V18* USA/Moderna COVID Vaccine mRNA-1273 Emergency Approval in the United States
Ending COVID
Covid-19 Vaccine mRNA-1273 NIAID/RNA Based Vaccine
Emergency Approval for USA as of 11/30/2020
The Covid-19 mRNA-1273 mRNA based vaccine produced by Moderna (Massachusetts) is requesting emergency approval in order to use within the American population as of November 2020. The mRNA-based Covid-19 vaccine, referred to as mRNA-1273, codes for the spike protein that is found on the surface of COVID. When the vaccine is injected into the body, the immune cells processing the mRNA and the manufactured protein will be subsequently marked for identifying certain parts of the virus. It is currently in Phase 3 and is pushing for public release as of November, 2020 to start limited vaccinations by December 2020 in order to initiate herd immunity in the United States.
The mRNA-1273 Covid vaccine is an mRNA based vaccine that targets the infusion site of the virus-immune system interaction in order to prevent a full response upon viral infection. mRNA vaccines elicit a potent immune response including antibodies and cytotoxic T cells. Efficient delivery of mRNA vaccines will be key for their success and translation to the clinic and hospital. Among potential non-viral vectors, lipid nanoparticles are particularly promising. Indeed, lipid nanoparticles can be synthesized with relative ease in a scalable manner, protect the mRNA against degradation, facilitate endosomal escape, can be targeted to the desired cell type by surface decoration with ligands, and as needed, can be co-delivered with adjuvants. This mRNA based vaccine has shown to be promising, and has shown to be upwards of 94% effective in trial data published.
The trial has released interim data from its preclinical trials in the journal Nature earlier in 2020. It is worthwhile to note that this data was released after they had published preliminary data on its Phase 1 trials. They tested their vaccine in mice by immunizing them with either the 0.01, 0.1, or 1 μg dose of the vaccine intramuscularly. Results showed that a high pseudo virus NAb response was seen with the 1 μg dose. Additionally, a high pseudo virus NAb response was also seen in mice expressing the mutated form of the spike protein, D614G, which is now beginning to be seen in cases worldwide. Furthermore, the 1 μg dose illustrated a robust cytotoxic T cell response along with a balanced Th1/Th2 response. This is important because a dominant Th2 response is linked to vaccine-associated enhanced respiratory disease (VAERD). It was also noted that no increased pathology was observed in the mice upon administration of the vaccine at a dose of 1 μg. The level of NAb response in a 1 μg dose in mice was stated to be comparable to a 100 μg dose in humans, thus supporting the selection of a 100 μg dose for large scale efficacy trials.
In Phase 1 trials, there were 45 healthy participants of ages 18–55 years old. Participants were split equally into 3 groups to account for 3 different doses (25, 100, and 250 μg) Two doses were administered intramuscularly 28 days apart. Two participants (1 in the 25 μg group and 1 in the 250 μg group) who were suspected of exposure to COVID-19, but later tested negative, missed their second dose. Based on a published preliminary report, interim results show that no serious adverse events were reported but one participant experienced transient urticaria, a hives rash, after the first 25 μg dose and was withdrawn from obtaining the second dose. There was no fever reported post the first dose but some participants in the 100 (6 out of 15; 40%) and 250 μg (8 out of 14; 57%) groups reported fever after the second dose. Local adverse events were primarily Grade 1 and Grade 2, with pain at the injection site being a commonly reported event. In addition, participants reported other systemic and local adverse effects including myalgia, headaches, fatigue and chills after both doses. Three patients in the 250 μg group (21%) reported severe systemic adverse effects following the second dose.
A specific antibody response was apparent depending on the dose administered and peaked at day 15 after the first dose. NAbs were detected in only less than half of the participants following the first vaccination but were detected in all participants following the second vaccination which infers the need for a two-dose vaccine regimen. A lower response was noted in the 25 μg group and high responses were noted in the other two dose groups. CD4+ T cell responses were detected with the 25 and 100 μg doses with an additional low CD8+ T cell response shown following a second 100 μg dose. Moderna is yet to release results from a second group consisting of older participants aged 55 and above and since older individuals have a reduced immune response, it will be important to see the dosage used and if any side-effects result from the possibly higher dose.
Moderna's Phase 2a trial involved 600 healthy participants recruited from the ages 18 and above to test for safety and observe adverse reactions and to also check for immunogenicity. This was a randomized, double blind trial which split the participants based on age and dose into 8 groups - 4 were taking 50 and 100 μg of the vaccine and the other 4 were taking 50 and 100 μg of saline (placebo). A Phase 3 trial was initiated at the end of July 2020 and is designed to test for efficacy by evaluating the 100 μg dose of the vaccine administered on days 1 and 29. This is a randomized trial incorporating quadruple blinding. It has set a broad inclusion criteria, which includes those who have pre-existing conditions provided such conditions are stable and do not require changes in their therapy in the 3 months prior to enrollment.
Based on the Phase 1 interim results, the two-dose regimen Moderna has certainly showed an immune response in a greater number of individuals but also reported side effects, although mostly mild to moderate, have also increased following the second dose. Despite these factors since the results imply that the vaccine is over 94% effective, it appears to be feasible. There has been an appeal for emergency approval to initiate vaccination, in order to facilitate herd immunity in the American population as early as December 2020.
The trial has released interim data from its preclinical trials in the journal Nature earlier in 2020. It is worthwhile to note that this data was released after they had published preliminary data on its Phase 1 trials. They tested their vaccine in mice by immunizing them with either the 0.01, 0.1, or 1 μg dose of the vaccine intramuscularly. Results showed that a high pseudo virus NAb response was seen with the 1 μg dose. Additionally, a high pseudo virus NAb response was also seen in mice expressing the mutated form of the spike protein, D614G, which is now beginning to be seen in cases worldwide. Furthermore, the 1 μg dose illustrated a robust cytotoxic T cell response along with a balanced Th1/Th2 response. This is important because a dominant Th2 response is linked to vaccine-associated enhanced respiratory disease (VAERD). It was also noted that no increased pathology was observed in the mice upon administration of the vaccine at a dose of 1 μg. The level of NAb response in a 1 μg dose in mice was stated to be comparable to a 100 μg dose in humans, thus supporting the selection of a 100 μg dose for large scale efficacy trials.
In Phase 1 trials, there were 45 healthy participants of ages 18–55 years old. Participants were split equally into 3 groups to account for 3 different doses (25, 100, and 250 μg) Two doses were administered intramuscularly 28 days apart. Two participants (1 in the 25 μg group and 1 in the 250 μg group) who were suspected of exposure to COVID-19, but later tested negative, missed their second dose. Based on a published preliminary report, interim results show that no serious adverse events were reported but one participant experienced transient urticaria, a hives rash, after the first 25 μg dose and was withdrawn from obtaining the second dose. There was no fever reported post the first dose but some participants in the 100 (6 out of 15; 40%) and 250 μg (8 out of 14; 57%) groups reported fever after the second dose. Local adverse events were primarily Grade 1 and Grade 2, with pain at the injection site being a commonly reported event. In addition, participants reported other systemic and local adverse effects including myalgia, headaches, fatigue and chills after both doses. Three patients in the 250 μg group (21%) reported severe systemic adverse effects following the second dose.
A specific antibody response was apparent depending on the dose administered and peaked at day 15 after the first dose. NAbs were detected in only less than half of the participants following the first vaccination but were detected in all participants following the second vaccination which infers the need for a two-dose vaccine regimen. A lower response was noted in the 25 μg group and high responses were noted in the other two dose groups. CD4+ T cell responses were detected with the 25 and 100 μg doses with an additional low CD8+ T cell response shown following a second 100 μg dose. Moderna is yet to release results from a second group consisting of older participants aged 55 and above and since older individuals have a reduced immune response, it will be important to see the dosage used and if any side-effects result from the possibly higher dose.
Moderna's Phase 2a trial involved 600 healthy participants recruited from the ages 18 and above to test for safety and observe adverse reactions and to also check for immunogenicity. This was a randomized, double blind trial which split the participants based on age and dose into 8 groups - 4 were taking 50 and 100 μg of the vaccine and the other 4 were taking 50 and 100 μg of saline (placebo). A Phase 3 trial was initiated at the end of July 2020 and is designed to test for efficacy by evaluating the 100 μg dose of the vaccine administered on days 1 and 29. This is a randomized trial incorporating quadruple blinding. It has set a broad inclusion criteria, which includes those who have pre-existing conditions provided such conditions are stable and do not require changes in their therapy in the 3 months prior to enrollment.
Based on the Phase 1 interim results, the two-dose regimen Moderna has certainly showed an immune response in a greater number of individuals but also reported side effects, although mostly mild to moderate, have also increased following the second dose. Despite these factors since the results imply that the vaccine is over 94% effective, it appears to be feasible. There has been an appeal for emergency approval to initiate vaccination, in order to facilitate herd immunity in the American population as early as December 2020.
