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A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran 1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P  =  0.007). In responders, autogene cevumeran induces CD8 + T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8 + T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination., Competing Interests: Competing interests: L.A.R., Z.M.S., B.D.G. and V.P.B. are inventors on patent applications related to work on antigen cross-reactivity and tracking vaccine-induced T cell clones. B.D.G. and V.P.B. are inventors on a patent application on neoantigen quality modelling. L.A.R. is an inventor of a patent related to oncolytic viral therapy. B.D.G. has received honoraria for speaking engagements from Merck, Bristol Meyers Squibb and Chugai Pharmaceuticals; has received research funding from Bristol Meyers Squibb, Merck and ROME Therapeutics; and has been a compensated consultant for Darwin Health, Merck, PMV Pharma, Shennon Biotechnologies, Synteny and Rome Therapeutics of which he is a co-founder. V.P.B. reports honoraria and research support from Genentech and research support from Bristol-Myers Squibb. A.S.E received royalties from Up-To-Date. A.V. reports research funding from Lilly, Verastem, BioMed Valley Discoveries, Bristol-Myers Squibb and Silenseed. A.C.W. reports the following: Histosonics, consulting and Ipsen, clinical trial funding. E.M.O. reports research funding to the institution from: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Digestive Care and Break Through Cancer; consulting via Data and Safety Monitoring Board (DSMB) for: Arcus, Alligator, Agenus, BioNTech, Ipsen, Merck, Moma Therapeutics, Novartis, Syros, Leap Therapeutics, Astellas, BMS, Fibrogen, Revolution Medicine, Merus Agios (spouse), Genentech-Roche (spouse), Eisai (spouse) and Servier (Spouse). J.D. owns stock in Alnylam Pharmaceuticals, Arrowroot Acquisition and Ionis Pharmaceuticals. T.M. is a co-founder and holds equity in IMVAQ Therapeutics; is a consultant for Immunos Therapeutics, ImmunoGenesis and Pfizer; has research support from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics and Aprea; and has patents on applications related to work on oncolytic viral therapy, alphavirus-based vaccine, neoantigen modelling, CD40, GITR, OX40, PD-1 and CTLA-4. J.D.W. is a consultant for Apricity, CellCarta, Ascentage Pharma, AstraZeneca, Bicara Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Dragonfly, Georgiamune, Imvaq, Larkspur, Psioxus, Recepta, Tizona and Sellas. J.D.W. receives grant and research support from Bristol-Myers Squibb and Sephora. J.D.W. has equity in Apricity, Arsenal IO, Ascentage, Imvaq, Linneaus, Georgiamune, Maverick and Tizona Therapeutics. W.P. reports research funding to institution from: Merck, Astellas, Miracogen and Amgen; consultancy or advisory board activity for: Astellas and EXACT Therapeutics; honoraria for Continuing Medical Education (CME) from: American Physician Institute and Integrity. O.T. and U.S. are co-founders, management board members and employees at BioNTech. E.D., L.M. and F.M. are employees at BioNTech. I.R., M.Y. and I.M. are employees at Genentech. The other authors declare no competing interests., (© 2025. The Author(s).)

Effective targeting of somatic cancer mutations to enhance the efficacy of cancer immunotherapy requires an individualized approach. Autogene cevumeran is a uridine messenger RNA lipoplex-based individualized neoantigen-specific immunotherapy designed from tumor-specific somatic mutation data obtained from tumor tissue of each individual patient to stimulate T cell responses against up to 20 neoantigens. This ongoing phase 1 study evaluated autogene cevumeran as monotherapy (n = 30) and in combination with atezolizumab (n = 183) in pretreated patients with advanced solid tumors. The primary objective was safety and tolerability; exploratory objectives included evaluation of pharmacokinetics, pharmacodynamics, preliminary antitumor activity and immunogenicity. Non-prespecified interim analysis showed that autogene cevumeran was well tolerated and elicited poly-epitopic neoantigen-specific responses, encompassing CD4 + and/or CD8 + T cells, in 71% of patients, most of them undetectable at baseline. Responses were detectable up to 23 months after treatment initiation. CD8 + T cells specific for several neoantigens constituted a median of 7.3% of circulating CD8 + T cells, reaching up to 23% in some patients. Autogene cevumeran-induced T cells were found within tumor lesions constituting up to 7.2% of tumor-infiltrating T cells. Clinical activity was observed, including one objective response in monotherapy dose escalation and in two patients with disease characteristics unfavorable for response to immunotherapy treated in combination with atezolizumab. These findings support the continued development of autogene cevumeran in earlier treatment lines. ClinicalTrials.gov registration: NCT03289962 ., Competing Interests: Competing interests: J.L. reports research funding to their institution from Roche-Genentech, Basilea, Astex, Merck, GSK, Eisai, Seagen, Immunocore, BicycleTx, AstraZeneca, Genmab, Bayer, Jansenn, Gilead, Anaveon, Affimed, Appollomics, Avacta, Byondis, Chugai, CellCentric, Daiichi, Iteos, Merck Serono, REDX, and Amgen, and a consulting and advisory role for Basilea, Roche-Genentech, Ellipses, Eisai, Pierre-Faber and GSK. T.P. reports a consulting and advisory role for Astellas Pharma, Bristol Myers Squibb, Exelixis, Incyte, Ipsen, Johnson & Johnson, Mashup Ltd, Merck Serono, MSD, Novartis, Pfizer, Roche and Seattle Genetics; travel, accommodation or expenses from Ipsen, MSD, Pfizer and Roche; and research funding from Astellas Pharma, Bristol Myers Squibb, Exelixis, Ipsen, Johnson & Johnson, Merck Serono, MSD, Novartis, Pfizer, Roche, Seattle Genetics. F.B. reports speaking engagements and advisory boards for Roche/Genentech, BMS, Lilly, EMD Serono, AstraZeneca and Regeneron, Merck, Seagen, Jazz Pharmaceuticals, Taiho, Incyte Deciphera and Astellas. L.L.S. reports a consulting and advisory role for Merck, Pfizer, AstraZeneca, Roche, GlaxoSmithKline, Voronoi, Arvinas, Navire, Relay, Daiichi Sankyo, Coherus, Amgen, Marengo, Medicenna, Tubulis, LTZ Therapeutics and Pangea; grants or support for clinical trials to their institution from Novartis, Bristol Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Mirati, BioNTech, 23Me and EMD Serono; stock ownership (spouse) of Agios; and leadership (spouse) at Treadwell Therapeutics. P.L. has served on the advisory boards of Abbvie, GenMab, Genentech, CytomX, Takeda, Cybrexa, Agenus, IQVIA, TRIGR, Pfizer, ImmunoMet, Black Diamond, GSK, QED Therapeutics, AstraZeneca, EMD Serono, Shattuck, Astellas, Salarius, Silverback, MacroGenics, Kyowa Kirin Pharmaceutical Development, Kineta, Inc, Zentalis Pharmaceuticals, Molecular Templates, STCube Pharmaceuticals, Bayer, I-Mab, Seagen, imCheck, Relay Therapeutics, Stemline, Compass BADX, Mekanist, Mersana Therapeutics, BAKX Therapeutics, Scenic Biotech, Qualigen, NeuroTrials and Actuate Therapeutics; on the data safety monitoring board for Agios, Five Prime, Halozyme and Tyme; and as a consultant for Roche-Genentech, SOTIO, SK Life Science and Roivant Sciences. C.F.F. reports a consulting and advisory role (self) for Seagen, Aadi Biosciences, Genentech/MyPathway (uncompensated) and Merck/LYNK-002 (uncompensated), and institutional funding from Bristol Myers Squibb, Daiichi, Hotspot Therapeutics, Marengo, AstraZeneca, Genentech/Roche, Immunocore, Seagen and Merck. A.S.B. reports serving on a speakers bureau for Genentech, BMS, Mirati, AstraZeneca, Regeneron and Merck and consulting for Pfizer and Abbvie, and is on a steering committee for Janssen. M.G. reports clinical trial support to their institution from Genentech/Roche, GSK, Abbvie, Merck Serono, Medimmune, Incyte, Pfizer, Amgen, Gilead Sciences, Zai Labs, Adanate, Fog Pharma, PEEL, Orionis, SQZ, YMABS, Iovance, Vincerx, Werewolf, Endocyte, Seattle Genetics, Plexxicon/Daiichi, Celldex, Tracon, Deciphera, Fujifilm, Minnemarita, Nektar, Novita, Biosplice, Corcept, Novartis, Toray, Genzada, Salarius, Agenus, Inhibrx, AADI, Revolution Medicine, Blueprint, Astellas, BioNTech, Helix, IgM Biosciences, ImmuneSensor, Bioeclipse, Bioline, Black Diamond, Codiak, Dracen, Elevation Oncology, Famewave, Forma Therapeutics, IntraImmun SG, Pionyr, Trishula, Tolero, Vedanta Biosciences, Coordination Therapeutics, Ideaya Biosciences, I-Mab, NiKang, Nimbus Therapeutics, OncoResponse, Riboscience, Rubius Therapeutics, Simcha Therapeutics, Siranomics, Synthorx and Theseus Pharmaceuticals; consulting fees from Pfizer, Imaging Endpoints and Curio; honoraria from Lisa Stearns Academy; a patent with Sphinx Health Solutions; and advisory boards for Daiichi, Qualigen, Springworks, Cardinal Healthcare, IQVIA and Medtronics. I.K. reports consulting fees from and serving in a speakers bureau for Delcath Inc., Immunocore Ltd and Pierre Fabre Inc; educational grants from BMS and Novartis; and travel grants from Delcath Inc, Genentech Inc, BMS and Merck Serono. G.A.F. reports serving on a data safety monitoring board for AstraZeneca and Hutchison Pharma and advisory boards for Bristol Myers Squibb and Merck. M. Schmidt reports personal fees from AstraZeneca, BioNTech, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pantarhei Bioscience, Pfizer, Pierre Fabre, Roche and SeaGen outside the submitted work; institutional research funding from AstraZeneca, BioNTech, Eisai, Genentech, German Breast Group, Novartis, Palleos, Pantarhei Bioscience, Pierre Fabre and SeaGen; and a patent for EP 2390370 B1 filed for EP 2951317 B1 filed. M. Schuler received consulting fees from Amgen, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, Takeda and Tacalyx; honoraria from Amgen, Bristol Myers Squibb, Janssen, MSD, Novartis, Roche and Sanofi; and research funding to their institution from AstraZeneca, Bristol Myers Squibb and Janssen. R.J.S. served as a consultant and in advisory boards for Marengo, Merck, Novartis, Pfizer and Replimune and has received research funding to their institution from Merck. H.B. reports research funding to their institution from AbbVie, Agios, ARMO Biosciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BeiGene, BioAtla, BioMed Valley Discoveries, BioTheryX, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, Celgene, CicloMed, Coordination Pharmaceuticals, eFFECTOR Therapeutics, Lilly, EMD Serono, Roche/Genentech, GlaxoSmithKline, Gossamer Bio, Harpoon Therapeutics, Hengrui Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, Moderna, NGM Biopharmaceuticals, Novartis, Pfizer, Revolution Medicines, Ryvu Therapeutics, Foundation Medicine, SeaGen, Tesaro, TG Therapeutics, Verastem, Vertex Pharmaceuticals, Xbiotech and Zymeworks; consulting (uncompensated) for Bristol Myers Squibb, Novartis and TG Therapeutics; consulting (payments to institution) for AstraZeneca, GRAIL, Incyte, Roche and Vincerx Pharma; and stock ownership in HCA Healthcare. V.G. reports institutional support from Seagen Inc., SOTIO Biotech AG, Shattuck Labs, Inc., T-knife GmbH, F. Hoffmann-La Roche Ltd, Janssen Research & Development, LLC, Novartis, Affimed GmbH, Anaveon AG, BioNTech SE, BicycleTx Ltd, Epizyme, Inc., Regeneron Pharmaceuticals, Inc., Boehringer Ingelheim, Genmab, Pieris Pharmaceuticals, Inc., Celgene Corporation, Debiopharm International S.A., F-star Therapeutics Limited, ImCheck Therapeutics, Gilead Sciences, Inc and Sanofi-Aventis Recherche & Développement. B.S.H. reports a consulting and advisory role for AstraZeneca, Ideaya, Jazz Pharmaceuticals, Sorrento Therapeutics, Genentech-Roche, OncLive, Veeva, Athenium, Boxer Capital, SAI-Med and DAVA Oncology, and research funding to their institution from NexImmune, Genentech-Roche, Johnson & Johnson, BMS Foundation/VCU, Stand Up 2 Cancer, V Foundation and National Cancer Institute. P.A.O. reports consulting for Array, Bristol Myers Squibb, Celldex, CytomX, Evaxion, Genentech, Imunon, Merck, MyNEO, Neon Therapeutics, Novartis, Pfizer, Phio, TRM Oncology and Servier, and grant and research support to their institution from Agenus, AstraZeneca/MedImmune, Bristol Myers Squibb, Celldex, CytomX, Genentech, Merck, Neon Therapeutics, Novartis and Pfizer. G.J. received consulting fees from Novartis, Amgen, Roche, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, Abbvie, Seagen and Diaccurate; honoraria from Novartis, Amgen, Roche, Pfizer, Bristol Myers Squibb, Lilly, AstraZeneca, Daiichi Sankyo, Abbvie and Seagen; and travel support from Novartis, Roche, Pfizer, Lilly, Amgen, Bristol Myers Squibb and AstraZeneca; served on a board for Novartis, Roche, Pfizer, Lilly, Amgen, Bristol Myers Squibb and AstraZeneca; and received materials or services from Novartis, Roche, Lilly, Amgen, Bristol Myers Squibb and AstraZeneca. L.F. reports research support from Abbvie, Bavarian Nordic, Bristol Myers Squibb, Dendreon, Janssen, Merck and Roche/Genentech, and ownership interests in Actym, Atreca, Bioatla, Bolt, Immunogenesis, Nutcracker, RAPT, Scribe and Senti. N.S. provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte and Luszana, and received research grants from Abbvie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GlaxoSmithKline, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, Merck Sharp & Dohme, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho and Takeda (all outside the submitted work; payment was made to the Netherlands Cancer Institute). R.S.L. reports research and grant funding from Bristol Myers Squibb, Clinigen, Celldex, Incyte and Ubivac, and consulting and advisory roles for Bristol Myers Squibb, Merck, CDR-Life and Vir. A.R. was a consultant and advisor for AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Daichi Sankyo, Eli Lilly, GSK, MSD, Novartis, Pfizer and Roche/Genentech. S.A.L. reports funding to their institution from Roche/Genentech. R.A. is a primary investigator on S1933 (atezolizumab). I. Melero reports grants from Roche, BMS, Genmab and AstraZeneca, and was a consultant for Roche, BMS, Genmab, AstraZeneca, Biontech, Pharmamar, F-Star, Numab, Mestag, Curon and Bright Peaks. R.L.S., I.R., M.R.M., L. Muller, G.D.F., M.Y., L.K., V.J.P.L., A.R., M.D., T.Q., J. Zhu, J. Zhang, P.T., G.K.R., D.W.L., C.P., A.A.L., J.M.S., L.D. and I. Mellman are or were employees of Genentech, Inc. and are or were Roche stockholders. L. Muller is now an employee and shareholder of Gilead Sciences. G.D.F. reports stock ownership in CARGO Therapeutics. F.M., E.D., A.C., L. Manning, D.M., S.B., V.L., T.O., E.G., D.B., C.H., C.W., C.A., C.K., A.D.T., J.D., M.V., A.J., A.P., J.B., O.H., A.N.K., U.S. and Ö.T. are employees of BioNTech, a company developing immunotherapies against cancer and other diseases, and may hold securities in the company. U.S. and Ö.T. are management board members of BioNTech SE (Mainz, Germany). M.L., M.V., A.D.T., J.D., A.N.K., U.S. and Ö.T. are co-authors on various issued or pending patents that cover parts of this Article. D.R.C. served on advisory boards and consulted for Roche/Genentech. J.Y., S.R., L.D., D.J., K.M.W., A.S. and E.G. report no competing interests., (© 2025. Genentech, Inc. and the Author(s).)

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3 . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 + T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence., (© 2023. The Author(s).)

Background: BNT162b2, an mRNA vaccine against COVID-19, is being utilised worldwide, but immunogenicity and safety data in Chinese individuals are limited., Methods: This phase 2, randomised, double-blind, placebo-controlled trial included healthy or medically stable individuals aged 18-85 years enrolled at two clinical sites in China. Participants were stratified by age (≤55 or >55 years) and randomly assigned (3:1) by an independent randomisation professional to receive two doses of intramuscular BNT162b2 30 μg or placebo, administered 21 days apart. Study participants, study personnel, investigators, statisticians, and the sponsor's study management team were blinded to treatment assignment. Primary immunogenicity endpoints were the geometric mean titers (GMTs) of neutralising antibodies to live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seroconversion rates (SCR) 1 month after the second dose. Safety assessments included reactogenicity within 14 days of vaccination, adverse events (AEs), and clinical laboratory parameters. Randomised participants who received at least one dose were included in the efficacy and safety analyses on a complete case basis (incomplete/missing data not imputed). Results up to 6 months after the second dose are reported., Findings: Overall, 959 participants (all of Han ethnicity) who were recruited between December 5th, 2020 and January 9th, 2021 received at least one injection (BNT162b2, n =720; placebo, n =239). At 1 month after the second dose, the 50% neutralising antibody GMT was 294.4 (95% CI; 281.1-308.4) in the BNT162b2 group and 5.0 (95% CI; 5.0-5.0) in the placebo group. SCRs were 99.7% (95% CI; 99.0%-100.0%) and 0% (95% CI; 0.0%-1.5%), respectively ( p <0.0001 vs placebo). Although the GMT of neutralising antibodies in the BNT162b2 group was greatly reduced at 6 months after the second dose, the SCR still remained at 58.8%. BNT162b2-elicited sera neutralised SARS-CoV-2 variants of concern. T-cell responses were detected in 58/73 (79.5%) BNT162b2 recipients. Reactogenicity was mild or moderate in severity and resolved within a few days after onset. Unsolicited AEs were uncommon at 1 month following vaccine administration, and there were no vaccine-related serious AEs at 1 month or 6 months after the second dose., Interpretation: BNT162b2 vaccination induced a robust immune response with acceptable tolerability in Han Chinese adults. However, follow-up duration was relatively short and COVID-19 rates were not assessed. Safety data collection is continuing until 12 months after the second dose., Funding: BioNTech - sponsored the trial. Shanghai Fosun Pharmaceutical Development Inc. (Fosun Pharma) - conducted the trial, funded medical writing., Clinicaltrialsgov Registration Number: NCT04649021. Trial status: Completed., Competing Interests: U.S. and Ö.T. are management board members and employees at BioNTech SE. U.S. has a leadership role at TRON Translational Oncology Mainz. He got the lecture payment from Johannes Gutenberg University as professor in 2022 and was awarded with German Future Prize 2021. Ö.T. has leadership role at HI-TRON Mainz, and is a founding member of TRON Translational Oncology Mainz. Ö.T. also got the lecture payment from Johannes Gutenberg University as professor in 2022 and was awarded with German Future Prize 2021. E.D., M.K., E.L., U.L., A.M., O.O., S.S., and Y. Shishkova are employees at BioNTech SE. M.B., S.H., and Z.K. are employees at BioNTech US. U.S., Ö.T., and A.M. are inventors on patents and patent applications related to RNA technology and COVID-19 vaccines. A.M., O.O., U.S., and Ö.T. hold securities from BioNTech SE. A.H., L.G., X.W., J.Q., W.W., and J. Zheng, are employees of Fosun Pharma. J.L., L.Z., R.T., H.Y., M.L., F.P., Z.W., X.G., Y.S., H.P., J. Zhu, Z.S., and F.Z. declare they have no conflicts of interests., (© 2022 The Authors.)

BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-19 1 . Here we extend a previous phase-I/II trial report 2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ + or IL-2 + CD8 + and CD4 + T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8 + T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8 + T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)