ABSTRACT
Background. DNA vaccines are safe, tolerable, elicit humoral and cellular responses, allow for repeated dosing over time, are thermostable at room temperature, and are easy to manufacture. We present a compilation of Phase 1 and Phase 2 data of Inovio's US COVID-19 DNA Vaccine (INO-4800) targeting the full-length Spike antigen of SARS-CoV-2. A South Korean Phase 2 study is ongoing. Methods. Participants in the open-label Phase 1 trial received 0.5 mg, 1.0 mg or 2.0 mg intradermally (ID) followed by electroporation (EP) at Days 0 and 28. An optional booster dose was administered >6 months post-dose 2. The Phase 2 further compared the 1.0 mg and 2.0 mg doses against placebo in a total of 401 participants randomized at a 3:3:1:1 ratio. ClinicalTrials.gov identifiers: NCT04336410 and NCT04642638 Results. The majority of adverse events (AEs) related to INO-4800 across both trials were mild in severity and did not increase in frequency with age and subsequent doses. In Phase 1, 78% (14/18) and 84% (16/19) of subjects generated neutralizing antibody responses with geometric mean titers (GMTs) of 17.4 (95%CI 8.3, 36.5) and 62.3 (95% CI 36.4, 106.7) in the 1.0 and 2.0 groups, respectively (Figure 1). By week 8, 74% (14/19) and 100% (19/19) subjects generated T cell responses by Th1- associated IFNγ ELISPOT assay . Following a booster dose, neutralizing GMTs rose to 82.2 (95% CI 38.2, 176.9) and 124.7 (95% CI 62.8, 247.7) in the 1.0 mg and 2.0 mg groups, respectively, demonstrating the ability of INO-4800 to boost (Figure 2). In Phase 2, neutralizing antibody responses demonstrated GMTs of 93.6 (95%CI 77.3, 113.4) in the 1.0 mg dose group and 150.6 (95%CI 123.8, 183.1) in the 2.0 mg dose group (Figure 3). Conclusion. INO-4800 appears safe and tolerable as a primary series and as a booster with the induction of both humoral and cellular immune responses. In addition to eliciting neutralizing antibodies, INO-4800 also induced T cell immune responses as demonstrated by IFNγ ELISpot. Finally, as a homologous booster, INO-4800, when administered 6-10.5 months following the primary series, resulted in an increased immune response without increase in reactogenicity. The 2.0 mg dose was selected for Phase 3 evaluation.
ABSTRACT
Background. Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with increased transmissibility, disease severity, and resistance to neutralization by current vaccines under emergency use authorization (EUA). Here we assessed cross-immune responses of INO-4800 vaccinated subjects against SARS-CoV-2 VOCs. Methods. We used a SARS-CoV-2 IgG ELISA and a pseudo neutralization assay to assess humoral responses, and an IFNγ ELISpot to measure cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. Results. IgG binding titers were not impacted between wild-type (WT) and B.1.1.7 or B.1.351 variants. An average 1.9-fold reduction was observed for the P.1 variant in subjects tested at week 8 after receiving two doses of INO-4800 (Figure 1a). We performed a SARS-CoV-2 pseudovirus neutralization assay using sera collected from 13 subjects two weeks after administration of a third dose of either 0.5 mg, 1 mg, or 2 mg of INO-4800. Neutralization was detected against WT and the emerging variants in all samples tested. The mean ID50 titers for the WT, B.1.1.7, B.1.351 and P.1. were 643 (range: 70-729), 295 (range: 46-886), 105 (range: 25-309), and 664 (range: 25-2087), respectively. Compared to WT, there was a 2.1 and 6.9-fold reduction for B.1.1.7 and B.1.351, respectively, while there was no difference between WT and the P.1 variant (Figure 1b). Next, we compared cellular immune responses to WT and SARS-CoV-2 Spike variants elicited by INO-4800 vaccination. We observed similar cellular responses to WT (median = 82.2 IQR = 58.9-205.3), B.1.1.7 (79.4, IQR = 38.9- 179.7), B.1.351 (80, IQR = 40.0-208.6) and P.1 (78.3, IQR = 53.1-177.8) Spike peptides (Figure 2). Conclusion. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested.
ABSTRACT
Background: Novel coronaviruses (CoV) caused 3 global outbreaks over the past 2 decades: SARS-CoV (2002), MERS-CoV (2012), and 2019-nCoV in Wuhan, China. Each caused pneumonia with mortality of 10%, 35% and 2%, respectively (2019-nCoV estimated). GLS-5300 DNA vaccine targeting MERS-CoV Spike (S) was first to enter clinical trial, was safe and immunogenic (Lancet ID;2019). In Phase I, a 3 dose series at Day0, 4 and 12 weeks of GLS-5300 at either 0.67, 2 or 6mg was given IM followed by electroporation (EP, IM+EP) with CELLECTRA-5P device. GLS-5300 induced antibodies (Abs) in 94%, Tcell response in 76%, and neutralizing Abs in 50% of participants. No dose response was observed. GLS-5300 response was similar to those recovered from natural MERS-CoV infection. The absence of dose response and prior experience showing benefits of ID+EP vs IM+EP (JID;2019) led us to design this trial of lower ID dosing with an arm for a 2-dose regimen. We report results from MERS-002, the ongoing Phase I/IIa study of GLS-5300. Methods: MERS-002 is an open label, dose ranging, phase I/IIa study of GLS-5300. Participants were enrolled at 2 Korean sites into 3 groups receiving GLS-5300 ID+EP with the CELLECTRA-3P device: Group 1 received three 0.3mg doses at Day0 and weeks 4 and 12;Group 2 received three 0.6mg doses at Day0 and weeks 4 and 12;Group 3 received two 0.6mg doses at Day0 and week 8. Safety and tolerability of GLS-5300 was evaluated at each visit. Samples were collected at baseline, before each dose, and at both 2 and 4 weeks post dose 2 and post dose 3. Study data through 4 weeks after the primary series for a subset of immunoassays were included here. Findings: GLS-5300 given ID+EP was well-tolerated with no vaccine-associated SAEs. Preliminary results were available for: full length S (flS) ELISA, EMC2012-Vero neutralization (MERS-neut) and MERS-CoV S IFNg ELISPOT. GLS-5300 at 0.6mg induced MERS-CoV-specific Abs by flS ELISA and MERS-neut in 74% and 48%, respectively, after 1 dose. After the 2 or 3 dose vaccine series at 0.6mg per dose, flS ELISA response was seen in 100% and 92% of participants, respectively. MERS-neut response was 92% in both 2 and 3 dose 0.6mg groups. Antibody responses and rates were higher during and after primary series in 0.6mg group regardless of regimen than 0.3mg per dose. GLS-5300 induced Tcell responses via MERS-CoV IFNg ELISPOT in 60% and 84% receiving 0.6mg after the 2 or 3 dose series, respectively. Compared to 0.67mg of GLS-5300 given IM+EP in the first trial, 0.6mg of GLS-5300 given ID+EP in MERS-002, binding Abs appeared sooner and neutralizing Abs were observed in a higher fraction of participants (92% vs 50%) while Tcell reactivity was similar between vaccination schema. Conclusions: GLS-5300 was well tolerated with no vaccine-associated SAEs. Like prior studies, DNA vaccines given by ID+EP had fewer injection-related AEs relative to IM+EP. In MERS-002, 0.6mg of GLS-5300 in a 2-dose regimen spanning 8 weeks had similar reactivity and rate to the longer 3-dose regimen. GLS-5300 was safe and immunogenic when given IM+EP and, similarly, when given ID+EP in both 2- and 3-dose regimens in this ongoing MERS-002 Phase I/IIa trial. A Phase II clinical evaluation of the use of GLS-5300 to prevent MERS-CoV infection in endemic regions is planned.