COVID-19 Vaccination Around ICI Initiation and Survival in Lung, Kidney, and Melanoma

COVID-19 Vaccination Around ICI Initiation and Survival in Lung, Kidney, and Melanoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Brief Communication COVID-19 Vaccination Around ICI Initiation and Survival in Lung, Kidney, and Melanoma Judy Zhong, Chen Lyu, Mila Sun, Paul Chapman, Jedd Wolchok This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8379790/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Emerging evidence suggests that concurrent COVID-19 mRNA vaccination may enhance immune checkpoint inhibitors (ICIs) effectiveness by augmenting antitumor immune activation. Yet real-world estimates of survival benefit across cancers and clinical subgroups are limited. We emulated a randomized trial comparing two strategies at initiation of first-line ICI therapy: receipt of ≥1 COVID-19 mRNA vaccine within 100 days of ICI initiation versus no vaccination. Using the TriNetX linked network, we identified 7,966 adults with lung, melanoma, or kidney cancers who initiated first-line ICI between Sep 2020 and Nov 2024, among whom 458 received a COVID-19 vaccine within ±100 days of initiation. Vaccination was associated with improved overall survival (OS) and treatment-free survival (TFS) in lung cancer (OS aHR, 0.81; 95% CI, 0.74–0.89; P<0.001), with a modestly longer 3-year mean OS of 2.33 months (95% CI, 1.41–3.23; P<0.001). Vaccination was not associated with TFS or OS improvement in kidney or melanoma. Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy Health sciences/Medical research/Outcomes research Figures Figure 1 Figure 2 Main text Recent work has suggested that SARS-CoV-2 mRNA vaccination may enhance antitumor immunity in the setting of immune checkpoint inhibitors (ICI) therapy in non-small cell lung cancer (NSCLC) and melanoma 1 . Mechanistic studies show that the vaccine induces a type I interferon surge, activates antigen-presenting cells, increases CD8⁺ T-cell priming, and upregulates PD-L1 on tumor cells, potentially sensitizing tumors to immune checkpoint blockade through enhanced innate and adaptive immune activation. These findings raise the possibility that RNA nanoparticle-based vaccines targeting non-tumor related antigens may function as immune modulators capable of augmenting ICI effectiveness. An ideal way to address this question would be a randomized controlled trial (RCT), but randomizing patients to withhold COVID-19 vaccination would present substantial ethical and practical challenges, making such a trial difficult to conduct. We therefore implemented a target trial emulation 2 in a separate, multi-site database, applying statistical techniques that partially compensate for the non-randomized nature of the data. The trial emulation was designed to mimic a hypothetical RCT comparing two strategies at the start of first-line ICI therapy: receipt of a COVID-19 mRNA vaccine within 100 days of ICI initiation versus no vaccination within the same window across three major cancers (lung, melanoma, and kidney), and to assess whether the association varied by demographic, clinical, and treatment-related characteristics (Extended Data Table 1). We applied this framework to a large, national, multi-institution electronic health record (EHR) and claims-linked dataset from the TriNetX network 3 , encompassing 29 U.S. health systems and representing contemporary oncology practice from 2015–2025. Data for this study were extracted on April 23 rd , 2025. We identified adults (≥18 years) in TriNetX with a primary diagnosis of lung, melanoma, or kidney cancer before ICI initiation who initiated first-line ICI therapy between September 2, 2020, and November 8, 2024. First-line treatment was defined as the initial systemic therapy, with no prior record of systemic therapy recorded (Extended Data Table 2). A total of 10 ICIs were included (PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors). Time zero was the earliest first-line ICI prescription date (ICI initiation). Patients were classified as vaccinated if they received a COVID-19 mRNA vaccine from 100 days before to 100 days after ICI initiation, and unvaccinated otherwise. Overall survival (OS) was defined as the time from ICI initiation to death from any cause, with mortality ascertained in TriNetX from EHRs, obituary records, and the Social Security Death Index 3 . Patients alive at the time of data extraction or lost to follow-up were censored at their last recorded encounter. Treatment-free survival (TFS) was defined as the time from first-line ICI initiation to the initiation of subsequent systemic therapy (first prescription after a >90-day 4,5 gap) or death 6 . Baseline covariates included age, sex, race and ethnicity, marital status, metastatic status at ICI initiation, comorbidity burden, ICI drug class (anti–PD-1 vs anti–PD-L1), concurrent chemotherapy, and pandemic period at ICI initiation (pandemic vs post-pandemic, defined as after May 10, 2023 7 ). Vaccination characteristics included brand; number of shots (including primary series and boosters); timing relative to ICI initiation (before vs. after); and finer timing windows (–100 to –30, –30 to 0, 0 to 30, and 30 to 100 days) around ICI initiation. We included 7,966 adults receiving first-line ICI therapy: 4,836 with lung cancer (4,554 unvaccinated; 282 vaccinated), 1,571 with kidney cancer (1,485 unvaccinated; 86 vaccinated), and 1,559 with melanoma (1,469 unvaccinated; 90 vaccinated, Extended Data Fig.1). Demographic and treatment characteristics were broadly similar between arms within each cancer type (Extended Data Table 3). Unadjusted survival curves are shown in Extended Data Fig.2 and 3; unadjusted hazard ratios, risk ratios, and mean survival times for each cancer type are provided in Extended Data Table 4. These data show a statistically significant improvement in OS and TFS for lung cancer patients but not for melanoma or kidney cancer patients. Adjusted hazard ratios (aHRs) from the clone–censor–weighted target trial emulation analysis confirmed that, in lung cancer, vaccination was associated with lower overall mortality in lung cancer (aHR, 0.81; 95% CI, 0.74–0.89; P < 0.001; Fig.1a) and improved TFS (aHR, 0.78; 95% CI, 0.71–0.85; P < 0.001; Fig.1d). At 3 years, vaccination was associated with modestly longer mean OS (2.33 months; 95% CI, 1.41–3.23; P<0.001; Fig.1a) and mean TFS (3.21 months; 95% CI, 2.21–4.22; P < 0.001; Fig.1d). In contrast, associations in kidney cancer (OS aHR, 0.76; 95% CI, 0.57–0.94; P = 0.03; Fig.1b) and melanoma (OS aHR, 0.95; 95% CI, 0.70–1.21; P = 0.68; Fig.1c) were not significant after multiple-testing correction for either OS or TFS (Fig. 1e and 1f). 3-year mean OS differences were not statistically significant after correction in kidney cancer (1.55 months; 95% CI, 0.33–2.89; P = 0.018; Fig. 1b) or melanoma (0.26 months; 95% CI, −1.08 to 1.55; Fig. 1c). Corresponding 1- and 2-year estimates were consistent with the 3-year results (Extended Data Table 5). In lung cancer, aHRs were consistent across age, sex, metastatic status, concurrent chemotherapy, vaccine brand, and number of doses. Vaccination after ICI initiation was associated with greater OS and TFS benefit than vaccination before ICI (Fig. 2a and 2d). Vaccination within 0–30 or 30–100 days after ICI initiation was similarly associated with improved OS and TFS, with intermediate benefit (but non-significant) for vaccination in the 0–30 days before initiation and little apparent benefit for vaccination 30–100 days before initiation. However, kidney (Fig. 2b and 2e) and melanoma (Fig. 2c and 2f) cancers showed no evidence of efficacy across demographic or clinical subgroups. For all cancers, results were similar among patients who initiated ICI treatment during versus after the pandemic era, although the post-pandemic subgroup could estimate the association between vaccination and survival only up to 18 months because of shorter follow-up (Extended Data Fig.4). Extending the vaccination window to 200 days (Extended Data Fig.5) yielded results consistent with the primary analysis. The negative control analysis using influenza vaccination demonstrated no survival differences between vaccinated and unvaccinated groups, supporting the specificity of the COVID-19 findings (Extended Data Fig.6). A recent retrospective study by Grippin and colleagues using a database from MD Anderson showed improved overall and progression-free survival associated with COVID19 vaccination in NSCLC and melanoma patients. 1 However, in their primary analysis, unvaccinated patients were enrolled between 2015 and 2022, whereas vaccinated patients were enrolled only between 2021 and 2022. We hypothesize that this difference in calendar time inclusion criteria may have contributed to the discrepancy between their findings and ours. When they restricted to a time-comparable pandemic era cohort (ICI on/after 9/2/2020), their estimates (NSCLC HR 0.66; 95% CI, 0.44–1.00; Extended Data Fig.1f 1 ) and non-significant melanoma results (Extended Data Fig.3e 1 ) closely aligned with ours. The immunologic mechanisms underlying this adjuvant effect of the COVID-19 vaccines remain an active topic of investigation. It is possible that an anti-spike protein immune response cross-reacts with a shared antigen on NSCLC and possibly other tumor types. A more likely mechanism is that the mRNA in nanoparticle form in the vaccines provide an immune adjuvant effect by binding to TNF-like receptors (or perhaps other receptors). However, using TNF-like receptor agonists to induce an immune adjuvant effect has been a strategy exhaustively explored in the past with little success. 8 Strengths of this study include multicenter coverage across multiple cancer types, follow-up of patients initiating ICI from 2020–2024 (through 2025), explicit alignment of first-line ICI eligibility, and extensive subgroup analyses. In our analysis, treatments were classified by the backbone ICI regimen despite heterogeneous combinations (e.g. nivolumab monotherapy vs nivolumab plus ipilimumab in melanoma; ICI+VEGF inhibitor in renal cancer). These patterns did not differ systematically by vaccination status (Extended Data Table 6), making confounding by regimen variation unlikely. Our dataset lacks key tumor characteristics and biomarkers (PD-L1 expression and other molecular features). We do not expect major systematic differences in these features by vaccination status, so strong confounding from these factors is unlikely, although estimates still average across heterogeneous tumor subgroups. In contrast, missing clinical characteristics such as ECOG performance status may be associated with vaccination uptake and could confound efficacy estimates. Vaccination status relied on TriNetX documentation and may miss doses given in pharmacies, community settings, or outside health systems, leading to exposure misclassification likely biasing toward the null. Finally, small vaccinated samples in kidney and melanoma cancers may limit power to detect modest associations. Taken together, in this large, multi-center target trial emulation, COVID-19 mRNA vaccination within 100 days after ICI initiation was associated with improved moderate survival in lung cancer, but not in melanoma or kidney cancers. References Grippin, A.J. , et al. SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. Nature 647 , 488-497 (2025). Hernán, M.A., Wang, W. & Leaf, D.E. Target trial emulation: a framework for causal inference from observational data. Jama 328 , 2446-2447 (2022). TriNetX. TriNetX: Real-world data for the life sciences and healthcare. Obeng, D. , et al. Assessment of the Application of a 90-Day-Gap Rule for Mitigating Frontline Treatment Sequence Misclassification in Electronic Health Records in the United States. in PHARMACOEPIDEMIOLOGY AND DRUG SAFETY , Vol. 33 604-604 (WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2024). Hess, L.M., Li, X., Wu, Y., Goodloe, R.J. & Cui, Z.L. Defining treatment regimens and lines of therapy using real-world data in oncology. Future Oncol 17 , 1865-1877 (2021). Regan, M.M. , et al. Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial. Clin Cancer Res 27 , 6687-6695 (2021). CDC. End of the Federal COVID-19 Public Health Emergency (PHE) Declaration. (2023). Rolfo, C., Giovannetti, E., Martinez, P., McCue, S. & Naing, A. Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer. NPJ Precis Oncol 7 , 26 (2023). Additional Declarations There is NO Competing Interest. Supplementary Files OnlineMethods.docx Online Methods SupplementaryMaterialsNMBCFINAL.docx Extended Data Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8379790","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Brief Communication","associatedPublications":[],"authors":[{"id":562543680,"identity":"394ca9ca-c3c0-489b-85c5-64b8b3d77a50","order_by":0,"name":"Judy Zhong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+klEQVRIiWNgGAWjYBACxgYGBoMEAzY5INsAIsTODBRjw6+l4EMFnzFCCzMjfi0g8HHGGbnEBqK1MM9If7iZt80sfW178waGHxX38vhBWj6UHcbtsBkJyca8bWm5284cK2DsOVNcLNnM2MA44xxeLceAWo7lbruRY8DM2JaQuOEwYwMzbxs+LYntv3nb/qeb3X8D0bIfpOUvXi3JDIYzzrAlmN3ggdoC9AuQgUdLzzMGgw8VbIbbzqQVHOw5k5A4A2jLwZ5z6Ti1GLanPwBFpbzZ8cMbH/yoSEjsb28++OBHmTVuLQ1InAMYDGxAHp/kKBgFo2AUjAIwAACAsluPzL4EeAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-2163-8447","institution":"Weill Cornell","correspondingAuthor":true,"prefix":"","firstName":"Judy","middleName":"","lastName":"Zhong","suffix":""},{"id":562543681,"identity":"0b0d8fc2-658e-4693-aeb7-9e1f8b62555e","order_by":1,"name":"Chen Lyu","email":"","orcid":"https://orcid.org/0000-0003-4406-5079","institution":"Cornell University","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Lyu","suffix":""},{"id":562543682,"identity":"d406205a-9ac2-4de3-a947-897b5098b0e5","order_by":2,"name":"Mila Sun","email":"","orcid":"","institution":"Weill Cornell","correspondingAuthor":false,"prefix":"","firstName":"Mila","middleName":"","lastName":"Sun","suffix":""},{"id":562543683,"identity":"4536bbb3-673e-4f0c-9a7f-406017b9028d","order_by":3,"name":"Paul Chapman","email":"","orcid":"https://orcid.org/0000-0003-1618-0811","institution":"Cornell","correspondingAuthor":false,"prefix":"","firstName":"Paul","middleName":"","lastName":"Chapman","suffix":""},{"id":562543684,"identity":"4bf77bd2-05fd-4121-bcfa-38c861eff576","order_by":4,"name":"Jedd Wolchok","email":"","orcid":"","institution":"Weill Cornell","correspondingAuthor":false,"prefix":"","firstName":"Jedd","middleName":"","lastName":"Wolchok","suffix":""}],"badges":[],"createdAt":"2025-12-16 21:11:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8379790/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8379790/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":99308593,"identity":"884038d2-8db9-4249-98b1-822e5a621f0f","added_by":"auto","created_at":"2025-12-31 16:08:48","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":341144,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTarget trial emulation adjusted overall survival and treatment-free survival curves by COVID-19 vaccine arms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes were A–C) overall survival and D–F) treatment-free survival: lung (A, D), kidney (B, E), and melanoma (C, F). The x-axis shows months since first-line ICI initiation. Curves were estimated from target trial emulation–adjusted models and colored by group (blue: unvaccinated; yellow: vaccinated); shaded bands indicate 95% bootstrap confidence intervals, with numbers at risk shown. Bootstrap methods were used to estimate adjusted hazard ratios (aHR; vaccinated vs unvaccinated) and 3-year adjusted RMST differences (ΔaRMST) with p-values.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8379790/v1/436f1bf07f2cd5e684c8a390.png"},{"id":99309148,"identity":"af2fd93e-e2b9-44c7-a8e4-b32bf037cc59","added_by":"auto","created_at":"2025-12-31 16:09:48","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":924524,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdjusted hazard ratio estimates for overall survival and treatment-free survival by subgroup.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOutcomes were A–C) overall survival and D–F) treatment-free survival: lung (A, D), kidney (B, E), and melanoma (C, F). “Death/N (%/yr)” denotes deaths/participants, with %/yr the incidence per 100 person-years. Adjusted hazard ratios (aHR; vaccination vs no vaccination) and 95% CIs were estimated using target trial emulation models, run separately for each subgroup. For vaccination-specific factors (timing, brand, window, doses), vaccinated subgroups were compared with a shared non-vaccinated control group. Some subgroups are not shown due to small sample sizes.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8379790/v1/48cb071c1e7c7ba1c326897a.png"},{"id":99322674,"identity":"e3e5928f-566e-49dc-92d4-c89426268ea3","added_by":"auto","created_at":"2025-12-31 16:43:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1554852,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8379790/v1/dbab2ef4-4777-4ab5-b619-2c5c45757916.pdf"},{"id":98862447,"identity":"63b164aa-19e1-4a81-b663-6e20f35e24d0","added_by":"auto","created_at":"2025-12-23 09:52:47","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33989,"visible":true,"origin":"","legend":"Online Methods","description":"","filename":"OnlineMethods.docx","url":"https://assets-eu.researchsquare.com/files/rs-8379790/v1/60267e047f4761c690e8d16c.docx"},{"id":98862449,"identity":"bb98a409-60d1-4128-9b1b-f9ba45f741f8","added_by":"auto","created_at":"2025-12-23 09:52:47","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":1685233,"visible":true,"origin":"","legend":"Extended Data","description":"","filename":"SupplementaryMaterialsNMBCFINAL.docx","url":"https://assets-eu.researchsquare.com/files/rs-8379790/v1/9704c322e66398b8c3ba26d0.docx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"COVID-19 Vaccination Around ICI Initiation and Survival in Lung, Kidney, and Melanoma","fulltext":[{"header":"Main text","content":"\u003cp\u003eRecent work has suggested that SARS-CoV-2 mRNA vaccination may enhance antitumor immunity in the setting of immune checkpoint inhibitors (ICI) therapy in non-small cell lung cancer (NSCLC) and melanoma\u003csup\u003e1\u003c/sup\u003e. Mechanistic studies show that the vaccine induces a type I interferon surge, activates antigen-presenting cells, increases CD8⁺\u0026nbsp;T-cell priming, and upregulates PD-L1 on tumor cells, potentially sensitizing tumors to immune checkpoint blockade through enhanced innate and adaptive immune activation. These findings raise the possibility that RNA nanoparticle-based vaccines targeting non-tumor related antigens may function as immune modulators capable of augmenting ICI effectiveness.\u003c/p\u003e\n\u003cp\u003eAn ideal way to address this question would be a randomized controlled trial (RCT), but randomizing patients to withhold COVID-19 vaccination would present substantial ethical and practical challenges, making such a trial difficult to conduct. We therefore implemented a target trial emulation\u003csup\u003e2\u003c/sup\u003e in a separate, multi-site database, applying statistical techniques that partially compensate for the non-randomized nature of the data. The trial emulation was designed to mimic a hypothetical RCT comparing two strategies at the start of first-line ICI therapy: receipt of a COVID-19 mRNA vaccine within 100 days of ICI initiation versus no vaccination within the same window across three major cancers (lung, melanoma, and kidney), and to assess whether the association varied by demographic, clinical, and treatment-related characteristics (Extended Data Table 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe applied this framework to a large, national, multi-institution electronic health record (EHR) and claims-linked dataset from the TriNetX network\u003csup\u003e3\u003c/sup\u003e, encompassing 29 U.S. health systems and representing contemporary oncology practice from 2015\u0026ndash;2025. Data for this study were extracted on April 23\u003csup\u003erd\u003c/sup\u003e, 2025. We identified adults (\u0026ge;18 years) in TriNetX with a primary diagnosis of lung, melanoma, or kidney cancer before ICI initiation who initiated first-line ICI therapy between September 2, 2020, and November 8, 2024. First-line treatment was defined as the initial systemic therapy, with no prior record of systemic therapy recorded (Extended Data Table 2). A total of 10 ICIs were included (PD-1, PD-L1, CTLA-4, and LAG-3 inhibitors). Time zero was the earliest first-line ICI prescription date (ICI initiation). Patients were classified as vaccinated if they received a COVID-19 mRNA vaccine from 100 days before to 100 days after ICI initiation, and unvaccinated otherwise. Overall survival (OS) was defined as the time from ICI initiation to death from any cause, with mortality ascertained in TriNetX from EHRs, obituary records, and the Social Security Death Index\u003csup\u003e3\u003c/sup\u003e. Patients alive at the time of data extraction or lost to follow-up were censored at their last recorded encounter. Treatment-free survival (TFS) was defined as the time from first-line ICI initiation to the initiation of subsequent systemic therapy (first prescription after a \u0026gt;90-day\u003csup\u003e4,5\u003c/sup\u003e gap) or death\u003csup\u003e6\u003c/sup\u003e.\u0026nbsp;Baseline covariates included age, sex, race and ethnicity, marital status, metastatic status at ICI initiation, comorbidity burden, ICI drug class (anti\u0026ndash;PD-1 vs anti\u0026ndash;PD-L1), concurrent chemotherapy, and pandemic period at ICI initiation (pandemic vs post-pandemic, defined as after May 10, 2023\u003csup\u003e7\u003c/sup\u003e). Vaccination characteristics included brand; number of shots (including primary series and boosters); timing relative to ICI initiation (before vs. after); and finer timing windows (\u0026ndash;100 to \u0026ndash;30, \u0026ndash;30 to 0, 0 to 30, and 30 to 100 days) around ICI initiation.\u003c/p\u003e\n\u003cp\u003eWe included 7,966 adults receiving first-line ICI therapy: 4,836 with lung cancer (4,554 unvaccinated; 282 vaccinated), 1,571 with kidney cancer (1,485 unvaccinated; 86 vaccinated), and 1,559 with melanoma (1,469 unvaccinated; 90 vaccinated, Extended Data Fig.1). Demographic and treatment characteristics were broadly similar between arms within each cancer type (Extended Data Table 3). Unadjusted survival curves are shown in Extended Data Fig.2 and 3; unadjusted hazard ratios, risk ratios, and mean survival times for each cancer type are provided in Extended Data Table 4. \u0026nbsp;These data show a statistically significant improvement in OS and TFS for lung cancer patients but not for melanoma or kidney cancer patients. \u0026nbsp;Adjusted hazard ratios (aHRs) from the clone\u0026ndash;censor\u0026ndash;weighted target trial emulation analysis confirmed that, in lung cancer, vaccination was associated with lower overall mortality in lung cancer (aHR, 0.81; 95% CI, 0.74\u0026ndash;0.89; P \u0026lt; 0.001; Fig.1a) and improved TFS (aHR, 0.78; 95% CI, 0.71\u0026ndash;0.85; P \u0026lt; 0.001; Fig.1d). At 3 years, vaccination was associated with modestly longer mean OS (2.33 months; 95% CI, 1.41\u0026ndash;3.23; P\u0026lt;0.001; Fig.1a) and mean TFS (3.21 months; 95% CI, 2.21\u0026ndash;4.22; P \u0026lt; 0.001; Fig.1d). In contrast, associations in kidney cancer (OS aHR, 0.76; 95% CI, 0.57\u0026ndash;0.94; P = 0.03; Fig.1b) and melanoma (OS aHR, 0.95; 95% CI, 0.70\u0026ndash;1.21; P = 0.68; Fig.1c) were not significant after multiple-testing correction for either OS or TFS (Fig. 1e and 1f). 3-year mean OS differences were not statistically significant after correction in kidney cancer (1.55 months; 95% CI, 0.33\u0026ndash;2.89; P = 0.018; Fig. 1b) or melanoma (0.26 months; 95% CI, \u0026minus;1.08 to 1.55; Fig. 1c). Corresponding 1- and 2-year estimates were consistent with the 3-year results (Extended Data Table 5).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn lung cancer, aHRs were consistent across age, sex, metastatic status, concurrent chemotherapy, vaccine brand, and number of doses. Vaccination after ICI initiation was associated with greater OS and TFS benefit than vaccination before ICI (Fig. 2a and 2d). Vaccination within 0\u0026ndash;30 or 30\u0026ndash;100 days after ICI initiation was similarly associated with improved OS and TFS, with intermediate benefit (but non-significant) for vaccination in the 0\u0026ndash;30 days before initiation and little apparent benefit for vaccination 30\u0026ndash;100 days before initiation. However, kidney (Fig. 2b and 2e) and melanoma (Fig. 2c and 2f) cancers showed no evidence of efficacy across demographic or clinical subgroups. For all cancers, results were similar among patients who initiated ICI treatment during versus after the pandemic era, although the post-pandemic subgroup could estimate the association between vaccination and survival only up to 18 months because of shorter follow-up (Extended Data Fig.4). Extending the vaccination window to 200 days (Extended Data Fig.5) yielded results consistent with the primary analysis. The negative control analysis using influenza vaccination demonstrated no survival differences between vaccinated and unvaccinated groups, supporting the specificity of the COVID-19 findings (Extended Data Fig.6).\u003c/p\u003e\n\u003cp\u003eA recent retrospective study by Grippin and colleagues using a database from MD Anderson showed improved overall and progression-free survival associated with COVID19 vaccination in NSCLC and melanoma patients.\u003csup\u003e1\u003c/sup\u003e However, in their primary analysis, unvaccinated patients were enrolled between 2015 and 2022, whereas vaccinated patients were enrolled only between 2021 and 2022. We hypothesize that this difference in calendar time inclusion criteria may have contributed to the discrepancy between their findings and ours. When they restricted to a time-comparable pandemic era cohort (ICI on/after 9/2/2020), their estimates (NSCLC HR 0.66; 95% CI, 0.44\u0026ndash;1.00; Extended Data Fig.1f\u003csup\u003e1\u003c/sup\u003e) and non-significant melanoma results (Extended Data Fig.3e\u003csup\u003e1\u003c/sup\u003e) closely aligned with ours.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe immunologic mechanisms underlying this adjuvant effect of the COVID-19 vaccines remain an active topic of investigation. \u0026nbsp;It is possible that an anti-spike protein immune response cross-reacts with a shared antigen on NSCLC and possibly other tumor types. \u0026nbsp;A more likely mechanism is that the mRNA in nanoparticle form in the vaccines provide an immune adjuvant effect by binding to TNF-like receptors (or perhaps other receptors). \u0026nbsp;However, using TNF-like receptor agonists to induce an immune adjuvant effect has been a strategy exhaustively explored in the past with little success.\u003csup\u003e8\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStrengths of this study include multicenter coverage across multiple cancer types, follow-up of patients initiating ICI from 2020\u0026ndash;2024 (through 2025), explicit alignment of first-line ICI eligibility, and extensive subgroup analyses. In our analysis, treatments were classified by the backbone ICI regimen despite heterogeneous combinations (e.g. nivolumab monotherapy vs nivolumab plus ipilimumab in melanoma; ICI+VEGF inhibitor in renal cancer). These patterns did not differ systematically by vaccination status (Extended Data Table 6), making confounding by regimen variation unlikely. Our dataset lacks key tumor characteristics and biomarkers (PD-L1 expression and other molecular features). We do not expect major systematic differences in these features by vaccination status, so strong confounding from these factors is unlikely, although estimates still average across heterogeneous tumor subgroups. In contrast, missing clinical characteristics such as ECOG performance status may be associated with vaccination uptake and could confound efficacy estimates. Vaccination status relied on TriNetX documentation and may miss doses given in pharmacies, community settings, or outside health systems, leading to exposure misclassification likely biasing toward the null. Finally, small vaccinated samples in kidney and melanoma cancers may limit power to detect modest associations.\u003c/p\u003e\n\u003cp\u003eTaken together, in this large, multi-center target trial emulation, COVID-19 mRNA vaccination within 100 days after ICI initiation was associated with improved moderate survival in lung cancer, but not in melanoma or kidney cancers.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eGrippin, A.J.\u003cem\u003e, et al.\u003c/em\u003e SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e647\u003c/strong\u003e, 488-497 (2025).\u003c/li\u003e\n\u003cli\u003eHern\u0026aacute;n, M.A., Wang, W. \u0026amp; Leaf, D.E. Target trial emulation: a framework for causal inference from observational data. \u003cem\u003eJama\u003c/em\u003e \u003cstrong\u003e328\u003c/strong\u003e, 2446-2447 (2022).\u003c/li\u003e\n\u003cli\u003eTriNetX. TriNetX: Real-world data for the life sciences and healthcare.\u003c/li\u003e\n\u003cli\u003eObeng, D.\u003cem\u003e, et al.\u003c/em\u003e Assessment of the Application of a 90-Day-Gap Rule for Mitigating Frontline Treatment Sequence Misclassification in Electronic Health Records in the United States. in \u003cem\u003ePHARMACOEPIDEMIOLOGY AND DRUG SAFETY\u003c/em\u003e, Vol. 33 604-604 (WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, 2024).\u003c/li\u003e\n\u003cli\u003eHess, L.M., Li, X., Wu, Y., Goodloe, R.J. \u0026amp; Cui, Z.L. Defining treatment regimens and lines of therapy using real-world data in oncology. \u003cem\u003eFuture Oncol\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 1865-1877 (2021).\u003c/li\u003e\n\u003cli\u003eRegan, M.M.\u003cem\u003e, et al.\u003c/em\u003e Treatment-free Survival after Immune Checkpoint Inhibitor Therapy versus Targeted Therapy for Advanced Renal Cell Carcinoma: 42-Month Results of the CheckMate 214 Trial. \u003cem\u003eClin Cancer Res\u003c/em\u003e \u003cstrong\u003e27\u003c/strong\u003e, 6687-6695 (2021).\u003c/li\u003e\n\u003cli\u003eCDC. End of the Federal COVID-19 Public Health Emergency (PHE) Declaration. (2023).\u003c/li\u003e\n\u003cli\u003eRolfo, C., Giovannetti, E., Martinez, P., McCue, S. \u0026amp; Naing, A. Applications and clinical trial landscape using Toll-like receptor agonists to reduce the toll of cancer. \u003cem\u003eNPJ Precis Oncol\u003c/em\u003e \u003cstrong\u003e7\u003c/strong\u003e, 26 (2023). \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8379790/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8379790/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Emerging evidence suggests that concurrent COVID-19 mRNA vaccination may enhance immune checkpoint inhibitors (ICIs) effectiveness by augmenting antitumor immune activation. Yet real-world estimates of survival benefit across cancers and clinical subgroups are limited. We emulated a randomized trial comparing two strategies at initiation of first-line ICI therapy: receipt of ≥1 COVID-19 mRNA vaccine within 100 days of ICI initiation versus no vaccination. Using the TriNetX linked network, we identified 7,966 adults with lung, melanoma, or kidney cancers who initiated first-line ICI between Sep 2020 and Nov 2024, among whom 458 received a COVID-19 vaccine within ±100 days of initiation. Vaccination was associated with improved overall survival (OS) and treatment-free survival (TFS) in lung cancer (OS aHR, 0.81; 95% CI, 0.74–0.89; P\u003c0.001), with a modestly longer 3-year mean OS of 2.33 months (95% CI, 1.41–3.23; P\u003c0.001). Vaccination was not associated with TFS or OS improvement in kidney or melanoma.","manuscriptTitle":"COVID-19 Vaccination Around ICI Initiation and Survival in Lung, Kidney, and Melanoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-23 09:52:42","doi":"10.21203/rs.3.rs-8379790/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"nm","sideBox":"Learn more about [Nature Medicine](http://www.nature.com/nm/)","snPcode":"","submissionUrl":"","title":"Nature Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"86e07d17-6f4e-41bd-8fbb-1752c82a7138","owner":[],"postedDate":"December 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59907838,"name":"Biological sciences/Cancer/Cancer therapy/Cancer immunotherapy"},{"id":59907839,"name":"Health sciences/Medical research/Outcomes research"}],"tags":[],"updatedAt":"2026-04-14T16:55:41+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-23 09:52:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8379790","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8379790","identity":"rs-8379790","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}