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Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates


Trial objectives, participants and expatriates

We assessed the safety and immunity of the three dose levels of Bnt162b1 and Bnt162b2. Healthy adults 1 Healthy to 55 years of age or 65 to 5 years of age were eligible to participate. The major exclusion criteria were known infections with human immunodeficiency virus, hepatitis C virus or hepatitis B virus; An immunocompromised condition; History of autoimmune disease; Previous clinical or microbiological diagnosis of Kovid-19; Receipt of drugs designed to stop Kovid-19; Any previous coronavirus vaccination; SARS-CoV-2 tested positive for IgM or IgG at the screening visit; And positive nasal-swab results on the SARS-CoV-2 nucleic acid amplification test within 24 hours prior to receipt of the trial vaccine or placebo.

BioNTech was the regulatory sponsor of the trial. Pfizer was responsible for Pfizer design; For the collection, analysis and interpretation of data; And for the writing of the report. The corresponding author had full access to all of the test data and had final responsibility for the decision to submit the manuscript for publication. All test data were available to all authors.

Test process

Using an interactive web-based response technology system, we randomly assigned trial participants to groups defined according to vaccine levels, dose level, and age range. A group of participants aged 18 to 55 years and 65 to 85 years old had to receive doses of 10 μg, 20 μg, or 30 μg of BNT162b1 or 30Tg or BNT162b2 (or placebo) on a two-dose schedule; A group of participants aged 18 to 55 years were assigned to receive 100-μg doses of BNT162b1 or placebo. All participants were assigned to receive active vaccines (BNT162b1 or BNT162b2) or two 0.5-mL injections of placebo in Delto, administered 21 days apart.

The first five participants in each new dose level or age group (with a randomization ratio of 4: 1 for the active vaccine: placebo) were observed 4 hours after injection to identify immediate adverse events. All other participants were observed for 30 minutes. Blood samples were obtained for safety and immunogenicity assessments.

Security

Phase 1 of this trial consisted of local responses to primary endpoints (such as specific local reactions recorded and recorded in an electronic diary), systemic events, and use of antipyretic or pain medication within 7 days after receipt of the vaccine. Was. Placebo, as recorded and recorded in electronic diaries; Unwanted adverse events and serious adverse events (ie, those reported by participants, without electronic-diary indications), assessed from receipt of the first dose through 1 month and 6 months, respectively, after receipt of the second dose; Clinical laboratory abnormalities, assessed 1 day and 7 days after receipt of vaccine or placebo; And grading shifting in laboratory assessments between baseline and 1 day to 7 days after the first dose and between 2 days and 7 days after the second dose. Protocol-specified safety stopping rules were effective for all participants in Phase 1 of the trial. complete Draft a contract, Including the Statistical Analysis Plan, is available at NEJM.org with the full text of this article. An internal review committee and an external data and security monitoring committee reviewed all security data.

Immunogenicity

Immunogenicity Assessment (SARS-CoV-2 Serum Neutralization Assay and Receptor-Binding Domain [RBD]-Binding or S1-binding IgG direct luminex immunoassays) are conducted before the administration of the vaccine or placebo, 7 days and 21 days after dosing, and on days 7 (ie, day 28) and day 14 (ie, day 35) Had gone. ) After the second dose. The indifference assay, which generates virus-neutralization data as described previously from trials of BNT 162 candidates,2,5 A previously described strain of SARS-CoV-2 (USA_WA1 / 2020) was used that was generated by reverse genetics and engineered by insertion of an amnogreen gene into the open reading frame 7 of the viral genome.11,12 Fluorescent viral foci were reported as 50% neutralization titers and 90% neutralization titers as the precipitated reciprocal of dilution dilutions in 50% and 90% reduction, respectively. Any serologic value below the lower limit of quantitation was set to 0.5 times the lower limit of quantitation. The available serological results were included in the analysis.

Immunogenicity data from a human convocation serum panel were included as a benchmark. A total of 38 serum samples were obtained from donors aged 18 to 83 years (mean age, 42.5 years) who recovered from SARS-CoV-2 infection or Kovid-19; Samples were taken at least 14 days after the confirmation of the polymerase chain reaction and the resolution after the signal resolution. Geometric mean titers (GMTs) in the subgroups of donors were indifferent: 90 among 35 donors with symptomatic infection; 156, between 3 donors with asymptomatic infection; And 618, in 1 donor, who was hospitalized. Each serum sample in the panel was from a different donor. Thus, most serum samples were obtained from individuals with moderate Kovid-19 who were not hospitalized. Serum samples were obtained from Sanguine Biosciences, MT Group and Pfizer Occupational Health and Wellness.

Statistical analysis

We report descriptive results of safety and immunogenicity analysis, and sample size was not based on statistical hypothesis testing. The results of the safety analysis are presented as counts, percentages, and 95% confidence intervals for local reactions, systemic events, and any adverse events after administration of the vaccine or placebo by the respective Clopper-Pearson conditions. accordingly Medical Dictionary for Regulatory ActivitiesVersion 23.0 for each vaccine group. Summary statistics are provided for abnormal laboratory values ​​and grading shifts. Given the low number of participants in each group, the test was not conducted for formal statistical comparisons between dose levels or between age groups.

Immunogenicity analysis titers neutralizing SARS-CoV-2 serum, S1-binding IgG and RBD-binding IgG concentrations, GMT and geometric mean concentrations (GMC) were calculated with associated 95% confidence intervals. GMT and GMC were calculated as means of assay results after logarithmic transformation; We then interpreted the mean to express the results on the original scale. Two-way 95% confidence intervals were obtained by performing logarithmic changes of titers or concentrations, calculating 95% confidence intervals with reference to the students’ t-distribution, and then reflecting the limits of confidence intervals.



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