Interim analysis from a phase 2 randomized trial of EuCorVac-19: a recombinant protein SARS-CoV-2 RBD nanoliposome vaccine

Background Numerous vaccine strategies are being advanced to control SARS-CoV-2, the cause of the COVID-19 pandemic. EuCorVac-19 (ECV19) is a recombinant protein nanoparticle vaccine that displays the SARS-CoV-2 receptor-binding domain (RBD) on immunogenic nanoliposomes. Methods Initial study of a phase 2 randomized, observer-blind, placebo-controlled trial to assess the immunogenicity, safety, and tolerance of ECV19 was carried out between July and October 2021. Two hundred twenty-nine participants were enrolled at 5 hospital sites in South Korea. Healthy adults aged 19–75 without prior known exposure to COVID-19 were vaccinated intramuscularly on day 0 and day 21. Of the participants who received two vaccine doses according to protocol, 100 received high-dose ECV19 (20 μg RBD), 96 received low-dose ECV19 (10 μg RBD), and 27 received placebo. Local and systemic adverse events were monitored. Serum was assessed on days 0, 21, and 42 for immunogenicity analysis by ELISA and neutralizing antibody response by focus reduction neutralization test (FRNT). Results Low-grade injection site tenderness and pain were observed in most participants. Solicited systemic adverse events were less frequent, and mostly involved low-grade fatigue/malaise, myalgia, and headache. No clinical laboratory abnormalities were observed. Adverse events did not increase with the second injection and no serious adverse events were solicited by ECV19. On day 42, Spike IgG geometric mean ELISA titers were 0.8, 211, and 590 Spike binding antibody units (BAU/mL) for placebo, low-dose and high-dose ECV19, respectively (p < 0.001 between groups). Neutralizing antibodies levels of the low-dose and high-dose ECV19 groups had FRNT50 geometric mean values of 129 and 316, respectively. Boosting responses and dose responses were observed. Antibodies against the RBD correlated with antibodies against the Spike and with virus neutralization. Conclusions ECV19 was generally well-tolerated and induced antibodies in a dose-dependent manner that neutralized SARS-CoV-2. The unique liposome display approach of ECV19, which lacks any immunogenic protein components besides the antigen itself, coupled with the lack of increased adverse events during boosting suggest the vaccine platform may be amenable to multiple boosting regimes in the future. Taken together, these findings motivate further investigation of ECV19 in larger scale clinical testing that is underway. Trial registration The trial was registered at ClinicalTrials.gov as # NCT04783311. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-022-02661-1.


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Evidence or history of serious acute, chronic, or progressive disease (e.g., cancer, diabetes, chronic pulmonary disease, acquired immune deficiency syndrome(AIDS), blood dyscrasias, or immune system, urinary system, mental, musculoskeletal system, cardiovascular system, respiratory system, endocrine, nervous system, hepatobiliary system, or renal disorders, etc.) which, in the opinion of the Investigator, makes the individual ineligible for the study.

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Positive serum tests during screening (type B hepatitis, human immunodeficiency virus [HIV], type C hepatitis).
14 History of treatment with antipsychotics or opioid analgesic dependence within 6 months prior to IP dosing.

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History of severe allergic reactions (e.g., anaphylaxis, Guillain-Barré Syndrome) or severe hypersensitivity reactions to the IP or any of its components.

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History of therapy that might affect immunity: treatment with immunosuppressants or immune modifying drugs, anticancer therapy, or radiotherapy within 3 months prior to screening.

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History of systemic steroids (prednisone ≥10mg/day for ＞14 consecutive days) within 3 months prior to screening. Topical, inhaled, and intranasal corticosteroids are allowed regardless of dose.

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Past treatment within 3 months prior to screening, or planned treatment during the study period, with immunoglobulin or blood derivatives.

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Individual with thrombocytopenia or other coagulation disorders for whom intramuscular (IM) injections are contraindicated or individual who is on anticoagulant therapy.* * Anticoagulant therapy: continuous use of anticoagulants such as coumarin/warfarin or new oral anticoagulants/antiplatelets. 20 History of excessive alcohol consumption or drug addiction.

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Women of childbearing potential who do not agree to use a medically accepted contraception* or to be heterosexually inactive for up to 60 days after the last dose of IP * Hormonal contraceptive, intrauterine device (IUD) or intrauterine system (IUS), tubal ligation, double-blocking method (condom for male and female, cervical cap or diaphragm, complex method such as contraceptive sponge), single-blocking method using spermicide Pregnant or lactating women

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Treatment with other IPs within 6 months prior to participation in this study.

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The Investigator who is directly related to this study or sub-Investigator/study coordinator who is supervised by the Investigator or their family member.

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Other reasons including medical reasons based on which the individual is considered to be ineligible for this study in the opinion of the Investigator. have not yet been completed and are not included in this report. b Clinical laboratory tests included hematology (RBC, hemoglobin, hematocrit, platelets count, WBC and WBC differential count), blood chemistry (glucose, BUN, creatinine, uric acid, total protein, total bilirubin, albumin, ALP, ALT, AST, γ-GT, total cholesterol, Ca, Na, P, Cl and K), urinalysis (albumin, glucose, WBC, ketone and RBC), blood coagulation (PT and aPTT), and virus test (HBs Ag, HIV Ag/Ab and HCV Ab). The blood coagulation and virus tests were performed only at Visit 1.    Figure 4 were replotted by age (A) or sex (B). Indicated ****, ** and * correspond to P values of < 0.0001, <0.01 and < 0.05, respectively, based on Mann-Whitney test.

Figure S5: EVC19 induces a higher ratio of anti-RBD to anti-S antibodies, compared to JnJ and
Pfizer sera. The anti-RBD and anti-S antibody levels of post-immune ECV19 (red, both high and lowdose groups, n=38), Pfizer (blue, n=15), JnJ (yellow, n=14) were plotted with the best-fit lines ECV19, each of three data set fits linear regressions well (R 2 > 0.95). Figure S6: Antigen specific T cell response. The T cell immune response index (spot forming counts per 10 5 cells) in peripheral blood cells was analyzed by IFN-γ or IL-4 ELISpot. A subset of participants was assessed for this exploratory analysis (n=7 in the placebo, n=17 in low-dose ECV19, and n=21 in high-dose ECV19). Lines show median and P < 0.5 (*), based on Kruskal-Wallis and Dunn's test .  Mary's Hospital (n=20, one sample was not tested due to the limitation of available) were diluted to 2 anti-RBD BAU/mL total antibody, then IgG subclass responses were determined using subclass-specific secondary antibodies. Individual (dot) and median (bar) values are shown.  Figure S9: Impact of ECV19 on variants of concern. 20 high-dose ECV19 post-immune sera samples were tested by MNA. A) Correlation of FRNT and MNA values. Pearson correlation P value is shown. B) Neutralization of indicated strains by ECV19 post-immune sera. NS = not significant; ****, P<0.0001; by Kruskal-Wallis test followed by Dunn's multiple comparison test.