SARS-CoV-2 DNA Vaccine INO-4800 Induces Durable Immune Responses Capable of Being Boosted in a Phase 1 Open-Label Trial

BackgroundAdditional SARS-CoV-2 vaccines that are safe and effective as primary vaccines and boosters remain urgently needed to combat the COVID-19 pandemic. We describe the safety and durability of the immune responses following two primary doses and a homologous booster dose of an investigational DNA vaccine (INO-4800) targeting the full-length spike antigen. MethodsThree dosage strengths of INO-4800 (0.5 mg, 1.0 mg, and 2.0 mg) were evaluated in 120 age-stratified healthy adults. Intradermal injection of INO-4800 followed by electroporation at 0 and 4 weeks preceded an optional booster 6-10.5 months after the second dose. ResultsINO-4800 appeared well tolerated, with no treatment-related serious adverse events. Most adverse events were mild and did not increase in frequency with age and subsequent dosing. A durable antibody response was observed 6 months following the second dose; a homologous booster dose significantly increased immune responses. Cytokine producing T cells and activated CD8+ T cells with lytic potential were significantly increased in the 2.0 mg dose group. ConclusionINO-4800 was well tolerated in a 2-dose primary series and as a homologous booster in all adults, including the elderly. These results support further development of INO-4800 for use as a primary vaccine and as a booster. Trial Registration: ClinicalTrials.gov NCT04336410 SummaryTwo-milligram dose of INO-4800, a DNA-based vaccine encoding the SARS-CoV-2 spike protein, appears safe and well-tolerated and elicits humoral and cell-mediated immunity persisting to 6 months after a second dose. A third dose 6-10.5 months later significantly boosts immune responses.

Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates

The enhanced transmissibility and immune evasion associated with emerging SARS-CoV-2 variants demands the development of next-generation vaccines capable of inducing superior protection amid a shifting pandemic landscape. Since a portion of the global population harbors some level of immunity from vaccines based on the original Wuhan-Hu-1 SARS-CoV-2 sequence or natural infection, an important question going forward is whether this immunity can be boosted by next-generation vaccines that target emerging variants while simultaneously maintaining long-term protection against existing strains. Here, we evaluated the immunogenicity of INO-4800, our synthetic DNA vaccine candidate for COVID-19 currently in clinical evaluation, and INO-4802, a next-generation DNA vaccine designed to broadly target emerging SARS-CoV-2 variants, as booster vaccines in nonhuman primates. Rhesus macaques primed over one year prior with the first-generation INO-4800 vaccine were boosted with either INO-4800 or INO-4802 in homologous or heterologous prime-boost regimens. Both boosting schedules led to an expansion of antibody responses which were characterized by improved neutralizing and ACE2 blocking activity across wild-type SARS-CoV-2 as well as multiple variants of concern. These data illustrate the durability of immunity following vaccination with INO-4800 and additionally support the use of either INO-4800 or INO-4802 in prime-boost regimens.

Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: a preliminary report of a randomized, blinded, placebo-controlled, Phase 2 clinical trial in adults at high risk of viral exposure

BackgroundVaccines against SARS-CoV-2 are still urgently needed as only 5% of the global population has been vaccinated. Here we report the safety and immunogenicity of a DNA vaccine (INO-4800) targeting the full-length Spike antigen of SARS-CoV-2 when given to adults at high-risk of exposure. MethodsINO-4800 was evaluated in 401 participants randomized at a 3:3:1:1 ratio to receive either INO-4800 (1 mg or 2 mg dose) or placebo (1 or 2 injections) intradermally (ID) followed by electroporation (EP) using CELLECTRA(R) 2000 at Days 0 and 28. ClinicalTrials.gov Identifier: NCT04642638 FindingsThe majority of adverse events (AEs) were of Grade 1 and 2 in severity and did not appear to increase in frequency with the second dose. The number of participants experiencing each of the most common AEs did not differ appreciably between the two dosing groups. The geometric mean fold rise (GMFR) of binding and neutralizing antibody levels were statistically significantly greater in the 2.0 mg dose group versus the 1.0 mg dose group. The T cell immune responses measured by the ELISpot assay were also higher in the 2.0 mg dose group compared to the 1.0 mg dose group. InterpretationINO-4800 at both the 1.0 mg and 2.0 mg doses when administered in a 2-dose regimen appeared to be safe and well-tolerated in all adult ages. However, the comparative immunogenicity analysis favored selection of INO-4800 2.0 mg dose for advancement into a Phase 3 efficacy evaluation. FundingThe trial was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, (JPEO-CBRND) in coordination with the Office of the Assistant Secretary of Defense for Health Affairs (OASD(HA)) and the Defense Health Agency. Research in contextINO-4800 is among several vaccines being tested against SARS-CoV-2, the virus that causes COVID-19 with the goal of inducing a protective immune response. The DNA vaccine, INO-4800, administered by ID injection followed by electroporation (EP) using the CELLECTRA(R) 2000 device, induces a balanced immune response that includes engagement of both T cells and B 1-5. Added value of this studyThis is the first report of a randomized, blinded, placebo-controlled clinical trial of INO-4800, a DNA vaccine targeting the SARS-CoV-2 Spike antigen delivered ID followed by EP, in adults at high risk of SARS-CoV-2 exposure.

Design and immunogenicity of a Pan-SARS-CoV-2 synthetic DNA vaccine

Here we have employed SynCon(R) design technology to construct a DNA vaccine expressing a pan-Spike immunogen (INO-4802) to induce broad immunity across SARS-CoV-2 variants of concern (VOC). Compared to WT and VOC-matched vaccines which showed reduced cross-neutralizing activity, INO-4802 induced potent neutralizing antibodies and T cell responses against WT as well as B.1.1.7, P.1, and B.1.351 VOCs in a murine model. In addition, a hamster challenge model demonstrated that INO-4802 conferred superior protection following intranasal B.1.351 challenge. Protection against weight loss associated with WT, B.1.1.7, P.1 and B.1.617.2 challenge was also demonstrated. Vaccinated hamsters showed enhanced humoral responses against VOC in a heterologous WT vaccine prime and INO-4802 boost setting. These results demonstrate the potential of the pan-SARS-CoV-2 vaccine, INO-4802 to induce cross-reactive immune responses against emerging VOC as either a standalone vaccine, or as a potential boost for individuals previously immunized with WT-matched vaccines.

INO-4800 DNA Vaccine Induces Neutralizing Antibodies and T cell Activity Against Global SARS-CoV-2 Variants

Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with broadened host specificity, pathogenicity, and immune evasion to vaccine induced immunity. Here we compared humoral and cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFN{gamma} T cell responses were fully maintained against all variants tested.

Intradermal-delivered DNA vaccine provides anamnestic protection in a rhesus macaque SARS-CoV-2 challenge model

Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health, social, and economic infrastructures. Here, we assess immunogenicity and anamnestic protective efficacy in rhesus macaques of the intradermal (ID)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800. INO-4800 is an ID-delivered DNA vaccine currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and neutralizing antibody responses against both the D614 and G614 SARS-CoV-2 spike proteins. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T and B cell responses. These responses were associated with lower viral loads in the lung and with faster nasal clearance of virus. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system which are likely important for providing durable protection against COVID-19 disease.