COVID-19 vaccination in cancer patients:
The World Health Organization (WHO) currently counts more than two hundred research projects for the development of a vaccine conferring protective immunity against the SARS-CoV-2 virus, among which more than fifty are in clinical development. New technologies, previous experience with vaccine projects against related viruses and the presence of a pandemic health hazard accelerated the usual development cycle from years to months. Presentation of SARS-CoV-2 antigens to the host, in the context of vaccine development, relied on technologies based on messenger RNA (mRNA), inactivated/attenuated or genetically modified viruses, synthetic long viral peptides and plasmid DNA vaccines. Four vaccines have been authorised until April 2021 for use in the European Union (Comirnaty Pfizer/BioNTech, COVID-19 Vaccine Moderna, Vaxzevria AstraZeneca, COVID-19 Vaccine Janssen) while three more are under rolling review by the European Medicines Agency (EMA; CVnCoV, NVX-CoV2373, Sputnik V). More vaccines are under clinical development and are being assessed for efficacy and safety.
Overall mRNA-based vaccines have shown >90% protection from COVID-19 disease with good tolerance, whereas non-replicating adenoviral vector-based vaccines have shown protection rates of 62%-90% conferred by different dosing regimens. Storage requirements and number of doses differ between vaccines and operational practicalities related to transport, administration, recording and follow-up of vaccinated people, and pharmacovigilance are pivotal for the successful roll-out of vaccination programmes and their optimal impact on public health. Despite some preclinical data of reduced neutralising potential of generated antibodies against new, mutated forms of the virus, available clinical evidence suggests that approved vaccines confer protective immunity against new mutational variants of SARS-CoV-2. Moreover, a rational strategy for minimising the risk of emergence of additional virus variants is based on effective mass vaccination programmes for establishment of vaccine-induced immunity in order to prevent new infections and, thus, mutations. Additional questions exist that necessitate generation of data, including long-term safety, duration of immunity, protective immunity against mild as opposed to severe cases of infection as well as immunity in the elderly, vaccine impact on contagious potential of vaccinated people and repeat vaccination intervals. A combination of severe thrombosis and thrombocytopaenia, of possible immune pathogenesis similar to that seen in heparin-induced thrombocytopaenia, has been observed very rarely following vaccination, mostly with adenoviral vector-based vaccines (Vaxzevria, COVID-19 Vaccine Janssen), occurring during the first few weeks after inoculation. Healthcare professionals and patients should be alert to the signs and symptoms of thromboembolism and/or thrombocytopaenia, and if present, seek specialist medical treatment promptly. In view of the rarity of the side-effect and the risk from COVID-19, the risk/benefit profile of the vaccines is considered favourable by the EMA. The use of all approved COVID-19 vaccines should be in accordance with official national recommendations.
Specifically, for patients with cancer or a history of cancer, strategies of continued generation of data within trials as well in real world settings will provide more insights on vaccine activity, optimal dose and frequency, safety, potential for interaction with malignant disease, antineoplastic therapies or other comorbidities. Consequently, prospective observational studies focusing on patients with active cancer receiving chemotherapy, targeted therapy or immunotherapy, as well as in patients in the chronic phase of disease or in the survivorship phase are warranted and may lead to interventional clinical trials, if needed.
A large array of other vaccine candidates against SARS-CoV-2 are currently under investigation applying various techniques such as mRNA-, protein subunit-, viral vector- or inactivated virus vaccines.
These recommendations should be used as guidance for prioritising the various aspects of cancer care in order to mitigate the negative effects of the COVID-19 pandemic on the management of cancer patients. The situation is evolving, and pragmatic actions may be required to deal with the challenges of treating patients, while ensuring their rights, safety and wellbeing.
Statements:
- Effective and safe vaccines against COVID-19, authorised after thorough, independent and robust scientific review by regulatory authorities, should be administered in the context of operationally sound vaccination programmes [V]. A pharmacovigilance plan is mandatory in the context of the vaccination programme.
- Effective mass vaccination programmes coupled to robust pharmacovigilance are key for preventing infections and emergence of viral mutations, while safeguarding favourable vaccine risk/benefit profiles [V].
- Ongoing scientific assessment by medical and regulatory authorities underpins the safe and effective use of COVID-19 vaccines. Use of the vaccine during vaccination campaigns take into account the pandemic situation and vaccine availability at national level.
- Continued research in the context of clinical trials and registries as well as in-trial and post-trial follow-up is advised in order to generate more data on vaccine efficacy and safety in the general population as well as in special populations, including patients with active cancer or history of cancer [V].
Patients with cancer as a group have been shown to be at higher risk of severe COVID-19 [1]. Among patients with cancer, it seems that haematological and lung malignancies and the presence of metastatic disease are associated with a persistently increased risk. Patients with solid tumours appear to suffer an increased risk, particularly in the first year after diagnosis which drops to baseline if diagnosis is >5 years ago [2]. For any malignancy, active disease confers a significantly increased risk of severe COVID-19 [IV] [3, 4]. However, the higher incidence and severity of COVID-19 in patients with cancer, as opposed to those without cancer, are observations based on non-comparative retrospective studies. Data on the true incidence and direct comparisons remain elusive. Most studies do not have the full denominator to calculate the true incidence [IV].
Severity and mortality rates from the COVID-19 and Cancer Consortium (CCC19) registry and other cohorts have ranged from 5% to 61% (meta-analysis showed 26%) which is much higher than in the overall population (~2%-3%), but this is with caveats of unadjusted rates, while the cancer population is an older population with more comorbidities, poorer performance status, and many unmeasured confounding and selection biases [IV].
SARS-Cov-2 infection may also result in significant and devastating delays in screening, diagnosis, treatment and monitoring/surveillance strategies in patients with cancer which can ultimately cause an increased risk of cancer-related morbidity and mortality, as well as major economic burden and high patient volumes needing care in the healthcare systems. Moreover, the impact on clinical trials accrual appears to be very significant and detrimental, although it is hard to measure.
Although evidence regarding vaccination in patients with cancer is limited, there is enough evidence to support anti-infective vaccination in general (excluding live-attenuated vaccines and replication-competent vector vaccines) even in patients with cancer undergoing immunosuppressive therapy [5-7]. Reduced protective effects may occur in patients treated with B cell-depleting agents (anti-CD19, anti-CD20, anti-CD10 monoclonal antibodies and CD19 CAR-T cells) in view of suboptimal immune response [8-12]. The level of efficacy may be expected to be generally reduced in certain populations of cancer patients with intense immunosuppression, such as recipients of haematopoietic stem cell transplantation [V] [5-7]. However, based on data extrapolation from other vaccines and the mechanism of action of the COVID-19 vaccines (not live), it is conceivable that the efficacy and safety of vaccination against COVID-19 may be estimated to be similar to that of patients without cancer, although data from clinical trials are lacking [V]. Beyond stem cell transplantation, the efficacy of COVID-19 vaccines can also vary in patients with distinct contexts of malignant disease (tumour type, disease extent, intrinsic or therapy-induced immunosuppression); however, the benefits of vaccination seem to significantly and substantially outweigh the risks [V].
The timing of vaccination depends on individual therapy scenarios and may ideally occur before systemic therapy starts; however, if the patient has already started systemic therapy, it is reasonable to vaccinate during therapy [V].
Vaccinating healthcare staff against influenza has been shown to reduce nosocomial transmission of the infection in cancer care [13]. Furthermore, certain immunocompromised cancer patients might not achieve a sufficient immune response to vaccination. This provides a rationale for vaccinating healthcare staff who work in a high-risk setting against COVID-19 as well [Evidence III for influenza]
Statements:
- Patients with cancer have an increased risk of severe COVID-19 (i.e. haematological malignancy requiring chemotherapy or active, advanced solid tumour or history of solid tumour <5 years ago) and should be vaccinated against SARS-CoV-2 regardless of any other indications (i.e. age) and positioned at high prioritisation [V]. Patients who have received B cell depletion in the past 6 months may derive reduced protection. The time-point for vaccination after allogeneic stem cell transplantation should follow general recommendations – usually, in the absence of graft-versus-host disease (GvHD), the vaccine can be applied 6 months post stem cell transplantation [V]. Patients in clinical trials, e.g. immunotherapy, should not be deprived of COVID-19 vaccination; therefore, efforts should be made for clinical trial protocols to allow concurrent COvID-19 vaccines.
- Healthcare workers caring for patients with cancer with increased risk should be prioritised in receiving vaccination to minimise nosocomial transmission.
- The efficacy and duration of immunity in patients with cancer are still unknown and unexplored. Given the often-immune compromised status and the frailty of these patients, we suggest monitoring in the context of registries and dedicated clinical trials.
- Close surveillance and monitoring of patients with cancer is required after COVID-19 vaccination to assess potential adverse events and measure clinical outcomes, e.g. infection, severity and mortality from COVID-19, complications from cancer, etc.
- Physical distancing measures, masks, face shields, sanitizers and other hygiene measures are still required during the pandemic, including for patients with cancer, and should certainly accompany the vaccination strategies.
