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Safety of mRNA-COVID-19 Vaccines in Patients With Thoracic Cancers

Published:October 20, 2022DOI:https://doi.org/10.1016/j.cllc.2022.10.004

      Highlights

      • Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population
      • In this cohort study we investigated the safety and efficacy of COVID-19 vaccines in 207 patients with thoracic cancer receiving anticancer treatments
      • After long follow-up, there were no safety signals of concern and only 0.5% of patients experienced grade 3 vaccine-related adverse events
      • In our cohort ∼10% of patients had a positive nasal swab after vaccination: 67% asymptomatic and 33% symptomatic (symptoms were mild)

      ABSTRACT

      Background

      Pivotal trials of COVID-19 vaccines did not include cancer patients with questions remaining in this population. Particularly in patients with thoracic malignancies receiving anticancer treatments, the safety of these vaccines has so far been little investigated.

      Methods

      This is a prospective trial of patients with thoracic cancer receiving anticancer treatments and COVID-19 vaccines at the Division of Thoracic Oncology of European Institute of Oncology between February and September 2021.

      Results

      A total 207 patients affected by thoracic cancers (199 lung cancers and 8 mesotheliomas) had received Covid-19 vaccines (206 mRNA vaccines and 1 virus-vectored vaccine). The majority of patients had at least one comorbidity (76.3%). They were concomitantly treating with targeted therapy (TT) (45.9%), immunotherapy (IO) (22.7%), and chemotherapy (CT) (14%). A total of 64 AEs (15.6%) were observed after administration of Sars-Cov-2 vaccine. The majority of AEs were grade 1 [G1] (6.3%) and G2 (8.8%), only two events were G3 (0.5%). The median follow-up was 9 months (range 1-22 months), during this follow-up 21 patients (10.1%) had a positive nasal swab, most of the patients were asymptomatic (67%) and the symptomatic ones (33%) had mild symptoms and fewer complications and hospitalizations.

      Conclusions

      COVID-19 m-RNA vaccines appear to be safe in the cohort of patients with thoracic malignances in active treatment, including those receiving immunotherapy. Considering the high morbidity and mortality associated with COVID-19 in patients with lung cancer receiving active treatments, our study supports the current vaccine prioritization, third and/or fourth dose, of all cancer patients with active treatment.

      Keywords

      Introduction

      Since its outbreak in December 2019 from Wuhan (China), coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (Sars-Cov-2) has rapidly spread all around the World,

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      In Italy, 19.3 million of cases and 169.062 deaths for COVID-19 have been documented (mortality rate 0.8 %).

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      The purpose of our work is to describe the safety profile of COVID-19 vaccines in patients affected by thoracic malignancies receiving antineoplastic drugs.

      Materials and Methods

      Patient recruitment and data collection

      We conducted a prospective trial, including all vaccinated patients with diagnosis of thoracic cancers at any stage undergoing treatment or follow-up in our department (Division of Thoracic Oncology, European Institute of Oncology, IRCCS) between February and September 2021.
      We have included patients who received at least one boost of one of the COVID-19 vaccines authorized in Italy in this period (ie, Pfizer-BioNTech [BNT162b2], Moderna [mRNA-1273], AstraZeneca [ChAdO × 1 nCoV-19] and Johnson & Johnson [Ad26.COV2.S]). Patients were included regardless type of anticancer therapy. Patients refusing the COVID-19 vaccination or postponing its administration were excluded.
      Patient demographic, pathological, and clinical characteristics (age, gender, performance status, smoking habits, comorbidities, type of cancer, TNM stage, type of ongoing anticancer treatments, previous anticancer therapy, and prior Sars-Cov-2 contagious) were extracted from outpatient/inpatient medical records.
      All enrolled patients were vaccinated in vaccination centers according to the Italian national vaccination campaign. After 1 week (±1 day), patients were contacted by telephone to collect information on early adverse events (AEs). During scheduled follow-up visits for continued cancer treatment, new AEs were investigated through a differential diagnosis. Both local (ie, pain, erythema, edema, induration at the injection site, and locoregional reactive lymphadenopathies) and systemic AEs (ie, fever, chills, headache, fatigue, myalgia, arthralgia, nausea, vomiting, and others) related to vaccination per investigator's evaluation were collected and graded according to Common Terminology Criteria for AEs (CTCAE) version 5.0.

      National Institutes of Health; National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.; U.S. Department of Health & Human Services. Washington, DC, USA.

      Finally, post-vaccination Sars-Cov-2 infection and related symptoms were recorded.

      Endpoints and Outcomes

      The principal purpose of this study was to describe the safety profile of COVID-19 vaccines in a cohort of patients with thoracic cancers receiving anticancer treatment. The primary outcome was to investigate the incidence of COVID-19 vaccine-related AEs reported by patients over the telephone one week after vaccination and during scheduled clinical visits. The secondary outcome was to assess the number of patients with post-vaccine SARS-Cov2 infections reporting the type and frequency of symptoms and complications.

      Ethics statement

      The study was conducted based on the prescriptions and recommendations of the Helsinki declaration for studies including human subjects, and aligns with the European, national and institutional policies for prospective data collection intended for medical research.
      This study was approved by the Institutional Review Board (IRB) of the European Institute of Oncology, Milan, Italy, and referenced with the IRB number UID 3519.
      Data were anonymized and collected with data minimization. Only the investigators are aware of the de-codification encryption to re-identify patients. The data are stored in the institutional dataset of medical records for research, protected with a password, and accessible only from hospital-based computers, provided an identification as a doctor or data management personnel of our clinical department.

      Statistical Analysis

      Clinical and pathological features were characterized using descriptive statistics. Quantitative variables were described using the usual statistics: n, mean, median, interquartile range, minimum and maximum. Qualitative variables were described using numbers and percentages. Missing values were not counted for percentage calculations.
      Statistical analysis was performed using R Statistical Software (version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria).

      Results

      Patient characteristics

      Of the total 214 patients, 207 (96.7%) adhered to the COVID-19 vaccination and were included in this study. Particularly, four patients had refused the vaccination and three patients had decided to postpone its administration, all of them were excluded from this trial. Clinical features of 207 patients affected by thoracic cancers enrolled in the study are summarized in Table 1. Just over half (51,2%) of the patients were male. The median age was 67 years (IQR: 60-73 years). Most of the patients were former smoker (50.2%) and had ECOG PS of 1 (66.6%). The majority of patients had at least one comorbidity (76.3%). Most patients were affected by hypertension (27%), cardiovascular disease (27%), obesity (14%), hypothyroidism (13%), diabetes (9%), rheumatological disease (5%), chronic obstructive pulmonary disease [CORPD] (5%) and other lung diseases (4%) as reported in Table A1. Thoracic tumors were distributed as follows: 181 (87.4%) lung adenocarcinoma (ADC), 6 (2.8%) squamous-cell lung carcinoma (SSC), 11 (5.4%) small cell lung cancer (SCLC), 1 (0.5%) large cell neuroendocrine carcinoma (LCNEC) and 8 (3.9%) mesothelioma. At the diagnosis, 101 (48.8%) patients have a stage IV cancer while 106 (51.2%) have an early-stage cancer. However, the majority of patients (92.3%) were metastatic at time of vaccination. Regarding treatment, most patients were receiving targeted therapy (TT) (45.9%), immunotherapy (IO) (22.7%), and chemotherapy (CT) (14%) and combination therapies in approximately 14% of cases, of these 1.9% received anti-(vascular endothelial growth factor) VEGF drugs. Only 3.4% of patients were not receiving any therapy. Table A2 provides more details of ongoing treatments during COVID-19 vaccination.
      Table 1Principal Characteristics of the Study Population.
      Total patientsN%
      207100%
      Sex
      Male10651.2%
      Female10148.8%
      age, median (IQR) yr67(60-73)
      Smoking status
      Never7837.7%
      Former10450.2%
      Current2512.1%
      Comorbidities
      No4923.7%
      Yes15876.3%
      PS ECOG
      05928.5%
      113866.6%
      2104.8%
      Subtype
      Adenocarcinoma18187.4%
      Squamous cell carcinoma62.8%
      LCNEC10.5%
      SCLC115.4%
      Mesothelioma83.9%
      Stage at diagnosis
      early-stage10651.2%
      advanced-stage10148.8%
      Current stage
      I-IIIA73.4%
      IIIB94.3%
      IV19192.3%
      Local therapy received in T/N in early stage
      Surgery6832.9%
      RT2914.0%
      CT+RT94.3%
      None10148.8%
      Number of previous systemic treatment
      010651.2%
      17234.8%
      22110.1%
      ≥ 383.9%
      Ongoing treatment
      CT2914.0%
      IO4722.7%
      TT9545.9%
      CT+IO209.7%
      CT+anti-VEGF41.9%
      IO+TT31.4%
      IO+IO21.0%
      None73.4%
      Abbreviations: anti-VEGF = antibodies against Vascular Endothelial Growth Factor; CT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; IQR = inter-quartile range; IO = immunotherapy; LCNEC = large cell neuroendocrine carcinoma; N = absolute number of patients; N = locoregional lymph nodes; RT = radiotherapy; SCLC = small cell lung cancer-; T = primary tumor; TT = targeted therapy; Yr = years; % = percentage.
      Nine patients (4.4%) were previously infected with Sars-Cov-2 as reported in Table A3. Of these, only one (11%) was asymptomatic and eight patients (89%) were symptomatic. The most common symptoms were cough (75%), fever (50%), dyspnea (38%) followed by dysgeusia (23%), anosmia (25%) and diarrhea (13%). Three patients (38%) had radiologically diagnosed pneumonia. Four patients (44%) were hospitalized and one patient (11%) was admitted to the ICU. Table A3 also reports the type of therapy received by these patients.

      Type of COVID-19 vaccine

      Most patients received mRNA-based vaccine (n = 206, 99.5%), of these 143 patients (69.1%) received BNT162b2/BioNTech/Pfizer vaccine and 63 patients (30.4%) received mRNA-1273/Moderna vaccine. Only one patient (0.5%) received chimpanzee adenovirus-vector vaccine, ChAdOx1 nCoV-19/AstraZeneca. Overall, 411 doses of vaccine were administered to 207 patients. All patients received at least one dose (D1) and 204 (98.6%) completed the vaccination course with the second dose (D2) (Table 2), three patients did not receive the booster for various reasons but not for serious AEs at D1.
      Table 2Characteristics of COVID-19 Vaccine and Adverse Events (AEs).
      Type of COVID-19 VaccineN%
      Pfizer (BNT162b2)14369.1%
      Moderna (mRNA 1273)6330.4%
      Astra-Zeneca (AZD1222)10.5%
      Doses
      D1207100%
      D220498.6%
      AEs after vaccine injection
      Total6415.6%
      Local Symptoms174.2%
      Systemic Symptoms4711.4%
      Grade of AEs
      G1266.3%
      G2368.8%
      G320.5%
      Abbreviations: AEs = adverse events; D1 = first dose; D2 = second dose (or boosted dose); G = grade (sec. CTCAE v.5.0); G1 = grade one; G2 = grade two; G3 = grade three; N = absolute number; % = percentage.

      Safety

      Forty-three patients (20.7%) experienced an AE after Sars-Cov-2 vaccines administration. A total of 64 AEs (15.6%) were observed after the administration of Sars-Cov-2 vaccine D1 (n = 207) and D2 (n = 204). The majority of AEs were grade 1 [G1] (6.3%) and G2 (8.8%), only two events were G3 (0.5%). No grade 4 or higher AEs were observed. The majority of patients experienced systemic symptoms (n = 47; 11.4%) rather than local symptoms (n = 17; 4.2%) (Table 2).
      For the total of 64 AEs reported (Figure 1A), the most common G1 AEs in patients receiving Sars-Cov-2 vaccine were local pain at injection site (n = 10; 15.6%), fever (n = 6; 9.4%), fatigue (n = 2; 3.1%), headache (n = 2; 3.1%), and diarrhea (n = 2; 3.1%). Instead, the most common G2 events were fever (n = 8; 12.5%), local pain (n = 7; 10.9%), myalgia (n = 7; 3.1%), fatigue (n = 6; 9.4%) headache (n = 2; 3.1%), and chills (n = 2; 3.1%). The two G3 AEs were fever and dyspnea.
      Figure 1
      Figure 1Incidence of adverse events (AEs) after COVID-19 vaccination in all patients. (A) Grade of AE, according to Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. (B) Days from vaccination to onset of AE. (C) Duration of AE.
      Most AEs (n = 62; 96.9%) started within 7 days of vaccination (Figure 1B). Regarding the duration of the AEs, most resolved within 3 days (n = 61; 95.3%), the symptom that persisted beyond 15 days in two cases was fatigue (Figure 1C). Thirty-two AEs required systemic pharmacologic intervention: local pain (n = 7), fever (n = 9), myalgia (n = 7), headache (n = 2), chills (n = 2), joint pain (n = 1), nausea (n = 1), diarrhea (n=1) and other (n = 2) (Table A4). One patient was hospitalized due to AEs vaccination for G3 fever.
      We reported in Table A5 the AEs according the different treatments in progress: there were differences in AE (we do not know if also of efficacy) between TKI, ICI and cytotoxic chemotherapy. A lower incidence of adverse events (10.5%) was recorded in the 28 patients receiving chemotherapy.
      No new safety concerns after the third boost of RNA vaccine (data not shown).

      COVID-19 infection after vaccination

      After a median follow up of 9 months (range 1-22 mos), we collected data on SARS-CoV-2 infection post-vaccination (Table A3). Twenty-one patients (10.1%) had a positive nasal swab, and specularly to the pivotal studies, we can consider a vaccine efficacy of 89.9%. COVID-19 infection was symptomatic in the majority of the cases (14 patients, 67%). The most common symptoms were fever (71%), cough (71%) and dysgeusia (29%) in symptomatic patients. In general, symptoms were mild, with a shorter course. Compared to patients with SARS-COV2 infection before vaccine, fewer cases of pneumonia occurred after vaccine (n = 1 vs. n = 3) as well as hospital admissions (n  = 1 vs. n = 4) and median number of days of hospitalization (5 days vs. 15 days); moreover, none intensive care unit (ICU) access was recorded (n = 0 vs. n = 1). However, in this rough comparison we must admit the presence of significant confounding factors and the most important is the different prevalence of the various Sars-Cov2 variants and subvariants between the time before the vaccination (original virus and Beta Variant, B.1.351) and the time frame of the study (the Delta variant, B.1.617.2, the Omicron variant, B.1.1.529 and its variants) in Italy.
      During this follow-up, 22 patients (10.6 %) died due to disease progression (no correlation with COVID-19 vaccine side effects was found).

      Discussion

      Our study was a prospective observational evaluation of patients affected by thoracic neoplasms (mainly LC) in active oncological treatment, undergoing vaccination against Sars-Cov-2 during active oncological treatment, in order to describe safety and efficacy of these vaccines in this population. Two-hundred and seven patients have been enrolled into this trial and followed for a period of 9 months (range 1-22 months). We observed 89.9% of efficacy as a protection against post-vaccine SARS-CoV2 infection. Around 10% of the patients contracted Sars-Cov-2 during the fourth epidemic wave in Italy without any experience of Covid-19 severe complications. The safety profile was manageable, causing less than 1% of G3-4 toxicity and only one case of hospitalization. We did not record any interfering with oncological treatments, including immunotherapy. All these results support the feasibility and the safety of these vaccines, helping the clinicians to confidently recommend also third and fourth dose if indicated per local guidelines.
      LC patients harbor a higher risk of COVID-19-related mortality (30% of infected patients) without vaccination, as previously reported.
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      • Shukarev G.
      • et al.
      Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.
      In Italy, vaccination against COVID-19 has been made available since December 27, 2020. Initially, no evidence was available about the efficacy and safety of COVID-19 vaccination in cancer patients because of their exclusion from pivotal clinical trials.
      • Polack P., F.
      • Thomas J., S.
      • Kitchin N.
      • et al.
      Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine.
      • Baden R., L.
      • El Sahly M., H.
      • Essink B.
      • et al.
      Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine.
      • Ramasamy N., M.
      • Minassian M., A.
      • Ewer J., K.
      • et al.
      Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial.
      • Sadoff J.
      • Le Gars M.
      • Shukarev G.
      • et al.
      Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine.
      • Dunkle M., L.
      • Kotloff L., K.
      • Gay L., C.
      • et al.
      Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.
      To date, published data of cancer patients vaccinated against COVID-19 derive from prospective observational studies (Table A6). Many of these studies have reported that immune response after COVID-19 vaccination are less effective in cancer patients than in healthy controls.
      • Goshen-Lago T.
      • Waldhorn I.
      • Holland R.
      • et al.
      Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.
      ,
      • Monin L.
      • Laing G., A.
      • Muñoz-Ruiz M.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      ,
      • Di Noia V.
      • Pimpinelli F.
      • Renna D.
      • et al.
      Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution.
      • Massarweh A.
      • Eliakim-Raz N.
      • Stemmer A.
      • et al.
      Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer.
      • Eliakim-Raz N.
      • Massarweh A.
      • Stemmer A.
      • Stemmer S.M.
      Durability of Response to SARS-CoV-2 BNT162b2 Vaccination in Patients on Active Anticancer Treatment.
      ,
      • Barrière J.
      • Chamorey E.
      • Adjtoutah Z.
      • et al.
      Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2 vaccine in patients treated for solid tumors.
      ,
      • Terpos E.
      • Zagouri F.
      • Liontos M.
      • et al.
      Low titers of SARS-CoV-2 neutralizing antibodies after first vaccination dose in cancer patients receiving checkpoint inhibitors.
      • Shroff T., R.
      • Chalasani P.
      • Wei R.
      • et al.
      Immune Responses to COVID-19 mRNA Vaccines in Patients with Solid Tumors on Active, Immunosuppressive Cancer Therapy.
      • Palich R.
      • Veyri M.
      • Vozy A.
      • et al.
      High seroconversion rate but low antibody titers after two injections of BNT162b2 (Pfizer-BioNTech) vaccine in patients treated with chemotherapy for solid cancers.
      ,
      • Oosting S.
      • Van der Veldt A.M., A.
      • GeurtsvanKessel H., C.
      • et al.
      LBA8 - Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors.
      In particular, various studies have shown that good efficacy is not achieved after just one dose of the vaccine.
      • Barrière J.
      • Chamorey E.
      • Adjtoutah Z.
      • et al.
      Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2 vaccine in patients treated for solid tumors.
      • Heudel P.
      • Favier B.
      • Assaad S.
      • Zrounba P.
      • Blay J.-Y.
      Reduced SARS-CoV-2 infection and death after two doses of COVID-19 vaccines in a series of 1503 cancer patients.
      • Terpos E.
      • Zagouri F.
      • Liontos M.
      • et al.
      Low titers of SARS-CoV-2 neutralizing antibodies after first vaccination dose in cancer patients receiving checkpoint inhibitors.
      ,
      • Oosting S.
      • Van der Veldt A.M., A.
      • GeurtsvanKessel H., C.
      • et al.
      LBA8 - Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors.
      A pronounced delay in antibody production compared to healthy controls has been observed, and seroconversion occurred in most patients after the second dose,
      • Dunkle M., L.
      • Kotloff L., K.
      • Gay L., C.
      • et al.
      Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.
      therefore, second boost dose is needed to reach a satisfactory humoral response.
      • Monin L.
      • Laing G., A.
      • Muñoz-Ruiz M.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      In these studies, the median IgG titer in cancer patients was reported to be lower than in health controls.
      • Dunkle M., L.
      • Kotloff L., K.
      • Gay L., C.
      • et al.
      Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico.
      ,
      • Ehmsen S.
      • Asmussen A.
      • Jeppesen S., S.
      • et al.
      Antibody and T cell immune responses following mRNA COVID-19 vaccination in patients with cancer.
      • Barrière J.
      • Chamorey E.
      • Adjtoutah Z.
      • et al.
      Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2 vaccine in patients treated for solid tumors.
      • Heudel P.
      • Favier B.
      • Assaad S.
      • Zrounba P.
      • Blay J.-Y.
      Reduced SARS-CoV-2 infection and death after two doses of COVID-19 vaccines in a series of 1503 cancer patients.
      • Terpos E.
      • Zagouri F.
      • Liontos M.
      • et al.
      Low titers of SARS-CoV-2 neutralizing antibodies after first vaccination dose in cancer patients receiving checkpoint inhibitors.
      ,
      • Oosting S.
      • Van der Veldt A.M., A.
      • GeurtsvanKessel H., C.
      • et al.
      LBA8 - Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors.
      However, the elicitation of the immune response was stronger after the second boost and the effect was even stronger after the third dose.
      • Shroff T., R.
      • Chalasani P.
      • Wei R.
      • et al.
      Immune Responses to COVID-19 mRNA Vaccines in Patients with Solid Tumors on Active, Immunosuppressive Cancer Therapy.
      • Palich R.
      • Veyri M.
      • Vozy A.
      • et al.
      High seroconversion rate but low antibody titers after two injections of BNT162b2 (Pfizer-BioNTech) vaccine in patients treated with chemotherapy for solid cancers.
      • Thakkar A.
      • Gonzalez-Lugo J.
      • Goradia N.
      • et al.
      Seroconversion rates following COVID-19 vaccination among patients with cancer.
      Furthermore, data on the duration of protection after vaccination are limited for healthy participants
      • Doria-Rose N.
      • Suthar S., M.
      • Makowski M.
      • et al.
      Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19.
      ,
      • Widge T., A.
      • Rouphael G., N.
      • Jackson A., L.
      • et al.
      Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination.
      and are very lacking for cancer patients.
      • Ehmsen S.
      • Asmussen A.
      • Jeppesen S., S.
      • et al.
      Antibody and T cell immune responses following mRNA COVID-19 vaccination in patients with cancer.
      Eliakim-Raz et al demonstrated that there is a negative linear correlation of IgG titer and time after the second dose for both patients (R = −0.34, P < .001) and controls (R = - 0.70, P < .001).
      • Eliakim-Raz N.
      • Massarweh A.
      • Stemmer A.
      • Stemmer S.M.
      Durability of Response to SARS-CoV-2 BNT162b2 Vaccination in Patients on Active Anticancer Treatment.
      However, the maximum interference was observed in patients with hematological malignancies respect to patients with solid tumors,
      • Monin L.
      • Laing G., A.
      • Muñoz-Ruiz M.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      ,
      • Ehmsen S.
      • Asmussen A.
      • Jeppesen S., S.
      • et al.
      Antibody and T cell immune responses following mRNA COVID-19 vaccination in patients with cancer.
      ,
      • Heudel P.
      • Favier B.
      • Assaad S.
      • Zrounba P.
      • Blay J.-Y.
      Reduced SARS-CoV-2 infection and death after two doses of COVID-19 vaccines in a series of 1503 cancer patients.
      ,
      • Thakkar A.
      • Gonzalez-Lugo J.
      • Goradia N.
      • et al.
      Seroconversion rates following COVID-19 vaccination among patients with cancer.
      • Addeo A.
      • Shah K., P.
      • Bordry N.
      • et al.
      Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer.
      • Benda M.
      • Mutschlechner B.
      • Ulmer H.
      • et al.
      Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients.
      ,
      • Shepherd T.C., S.
      • Fendler A.
      • Au L.
      • et al.
      1557O - Adaptive immunity to SARS-CoV-2 infection and vaccination in cancer patients: The CAPTURE study.
      ,
      • Oosting S.
      • Van der Veldt A.M., A.
      • GeurtsvanKessel H., C.
      • et al.
      LBA8 - Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors.
      and in details patients with hematologic cancers could elicit inadequate humoral and cellular responses while patients with solid tumors obtain excellent humoral response but inadequate cellular response.
      • Ehmsen S.
      • Asmussen A.
      • Jeppesen S., S.
      • et al.
      Antibody and T cell immune responses following mRNA COVID-19 vaccination in patients with cancer.
      ,
      • Thakkar A.
      • Gonzalez-Lugo J.
      • Goradia N.
      • et al.
      Seroconversion rates following COVID-19 vaccination among patients with cancer.
      Another factor that could influence the immune response is advanced age, due to immunosenescence; studies are conflicting in this sense and few have found a true correlation between advanced age and poor response at multivariate analyzes.
      • Gounant V.
      • Ferré M., V.
      • Soussi G.
      • et al.
      Efficacy of Severe Acute Respiratory Syndrome Coronavirus-2 Vaccine in Patients With Thoracic Cancer: A Prospective Study Supporting a Third Dose in Patients With Minimal Serologic Response After Two Vaccine Doses.
      Instead, Iacono et al. confirm adequate seroconversion in old patients with cancer (>80 years).
      • Iacono D.
      • Cerbone L.
      • Palombi L.
      • et al.
      Serological response to COVID-19 vaccination in patients with cancer older than 80 years.
      On the other hand, regarding young cancer patients (AYA), one very small study demonstrated 90% efficacy after the second dose.
      • Revon-Riviere G.
      • Ninove L.
      • Min V.
      • et al.
      The BNT162b2 mRNA COVID-19 vaccine in adolescents and young adults with cancer: A monocentric experience.
      In previous studies, a significant difference in seroconversion rate was noted between the various anti-cancer treatment modalities. Patients who no received therapy (ie, clinical surveillance) or on endocrine therapy (ET) were reported the best outcomes with high seroconversion rates (98-100%) and excellent median antibody titers, compared to those patients who received cytotoxic chemotherapy alone or in combination with IO or biological treatments that had significantly lower levels of antibody titers.
      • Addeo A.
      • Shah K., P.
      • Bordry N.
      • et al.
      Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer.
      Some data suggest that cancer therapy hinders immune responses to vaccines, particularly chemotherapy.
      • Goshen-Lago T.
      • Waldhorn I.
      • Holland R.
      • et al.
      Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.
      ,
      • Monin L.
      • Laing G., A.
      • Muñoz-Ruiz M.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      ,
      • Di Noia V.
      • Pimpinelli F.
      • Renna D.
      • et al.
      Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution.
      ,
      • Barrière J.
      • Chamorey E.
      • Adjtoutah Z.
      • et al.
      Impaired immunogenicity of BNT162b2 anti-SARS-CoV-2 vaccine in patients treated for solid tumors.
      ,
      • Palich R.
      • Veyri M.
      • Vozy A.
      • et al.
      High seroconversion rate but low antibody titers after two injections of BNT162b2 (Pfizer-BioNTech) vaccine in patients treated with chemotherapy for solid cancers.
      ,
      • Oosting S.
      • Van der Veldt A.M., A.
      • GeurtsvanKessel H., C.
      • et al.
      LBA8 - Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors.
      Also, patients with solid tumors receiving chronic use of steroids could elicit poor immune response.
      • Di Noia V.
      • Pimpinelli F.
      • Renna D.
      • et al.
      Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution.
      ,
      • Gounant V.
      • Ferré M., V.
      • Soussi G.
      • et al.
      Efficacy of Severe Acute Respiratory Syndrome Coronavirus-2 Vaccine in Patients With Thoracic Cancer: A Prospective Study Supporting a Third Dose in Patients With Minimal Serologic Response After Two Vaccine Doses.
      Concerning immunotherapy, particularly immune checkpoint inhibitors (I-CIs), contrasting studies have been reported, some studies reported equal and non-interfering efficacy
      • Goshen-Lago T.
      • Waldhorn I.
      • Holland R.
      • et al.
      Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.
      ,
      • Thakkar A.
      • Gonzalez-Lugo J.
      • Goradia N.
      • et al.
      Seroconversion rates following COVID-19 vaccination among patients with cancer.
      and other studies reported low effectiveness.
      • Eliakim-Raz N.
      • Massarweh A.
      • Stemmer A.
      • Stemmer S.M.
      Durability of Response to SARS-CoV-2 BNT162b2 Vaccination in Patients on Active Anticancer Treatment.
      ,
      • Ehmsen S.
      • Asmussen A.
      • Jeppesen S., S.
      • et al.
      Antibody and T cell immune responses following mRNA COVID-19 vaccination in patients with cancer.
      ,
      • Karacin C.
      • Eren T.
      • Zeynelgil E.
      • et al.
      Immunogenicity and safety of the CoronaVac vaccine in patients with cancer receiving active systemic therapy.
      Regarding the safety, a debated topic previously, it appears to be safe. Waissengrin et al. observed a similar side-effect profile in healthy controls and in cancer patients treated with IO and no new immune-related side effects or exacerbation of existing immune-related side effects were observed.
      • Goshen-Lago T.
      • Waldhorn I.
      • Holland R.
      • et al.
      Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.
      In our study, no specific safety concerns were observed in ICI-treated patients, particularly with regard to immune-related adverse effects, as reported in previous cases.
      • Corti C.
      • Crimini E.
      • Tarantino P.
      • et al.
      SARS-CoV-2 vaccines for cancer patients: a call to action.
      ,
      • Goshen-Lago T.
      • Waldhorn I.
      • Holland R.
      • et al.
      Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.
      In particular, our study confirms the safety profile of vaccines during immunotherapy with approved antagonists of programmed cell death protein 1 (PD-1) and its ligand PD-L1.
      • Waissengrin B.
      • Agbarya A.
      • Safadi E.
      • Padova H.
      • Wolf I.
      Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors.
      Furthermore, it appears to be safe in their combination with other investigative agents, as reported by previous studies.
      • Trillo Aliaga P.
      • Trapani D.
      • Sandoval L., J.
      • et al.
      Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials.
      However, perhaps these events may be too rare to be captured in our analysis and would require longitudinal pharmacovigilance.
      When reported, AEs of any grade ranged from 18.9% to 74% after the first dose and from 23.1% to 72% after the second dose.
      • Goshen-Lago T.
      • Waldhorn I.
      • Holland R.
      • et al.
      Serologic Status and Toxic Effects of the SARS-CoV-2 BNT162b2 Vaccine in Patients Undergoing Treatment for Cancer.
      • Monin L.
      • Laing G., A.
      • Muñoz-Ruiz M.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      • Waissengrin B.
      • Agbarya A.
      • Safadi E.
      • Padova H.
      • Wolf I.
      Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors.
      ,
      • Terpos E.
      • Zagouri F.
      • Liontos M.
      • et al.
      Low titers of SARS-CoV-2 neutralizing antibodies after first vaccination dose in cancer patients receiving checkpoint inhibitors.
      ,
      • Thakkar A.
      • Gonzalez-Lugo J.
      • Goradia N.
      • et al.
      Seroconversion rates following COVID-19 vaccination among patients with cancer.
      ,
      • Benda M.
      • Mutschlechner B.
      • Ulmer H.
      • et al.
      Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients.
      ,
      • Karacin C.
      • Eren T.
      • Zeynelgil E.
      • et al.
      Immunogenicity and safety of the CoronaVac vaccine in patients with cancer receiving active systemic therapy.
      ,
      • Oosting S.
      • Van der Veldt A.M., A.
      • GeurtsvanKessel H., C.
      • et al.
      LBA8 - Vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors.
      ,
      • Revon-Riviere G.
      • Ninove L.
      • Min V.
      • et al.
      The BNT162b2 mRNA COVID-19 vaccine in adolescents and young adults with cancer: A monocentric experience.
      • Trillo Aliaga P.
      • Trapani D.
      • Sandoval L., J.
      • et al.
      Safety of COVID-19 mRNA Vaccines in Patients with Cancer Enrolled in Early-Phase Clinical Trials.
      • Giugliano F.
      • Zucali A., P.
      • Galli G.
      • et al.
      SARS-CoV-2 vaccine in patients with thymic epithelial tumors with and without active or pre-existing autoimmune disorders: Brief report of a TYME network safety analysis.
      Very few G3 or higher AEs were recorded
      • Di Noia V.
      • Pimpinelli F.
      • Renna D.
      • et al.
      Immunogenicity and Safety of COVID-19 Vaccine BNT162b2 for Patients with Solid Cancer: A Large Cohort Prospective Study from a Single Institution.
      ,
      • Thakkar A.
      • Gonzalez-Lugo J.
      • Goradia N.
      • et al.
      Seroconversion rates following COVID-19 vaccination among patients with cancer.
      ,
      • Benda M.
      • Mutschlechner B.
      • Ulmer H.
      • et al.
      Serological SARS-CoV-2 antibody response, potential predictive markers and safety of BNT162b2 mRNA COVID-19 vaccine in haematological and oncological patients.
      and vaccine doesn't seem to augment oncological treatment toxicity.
      • Waissengrin B.
      • Agbarya A.
      • Safadi E.
      • Padova H.
      • Wolf I.
      Short-term safety of the BNT162b2 mRNA COVID-19 vaccine in patients with cancer treated with immune checkpoint inhibitors.
      ,
      • Giugliano F.
      • Zucali A., P.
      • Galli G.
      • et al.
      SARS-CoV-2 vaccine in patients with thymic epithelial tumors with and without active or pre-existing autoimmune disorders: Brief report of a TYME network safety analysis.
      A curious finding reported by one study is that AEs after booster predicted a higher likelihood of vaccine response (P = .003).
      • Monin L.
      • Laing G., A.
      • Muñoz-Ruiz M.
      • et al.
      Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study.
      In these prospective studies, LC were mixed with the other types of cancers. To our knowledge, only one prospective study concerning only thoracic tumors has been published so far. This study reported efficacy and safety profile in 306 patients with thoracic cancer (93% received two vaccine doses). The efficacy of mRNA COVID-19 vaccines reported was 98.4%. Serological conversion was also reported with only 6.3% of patients negative after the second dose. In multivariate analysis, only age (P < .01) and long-term corticosteroid treatment (P = .01) were significantly associated with a lack of immunization. In this study 30 patients received a third vaccine dose, with only three patients showing persistently negative serology thereafter, whereas the others exhibited clear seroconversion. Safety data were available for 90.1%, without significant safety concerns. No anaphylactic reaction occurred and no vaccine-related death occurred.
      • Gounant V.
      • Ferré M., V.
      • Soussi G.
      • et al.
      Efficacy of Severe Acute Respiratory Syndrome Coronavirus-2 Vaccine in Patients With Thoracic Cancer: A Prospective Study Supporting a Third Dose in Patients With Minimal Serologic Response After Two Vaccine Doses.
      Similarly, our study reports a median follow-up of 9 months of a group of patients with thoracic cancers (mainly LC) in active treatment boosted with mRNA vaccines recording neither vaccine safety alerts or oncological treatment interferences. Also, we observed an excellent post-vaccine protection.
      In fact, during the follow-up, around 10% of our patients were contaminated with Sars-Cov-2 without developing serious complications from Covid-19. This could be considered indirect evidence of the efficacy of mRNA-COVID-19 vaccines in this subset of frailty patients. Some observational studies have also shown that these vaccines are highly effective against asymptomatic infections and suppress viral load in breakthrough infections.
      • Schmidt L., A.
      • Labaki C.
      • Hsu Y., C.
      • et al.
      COVID-19 vaccination and breakthrough infections in patients with cancer.
      However, it should be emphasized that the development of immunogenicity alone does not mean absolute protection from COVID-19 infection, in fact, it is necessary to continue with social norms (social distancing, masks, hand disinfection, etc.) to avoid contagion.
      Some highly transmissible SARS-CoV-2 variants of concern that partially evade antibody responses are suspected to have arisen following prolonged evolution within immunocompromised patients.
      • Hirabara M., S.
      • Serdan D., T.
      • Gorja R.
      • et al.
      SARS-COV-2 Variants: Differences and Potential of Immune Evasion.
      • Choi B.
      • Choudhary C., M.
      • Regan J.
      • et al.
      Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host.
      • Hensley M.K.
      • Bain G., W.
      • Jacobs J.
      • et al.
      Intractable Coronavirus Disease 2019 (COVID-19) and Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Replication in a Chimeric Antigen Receptor-Modified T-Cell Therapy Recipient: A Case Study.
      We have seen how compared to individuals not on immunosuppressive therapy, the magnitudes of vaccine-induced antibody and T cell responses induced by the vaccine is substantially reduced in cancer patients. These reduced levels can be particularly problematic in the face of variants (from beta to omicron subvariants) that possess some neutralizing mutations that evade antibodies. Indeed, the level of protection of the different COVID-19 vaccines against the different variants of SARS-CoV-2 is still poorly understood. There are studies that investigates the effectiveness of COVID-19 vaccination in preventing infection by the newly discovered SARS- CoV-2 variants. One study evaluated the effectiveness of the mRNA- 1273 vaccine against SARS-CoV-2 variants and assess its effectiveness by time against the delta variant since vaccination in 8153 cases and obtained an effectiveness after two doses of 86.7% against infection with the delta variant, 98.4% against alpha, 96-98% against other identified variants, and 79.9% against unidentified variants.
      • Bruxvoort K.J.
      • Sy S., L.
      • Qian L.
      • et al.
      Effectiveness of mRNA-1273 against delta, mu, and other emerging variants of SARS-CoV-2: test negative case-control study.
      Our study presents several limitations. First of all, humoral (anti-S IgG) and cellular (specific anti-SARS-CoV2 CD4+/CD8+ T cell) immune responses were not evaluated for logistical and financial reasons. Our population was heterogeneous, confounding factors such as cancer type, cancer treatment, and vaccine type could not be accounted reliably in our statistics. In addition, the small cohort limited the potential identification of rare events, for example, the occurrence of exceptional toxicities of special interest, and their delayed occurrence. This is a general issue with vaccine development. Most of patients in our series received mRNA vaccines, with possible problems of generalizability for viral-vector or inactivated vaccine.
      • Karacin C.
      • Eren T.
      • Zeynelgil E.
      • et al.
      Immunogenicity and safety of the CoronaVac vaccine in patients with cancer receiving active systemic therapy.
      The choice of mRNA vaccines for patients with cancer was determined by the national policy-makers, recommending this type for the most vulnerable populations. Finally, the monocentric nature of the study may hinder its external validity.
      The strengths of this study are that, for the first time, the safety profile of COVID-19 vaccines was investigated in a cohort of patients with thoracic malignances particularly, in patients receiving immunotherapy and targeted therapies with a median follow-up of 9 months (one of the longest reported so far, to our knowledge).

      Conclusion

      The safety profile of COVID-19 vaccines in patients with thoracic malignancies, including those in treatment with immune checkpoint inhibitors and specific target therapies, does not seem to differ from that of the general population of patients. Considering the high morbidity and mortality associated with COVID-19 in patients with lung cancer receiving active treatments, our study supports the current vaccine prioritization of all cancer patients with active treatment. Taken together our data with those from literature, that observed that immune response after COVID-19 vaccination is less effective in cancer patients than in healthy controls, we strongly recommend the booster dose (4th administration) for the patients with thoracic malignancies especially those who are in active treatment.

      Authors Contribution

      Conceptualization: GS; Data curation; GS, PTA; Formal analysis: GS, PTA; Funding acquisition: FdM; Investigation: GS, PTA, CC, EDS, AI, CS, FG, PPMBG, GC, AP, FdM; Methodology: GS, PTA; Project administration: GS, FdM; Resources: GS, PTA; Supervision: FdM; Validation: GS, FdM; Visualization: GS, PTA; Roles/Writing - original draft: GS, PTA; Writing – review and editing: GS, PTA, CC, EDS, AI, CS, FG, PPMBG, GC, AP and FdM.

      Funding

      This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 × 1000 funds.

      Clinical Practice Points

      Although cancer patients represent a priority population for vaccination, they were initially excluded from these studies. To date, available data of immunogenicity and safety for this population derives mainly from non-randomized prospective studies. The purpose of our work is to describe the safety profile and efficacy of COVID-19 vaccines in patients affected by thoracic malignancies receiving antineoplastic drugs.
      We found out that the safety profile of COVID-19 vaccines in patients with thoracic malignancies in active treatment (including immune checkpoint inhibitors and specific targeted therapies) was manageable, causing less than 1% of G3-4 toxicity and only one case of hospitalization.
      Considering the high morbidity and mortality associated with COVID-19 in patients with lung cancer receiving active treatments, our study supports the current vaccine prioritization, third and/or fourth dose, of all cancer patients with active treatment.

      Disclosure

      GS served as advisor for Takeda outside the submitted work. CC served as advisor for AstraZeneca outside the submitted work. GC served as consultant or advisor for Roche, Lilly and Bristol-Myers Squibb, served on the speaker's bureau for Roche, Pfizer and Lilly, received travel funding from Pfizer and Roche, and received honoraria from Roche, Pfizer, Lilly, Novartis, AstraZeneca and SEAGEN, all outside the submitted work. AP served as consultant or advisor for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Pfizer and Roche/Genentech; received speaker bureau from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Jansenn, Eli Lilly, Merck Sharp & Dohme, eCancer and Medscape, all outside the submitted work. FdM receiving advisory fees from Roche, Bristol-Myers Squibb, and AstraZeneca and consulting. fees from Merck Sharp & Dohme, all outside the submitted work. Other authors do not report potential conflicts of interest.

      Acknowledgments

      We thank all the patients enrolled in our departmental clinical care to contribute to data collection and compliance with follow-up.

      Appendix. Supplementary materials

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