Severe Acute Respiratory Syndrome (SARS-CoV-2) coronavirus 2, responsible for COVID-19 disease, emerged at the end of 2019 and spread globally, prompting an international effort to accelerate vaccine development.

Moderna’s mRNA-1273 candidate encodes the stabilized prefusion SARS-CoV-2 peak protein. The company announced last week that its coronavirus vaccine produced antibodies that neutralized the disease.

Scientists conducted an open phase 1 trial, with an increase in the dose, including 45 healthy adults, aged 18 to 55, who received two vaccines, 28 days apart, with mRNA-1273 at a dose of 25 micrograms, 100 micrograms or 250 micrograms, organized with 15 participants in each dose group.

“We report interim findings from this clinical trial of the mRNA-1273 SARS-CoV-2 vaccine that encodes an S-2P stabilized prefusion spike trimer, where experience with the mRNA platform for other candidate vaccines and rapid manufacturing enabled the deployment of the first candidate clinical vaccine in record time,” the scientific paper reads, adding: “Product development processes that normally require years were completed in about 2 months. Vaccine development began after the SARS-CoV-2 genome was published on 10 January 2020; the manufacture and delivery of clinical trial material were completed within 45 days, and the first participants of the trial were vaccinated on March 16, 2020, just 66 days after the publication of the genomic sequence of the virus.”

“The accelerated timeline generated key interim data needed to launch advanced large-scale clinical trials within 6 months of the initial awareness of a new pandemic threat”.

Researchers determined that after the first vaccination, antibody responses were higher at higher doses. After the second vaccination, the titers – from defenses against the virus – increased. In turn, at that point, the neutralizing activity of the serum was detected by two methods in all participants evaluated.

Requested adverse events that occurred in more than half of the participants included fatigue, chills, headache, myalgia and pain at the injection site. Systemic adverse events were most common after the second vaccination.

In the study’s findings, published by the scientific journal The New England Journal of Medicine (NEJM), they explained that the mRNA-1273 vaccine-induced anti-SARS-CoV-2 immune responses in all participants and no serious or limiting safety problems were identified from the trials.

The urgent need for vaccines provoked an international response, with more than 120 candidate vaccines to combat developing SARS-CoV-2 within the first 5 months of 2020. The candidate vaccine mRNA-1273 uses a modified messenger with nucleosides encapsulated in lipid nanoparticles, i.e. it is an RNA-based vaccine (mRNA) that encodes the glycoprotein of the SARS-CoV-2 virus spike stabilized in its prefusion conformation. Mean glycoprotein at host cell binding is necessary for viral entry and is the primary target to attack from both Modern and many candidates for SARS-CoV-2.

Moderna’s mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no serious or limiting safety concerns were identified from the trials

The authors of the scientific paper, Lisa A. Jackson, Evan J. Anderson, Nadine G. Rouphael, Paul C. Roberts, Mamodikoe Makhene, Rhea N. Coler, Michele P. McCullough, James D. Chappell, Mark R. Denison, Laura J. Stevens, Andrea J. Pruijssers and Adrian McDermott conducted the first phase 1 clinical trial in healthy adults to assess the safety and immunogenicity of the Moderna vaccine. And so they reported the provisional results of the test.

Eligible participants were healthy adults aged 18 to 55 who received two injections of the test vaccine 28 days apart, at a dose of 25 micrograms or, 100 microgram or 250 micrograms. Based on the results obtained in patients with these dose levels, additional groups were added to the protocol; results will be reported in a subsequent publication. Participants were not evaluated for SARS-CoV-2 infection by serology or polymerase chain reaction prior to enrollment. The trial was conducted at the Kaiser Permanente Washington Research Institute in Seattle and Emory University School of Medicine in Atlanta.

The study was reviewed and approved by Advarra’s institutional review board, which functioned as a single board and was overseen by an independent safety monitoring committee. All participants gave their written informed consent before enrollment. The vaccine was developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID, trial sponsor) and at Moderna (Cambridge, Massachusetts). The laboratory participated in the discussions on the design of the trial, provided the vaccine candidate project and, as part of the drafting group, contributed to the preparation of the manuscript.

The 1273 mRNA vaccine was provided as a sterile liquid for injection at a concentration of 0.5 mg per milliliter. Normal saline was used as a diluent to prepare the administered doses.

Testing procedures

The vaccine was given as a 0.5 ml injection into the deltoid muscle – located around the shoulder – of the volunteers on days 1 and 29; follow-up visits were scheduled for 7 and 14 days after each vaccination and on days 57, 119, 209 and 394. The dose increase plan specified the enrollment of four sentinel participants in the 25 μg group, followed by four sentinel participants in the 100-μg group, followed by the full enrollment of those two dose groups. If the detention rules were not complied with after all the participants in those two dose groups completed on day 8, four sentinel participants were enrolled in the 250-μg group, followed by the rest of that dose group.

Participants recorded local and systemic reactions, using a memory aid, for 7 days after each vaccination. They were not instructed to routinely use acetaminophen or other pain relievers or antipyretics before or after vaccinations, but were asked to register any new medicines taken. Adverse events were classified according to a standard toxicity classification scale.

Evaluation of binding antibodies of SARS-CoV-2

The responses of binding antibodies against S-2P and the isolated receptor binding domain, located in the S1 subunit, were evaluated by an enzyme-linked immunosorbent assay (ELISA). Vaccine-induced neutralizing activity was evaluated by a trial to neutralize a round of infection by a pseudotyping lentivirus informant (PsVNA) and by a live wild SARS-CoV-2 plaque neutralization (PRNT) assay. ELISA and PsVNA were made in samples collected from all participants on days 1, 15, 29, 36, 43 and 57. Due to the time-intensive nature of the PRNT assay, for this intermediate analysis report, the results were only available for day 1 and day 43 at time points and within the 25 µg and 100 µg dose groups.

To compare participants’ immune responses with those induced by SARS-CoV-2 infection, 41 convalescent serum samples were also tested. The trials were conducted at the NIAID Vaccine Research Center (ELISA and PsVNA) and Vanderbilt University Medical Center (PRNT).

Results

Test statistic

The 45 enrolled participants received their first vaccine between March 16 and April 14, 2020. Three participants did not receive the second vaccine, including one in the 25 μg group who had hives on both legs, starting 5 days after the first vaccination, and two (one in the 25 μg group and one in the 250 μg group) that the second vaccination was missed due to the isolation of suspected COVID-19, while the ultimately negative test results were pending. All continued to attend scheduled test visits.

Vaccine safety

No serious adverse events were observed and the previously specified test detention rules were not complied with. As noted above, a participant in the 25 μg group withdrew due to an unsolicited adverse event, transitional hives, which was considered to be related to the first vaccine.

After the first vaccination, 5 participants (33%) in the group of 25 μg reported systemic adverse events requested, 10 (67%) in the group of 100 μg and 8 (53%) in the group of 250 μg; were all of mild or moderate severity. The requested systemic adverse events were most common after the second vaccination and occurred in 7 out of 13 participants (54%) in the group of 25 μg, the 15 in the 100-μg group and the 14 in the 250-μg group, with 3 of those participants (21%) reported one or more serious events.

None of the participants had a fever after the first vaccination. After the second vaccination, no participants in the group of 25 µg, 6 (40%) in the group of 100 µg and 8 (57%) in the group of 250 µg reported fever; One of the events (maximum temperature, 39.6 degree C) in the 250- µg group was classified as severe. (Additional details on adverse events for that participant are provided in the supplementary appendix).

Local adverse events, when present, were almost all mild or moderate, and pain at the injection site was common. In both vaccines, the requested 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 grade 2 or higher clinical laboratory safety values and unsolicited adverse events revealed no patterns of concern.

Antibody response of participants

The binding of geometric mean titers of IgG antibodies increased rapidly after the first vaccination, with seroconversion in all participants on day 15. The dose-dependent responses to the first and second vaccinations were evident. Antibody responses specific to the receptor binding domain were similar in pattern and magnitude. For both trials, the mean magnitude of antibody responses after first vaccination in the 100 µg and 250 µg dose groups was similar to the mean magnitude in convalescent serum samples, and in all dose groups the mean magnitude after the second vaccination was the upper quartile of values in convalescent serum samples.

The pharmaceutical company Moderna announced that it will begin the third and final stage of testing around July 27. Vaccines will then be given to 30,000 people in 87 different locations across the United States.

Even older people and others with pre-existing conditions will be included. That is, those who have accounted for the most death as a result of the new coronavirus.

The Cambridge-based Massachussetts said it could manufacture between 500 and 1 billion doses per year from 2021, thanks to a collaboration agreement with Swiss pharmaceutical company Lonza, which has also ensured the distribution of the doses needed to complete the study.