ABSTRACT
Background. SARS-CoV-2 monoclonal antibodies (SMA) have demonstrated efficacy in treatment of early, mild to moderate COVID-19 in patients at high risk for progression to severe COVID-19. We created an SMA infusion clinic at a large, urban academic medical center using both internal and community-based referral mechanisms to promote the equitable distribution of treatment. Methods. Data were analyzed from clinic referrals from December 13, 2020 through April 20, 2021. Patient demographics, census-based area deprivation index (ADI) scores (scale of 1-10, with 1 representing least socioeconomic deprivation and 10 representing most), and relevant comorbidities were collected. Outcomes included days of symptoms until referral, patient receipt of SMA therapy after referral, adverse events, and ER visits and hospitalizations within 14 days of SMA administration. Association between demographic factors and relevant outcomes were determined using chi-square or Wilcoxon rank-sum tests as appropriate. Results. 47/433 (11%) referred patients were ineligible based on inclusion and exclusion criteria. Of eligible patients, 310/386 (80%) received treatment;patients who did not receive treatment either declined (93%), could not be contacted (5%), no-showed (1%), or were admitted for hypoxia (1%). Of treated patients, only 3 (1%) had adverse reactions. Within 14 days of SMA administration, 28 (9%) patients visited the ER or were admitted for COVID-19. Black patients had a longer median duration of symptoms prior to referral compared to White patients (5 vs. 3 days, p < 0.01) (Figure 1). White patients were more likely to receive SMA after referral compared to Black patients (88% vs. 64%, p < 0.01), as were patients with ADI score 1-5 compared to those with ADI score 6-10 (88% vs. 70%, p < 0.01) (Figures 2 and 3). Black patients who received SMA had a higher rate of ER visits or admissions than White patients, although the difference was not statistically significant (14% vs. 7%, p = 0.10). Conclusion. Rate of adverse reactions and COVID-related ER visits or admissions were low in patients who received SMA. Despite efforts to promote the equitable distribution of treatment through multiple referral mechanisms, racial and socioeconomic disparities still exist.
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.