As the pandemic continues to affect millions of lives around the globe every day, researchers, healthcare professionals, industry experts and other stakeholders have been working at a rate never seen before to develop therapeutics and diagnostic solutions along with the most eagerly awaited vaccine against COVID-19. Globally, 25 investigational vaccines are at various stages of clinical evaluations. Moderna Inc. has been one of the forerunners among the prime candidates and has been backed up by the US Government under the Operation Warp Speed.
Earlier in May, Moderna had announced positive interim results from phase I trial, and the data supporting the claim was published recently in The New England Journal of Medicine. Data from the open label Phase I study of mRNA-1273, its investigational vaccine candidate against COVID-19 indicated that the vaccine induced an immune response against SARS-CoV-2 with no trial limiting safety concerns, making way for future development of the vaccine.
Moderna leverages its messenger RNA (mRNA) platform to develop multiple vaccine products and is co-developing its investigational COVID-19 vaccine candidate with National Institute of Allergy and Infectious Diseases (NIAID), an institute under NIH which is also the sponsor of the trial. The vaccine candidate is a lipid nanoparticle-encapsulated nucleoside-modified messenger RNA (mRNA) encoding the S-2P antigen. This S-2P has been the most preferred target in the current candidates under development as it assists the virus entering into the host cell with help of attachment through the S glycoprotein and these vaccines aim to restrict the entry of virus into the host cell.
The phase I trial was focused on determining the safety, reactogenicity and immunogenicity of the mRNA-1273. The trial was conducted at the Kaiser Permanente Washington Health Research Institute in Seattle and Emory University School of Medicine in Atlanta. Trial involved 45 candidates aged between 18 to 55 years, they received two 0.5 ml injection of the mRNA-1273 28 days apart, on day 1 and day 29 respectively. The candidates were divided into 3 groups of 15 each for group-wise receiving doses of 25 µg, 100 µg and 250 µg each. First dose of vaccination was administered between March 16 and April 14, 2020. All the participants seroconverted on day 15. ELISA anti-S-2P antibody geometric mean titer on day 29 indicated higher dose dependent antibody response and a significant increase in the measure of the same was observed in the analysis conducted on day 57. Serum neutralizing activity was analysed after the second vaccination was administered and the neutralization titers identified were at par with those identified in convalescent sera specimens collected from the 38 COVID-positive individuals. Based on the Pseudo-virus, Neutralization Assay antibody levels on day 57 from the 100 µg dose received group was found to be 2.1-fold higher in comparison to the specimens of convalescent sera from recovered patients. T-cell response analysis indicated Th1-biased CD4 T-cell response, which is responsible for acting on intracellular parasites like bacteria and viruses.
Based on the data, Moderna has finalised a dose of 100 µg for the Phase III study which is to be conducted on 30,000 people. The selection of dose was based on several reasons including the 4.1-fold increase in the geometric antibody titer levels observed on day 43 for the same dose level as identified by the Plaque Reduction Neutralization Test (PRNT80) assay. The next level of dose of 250µg did not elicit significant increase in the levels of antibodies and adverse events were notably high at this dose level. Mild adverse events of fatigue, chills, headaches, myalgia and pain at the injection site were amongst those which occurred in more than 50% of the participants. The durability of the immune response will be studied and the participants will be followed up for one year.
However, the current study did not involve a wide demographics of people, especially the race and ethnicity, it will be relevant to analyse this correlation in a larger study with population from diverse backgrounds. The effect of candidate in a high-risk population set is also yet to be analysed. Moderna on July 27, 2020 announced commencement of COVE (Coronavirus Efficacy), the phase III study, and we hope that this study will encompass these objectives as well. Currently, mRNA-1273 is being tested in a phase II trial in 600 adults, evaluating doses of 50 µg and 100 µg, it completed its enrolment on July 8, 2020. Overall, the researchers concluded that the vaccine candidate had safe and acceptable levels of immunogenic response.