An mRNA Vaccine against SARS-CoV-2 — Preliminary Report

Abstract

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. Methods We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 μg, 100 μg, or 250 μg. There were 15 participants in each dose group. Results After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti–S-2P antibody geometric mean titer [GMT], 40,227 in the 25-μg group, 109,209 in the 100-μg group, and 213,526 in the 250-μg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-μg dose group reported one or more severe adverse events. Conclusions The mRNA-1273 vaccine induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461 ).

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment immunogen

“…For the present mRBD formulation both the IC 50 values in the ACE2 competition assay and the viral neutralization titers were about 2% of the corresponding ELISA endpoint titers, suggesting that a significant fraction of the elicited antibodies are neutralizing. This is in contrast to results with spike ectodomain immunogens reported in the recent Moderna vaccine trial where neutralization titers were less than 0.1% of the endpoint ELISA titers 37 . The mRBD glycan engineered monomer also induced considerably higher neutralization titers compared to another longer RBD monomer that did not elicit detectable NAbs in most of the immunized animals after two immunizations in a recently reported mouse immunization study 43 .…”

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

“…Effect of spike mutation D614G on neutralization susceptibility. All of the COVID-19 vaccines currently in clinical trials are based on the original D614 spike sequence 19,20 . An important question is whether substitution D614G could reduce vaccine e cacy, assuming G614 virus continues to circulate.…”

TMPRSS2, a SARS-CoV-2 Internalization Protease is Downregulated in Head and Neck Cancer Patients.

“…It is particularly noteworthy to mention that part of the most signi cantly predicted pathways targeted by the six microRNAs, were related to respiratory virus infections (e.g., In uenza A) and other viral infections (e.g., Herpes Simplex). The observed microRNA-induced modulation of TMPRSS2 provides new insights for potential assessment of agents capable of regulating the microRNA expression and induces TMPRSS2 downregulation, as SARS-CoV-2 infection prevention strategy [33,34].…”