CAMBRIDGE, Mass. — In the shadow of the COVID-19 pandemic, the world anxiously awaits the availability of a safe and effective vaccine. This week, Moderna, Inc. took a significant step toward being the first U.S. company to bring a COVID-19 vaccine to market, announcing the interim results for the Phase 1 clinical trial of their vaccine, dubbed “mRNA-1273.” The scientists report that all participants in the study mounted a strong immune response against SARS-CoV-2, and final preparations are being made for the start of a Phase 3 clinical trial.
Moderna’s mRNA-1273 vaccine received a lot of attention when they announced their initial findings on May 18th. Those results, though generally positive, generated some doubt in the scientific community because results were only shared from a small sample subset, just 8 of the 45 study participants. The new study, published in the New England Journal of Medicine, expands upon and reaffirms those initial findings. Perhaps most importantly, it provides a legitimate light of hope for COVID-19 vaccine development.
Although the technology driving Moderna’s vaccine platform is new to the field of vaccinology, it is based on a molecule that is fundamental to human biology. This molecule, called messenger RNA (mRNA), is a type of genetic material that carries out the instructions encoded in DNA to make all the proteins required in a living cell.
The Moderna vaccine is composed of a specific sequence of mRNA that is synthesized in a lab and then enclosed within a proprietary type of gene delivery system, called a lipid nanoparticle. The mRNA-containing lipid nanoparticles are administered to humans as an injection. Once inside the body, the lipid nanoparticles deliver the mRNA molecules into cells, where they can instruct the creation of protein.
In the case of the mRNA-1273 vaccine, the mRNA encodes the sequence for a full-length protein from SARS-CoV-2, called spike. Spike is normally found on the surface of SARS-CoV-2, where it functions to allow the virus to enter human cells. Scientists believe that an immune response directed against the spike protein could prevent SARS-CoV-2 infection.
In Moderna’s Phase 1 study, 45 healthy participants, ages 18 to 55, were given two doses of the mRNA-1273 vaccine. The participants were split into three cohorts, each receiving the vaccine at a different dose level: 25, 100, or 250 micrograms (μg). The vaccine doses were given 28 days apart.
Researchers write that every participant developed antibodies to SARS-CoV-2 spike protein within 15 days after the first vaccine dose. A further look at the ability of the antibodies to prevent the virus from infecting cells in culture shows that by day 57, all participants also developed antibodies that did indeed neutralize SARS-CoV-2. None of the participants had neutralizing antibodies prior to vaccination.
In the cohort of people receiving the 100 μg dose of vaccine, levels of neutralizing antibodies were four times the level seen in blood samples from patients who had recovered from natural infection of SARS-CoV-2. This is the dose that will be carried over into the Phase 3 trial of this vaccine.
The study also reports elevated T cells in blood from vaccine recipients. Although scientists do not yet know which components of the immune response correlate with immunity to SARS-CoV-2, T cells are believed to be important.
Monitoring for immune enhancement
One of the potential pitfalls a successful COVID-19 vaccine must avoid is the so-called “immune enhancement.” In this paradoxical phenomenon, some people who receive a vaccine develop worse disease after exposure to the virus.
“Previous experience with veterinary coronavirus vaccines and animal models of SARS-CoV and MERS-CoV infection have raised safety concerns about the potential for vaccine-associated enhanced respiratory disease,” the authors write in the study.
Immune enhancement can manifest when vaccination produces significant levels of antibodies that bind to, but do not neutralize, the virus. The authors note that mRNA-1273 resulted in high levels of neutralizing antibody both in this study and in a previously published preclinical study, suggesting a low risk of immune enhancement.
Certain types of T cells can also cause immune enhancement. One subset of T cells, called Th2 cells, is known to be associated with worse disease in a failed vaccine candidate for respiratory syncytial virus (RSV). Moderna scientists did not find any significant elevation of Th2 cell responses in study participants.
Adverse reactions to COVID-19 vaccine?
According to the study, the mRNA-1273 vaccine is generally safe and well-tolerated. All adverse events were transient and mild or moderate in severity, and no severe adverse events were reported.
More adverse events were reported after the second dose of vaccine, with the greatest number occurring in the highest dose group. The most common adverse events included fatigue, chills, headache, myalgia, and pain at the injection site.
“These Phase 1 data demonstrate that vaccination with mRNA-1273 elicits a robust immune response across all dose levels and clearly support the choice of 100 μg in a prime and boost regimen as the optimal dose for the Phase 3 study,” says Dr. Tal Zaks, Chief Medical Officer of Moderna, in a statement. “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.”
Moderna’s mRNA-1273 Phase 3 trial is set to launch on July 27th.
Disclosure: The author of this post owned stock in Moderna at the time of publication. We encourage readers to refer to the study findings in the New England Journal of Medicine.