mRNA vaccine against SARS-CoV-2 – preliminary report

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Characteristics of participants in the mRNA-1273 trial at enrollment.

The 45 registered participants received their first vaccination between 16 March and 14 April 2020 (Figure S1). Three participants who did not receive the second vaccination, including one in the 25 μg group had urticaria in both legs, with onset 5 days after the first vaccination, and two (one in the 25 μg group and one in the 250 μg group) who missed the second vaccination window due to isolation Covid-19 suspected while test results, ultimately negative, are pending. Everyone continued to attend the scheduled court visits. The demographic characteristics of the participants are provided to enroll in Table 1.

Vaccine safety

No serious adverse events were observed, and no predetermined rules for discontinuation of trials were met. As noted above, one participant in the 25-mcg group was withdrawn due to an adverse event, transient urticaria, believed to be related to the first vaccination.

Systemic and local adverse events.

The severity of the adverse events required was categorized as mild, moderate, or severe (see Table S1).

After the first vaccination, required systemic adverse events were reported by 5 participants (33%) in the 25 μg group, 10 (67%) in the 100 μg group, and 8 (53%) in the 250 μg group; All were mild or moderate in severity (shape 1 and Table S2). Required systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25 μg group, all 15 in the 100 μg group, and all 14 in the 250 μg group, with 3 of these participants (21%) reporting One or more severe events.

None of the participants experienced a fever after the first vaccination. After the second vaccination, no participant in the 25 mcg group, 6 (40%) in the 100 mcg group, and 8 (57%) in the 250 mcg group reported fever; One of the events (maximum temperature, 39.6 °C) in the 250 μg group was classified as severe. (Additional details regarding adverse events for this participant are provided in the Supplementary Appendix.)

Local adverse events, when present, were approximately mild or moderate, and injection site pain was common. In both vaccinations, systemic and local adverse events that occurred in more than half of the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of clinical safety laboratory values ​​of grade 2 or higher and unwanted adverse events did not reveal any patterns of concern (Supplementary Appendix and Table S3).

Antibody-binding responses to SARS-CoV-2

Mean engineered humoral immunoassay responses to mRNA-1273 in participants and in convalescent serum samples. SARS-CoV-2 antibody responses and neutralization.

Shown is the geometric mean IgG enzyme-linked immunosorbent assay (ELISA) to S-2P (panel A) and receptor-binding domain (panel B), and the PsVNA ID50 Responses (panel C), live virus PRNT80 Responses (panel D). In panel A and panel B, the boxes and horizontal bars indicate the interquartile range (IQR) and mean area under the curve (AUC), respectively. Whisker end points are equal to maximum and minimum values ​​that are less than or greater than the mean ± 1.5 times the IQ. The convalescent serum panel includes samples from 41 participants. The red dots indicate the three samples also tested in the PRNT assay. The other 38 samples were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, the squares and horizontal bars indicate the IQR and median ID50, Straight. Whisker end points are equal to maximum and minimum values ​​that are less than or greater than the mean ± 1.5 times the IQ. In the convalescent serum panel, the red dots indicate the three samples that were also tested in the PRNT assay. The other 38 samples were used to calculate summary box plot statistics in the recovery panel. In panel D, the boxes and horizontal bars indicate the median IQR and PRNT80, Straight. Whisker end points are equal to maximum and minimum values ​​that are less than or greater than the mean ± 1.5 times the IQ. The three convalescent serum samples were also tested in ELISA and PsVNA assays. Due to the time-consuming nature of the PRNT assay, for this initial report, PRNT results were only available for the 25-mcg and 100-mcg dose groups.

The mean titer of S-2P-binding IgG antibodies (GMTs) increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 And the Figure 2a). Dose-dependent responses to the first and second vaccinations were evident. Antibody responses to the receptor-binding domain were similar in pattern and size (Figure 2b). For both tests, the mean volume of antibody responses after the first vaccination in the 100 μg and 250 μg dose groups was similar to the mean volume in convalescent serum samples, and in all dose groups the mean volume after the second vaccination was in the upper quartile of values ​​in Convalescent serum samples. S-2P ELISA GMTs at Day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] In the 25 mcg range, 782.719 [95% CI, 619,310 to 989,244] In the 100 mcg group and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250 µg group) in convalescent serum samples (142,140 [95% CI, 81,543 to 247,768]).

SARS-CoV-2 neutralization responses

No participant had detectable PsVNA responses prior to vaccination. After the first vaccination, PsVNA responses were detected in less than half of the participants, and a dose effect (50% inhibitory dilution) was observed. [ID50]: Figure 2cand figure S8 and Table 2; 80% dilution inhibitor [ID80]: Figure S2 and Table S6). However, after the second vaccination, PsVNA responses were determined in serum samples from all participants. The lowest responses were in the 25 mcg dose group, with a geometric mean identifier50 from 112.3 (95% CI, 71.2 to 177.1) at day 43; The higher responses in the 100 μg and 250 μg groups were similar in size (geometric mean identifier).50343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, on day 43). These responses were similar to the values ​​in the upper half of the distribution of values ​​for convalescent serum samples.

Prior to vaccination, no participant had 80% neutralization of live virus detectable at the highest tested serum concentration (1:8 dilution) in the PRNT assay. At day 43, neutralizing activity of the wild-type virus is able to reduce SARS-CoV-2 infection by 80% or more (PRNT).80) in all participants, with a geometric mean PRNT80 339.7 (95% CI, 184.0 to 627.1) responses in the 25 μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100 μg group (Figure 2d). Neutralize PRNT80 The average responses were generally at or above the values ​​of the three convalescent serum samples tested in this assay. Good agreement was observed within and between values ​​from the S-2P binding and receptor-binding domain assays and the neutralization activity measured by PsVNA and PRNT (Figures S3 to S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273.

SARS-CoV-2 T-Cell Responses

Doses of 25 μg and 100 μg elicited CD4 T cell responses (Figures S9 and S10) that were strongly biased upon stimulation by S-specific peptide pools toward the expression of Th1 cytokines (tumor necrosis factor α > interleukin 2 > interferon γ), with the reduction Lowest cellular expression of type 2 (Th2) helper T cells (interleukin-4 and interleukin-13). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100 μg dose group (Fig.

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