No trial-limiting safety concerns were reported

The Covid-19 vaccine farthest along in clinical trials showed immune response against SARS-CoV-2 in all participants with no trial-limiting safety concerns, according to results from the first human studies of the candidate vaccine.

Phase I findings from the mRNA-1273 dose-escalation trial, reported Tuesday afternoon, July 14, in the New England Journal of Medicine, “support the advancement of the mRNA-1273 vaccine to later-stage clinical trials,” the researchers wrote.

Earlier on the same day, biotech company ModernaTX (Cambridge, Mass), which is developing the vaccine, confirmed on clinicaltrials.gov that a phase III trial of the vaccine will begin on July 27, with trial enrollment set to begin on July 21. The trial is designed to evaluate the efficacy, safety, and immunogenicity of mRNA-1273 for the prevention of Covid-19 for up to two years.

Findings from another Phase I study of the vaccine, which enrolled only adults older than 55, are forthcoming.

The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated, nucleoside-modified messenger RNA (mRNA)-based vaccine that encodes the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation.

“The S glycoprotein mediates host cell attachment and is required for viral entry; it is the primary vaccine target for many candidate SARS-CoV-2 vaccines,” the researchers wrote.

A phase II study involving 300 healthy younger adults (age 18-54 years) is fully enrolled, according to a company press release, and a second phase II study of older adults (>55 years) is also underway.

The target enrollment for the phase III trial is 30,000, and all participants will be age 18 years or older with a high risk for contracting the novel coronavirus. The phase III participants will receive two 100 μg injections of the mRNA-1273 vaccine or placebo on trial days 1 and 29.

The key primary endpoint will be prevention of symptomatic Covid-19, while secondary endpoints will include prevention of severe Covid-19 requiring hospitalization and prevention of infection by SARS-CoV-2.

The 100 μg was chosen for the phase II and phase III studies based on findings from the phase I dose-escalation trial reported Tuesday in NEJM.

The open-label phase I trial included 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart at doses of 25 μg, 100 μg, or 250 μg.

Among the main findings from the preliminary study:

  • 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).
  • Serum- neutralizing activity was detected after the second vaccination by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of controls. 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. No serious adverse events were reported at the lower dosages. “Of the three doses evaluated, the 100 μg dose elicits high neutralization responses and Th1-skewed CD4 T cell responses, coupled with a reactogenicity profile that is more favorable than that of the higher dose,” wrote researcher Lisa A. Jackson, MD, of Kaiser Permanente Washington Health Research Institute, Seattle, and colleagues.

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In an editorial published with the phase I findings, Penny M. Heaton, MD, of the Bill and Melinda Gates Medical Research Institute, called the rapid development of this and other vaccine candidates against SARS-CoV-2 “remarkable.”

“The rapid pace of the development of candidate vaccines against Covid-19 is enabled by prior knowledge of the role of the spike protein in coronavirus pathogenesis and evidence that neutralizing antibodies against the spike protein is important for immunity; the evolution of nucleic acid vaccine technology platforms that allow creation of vaccines and prompt manufacture of thousands of doses once a genetic sequence is known; and development activities that can be conducted in parallel, rather than sequentially, without increasing risks for study participants.”

She called the preliminary data “promising” and agreed that they support the continued development of the candidate vaccine.

“However, we must bear in mind the complexity of vaccine development and the work still to be done before Covid-19 vaccines are widely available,” she wrote.

“Many phase III studies fail because of incorrect identification of the dose that best balances safety and efficacy,” Heaton wrote. “The dosing regimen for this mRNA vaccine is still under study. The 250-μg dose did not appear to be associated with markedly higher antibody titers than the 100 μg dose, but it was associated with a higher proportion of severe systemic adverse events.”

She noted that a higher dose of the vaccine may prove necessary for older adults, given that immune function declines with age.

She wrote that a challenge for phase III Covid-19 vaccine studies will be matching the location of vaccinated participants with pandemic hot spots.

“Accelerating the development of Covid-19 vaccine candidates beyond phase I depends on continued parallel tracking of activities and fulsome resources,” Heaton concluded. “The world has now witnessed the compression of 6 years of work into 6 months. Can the vaccine multiverse do it again, leading to a reality of a safe, efficacious Covid-19 vaccine for the most vulnerable in the next 6?”

  1. Phase I findings from the mRNA-1273 dose-escalation trial support the advancement of the mRNA-1273 vaccine to later-stage clinical trials.
  2. On Tuesday, July 14, ModernaTX Inc., which is developing the vaccine, announced that a phase III trial of the vaccine will begin on July 27, with trial enrollment set to begin on July 21.

Salynn Boyles, Contributing Writer, BreakingMED™

This trial is being funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461

Lead researcher Lisa A. Jackson reported receiving grants and non-financial support from NIH, during the conduct of the study. Principal researcher John Beigel reported no disclosures. Editorial writer Penny M. Heaton, MD, also reported no relevant disclosures.

 

Cat ID: 31

Topic ID: 79,31,930,31,926,561,927,151,928,934