Overall:
- No serious adverse events were noted
- No trial halting rules were met
- One participant in the 25-μg group was withdrawn because of urticaria, judged to - be related to the first vaccination
- Three participants did not receive the second vaccination

After the First Vaccination:
- 5 participants reported solicited systemic adverse events in the 25-μg group
- 10 participants reported solicited systemic adverse events in the 100-μg group
- 8 participants reported solicited systemic adverse events in the 250-μg group
- All were mild or moderate in severity

After the Second Vaccination 
- 7 of 13 participants reported solicited systemic adverse events in the 25-μg group
- All 15 participants reported solicited systemic adverse events in the 100-μg group
- All 14 participants reported solicited systemic adverse events in the 250-μg group, with 3 of those participants reporting one or more severe events


mRNA-1273 Phase I Results - Vaccine Safety

The team conducted a phase 1, dose-escalation, open-label trial with 45 healthy adults, 18 to 55 years of age. Each adult received two vaccinations, 28 days apart, with mRNA-1273 in different dosages: 25 μg, 100 μg and 250 μg. There were 15 participants in each dose group. 


The vaccine was administered as a 0.5-ml injection in the deltoid muscle on days 1 and 29 and follow up visits were scheduled after each vaccination. Normal saline was used as a diluent to prepare the doses administered.


The dose-escalation plan specified four sentinel participants to be enrolled in both the 25-μg group and the 100-μg group, followed by full enrollment of those two dose groups. Sentinel participants are dosed in advance of the full study and are monitored to ensure no adverse effects take place. If no halting rules were met after all participants in those two dose groups completed day 8, four sentinel participants in the 250-μg group were enrolled, followed by the remainder of that dose group.


Participants recorded reactions using a memory aid for 7 days after each vaccination and adverse events were graded according to a standard toxicity grading scale.

mRNA-1273 Phase I Trial and Participant Details

ANTIBODY RESPONSES
- Antibody binding increased rapidly after first vaccination, and dose-dependent responses were evident

NEUTRALIZATION RESPONSES
- PsVNA (lentivirus reporter single-round-of-infection neutralization assay) was used to determine the presence of vaccine-induced neutralizing activity. This procedure basically identifies the presence of neutralizing antibodies.
- After the first vaccination, PsVNA was detected in less than half of the participants. However, after the second vaccination PsVNA was identified in all participants, with the lowest responses being from the 25-μg group, and the higher responses in the 100-μg and 250-μg groups. Both the 100-μg and 250-μg groups were similar in magnitude.
- Live wild-type SARS-CoV-2 PRNT (plaque-reduction neutralization testing) was also used to identify the efficiency of the neutralizing antibodies to prevent viral activity. At day 43, “wild-type virus–neutralizing activity was capable of reducing SARS-CoV-2 infectivity by 80% or more” and before the vaccination, “no participant had 80% detectable live-virus neutralization” even at the highest concentration tested.

T-CELL RESPONSES
- The 25-ug and 100-ug doses elicited CD4 T-cell responses as expected after the first vaccination.
- CD8 T-cell responses were detected at low levels after the second vaccination in the 100-ug dose group.


mRNA-1273 Phase I Results - Vaccine Effectiveness

TIMELINE AND EFFICIENCY
- The mass production of this vaccine is much easier than it has been for vaccines in the past
i Manufacture and delivery of clinical trials material was completed in 45 days, and the first trial vaccines were given 66 days after the genomic sequence of the virus was released

SAFETY PROFILE
- The two-dose vaccine series was completed without serious toxicity, and adverse effects were mild or moderate for the most part.
- Local injection-site reactions were mild, similar to other mRNA vaccines that were investigated.

PERFORMANCE OF THE VACCINE
- The mRNA-1273 vaccine was immunogenic, meaning it was successful in inducing robust binding antibody responses.
- Seroconversion was rapid for binding antibodies, and was seen within 2 weeks after the first vaccination.
- Pseudovirus neutralizing activity was low before the second vaccination -> supports the need for a second vaccination
- Measurements of serum neutralizing activity were similar to mechanisms seen in protecting for other respiratory viruses, like influenza.
- In phase 3, efficacy trials will allow assessment of the correlation of vaccine-induced immune responses with clinical protection.
- Durability of immune response will be tested in 1 year.
- The speed and efficiency of mRNA-1273 probably comes from an innovative antigen design, coupled with a potent lipid-nanoparticle delivery, alongside the use of modified nucleotides to avoid early intracellular activation of interferon-associated genes. These features lead to prolonged protein expression, induction of antigen-specific T-follucular helper cells, and activation of germinal center B cells
- Previous animal trials have raised concern about vaccine-associated enhanced respiratory disease. Evidence suggests this won't happen in humans and that it is safe to proceed.

mRNA-1273 Phase I Discussion

Link to Study: https://www.nejm.org/doi/full/10.1056/NEJMoa2022483

Michigan State University

mRNA-1273 is a candidate vaccine proposed by Moderna. The candidate vaccine is a lipid nanoparticle that contains an encapsulated, nucleoside-modified messenger RNA (mRNA). The mRNA codes for the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation, or the structure it has before it infects a cell. The S glycoprotein is a primary vaccine target as it controls host cell attachment and is needed for viral entry.

mRNA-1273 Vaccine against SARS-CoV-2 Overview

Jackson, L.A. et al. (2020). An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. N Engl J Med. 10:1056. https://www.nejm.org/doi/full/10.1056/NEJMoa2022483

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

The mRNA-1273 vaccine candidate is capable of triggering an adaptive immune response. This mRNA encodes for the viral spike S-2P antigen. This includes:
- SARS-CoV-2 glycoprotein with a transmembrane anchor that is involved in receptor recognition with ACE2 receptors in host cells.
- an intact S1–S2 cleavage site

According to the article, "S-2P is stabilized in its prefusion conformation by two consecutive proline substitutions at amino acid positions 986 and 987, at the top of the central helix in the S2 subunit." It uses lipid nanoparticle dispersion that contains mRNA encoding the stabilized prefusion SARS-CoV-2 spike protein. The lipid nanoparticle capsule is composed of four lipids and was formulated in a fixed ratio of mRNA and lipid.

- In pre-clinical trials with Rhesus macaque, 10 or 100μg of mRNA-1273 showed successful induction of type 1 helper T-cells (Th1) and no detectable viral antigens over the next few days  
- These non-human primates also showed regression of upper and lower airway infection over the 2 weeks
- mRNA-1273 nucleoside modifications and purification were optimized to stimulate the innate immune system in order to enhance translation and duration. 
- One remaining concern was half-life of antibodies against spike protein. 
- Recent human data shows reduction of antibodies over time after initial infection.

mRNA-1273 Vaccine Specificities

mRNA-1273 Phase I Trial and Results

Link to Study: https://clinicaltrials.gov/ct2/show/NCT04405076?term=NCT04405076&draw=2&rank=1

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