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
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Abstract
Background
Vaccines 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.
Methods
INO-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® 2000 at Days 0 and 28. ClinicalTrials.gov Identifier: NCT04642638
Findings
The 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.
Interpretation
INO-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.
Funding
The 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 context
INO-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 ® 2000 device, induces a balanced immune response that includes engagement of both T cells and B 1-5 .
Added value of this study
This 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.
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SciScore for 10.1101/2021.05.07.21256652: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The clinical protocol was approved by a central and site-specific institutional review board.
Consent: All participants provided written informed consent prior to enrollment.Sex as a biological variable Key exclusion criteria included the following: acute febrile illness with temperature higher than 100.4°F (38.0°C) or acute onset of upper or lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); positive serologic or molecular (reverse transcription polymerase chain reaction [RT-PCR]) test for SARS-CoV-2 at Screening; pregnant or breastfeeding, or intending to become pregnant or intending to father children within the projected duration of the trial starting … SciScore for 10.1101/2021.05.07.21256652: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The clinical protocol was approved by a central and site-specific institutional review board.
Consent: All participants provided written informed consent prior to enrollment.Sex as a biological variable Key exclusion criteria included the following: acute febrile illness with temperature higher than 100.4°F (38.0°C) or acute onset of upper or lower respiratory tract symptoms (e.g., cough, shortness of breath, sore throat); positive serologic or molecular (reverse transcription polymerase chain reaction [RT-PCR]) test for SARS-CoV-2 at Screening; pregnant or breastfeeding, or intending to become pregnant or intending to father children within the projected duration of the trial starting from the Screening visit until 3 months following the last dose; known history of uncontrolled HIV based on a CD4 count less than 200 cells/mm3 or a detectable viral load within the past 3 months; currently participating or has participated in a study with an investigational product within 30 days preceding Day 0; previous receipt of an investigational vaccine for prevention or treatment of COVID-19, MERS, or SARS (documented receipt of placebo in previous trial would be permissible for trial eligibility); respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease) requiring significant changes in therapy or hospitalization for worsening disease during the 6 weeks prior to enrollment; immunosuppression as a result of underlying illness or treatment; lack of acceptable sites for ID injection and EP. Randomization Study Design and Endpoints: The clinical trial is designed as a Phase 2/3, randomized, blinded, placebo-controlled, multi-center trial (NCT04642638) to evaluate the safety, immunogenicity, and efficacy of INO-4800 administered ID followed by electroporation (EP). Blinding Study Design and Endpoints: The clinical trial is designed as a Phase 2/3, randomized, blinded, placebo-controlled, multi-center trial (NCT04642638) to evaluate the safety, immunogenicity, and efficacy of INO-4800 administered ID followed by electroporation (EP). Power Analysis not detected. Table 2: Resources
Recombinant DNA Sentences Resources INO-4800 contains plasmid pGX9501 expressing a synthetic, full-length sequence of the SARS-CoV-2 Spike glycoprotein of the original Wuhan strain, created using Inovio’s proprietary in silico Gene Optimization Algorithm to enhance expression as previously described30. pGX9501suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:These results further suggest that in addition to being a primary vaccine candidate, INO-4800 could represent a safe booster vaccine without significant limitations such as anti-vector responses or dosing-incremented toxicities. We have observed directly in the Phase 1 trial participants who were boosted with a third dose of their INO-4800 vaccine between 6 and 10 months resulted in higher levels of humoral and cellular immune responses without increased levels of AEs (Manuscript in preparation). Given the uncertainty about the durability of the natural infection or vaccine induced responses against COVID-19 disease, vaccine boosting by a benign approach like INO-4800 may be an important way to maintain protection over subsequent epidemic waves of COVID-19. It is also possible that INO-4800 could serve as a useful booster shot for other S protein-targeted vaccine candidates with limitations in boosting ability, and this potential should be further investigated. One of the major areas of research for COVID-19 is the investigation of the impact of recently emerged major variants of concern - first detected in the United Kingdom (B.1.1.7), South Africa (B.1.351), and Brazil (P.1 ) - on the protective efficacy of vaccines recently approved for emergency use as well as those vaccines currently in development. Previous studies indicated that neutralization activity in vaccinees’ sera only showed a minor reduction for B.1.1.734, but neutralization was significantly decreased against...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04642638 Active, not recruiting Safety, Immunogenicity, and Efficacy of INO-4800 for COVID-1… NCT03721718 Completed Evaluate the Safety, Tolerability and Immunogenicity Study o… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a protocol registration statement.
Results from scite Reference Check: We found no unreliable references.
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