaccines require the use of adjuvants to boost the immune response, which can have its own potential adverse effects. Moreover, their immunity may not be as long lasting compared to vaccines that use the whole virus. Furthermore, they may take longer to develop than vaccines using newer technologies, for example, mRNA vaccines. Nevertheless, they are safe to administer as the whole pathogen is not injected.
| Development of a Vaccine|| |
Developing and manufacturing vaccines is complex and time-consuming. The demands on quality, effectiveness, and especially safety are high. Therefore, the manufacture of a vaccine has to go through different development phases [Figure 3]. Only if one phase shows good results, does the vaccine move on to the next phase of further development.
|Figure 3: New vaccines have to go through preclinical and clinical phases before approval. In preclinical phase, the vaccine is tested in the laboratory, usually in vitro, on organic molecular compounds and human cell cultures. This is followed by tests on living, nonhuman organisms – from simple bacteria to laboratory animals. In clinical Phase I, the vaccine is first tested on healthy, voluntary candidates to demonstrate the general compatibility and harmlessness of the vaccine. If this phase is successful, the vaccine moves on to Phase II and Phase III. In Phase II, the dose is determined and the immunogenicity as well as the safety is studied on a small group of actual patients. In Phase III, a larger group of patients is vaccinated to demonstrate the efficacy and safety, which includes the dosage and side effects. Only after successful Phase III, marketing for a drug can be authorized and approved. After this, Phase IV studies are undertaken as a follow-up to evaluate and document further efficacy and safety of the studied vaccines|
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The phases which are required for developing the vaccines start with the preclinical phase. In this phase, the vaccine is tested in the laboratory and/or on animals. The second phase is the clinical phase that is divided into the following four phases: Clinical Phase I: A small number of healthy volunteers are tested for the first time to know how humans react to the vaccine and how tolerable different doses are. Dosage means how often and with what amount is vaccinated. In this phase, the first common side effects can also be recognized. Clinical Phase II: In this phase, the vaccine is tested on several hundred volunteers. This shows whether the vaccine triggers the desired immunity and which dosage is optimal. In addition, knowledge is collected about the frequency and severity of possible side effects. Clinical Phase III: The vaccine is tested on several thousand volunteers. This phase shows whether the vaccine actually protects against the disease. In addition, rare side effects and risks are recognized. It is also checked for which age or population groups the vaccine can be used. After the third clinical phase, the vaccine manufacturer submits an application for approval to the responsible authorities to review all available results from clinical Phases I–III. If the authority confirms the effectiveness, safety, and quality of the vaccine, it will grant marketing authorization. Vaccination is only recommended if the benefits of prevented diseases and their complications far outweigh the risks associated with the vaccinations. The last clinical Phase IV, also called follow-up studies, is usually performed after approval and wide use of the vaccine in routine. In this phase, vaccine manufacturers must continue to monitor safety, efficacy, and quality during routine use. The manufacturers continuously check whether there are rare or serious side effects and report them to the authority that has given the license.
| COVID-19 Vaccination in Hematological Malignancies|| |
Patients with hematological malignancies are at increased risk of mortality due to COVID-19 as shown in multiple studies. Vaccination against COVID-19 in this population is expected to significantly reduce mortality and morbidity. Moreover, vaccination may enable such patients to proceed with anticancer therapy without delay. Some patients with hematological malignancies or those undergoing immunosuppressive treatments may not mount a fully satisfactory response to COVID-19 vaccination. This is because the ability to generate optimal response is dependent on intact host immunity, particularly with respect to antigen presentation, B- and T-cell activation, and plasma B-cell antibody generation. Nevertheless, it might be advisable for such patients to receive the vaccine even though the response might be blunted. The following immunocompromised patient populations could have attenuated or absent response to SARS-CoV-2 vaccines: primary and secondary immunodeficiencies involving adaptive immunity, splenectomy or functional asplenia (e.g. sickle cell disease), B-cell-directed therapies (e.g. blocking monoclonal antibodies against CD20 or CD22, bispecific agents such as blinatumomab, CD19- or CD22-directed chimeric antigen receptor [CAR]-T-cell therapies, and Bruton's tyrosine kinase inhibitors), T-cell-directed therapies (e.g. calcineurin inhibitors, antithymocyte globulin, and alemtuzumab [ATG]), many chemotherapy regimens, high-dose corticosteroids (>2 mg/kg/day daily prednisone or equivalent), hematopoietic cell transplantation (HCT), especially within the first 3–6 months after autologous HCT and often longer after allogeneic HCT, and underlying aberrant immunity (e.g. graft-versus-host disease [GVHD], graft rejection, absent or incomplete immune reconstitution, neutropenia (absolute neutrophil count <500/μL), and lymphopenia (absolute lymphocyte count <200/μL). The recommendations to vaccinate patients with hematological malignancies and disorders are listed in [Table 1].
|Table 1: COVID-19 vaccination recommendations for patients with hematological malignancies|
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| COVID Vaccination following Hematopoietic Stem Cell Transplantation|| |
The following recommendations for COVID vaccine posthematopoietic stem cell transplantation (HSCT)/CAR-T-cell therapy are implemented in different countries of the world: (1) HCT patients could be vaccinated with whatever an approved vaccine is available. (2) If the transmission rate in the surrounding society is high, vaccination could be initiated at the earliest 3 months after HCT and take priority over the regular vaccination program. (3) If transmission in the surrounding society is well controlled, it would be advisable to wait until 6 months after transplantation to initiate vaccination. (4) For patients receiving tandem auto-HSCT, vaccination should be initiated after last planned stem cell infusion. (5) Patients undergoing ex vivo T-cell depleted HSCT and posttransplant cyclophosphamide HSCT can receive vaccine around 6 months post-HCT with confirmed presence of B-cells (>50 cells per microliter) and CD4 + T-cells (>100 cells per microliter). (6) Patients with ongoing moderately severe GVHD should also be offered COVID-19 vaccine. (7) Household contacts should be vaccinated, especially when the HCT recipient is early after transplant or receiving intensive immunosuppression. (8) Reasonable criteria to postpone COVID-19 vaccination based on current knowledge are: a) severe, uncontrolled acute GVHD grades III – IV, b) recipients, who have received anti-CD20 antibodies such as rituximab during the past six months or other B-cell depleting therapy such as obinutuzumab, inotuzumab, blinatumomab, c) CAR T cell patients with B-cell aplasia earlier than six months after treatment (absolute B-cell count <50 cells/μL or intravenous immunoglobulin dependence), d) Recent therapy with ATG or alemtuzumab, e) Children <12 years of age.,
| Safety of COVID Vaccines in Immunocompromised Patients|| |
Currently, data regarding safety and efficacy of COVID vaccines are lacking in immunocompromised patients, although more data are accumulating in this population. Fortunately, the vast majority of the currently available COVID-19 vaccines are not live vaccines and therefore can be safely administered to immunocompromised people. Live vaccines should be avoided in immunocompromised patients. The optimal timing of COVID-19 vaccination among people who are planning to receive immunosuppressive therapies is unknown. However, the US Centers for Disease Control and Prevention (CDC) recommends completing the COVID-19 vaccination at least 2 weeks before initiation of immunosuppressive therapies, based on general best practices for vaccination of immunocompromised people. When it is not possible to administer a complete COVID-19 vaccine series in advance, people on immunosuppressive therapy can still receive COVID-19 vaccination. Any decision to delay immunosuppressive therapy to complete COVID-19 vaccination should consider the specific patients' risks related to their underlying condition. Many international regulatory bodies, including US CDC do not recommend measuring antibody levels to assess immunity to SARS-CoV-2 following COVID-19 vaccination. Also, revaccination is currently not recommended for people who received COVID-19 vaccines during chemotherapy or treatment with other immunosuppressive drugs, after they have regained immune competence. However, the duration of protection from vaccine in immunocompromised patients is unknown, but it conceivable that it might be shorter in such population than in healthy individuals, as has been shown previously with other vaccines. Thus, booster doses may be needed, but till now, it is unclear when they should be given, as these aspects were not tested by manufacturing companies. In general, people with hematological malignancies should be encouraged to receive COVID-19 vaccine to reduce mortality and morbidity. However, they should be counseled about the unknown vaccine safety profile and effectiveness in immunocompromised populations, the potential for reduced immune responses, and the need to continue to follow current guidance to protect themselves against COVID-19.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]