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• Heterologous mRNA boost following GLS-5310 DNA vaccination was well tolerated. • Neutralizing antibody responses were enhanced 110 fold to GMT of 1244.8. • Binding antibody responses were enhanced 1,187-fold to GMT of 405,920. • Boosted antibody responses similar to other vaccine combinations. • Boosted T cell responses were many-fold higher than other vaccine combinations. Heterologous boost regimens are being increasingly considered against SARS-CoV-2. We report results for the 32 of 45 participants in the Phase 1 CoV2-001 clinical trial (Kim et al., Int J Iinfect Dis 2023, 128:112–120) who elected to receive an EUA-approved SARS-CoV-2 mRNA vaccine 6 to 8 months following a two-dose primary vaccination with the GLS-5310 bi-cistronic DNA vaccine given intradermally and followed by application of suction using the GeneDerm device. Receipt of EUA-approved mRNA vaccines after GLS-5310 vaccination was well-tolerated, with no reported adverse events. Immune responses were enhanced such that binding antibody titers, neutralizing antibody titers, and T-cell responses increased 1,187-fold, 110-fold, and 2.9-fold, respectively. This paper is the first description of the immune responses following heterologous vaccination with a DNA primary series and mRNA boost. [ABSTRACT FROM AUTHOR]

• This study reports the safety and immunogenicity of the GLS-5310 DNA vaccine through 48 weeks. • First clinical application of the GeneDerm suction device for DNA vaccine delivery. • GLS-5310 was well tolerated and without vaccine-associated severe adverse effects. • T cell responses of ∼1200 site forming units/106 peripheral blood mononuclear cells were maintained through 48 weeks. • T cell responses were many-fold higher than all other vaccine platforms. • Antibody responses were induced in 95.5% and maintained through 48 weeks. The CoV2-001 phase I randomized trial evaluated the safety and immunogenicity of the GLS-5310 bi-cistronic DNA vaccine through 48 weeks of follow-up. A total of 45 vaccine-naïve participants were recruited between December 31, 2020, and March 30, 2021. GLS-5310, encoding for the SARS-CoV-2 spike and open reading frame 3a (ORF3a) proteins, was administered intradermally at 0.6 mg or 1.2 mg per dose, followed by application of the GeneDerm suction device as part of a two-dose regimen spaced either 8 or 12 weeks between vaccinations. GLS-5310 was well tolerated with no serious adverse events reported. Antibody and T cell responses were dose-independent. Anti-spike antibodies were induced in 95.5% of participants with an average geometric mean titer of ∼480 four weeks after vaccination and declined minimally through 48 weeks. Neutralizing antibodies were induced in 55.5% of participants with post-vaccination geometric mean titer of 28.4. T cell responses were induced in 97.8% of participants, averaging 716 site forming units/106 cells four weeks after vaccination, increasing to 1248 at week 24, and remaining greater than 1000 through 48 weeks. GLS-5310 administered with the GeneDerm suction device was well tolerated and induced high levels of binding antibodies and T-cell responses. Antibody responses were similar to other DNA vaccines, whereas T cell responses were many-fold greater than DNA and non-DNA vaccines. [ABSTRACT FROM AUTHOR]