Associations between vaccine breakthrough cases and infection by SARS coronavirus 2 (SARS-CoV-2) variants have remained largely unexplored. Here we analyzed SARS-CoV-2 whole-genome sequences and viral loads from 1,373 persons with COVID-19 from the San Francisco Bay Area from February 1 to June 30, 2021, of which 125 (9.1%) were vaccine breakthrough infections. Fully vaccinated were more likely than unvaccinated persons to be infected by variants carrying mutations associated with decreased antibody neutralization (L452R, L452Q, E484K, and/or F490S) (78% versus 48%, p = 1.96e-08), but not by those associated with increased infectivity (L452R and/or N501Y) (85% versus 77%, p = 0.092). Differences in viral loads were non-significant between unvaccinated and fully vaccinated persons overall (p = 0.99) and according to lineage (p = 0.09 – 0.78). Viral loads were significantly higher in symptomatic as compared to asymptomatic vaccine breakthrough cases (p < 0.0001), and symptomatic vaccine breakthrough infections had similar viral loads to unvaccinated infections (p = 0.64). In 5 cases with available longitudinal samples for serologic analyses, vaccine breakthrough infections were found to be associated with low or undetectable neutralizing antibody levels attributable to immunocompromised state or infection by an antibody-resistant lineage. These findings suggest that vaccine breakthrough cases are preferentially caused by circulating antibody-resistant SARS-CoV-2 variants, and that symptomatic breakthrough infections may potentially transmit COVID-19 as efficiently as unvaccinated infections, regardless of the infecting lineage. ### Competing Interest Statement C.Y.C. is the director of the UCSF-Abbott Viral Diagnostics and Discovery Center and receives research support from Abbott Laboratories, Inc. E.F. and J.H.,Jr. are employees and shareholders of Abbott Laboratories. E.T., A.Z., and S.T. are employees of Color Genomics. The other authors declare no competing interests. ### Funding Statement This work has been funded by US CDC Epidemiology and Laboratory Capacity (ELC) for Infectious Diseases Grant 6 NU50CK000539 to the California Department of Public Health (M-K.M., C.H., D.A.W.), the Innovative Genomics Institute (IGI) at UC Berkeley and UC San Francisco (C.Y.C.), National Institutes of Health grant R33AI129455 (C.Y.C.), US Centers for Disease Control and Prevention contract 75D30121C10991 (C.Y.C.), and Heluna Health/California Department of Public Health contract 5NU50CK000539‐01‐12 (C.Y.C.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Remnant nasopharyngeal and/or oropharyngeal (NP/OP) samples and plasma samples from laboratory confirmed SARS-CoV-2 positive patients were retrieved from the UCSF Clinical Laboratories and stored in a biorepository until processed. Remnant samples were biobanked and retrospective medical chart review for relevant clinical and demographic metadata were performed under a waiver of consent and according to protocols approved by the UCSF Institutional Review Board (protocol number 10-01116, 11-05519). De-identified samples from community COVID-19 testing were obtained from Color Genomics Laboratory as part of a research collaboration. Vaccine breakthrough data corresponding to the de-identified samples from Color Genomics were obtained from the San Francisco Department of Public Health. Approval for sequencing and analysis of these de-identified samples and metadata was obtained from the UCSF Institutional Review Board (protocol number 11-05519). All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data Availability Assembled SARS-CoV-2 genomes in this study were uploaded to GISAID (accession numbers in Supplementary Table S2) and can be visualized in NextStrain. Viral genomes were also submitted to the National Center for Biotechnology Information (NCBI) GenBank database (accession numbers pending). Raw sequence data were submitted to the Sequence Read Archive (SRA) database. (BioProject accession number PRJNA722044 and umbrella BioProject accession number PRJNA171119). Code Availability FASTA files and scripting code for data analyses are available in a Zenodo data repository (https://doi.org/10.5281/zenodo.5207242).