key: cord-0987531-jw18u3t2
authors: Corti, Chiara; Crimini, Edoardo; Tarantino, Paolo; Pravettoni, Gabriella; Eggermont, Alexander M.M.; Delaloge, Suzette; Curigliano, Giuseppe
title: Current Perspectives: SARS-CoV-2 vaccines for cancer patients: a call to action
date: 2021-02-25
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2021.01.046
sha: 233ac1b4800000056ab7e5e2db24cb77cad32f09
doc_id: 987531
cord_uid: jw18u3t2

Coronavirus disease 2019 (COVID-19) has affected more than 96 million people worldwide, leading the World Health Organization (WHO) to declare a pandemic in March 2020. Although an optimal medical treatment of COVID-19 remains uncertain, an unprecedented global effort to develop an effective vaccine hopes to restore pre-pandemic conditions. Since cancer patients as a group have been shown to be at higher risk of severe COVID-19, the development of safe and effective vaccines is crucial. However, cancer patients may be underrepresented in ongoing phase 3 randomized clinical trials investigating COVID-19 vaccines. Therefore, we encourage stakeholders to provide real-time data about the characteristics of recruited participants, including clearly identifiable subgroups, like cancer patients, with sample sizes large enough to determine safety and efficacy. Moreover, we envisage a prompt implementation of suitable registries for pharmacovigilance reporting, in order to monitor the effects of COVID-19 vaccines and immunization rates in patients with cancer. That said, data extrapolation from other vaccines trials (e.g. anti-influenza virus), showed a favorable safety and efficacy profile for cancer patients. On the basis of the evidence discussed, we believe that the benefits of the vaccination outweigh the risks. Consequently, healthcare authorities should prioritize vaccinations for cancer patients, with time-point of administration agreed on a case-by-case basis. In this regard, the American Society of Clinical Oncology and the European Society of Medical Oncology are advocating for cancer patients a high priority status, in the hope of attenuating the consequences of the pandemic in this particularly vulnerable population.

Since the first reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, coronavirus disease 2019 (COVID-19) affected more than 96 million people worldwide, leading the World Health Organization (WHO) to claim a public health emergency in late January 2020 and a pandemic in March 2020 [1] . At present, an optimal medical treatment of COVID-19 remains uncertain. Beside oxygen therapy and positive pressure ventilation, glucocorticoids, dexamethasone in particular, showed a mortality benefit in patients requiring respiratory support, while this benefit was not clear among patients who did not require respiratory support [2, 3] . As for remdesivir, a novel antiviral, although it may accelerate time to recovery, it did not show an overall mortality benefit [4, 5] . As well, convalescent plasma did not demonstrate a clear clinical benefit in hospitalized patients with severe COVID-19 [6] . Consistently, on 14 January 2021 the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial independent Data Monitoring Committee (DMC) closed recruitment to the convalescent plasma arm of the trial [7] . Finally, two monoclonal antibody therapies targeting SARS-CoV-2 (bamlanivimab and the combination casirivimab-imdevimab) have received emergency use authorization from the Food and Drug Administration (FDA) for non-hospitalized patients who have mild to moderate COVID-19 and certain risk factors for severe disease on the basis of preliminary reports of randomized trials [8] [9] [10] . However, an unprecedented global effort in order to develop an effective vaccine strategy hopes to restore pre-pandemic routine [11, 12] .

Since history of cancer seems to be related to higher mortality rates due to COVID-19, the development of safe and effective vaccines may be crucial for this group of patients [13] . Indeed, there are about 32 million cancer survivors worldwide, with almost 1.8 million new cancer cases projected to have occurred in the United States in 2020 [14] . This review will highlight the current landscape of SARS-CoV-2 vaccine candidates, with a special focus on implications for cancer patients. [15] . The N protein holds the RNA genome, and the S, E, and M proteins together form the viral envelope. The spike glycoprotein is responsible for allowing the virus to attach to and fuse with the membrane of a host cell. Specifically, its S1 subunit catalyzes attachment and the S2 subunit enables fusion (not shown) [15] . Abbreviations: S, spike; E, envelope; M, membrane; N, nucleocapsid; ACE, angiotensin-converting enzyme; mRNA, messenger ribonucleic acid; APC, antigen-presenting cell; Abs, antibodies.

Symptomatic SARS-CoV-2 infection can range from mild to critical, with mild disease (asymptomatic patient or mild pneumonia) accounting for ~80% of cases [16] . However, the proportion of infections that are asymptomatic has not been systematically and prospectively studied [16] . The average prevalence of critical illness is higher among hospitalized patients [17] .

Severe disease predominantly occurs in adults with advanced age or harboring medical comorbidities, such as cancer [17] . Cough, headache and myalgias are the most frequent symptoms [17] . Other features, including sore throat, diarrhea and smell or taste abnormalities, are described as well [17] . Pneumonia is the most common serious manifestation of the infection, characterized by cough, fever, dyspnea, with bilateral infiltrates on chest imaging [17] . Humoral immune responses to SARS-CoV-2 are mediated by antibodies that are directed to viral surface glycoproteins, such as the spike glycoprotein receptor-binding domain (RBD) and the nucleocapsid protein [18] . Both CD4+ T-cell and CD8+ T-cell responses have been described in patients infected by SARS-CoV-2, with Th1 cytokine production [19] . However, the contribution of cellular immunity to protection against COVID-19 is not entirely clear [19] .

Because vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for controlling the pandemic, an unprecedented effort was made since the beginning of 2020 in order to develop an effective vaccine strategy. As of 17 January 2021, 40 vaccine candidates are being tested for prevention of COVID-19 in phase I clinical trials, followed by 24 and 20 vaccine candidates investigated in phase 2 and 3 trials, respectively (Figure 2 ) [20] . Since early-phase trials, numerous candidates were shown to induce binding antibodies, neutralizing activity, and T cell responses in healthy adults [3] . A few candidates appeared to be immunogenic in healthy older individuals, as well [3] . To date, BNT162b2 (Comirnaty -Pfizer/BioNTech) and mRNA-1273 (Moderna) are the only vaccines authorized for Emergency Use by both the FDA and the European Medicines Agency (EMA). They are messenger ribonucleic acid (mRNA) vaccines delivered in a lipid nanoparticle to express a full-length spike protein.

BNT162b2 and mRNA-1273 are given intramuscularly in two doses, 21 and 28 days apart, respectively. In phase III randomized controlled trials (RCTs), these vaccines showed 95% J o u r n a l P r e -p r o o f (BNT162b2, CI 95%, 90.3-97.6) and 94.1% efficacy (mRNA-1273, CI 95%, 89.3-96.8) in preventing symptomatic COVID-19 after the second dose [21, 22] . On 31 December 2020, the WHO issued its first emergency use validation for Comirnaty, aiming to speed up authorization in many countries. A summary of COVID-19 vaccine candidates approved or in phase III trials as of January 17, 2021 is provided in Table 1 , with temporal milestones (Figure 3 ). 

In 2020, about 1.8 million new cancer cases are projected to have occurred in the United States, with an estimated 32 million cancer survivors worldwide [14] . COVID-19 seems to be related to a higher mortality in cancer patients, with rates ranging from 5% to 61% according to the cohorts studied [13] . Overall, active disease confers a significantly increased risk of severe COVID-19;

similarly, hematological, lung malignancies and the presence of metastatic disease are associated with a persistently increased risk [13, [23] [24] [25] [26] [27] [28] . To appropriately assess COVID-19 outcomes in cancer patients, the COVID-19 and Cancer Consortium (CCC19) database collected data of patients from the USA, Canada and Spain with active or previous malignancy and a confirmed SARS-CoV-2 infection [13] . Mortality reached 13% (121/928), with all dying patients experiencing the event within 30 days from COVID-19 diagnosis [13] . Another international effort, namely the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT) registry, focused on outcomes of patients with thoracic malignancies developing COVID-19 [29] . Across 200 patients with a thoracic tumor and a confirmed or suspected diagnosis of COVID-19, 66 (33%) died, with few people (10%) ultimately admitted to an intensive care unit [29] . The high lethality of thoracic tumors, together with the possible exclusion from intensive care due to triage reasons, might have accounted for the high mortality observed [29] . As well, big national cohorts from Canada, France and the Netherlands confirmed such worse outcome [24] [25] [26] . A pooled analysis of 52 registries of cancer patients with COVID-19 identified a pooled case mortality rate of 25.6%, supporting the J o u r n a l P r e -p r o o f idea that oncological patients may be a particularly vulnerable population to SARS-CoV-2 infection [27] . Finally, a recent metanalysis including sixteen studies highlighted that administering chemotherapy within the last thirty days before COVID-19 diagnosis may increase the risk of death in cancer patients (odds ratio: 1.85; 95% CI: 1.26-2.71) [28] . However, the higher severity of COVID-19 observed in patients with cancer is based on non-comparative retrospective studies, which may be potentially affected by unmeasured confounding and selection biases [30] . It should be noted that the majority of registries did not identify a detrimental effect of most cancer medical therapies, highlighting the importance of continuing treatment amidst a global healthcare emergency [25, 28, 31] . In fact, due to COVID-19 pandemic, cancer patients are experiencing significant delays in screening, diagnosis, treatment and surveillance, with consequent additional psychological distress [31] [32] [33] . As a consequence, an increased risk of cancer-related morbidity and mortality may occur, as well as major economic burden and a negative impact on clinical trials accrual [31, 34, 35] . Conversely, an accurate balance of risks and benefits is recommended for each treatment, with a particular priority reserved to curative settings [31] .

Since cancer patients as a group have been shown to be at higher risk of severe COVID-19, the development of safe and effective COVID-19 vaccines may be crucial in this subpopulation [13] .

Although IgG antibody response to SARS-CoV-2 infection does not seem to be different between healthy subjects and cancer patients [36] , it is unknown whether an effective immunization will be achieved in this subset of people. In this regard, data about how many individuals with history of cancer have been involved in all phase 3 vaccine RCTs are lacking [37] . Yet, eligibility of cancer patients can be deduced from inclusion and exclusion criteria of the trials, since some manufacturers made their full study protocols publicly available [37] . Most protocols excluded cancer patients on the basis of conditions that can be summarized in three categories ( Table 1) :

(a) any prior history of cancer; (b) recent immunosuppressive therapies (e.g. chemotherapy, radiotherapy, immunomodulating agents, systemic immunosuppressants); (c) immunodeficiency and lack of stable disease, at the discretion of the investigator [37] . So, people at higher risk, like J o u r n a l P r e -p r o o f cancer patients, that should be sensibly prioritized to receive an approved vaccine, may be underrepresented in ongoing phase 3 clinical trials [37] . We therefore encourage manufacturers and investigators to provide real-time data about the characteristics of recruited participants, preferably including clearly identifiable subgroups, like cancer patients, with sample sizes large enough to determine safety and efficacy in these categories [37] . Besides, we envisage a prompt implementation of suitable registries for pharmacovigilance reporting, in order to monitor the effects of COVID-19 vaccines and immunization rates in patients with cancer.

Although evidence from RCTs is lacking, it is plausible that safety and efficacy of vaccination against SARS-CoV-2 for cancer patients may be similar to that of patients without cancer, considering data extrapolation from other vaccines and the mechanism of action of most COVID-19 vaccines [38] . For example, considering anti-influenza vaccination, seroconversion and seroprotection appear to be lower in patients receiving chemotherapy than in the general population, but not in patients receiving single-agent immune checkpoint inhibitors (ICI) [39] .

However, good tolerability and safety of anti-influenza vaccination in patients with cancer receiving ICI, as well as in patients on cytotoxic therapy or targeted agents are suggested by retrospective evidence [40] . So, although enrolment of cancer patients in COVID-19 vaccination trials is limited, enough evidence supports anti-infective vaccination in general (except live-attenuated vaccines and replication-competent vector vaccines), even in patients under immunosuppressive therapy [41] . Therefore, we strongly encourage the healthcare authorities to prioritize vaccinations for cancer patients, even with active disease or receiving anticancer treatment. The time-point for vaccination should be discussed on a case-by-case basis ( Table 2 ) [42] . When feasible, COVID-19 vaccine should be given at least 2 weeks before initiation of chemotherapy, immunosuppressive drugs or radiation therapy [42] . Alternatively, patients can be immunized about a week after the start of a chemotherapy cycle, according to limited data from patients with solid tumors receiving chemotherapy, in whom immunization on day 4-5 of a cycle resulted more immunogenic than on day 16 [42] . In case of allogeneic stem cell transplantation o cellular therapy, the vaccine should be J o u r n a l P r e -p r o o f administered around 3-6 months after the procedure, in the absence of graft-versus-host disease ( Of note, patients who underwent B cell depletion in the previous 6 months may derive reduced protection [42] . Finally, patients enrolled in clinical trials with experimental cancer drugs or combinations should not be arbitrarily deprived of COVID-19 vaccination [30] ; therefore, we invite clinical trial sponsors and investigators to allow for concurrent COVID-19 vaccines. Concurrently, psychological interventions could be useful to promote vaccinations and overcome possible vaccine hesitancy in the general and oncological populations [44] .

As vaccination plans have been published worldwide in order to prioritize vaccine administration in different populations, the WHO considers the healthcare professionals and the elderly as first priorities, putting cancer patients in phase 2 [45] . On the basis of the evidence discussed, we strongly believe that healthcare authorities should prioritize vaccinations for cancer patients in current vaccination priority policies, even for those with active disease or receiving anticancer treatment, with time-point of administration agreed on a case-by-case basis [30, 42] . In this regard, Funding: This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Acknowledgements: CC contributed to the literature search, conception and design of the article