The Moderna vaccine is being developed and produced by Moderna, Inc. and is a genetic mRNA vaccine (mRNA-1273) currently in ongoing Phase 3 clinical trials in the U.S. and a Phase 1/2 trial in Japan (announced January 21, 2021). This vaccine is approved for emergency use in the US (December 18, 2020), Canada (December 23, 2020), Israel (January 4, 2021), the European Union (January 6, 2021), the United Kingdom (January 8, 2021) and Switzerland (January 12, 2021). Here's a breakdown of everything you need to know so far about this vaccine's development.
**Collaborators:** Moderna is collaborating with Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID) on vaccine development and testing for the vaccine.
**Latest information on how well the vaccine works:** Primary efficacy analysis data from the Phase 3 trial was published on November 30, 2020 and further peer-reviewed analysis was published on December 30, 2020. In both papers, the experimental COVID-19 vaccine was reported to have 94.1% efficacy. Protection against severe COVID-19 was reported at 100%.
The study recorded a total of 196 infections among the 30,420 trial participants who received either the vaccine or a placebo (injections of saltwater). Of the 196 infections, 11 occurred among those who received the experimental (mRNA-1273) vaccine, and 185 infections occurred among those who did not receive the experimental vaccine (participants in the placebo group). Of the 30 severe cases of COVID-19 reported in the study, all were in the placebo group. There has been one COVID-19-related death in the study, which occurred in the placebo group.
The results published in late November and late December are consistent with the first interim analysis conducted during the study (announced on November 16th, 2020) that reported efficacy of 94.5%. In a "Letter to the Editor" published in the New England Journal of Medicine on December 3, 2020, Moderna shared interim analysis findings from their Phase 1 trial that suggested that at "day 119" (119 days following a patient's first vaccine dose; 90 days after the second vaccine dose), binding and neutralizing antibody titers remained high in Phase 1 patients across age groups. In other words, the results suggested ongoing immunity, although precise levels for protection against COVID-19 have not yet been established.
On January 25, 2021, Moderna announced the submission of a preprint study with results from an in vitro (laboratory-based) study suggesting the vaccine protects against new COVID-19 variants (B.1.1.7 first identified in the United Kingdom and B.1.351 first identified in the Republic of South Africa). The press release states that the vaccine "produced neutralizing titers [neutralizing antibodies] against all key emerging variants tested." However, the level of immunity against the B.1.351 variant was far less than the protection provided against earlier variants. To provide additional protection, Moderna plans to test another booster (injection) of the mRNA-1273 vaccine to see if immunity can be increased. Moderna is also beginning a preclinical study and a US-based Phase 1 trial of a new vaccine (mRNA-1273.351) specifically aimed at increasing immunity against the new variant by boosting strain-specific spike proteins.
**Distribution timeline:** Applications for US FDA Emergency Use Authorization and Conditional Marketing Authorization (CMA) with the European Medicines Agency (EMA) were filed on November 30th, 2020. Safety and efficacy data was reviewed by the U.S. regulators an an Emergency Use Authorization was issued on December 18, 2020. Additional international approvals and distribution plans are further detailed in the following sections.
**Approvals:** This vaccine is approved for emergency or interim use in individuals 18 years of age and older in the US (United States Food and Drug Administration)(December 18, 2020), Canada (Health Canada) (December 23, 2020), Israel (Israel's Ministry of Health)(January 4, 2021), the European Union (European Medicines Agency) (January 6, 2021), the United Kingdom (Medicines and Healthcare Products Regulatory Agency)(January 8, 2021), Switzerland (SwissMedic) (January 12, 2021), Singapore (Singapore Health Sciences Authority)(February 3, 2021), Qatar (Qatar Ministry of Public Health)(February 11, 2021). Additional authorizations are currently under review in other countries and by the World Health Organization. On January 26, 2021, the World Health Organization (WHO) Strategic Advisory Group of Experts issued interim recommendations for the use of the Moderna vaccine for people over 18 years of age. The group of experts concluded that "the known and potential benefits of mRNA-1273 outweigh the known and potential risks." Moderna is working with the WHO to obtain Emergency Use Listing (EUL) which would support wider access to the vaccine.
**Distribution plan: **As of January 26th, 2021, Moderna has supplied approximately 30.4 million doses to the US government, and additional doses have been supplied to Canada, the UK and the EU. Moderna expects to supply 100 million doses to the US in the first quarter of 2021 (200 million total doses by the end of the second quarter and 300 million total doses by the end of the third quarter). In total, the company plans to manufacture 600 million doses globally in 2021, though it is continuing to invest with the goal of supplying 1 billion doses during 2021. Pending approval in Japan, Moderna has said that they plan to distribute 50 million doses in the first half of 2021.
**How the vaccine is being studied:** Vaccines are tested and studied in multiple phases (phased testing) to determine if they are safe and work to prevent illness. Before a vaccine is tested on humans, in the preclinical phase it is tested on laboratory cells or animals. Once it is approved for human research, there are three phases that take place before the vaccine can be considered for approval for public use. During the first stage (Phase I), the new vaccine is provided to small groups of people—the first time the vaccine is tested in humans. The second stage (Phase II) involves testing the vaccine on people who have similar characteristics (such as age and physical health) to the target population, or the group for which the vaccine is intended. The goal of this stage is to identify the most effective dosages and schedule for Phase III trials. The final stage (Phase III) provides the vaccine to thousands of people from the target population to see how safe and effective it is. Once the vaccine has undergone Phase 3 testing, the manufacturer can apply for a license from regulatory authorities (like the FDA in the US) to make the vaccine available for public use. Once approved, the drugmaker will work with national governments and international health organizations to monitor vaccine recipients for potential side effects from the vaccine that were not seen in clinical trials (this is called surveillance). This phase also helps researchers understand how well a vaccine works over a longer time frame and how safe it is for the population.
**Type of vaccine:** The mRNA-1273 vaccine is what scientists are calling a genetic mRNA vaccine. This type of vaccine works by using genetic information from the coronavirus once it is injected into the body. The genetic information enters into human cells, instructs the body to make special spike proteins like the coronavirus, and causes the immune system to respond.
**Dosage:** In the current Phase 3 clinical trial, participants receive two injections of 100 micrograms each into their upper arm muscle. The injections are given 28 days apart. If approved, researchers expect that the same dosage and schedule will be prescribed to the public.
**Vaccine storage conditions:** Storage requirements are important to consider for new vaccines. In order for vaccines to be safe and effective, they must be held at the correct temperature during distribution and storage in health centers, pharmacies, and clinics. Maintaining the correct storage temperature can be difficult, especially if the vaccine's temperature requirement is very cold. The Moderna vaccine can be stored in a standard refrigerator temperature range (2 to 8 degrees Celsius or 36 to 46 degrees Fahrenheit) for up to 30 days. The vaccine can also be kept in long-term storage at a standard freezer temperature (-20 degrees Celsius or -4 degrees Fahrenheit) for up to six months. Maintaining these storage temperatures is already possible across vaccine distribution channels.
**Preclinical testing:** Before testing could begin on humans, the trial vaccine was tested on primates. Vaccine doses of 10 micrograms or 100 micrograms of the experimental vaccine were tested. On July 28, 2020, results were published and showed that the vaccine was protective against COVID-19. The vaccine was then permitted to advance to clinical trials in humans.
**Phase 1 trial:** The first patient dose of mRNA-1273 was given on March 16, 2020 and results from the Phase 1 trial were published on July 14, 2020. The Phase 1 trial included 45 participants, between age 18 and 55, who received two vaccine doses each, 28 days apart. Participants were divided into 3 groups (of 15 each) to test vaccine doses: 25 micrograms (two doses of 25 micrograms each given 28 days apart), 100 micrograms (two doses of 100 micrograms each given 28 days apart), and 250 micrograms (one dose). By day 43 of the trial, researchers observed immune responses in all participants that could reduce the ability of COVID-19 to infect people by 80% or more. By day 57, participants who received 100 microgram doses of the vaccine had average levels of neutralizing antibodies (special proteins that disable viruses in the body) that were about twice the average levels found in patients who have recovered from COVID-19. On day 119 (119 days following the first vaccine dose; 90 days after the second vaccine dose), binding and neutralizing antibody titers remained high in Phase 1 patients across age groups. These titers suggest ongoing immunity, though precise levels for protection against COVID-19 have not yet been established yet.
**Phase 2 trial:** Phase 2 approval was given on May 6th, 2020, and the Phase 2 trials started on May 29th, 2020. Phase 2 evaluated the two doses of 50 micrograms (given as two injections of 50 micrograms each) and 100 micrograms (given as two injections of 100 micrograms each). On June 11th, 2020, recruitment of participants was completed with a total of 300 participants between 18 and 55 years of age (50 total participants were over 55 years of age). On September 29th, 2020, Phase 2 findings were published and examined the immune responses for the vaccine in 40 older adults at different doses. The study examined two different vaccine doses (25 micrograms and 100 micrograms given in two doses each, 28 days apart) and found that the higher dose (100 micrograms) produced a greater antibody titer (immune) response in the older adult population.
**Phase 1/2 trial: **On January 21, 2021, Moderna announced that a new combined Phase 1/2 study of 200 adult patients was being launched with Takeda Pharmaceuticals in Japan. Similar to prior studies, the study will evaluate the safety and immune response to two doses (100 micrograms each) of the mRNA-1273 vaccine given 28 days apart. Participants will be monitored for 12 months following the second vaccine.
**Phase 3 trial:** This clinical study was registered as a randomized, placebo controlled trial (participants are selected for participation and randomly assigned to either receive the experimental vaccine or a placebo injection) on July 14th, 2020, and the study began on July 27, 2020 in study centers across the US. The total Phase 3 study enrollment was 30,420 participants age 18 and older (15,210 in the study group and the same number in the placebo group). On October 22, 2020 the company announced that recruitment was complete, and that 25,650 participants had already received two shots. 37% of study participants were from Communities of Color (>11,000 total with >6,000 who identify as Hispanic or LatinX, >3,000 who identify as Black or African American), and 42% were from populations considered high risk (7,000 Americans over the age of 65, and 5,000 who are under the age of 65 but have high-risk chronic diseases including diabetes, severe obesity, and cardiac disease that put them at higher risk of COVID-19). During the study, 96% of the study participants received both injections. Data collection from the Phase 3 trial is ongoing and will continue for two years; efficacy results are noted in the findings section above with current a efficacy of 94.1% (as published in the Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine paper in the _New England Journal of Medicine_ on December 30, 2020). Efficacy results as reported were consistent across age, race and ethnicity, and gender.
**Reported side effects and safety concerns:** No safety concerns have been reported in the Phase 3 study, and most side effects have been mild to moderate in severity. Severe concerns that have occurred in >2% of cases include injection site pain (reported by 86% or participants), fatigue, muscle aches and headache. In the Phase 1 trial, side effects including fatigue, chills, headache, muscle aches, and pain at the injection site were commonly reported, particularly after the second vaccine dose. In the early phases of research, participants who received the highest vaccine dose (250 micrograms) had more severe side effects than those in the other experimental groups. The most commonly reported severe symptoms included fatigue, fever (39-40 degrees C), and chills (significant, prevents daily activities).
**Special populations:** On December 2, 2020, Moderna registered a new Phase 2/3 (combined phases) randomized, placebo controlled study with plans to enroll 3,000 healthy adolescents between 12 and <18 years of age from across the US. On December 10, 2020, Moderna announced that the first participants had received the experimental vaccine. Using the same dosing schedule as adults (two injections of 100 micrograms each given 28 days apart), the study aims to evaluate the safety and efficacy of the vaccine (including the type of side effects participants experience and the frequency of those events). The estimated study completion date is June 30, 2022. Though studies are planned, the mRNA-1273 vaccine has not yet been tested on children under 12 years of age, pregnant or lactating women, or other special groups (e.g. immunocompromised patients).
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