key: cord-0719067-k31kbxc3 authors: Pinato, David J.; Ferrante, Daniela; Aguilar-Company, Juan; Bower, Mark; Salazar, Ramon; Mirallas, Oriol; Sureda, Anna; Bertuzzi, Alexia; Brunet, Joan; Lambertini, Matteo; Maluquer, Clara; Pedrazzoli, Paolo; Biello, Federica; Lee, Alvin JX.; Sng, Christopher CT.; Liñan, Raquel; Rossi, Sabrina; Carmona-García, M. Carmen; Sharkey, Rachel; Eremiev, Simeon; Rizzo, Gianpiero; Bain, Hamish DC.; Yu, Tamara; Cruz, Claudia Andrea; Perachino, Marta; Saoudi-Gonzalez, Nadia; Fort-Culillas, Roser; Doonga, Kris; Fox, Laura; Roldán, Elisa; Zoratto, Federica; Gaidano, Gianluca; Ruiz-Camps, Isabel; Bruna, Riccardo; Patriarca, Andrea; Shawe-Taylor, Marianne; Fusco, Vittorio; Martinez-Vila, Clara; Berardi, Rossana; Filetti, Marco; Mazzoni, Francesca; Santoro, Armando; Delfanti, Sara; Parisi, Alessandro; Queirolo, Paola; Aujayeb, Avinash; Rimassa, Lorenza; Prat, Aleix; Tabernero, Josep; Gennari, Alessandra; Cortellini, Alessio title: Vaccination against SARS-CoV-2 protects from morbidity, mortality, and sequelae from COVID19 in patients with cancer date: 2022-05-23 journal: Eur J Cancer DOI: 10.1016/j.ejca.2022.04.036 sha: 7593a60fdff4c1fafe7b83d032e235a4edae4afa doc_id: 719067 cord_uid: k31kbxc3 BACKGROUND: Although SARS-CoV-2 vaccines immunogenicity in patients with cancer has been investigated, whether they can significantly improve the severity of COVID-19 in this specific population is undefined. METHODS: Capitalizing on OnCovid (NCT04393974) registry data we reported COVID-19 mortality and proxies of COVID-19 morbidity, including post COVID-19 outcomes, according to the vaccination status of the included patients. RESULTS: 2090 eligible patients diagnosed with COVID-19 between 02/2020 and 11/2021 were included, of whom 1930 (92.3%) unvaccinated, 91 (4.4%) fully vaccinated and 69 (3.3%) partially vaccinated. With the exception of a higher prevalence of patients from the UK (p=0.0003) and receiving systemic anticancer therapy at COVID-19 diagnosis (p=0.0082) among fully vaccinated patients, no demographics/oncological features were associated with vaccination status. The 14-days case fatality rate (CFR) (5.5% vs 20.7%, p=0.0004) and the 28-days CFR (13.2% vs 27.4%, p=0.0028) demonstrated a significant improvement for fully vaccinated patients in comparison with unvaccinated patients. The receipt of prior full vaccination was also associated with reduced symptomatic COVID-19 (79.1% vs 88.5%, p=0.0070), need of COVID-19 oriented therapy (34.9% vs 63.2%, p<0.0001), complications from COVID-19 (28.6% vs 39.4%, p=0.0379), hospitalizations due to COVID-19 (42.2% vs 52.5%, p=0.0007), and oxygen therapy requirement (35.7% vs 52%, p=0.0036). Following Inverse Probability Treatment Weighting (IPTW) procedure no statistically significant difference according to the vaccination status was confirmed; however, all COVID-19 related outcomes were concordantly in favour of full vaccination. Among the 1228 (58.8%) patients who underwent a formal reassessment at participating centers after COVID-19 resolution, fully vaccinated patients experienced less sequelae than unvaccinated patients (6.7% vs 17.2%, p=0.0320). CONCLUSIONS: This analysis provides initial evidence in support of the beneficial effect of SARS-CoV-2 vaccines against morbidity and mortality from COVID-19 in patients with cancer. Patients with cancer are intrinsically more vulnerable to morbidity and mortality from Coronavirus Disease 2019 (COVID-19) 1,2 . All levels of cancer care including screening, diagnosis and treatment have been heavily impacted by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic 3, 4 . In addition to the threat imposed by acute morbidity and mortality from COVID-19 in cancer patients, recent evidence highlights that oncological continuity of care can be further disrupted by long term consequences from COVID-19, which affect approximately 15% of patients with cancer who recover from the acute phase 5 . Widespread vaccination against SARS-Cov-2 represents a highly important public health measure to reduce severity and lethality of SARS-Cov-2. The immunogenicity and safety profile of SARS-Cov-2 vaccines have been widely investigated across several type of cancers and irrespective of exposure to recent anticancer therapy [6] [7] [8] . Evidence of seroconversion following SARS-Cov-2 vaccination confirmed an antibody response in >90% of patients with solid tumours 9,10 , which is comparable to the general population 11 . However, several reports highlight that a proportion of patients with cancer, such as those with haematological malignancies undergoing anti-CD20 treatments, elicit a diminished immune response to vaccines with seroconversion rates of <60% 9, 10 Evidence on the efficacy of SARS-Cov-2 vaccines from randomized clinical trials is limited to patients with stable oncological disease and off immunosuppressive anticancer therapy at the time of vaccination 12 . Therefore, unresolved questions exist around whether SARS-CoV-2 vaccination is effective independent of anti-cancer treatment and whether vaccinal immunity protects from long-term consequences from COVID-19. With these premises in mind, we performed a dedicated update of the OnCovid registry to provide initial evidence regarding the magnitude of clinical benefit of SARS-CoV-2 vaccines in influencing outcome from COVID-19 in a large real-world oncological population. OnCovid (NCT04393974) is a European registry study that collects data from consecutive patients with solid/hematologic malignancy diagnosed with COVID-19. The primary objective of this study was to describe COVID-19 mortality in patients with cancer according to SARS-CoV-2 vaccination status. As secondary objectives we estimated the impact of COVID-19 vaccines on COVID-19 symptoms and morbidity. In addition, we evaluated whether receipt of SARS-CoV-2 vaccination was associated with the occurrence of COVID-19 sequelae among patients who underwent a clinical reassessment at the participating centers. Patients were categorized as fully vaccinated at the time of COVID-19 diagnosis if they had received two doses for the BNT162b2, mRNA-1273, and ChAdOx1-S vaccines or in case of infection diagnosed at least 28 days after a single dose of the Ad.26.COV2.S vaccine 13 . Patients who received at least one vaccination, without meeting the abovementioned criteria, were considered partially vaccinated. Acknowledging the competing influence of the underlying malignancy in determining clinical outcomes, we elected the all-cause 14-days case fatality rate (CFR) as the clinical endpoints of interest, in an attempt of differentiating early (COVID-19 related) from late (cancer-related) mortality as already done in with our registry 14 . Considering the limited number of 14-days events recorded among fully vaccinated patients, which prevented the planned Inverse Probability of Treatment Weighting (IPTW) procedure, we also evaluated the 28-days CFR. First, we reported the distribution of key demographics and oncological characteristics consistently associated with clinical outcome in the study population 5,14-18 across the vaccination categories, subsequently, we analyzed COVID-19 related outcomes according to the vaccination status, with a formal comparison between fully vaccinated and unvaccinated patients. We then reported prevalence and distribution of COVID-19 associated symptoms, and as proxy of COVID-19 morbidity, we analyzed other COVID-19 related outcomes reproducibly described in the registry 5,14-17 , including the need of COVID-19 oriented therapy, the incidence of COVID-19 complications, the hospitalization rate and the need of oxygen therapy. Although recognizing that the unbalanced sample size of the vaccination subgroups did not allow a powered and formal weighted comparison, we performed as exploratory analysis an IPTW procedure including key baseline demographics and oncological characteristics, to provide a preliminary adjusted estimation of the CFR and COVID-19 related outcomes. Considering the evidence of a mild decrease over time of the antibody response to SARS-CoV-2 vaccination 19,20 , we also provided a descriptive analysis of COVID-19 outcome according to vaccination timing, including only patients with available date of vaccination. For this purpose, fully vaccinated patients were considered those who had received two doses of the BNT162b2, mRNA-1273, and ChAdOx1-S vaccines at least 7 days before the infection and those who received one dose of the Ad.26.COV2.S vaccine at least 28 days before the breakthrough infection 13, [21] [22] [23] . Patients who received at least one vaccination, without meeting the above-mentioned criteria, were considered partially vaccinated, while those patients diagnosed with COVID-19 more than 6-months following the complete vaccination were considered separately. Lastly, in order to describe the potential role of SARS-CoV-2 vaccines in reducing the occurrence of COVID-19 sequelae in patients with cancer, we focused on those patients who underwent a formal clinical assessment at the participating centers after COVID-19 recovery as previously done 5 A detailed description of study methodology and statistical analysis is provided in Supplementary eMethods. Table 2 provides a summary of COVID-19 related outcomes according to the vaccination status, also visualized in Figure 2A and reported as unadjusted OR in Figure 3A . Table 5 ). Vaccinal immunity to SARS-CoV-2 has radically changed the natural history of COVID- 19 . Whilst only partially effective in controlling viral transmission, especially after the emergence of novel variants of concern, vaccines remain widely effective in reducing the severity of COVID-19 [23] [24] [25] [26] The retrospective design of our study and the relatively low proportion of fully vaccinated subjects by data cut-off underscores the preliminary nature of our findings. Baseline characteristics were comparable across exposed and unexposed groups, lending credence to the view that the improvement in outcomes observed in vaccinated patients may be truly due to SARS-Cov-2 immunity. While primary analyses confirmed our hypothesis, IPTW models yielded non statistically significant trends towards improvement of outcomes, as a likely result of largely unbalanced sample size of patients' subgrouping. In a clinical setting that is deprived from solid level I evidence and within the limitation of a registry study, our findings provide a meaningful contribution to the growing body The evidence that vaccine response may decrease over time 19, 20 mirrors our descriptive analysis of vaccination timing, which suggests that the protection provided by SARS-CoV-2 vaccines declines beyond the 6-months landmark. These findings may also be related with the emergence of new variants of concern, such as the B.1.617.2 (delta), which has a higher transmissibility than previous strains and proved to cause a higher rate of breakthrough infections 30, 31 . Taken together, these results support the need of prioritizing frail patients for booster doses, to sustain vaccines immunogenicity over time 32 . Another important question that has not been addressed in any previous study in oncological patients is whether vaccinal immunity may affect the risk of developing OnCovid is sponsored by Imperial College London and received direct project funding and infrastructural support by the NIHR Imperial Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Neither sponsor nor the funders of the study had any role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had access to all the data reported in the study. OnCovid was granted central approval by the United Kingdom Health Research Authority (20/HRA/1608) and by the corresponding research ethics committees at each participating institution. Full waiver of consent due to the retrospective nature of the study was granted by the UK HRA in accordance with UK law. All authors contributed to the publication according to the ICMJE guidelines for the authorship. All authors read and approved the submitted version of the manuscript (and any substantially modified version that involves the author's contribution to the study). Each author has agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Informed consent was waived by competent authorities due to anonymized nature of patient data and retrospective design of the study. Study data made available upon reasonable request. 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