The NEJM published an interim analysis Tuesday of an ongoing Phase I trial showing that Moderna's experimental COVID-19 vaccine mRNA-1273 induced anti–SARS-CoV-2 immune responses in all participants, with the authors saying there were "no trial-limiting safety concerns." Moderna chief medical officer Tal Zaks said the data "demonstrate that vaccination with mRNA-1273 elicits a robust immune response across all dose levels," and also "clearly support the choice of 100 mcg in a prime and boost regimen as the optimal dose for the Phase III study" slated to begin July 27.
The interim analysis evaluated a two-dose vaccination schedule of mRNA-1273, administered via intramuscular injections given 28 days apart, in 45 healthy participants aged 18 to 55 years. The Phase I study is testing the 25-, 100- and 250-mcg dose levels, and this analysis reports results through day 57. Early data released in May showed that the vaccine, which is being co-developed with the US National Institute of Allergy and Infectious Diseases (NIAID), had elicited neutralising antibody titer levels in all eight initial participants in the low- and mid-dose cohorts.
Antibody, T-cell responses
Moderna explained that in the latest analysis, mRNA-1273 induced binding antibodies to the full-length SARS-CoV-2 spike protein in all participants after the first vaccination, with dose dependent increases seen across the three dose levels, and between prime and boost vaccinations within the cohorts. All participants seroconverted by the 15-day mark. After two vaccinations, at day 57, geometric mean titers exceeded those seen in convalescent sera obtained from 38 patients with confirmed COVID-19, of whom 15% were classified as having severe symptoms, 22% had moderate symptoms and 63% had mild symptoms.
Moderna also said mRNA-1273 elicited "robust" neutralising antibody titers after two vaccinations, with neutralising activity against SARS-CoV-2 seen in all evaluated participants at day 43. Further, at the Phase III selected dose of 100 mcg, geometric mean titer levels at day 57 were 2.1-fold above those seen in reference convalescent sera. "A clear dose response was seen in geometric mean titers between the 25-mcg and 100-mcg dose levels, with minimal additional increases at the 250-mcg dose," the company noted.
T-cell responses were also evaluated at the 25- and 100-mcg dose levels. Moderna said that after the second vaccination, mRNA-1273 "elicited Th1-biased CD4 T-cell responses without significant elevation of Th2-biased CD4 T-cell responses." Evaluation of the durability of immune responses is ongoing, and participants will be followed for one year after the second vaccination.
Side effects more common after second dose
The two-dose vaccine series was generally safe, with no serious toxicity through day 57, and when systemic adverse events were reported after the first vaccination, they were graded as mild or moderate. However, solicited systemic adverse events were more common after the second vaccination and occurred in seven of 13 participants in the 25-mcg group, all 15 subjects in the 100-mcg group, and all 14 of those in the 250-mcg group. Across both vaccinations, solicited systemic and local adverse events that occurred in more than half the participants included fatigue (80%), chills (80%), headache (60%) and myalgia (53%), as well as pain at the injection site.
"These safety and immunogenicity findings support advancement of the mRNA-1273 vaccine to later-stage clinical trials," the authors said. Meanwhile, Moderna noted that additional cohorts in this Phase I study have completed enrollment, including three involving older adults ages 56 to 70, and another three of elderly adults ages 71 and above. These data are expected to be published separately. In addition, a Phase II trial of mRNA-1273 in 600 healthy adults, evaluating doses of 50 mcg and 100 mcg, is also ongoing.
With the Phase III dose being finalised at 100 mcg, Moderna stated that it remains on track to be able to deliver "approximately 500 million doses per year, and possibly up to 1 billion doses per year," beginning in 2021.
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