M.S. assisted with TCR cloning. Immunological analysis by IFNγ ELISpot was performed by E.D. (BioNTech). L.A.R., Z.S., B.D.G. and V.P.B. developed CloneTrack. Z.S. performed all computational analyses using CloneTrack. M.Ł., Z.S., L.A.R., B.D.G. and V.P.B. conceived and developed the neoantigen quality model. Z.S., J.L., A.C. and M.Ł. performed the clonality reconstructions. Z.S. performed the neoantigen quality assessments. Exome sequencing, RNA sequencing, identification of neoantigens, neoantigen selection, individualized mRNA vaccine design and manufacturing were performed by the BioNTech team coordinated by F.M. Z.S. and N.Ceglia performed the single-cell analyses. M.G. provided statistical oversight. The MSK team collected, analysed and interpreted all data, with critical feedback from all authors. L.A.R., Z.S., E.P., E.D., F.M., I.R., M.Y., T.M., J.D.W., I.M., U.S., Ö.T., B.D.G. and V.P.B. participated in critical discussions and manuscript writing. The funders had no role in the conduct of the trial or end point analyses. The authors assume responsibility for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and statistical analysis plan. Competing interests L.A.R. is an inventor of a patent related to oncolytic viral therapy (US20170051022A1). L.A.R., Z.S., B.D.G. and V.P.B. are inventors on patent applications related to work on antigen cross-reactivity (PCT/US2023/011643) and tracking vaccine-expanded T cell clones. M.Ł., B.D.G. and V.P.B. are inventors on a patent application on neoantigen quality modelling (63/303,500). 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 and Rome Therapeutics of which he is a co-founder. R.K.D. received one-time consulting fees from GE Healthcare and Bayer Healthcare. A.S.E. received royalties from Up-To-Date. A.M.V. discloses the following relationships (provision of services, uncompensated): Bristol-Myers Squibb, GlaxoSmithKline, Lilly Oncology, OBI Pharma, and Silenseed. M.S. has collaborative research agreements with Atara Biotherapeutics, Fate Therapeutics, Mnemo Therapeutics, and Takeda Pharmaceuticals. A.C.W. is a consultant for Histosonics and Biosapien; received honorarium from Medtronic and AstraZeneca; and received travel support from Intuitive Surgical. T.P.K. received a one-time consulting fee from Olympus Surgical. J.D. owns stock in Alnylam Pharmaceuticals, Arrowroot Acquisition, and Ionis Pharmaceuticals. W.P. receives grant and research support from Astellas, Merck, NIH/NCI, Parker Institute for Cancer Immunotherapy, and Break Through Cancer. E.M.O. receives grant and research support from Genentech/Roche, Celgene/ Bristol-Myers Squibb, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, and the NIH/NCI. T.M. is a co-founder and holds equity in IMVAQ Therapeutics; he is a consultant for Immunos Therapeutics, ImmunoGenesis and Pfizer; he has research support from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Peregrine Pharmaceuticals, Adaptive Biotechnologies, Leap Therapeutics and Aprea; he 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. V.P.B. has received honoraria for speaking engagements from Genentech, and research support from Bristol-Myers Squibb and Genentech. Ö.T. and U.S. are co-founders, management board members and employees at BioNTech. E.D. and F.M. are employees at BioNTech. I.R., M.Y. and I.M. are employees at Genentech. The other authors (K.C.S., C.O., N.P., E.P., J.L., N. Ceglia, P.G., A.C., R.Y., A.K.C., T.W., J.R., M.A., A.Z., Z.O., G.P., A. Dobrin, N. Cohen, L.T., O.B., M.G., S.K., P.M., E.W., R.S., A. Desai, M.I.D. and W.R.J.) declare no competing interests. Additional information Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41586-023-06063-y . Correspondence and requests for materials should be addressed to Benjamin D. Greenbaum or Vinod P. Balachandran. Peer review information Nature thanks Patrick Ott, Robert Vonderheide and Neeha Zaidi for their contribution to the peer review of this work.