Moderna's COVID-19 Vaccine Shows Positive Interim Results in Phase I Trial
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Vaccine development, testing and manufacturing is typically a lengthy process which, under normal circumstances, can take up to several years to complete.
However, in the extraordinary times of the COVID-19 global pandemic, we've witnessed certain vaccine candidates against SARS-CoV-2 receive "fast track" approvals from the Food and Drug Administration (FDA) and unprecedented levels of funding that have accelerated the process.
The number of research groups – both academic and industry-based – in pursuit of a safe and effective vaccine against SARS-CoV-2 continues to expand almost daily. In June, Technology Networks reported on the 13 vaccine candidates that were in clinical trials at that stage. Just a few weeks later, that number now stands at 23.
One of the candidates that received fast track designation by the FDA is mRNA-1273, developed by Moderna, a clinical stage biotechnology company. On July 14, the company shared the "positive" interim results from a Phase I clinical trial of the vaccine in The New England Journal of Medicine.1
RNA-based vaccines are designed to induce antibody production in an individual against a specific pathogen and trigger immunity.
In simplistic terms, mRNA is an intermediate molecule between DNA and proteins. It is an RNA version of a gene that exits the cell's nucleus, travels to the cytoplasm and is translated to produce proteins.
To date, there are no mRNA vaccines that have been approved for human use by regulatory authorities. However, an increasing number of studies are demonstrating safety and efficacy properties to RNA-based vaccines that may be advantageous in comparison to DNA-based vaccines.2
Ongoing Phase I trial of mRNA-1273
mRNA-1273 encodes for a perfusion stabilized form of the SARS-CoV-2 spike protein, part of the virus' structure that enables its entry into host cells. The Phase I trial is ongoing and is supported by the National Institute of Allergy and Infectious Disease (NIAID), part of the National Institutes of Health.
The interim analysis assessed a two-dose vaccination schedule of the candidate that was given 28 days apart across three dose levels (25, 100 and 250 µg) in a cohort of healthy adults aged between 18 and 55 years. All the enrolled participants received at least one injection, and 42 received both injections as per the trial schedule. The interim analysis reports results through to Day 57.
Safety and efficacy of mRNA-1273
The interim results demonstrate that mRNA-1273 was generally safe and well-tolerated by participants, and no serious adverse events were reported through to Day 57. Adverse events did occur, but these were noted as generally transient, and mild to moderate in severity.
To assess vaccine-induced neutralizing activity, the trial adopted both a pseudotyped lentivirus single-round-of-infection neutralization assay (PsVNA) and a live wild-type SARS-CoV-2 plaque-reduction neutralization testing (PRNT) assay.
To compare the trial participants' immune response to the vaccine with the immune response induced by SARS-CoV-2, 41 convalescent serum specimens were tested from individuals that had received confirmed diagnosis of COVID-19.
mRNA-1273 was found to induce robust neutralizing antibody titers; at day 43, neutralizing activity against SARS-CoV-2 was seen in all trial participants, and participants receiving the dose of 100 µg were found to have mean titer levels that were 4.1-fold above the levels analyzed in the reference convalescent serum. After receiving the second vaccination, neutralizing antibody titers from the PsVNA assay were detected in all participants across all dose cohorts.
In terms of dosage, a dose response was detectable in antibody titers between the 25 and 100 µg dose levels. However, there was minimal additional increase at the 250 µg dose.
These interim results warrant later-stage clinical trials of mRNA-1273, the authors state in the paper: "These safety and immunogenicity findings support advancement of the mRNA-1273 vaccine to later-stage clinical trials. 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."
“These positive Phase 1 data are encouraging and represent an important step forward in the clinical development of mRNA-1273, our vaccine candidate against COVID-19, and we thank theNIH for their ongoing collaboration. The Moderna team continues to focus on starting our Phase 3 study this month and, if successful, filing a BLA." - Stéphane Bancel, Chief Executive Officer of Moderna in a press release.
Commenting on the paper, Dr Andrew Freedman, reader in infectious diseases and honorary consultant physician at the University of Cardiff, said: “This is a draft abstract and we need to await the full report to make firm conclusions. However, it does suggest that this novel vaccine, using messenger RNA rather than protein, is able to stimulate antibody production in a dose-dependent fashion. Importantly, the antibodies generated were able to neutralise the virus in laboratory assays."
Next stages of clinical testing
A Phase II trial of mRNA-1273 began enrolment in May 2020, and a Phase III trial is set to begin in July. The interim data from these analyses informed or will inform the doses used across the Phase II/ III clinical trials of the candidate. The Phase II study of mRNA-1273 is a placebo-controlled, dose-confirmation study that is assessing the safety, reactogenicity and immunogenicity of two vaccinations given 28 days apart. Each participant will be assigned to receive either a placebo, a 50 μg or a 100 μg dose at both vaccinations.
The Phase III trial, a randomized, 1:1 placebo-controlled trial, is anticipated to enroll approximately 30,000 participants across the U.S. and will test a dosage of 100 μg. “We look forward to beginning our Phase 3 study of mRNA-1273 this month to demonstrate our vaccine’s ability to significantly reduce the risk of COVID-19 disease.” - Tal Zaks, MD, PhD, Chief Medical Officer of Moderna, in a press release.
References:
1. Jackson et al. (2020). An mRNA Vaccine against SARS-CoV-2 — Preliminary Report. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2022483.
2. Pardi, Hogan, Porter and Weissman. (2018). mRNA vaccines — a new era in vaccinology. Nature Reviews Drug Discovery. DOI: https://doi.org/10.1038/nrd.2017.243.
