The National Institute of Allergy and Infectious Diseases (NIAID) headed by Dr. Anthony Fauci issued a press release on March 16, 2020 announcing that a Phase 1 human clinical trial conducted by Kaiser Permanente Washington Health Research Institute in Seattle had begun to evaluate an experimental mRNA vaccine for COVID-19 (mRNA-1273) co-developed by NIAID scientists and scientists at Moderna, Inc, based in Cambridge, Massachusetts. The Coalition for Epidemic Preparedness (CEPI) helped fund the manufacturing of the vaccine for the Phase 1 clinical trial.
Moderna and NIAID began conducting human trials of the experimental mRNA-1273 COVID-19 vaccine prior to first conducting pre-clinical animal trials, which has been an important and customary part of vaccine development and testing process. On March 30, 2020, Moderna stated that its COVID-19 vaccine might be ready for emergency use in certain individuals, including healthcare workers, by the fall of 2020.
Although neither DNA or mRNA vaccines had been tested in large-scale clinical trials, an April 3, 2020 article in Chemical and Engineering News highlighted the breakneck speed at which COVID-19 vaccines “are moving new technologies from the computer and into the clinic at an unprecedented rate.” What should be separate pre-licensure phases for proving safety and effectiveness – preclinical animal models, clinical testing, and manufacturing – were now “happening all at once.”
Moderna announced on May 18, 2020, that Phase 1 human clinical trials of its experimental COVID-19 vaccine showed positive results, with eight of the 45 healthy adult volunteer trial subjects developing antibodies that may provide protection against the SARS-CoV-2 virus.
The company also reported that four participants suffered Grade 3 vaccine reactions. Of the four participants who experienced Grade 3 reactions, three had received the 250-µg dose level and one had received the 100-µg dose level. The U.S. Department of Health and Human Services (HHS) describes a Grade 3 adverse event as
“severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care” such as “bathing, dressing and undressing, feeding self, using the toilet, taking medications.”
On July 27, 2020, National Institute of Allergy and Infectious Diseases (NIAID) announced that Phase 3 clinical trials of the Moderna COVID-19 vaccine had begun. The vaccine, a joint venture between Moderna, Inc., and the NIAID, part of the National Institutes of Health (NIH), was expected to enroll 30,000 healthy COVID-19-negative adults at 89 clinical test sites.
According to NIAID, study participants would be randomly assigned 1:1 to receive either two doses of the 100- µg experimental mRNA COVID-19 vaccine or two normal saline placebo doses. NIAID officials reported that the study’s primary goal was to evaluate vaccine safety and whether two vaccine doses could prevent symptoms of COVID-19. Additional secondary goals included evaluation of the vaccine’s ability to prevent severe COVID-19 disease or death, and the effectiveness of a single vaccine dose in preventing symptomatic COVID-19.
Moderna COVID-19 Vaccine EUA
In the U.S., Moderna’s mRNA COVID-19 vaccine Phase 3 clinical trials initially stalled due to the inability by company officials to recruit enough minority volunteers – a requirement of the FDA for any vaccine maker seeking Emergency Use Authorization (EUA) for its product. Health officials blamed past unethical and immoral medical experiments that targeted minority populations and not employing people of color to recruit minority clinical trial volunteers. However, on October 22, 2020, Moderna reported that it had completed enrollment of trial participants and had recruited 11,000 participants from ethnically diverse communities and participants between 18 and 65 years of age with underlying conditions.
On November 16, 2020, Moderna announced that its experimental mRNA vaccine candidate showed a 94.5 percent efficacy against COVID-19. Company officials reported that their first interim results found a total of 95 COVID-19 cases among trial participants, with 90 cases in the placebo group and five in the vaccine group. According to Moderna, no severe cases of COVID-19 occurred among the vaccine recipients while 11 severe cases occurred in the placebo cases.
There was insufficient data on the use of Moderna’s COVID-19 vaccine in persons who were positive for SARS-CoV-2 at baseline. In clinical trials, there were no cases of COVID-19 illness in persons who were determined to be positive for SARS-CoV-2 at baseline in the vaccine group, and only one case among the SARS-CoV-2 positive individuals at baseline who were part of the placebo group.
Moderna’s Phase 3 clinical trials were not designed to determine whether their vaccine could reduce the impact of COVID-19 illness by decreasing hospitalizations, intensive care stays, or death. Additionally, Moderna did not study the vaccine to determine whether it could halt SARS-CoV-2 virus transmission. The durability of vaccine-acquired immunity was not known, and safety and efficacy data were limited in immunocompromised persons and in children and adolescents.
On December 18, 2020, the FDA issued an EUA for Moderna’s mRNA COVID-19 Vaccine for use in persons 18 years of age and older.
Within days of the EUA approval, cases of anaphylaxis following vaccination with Moderna’s COVID-19 vaccine began occurring. According to a report published by the CDC, between December 21, 2020 and January 10, 2021, 108 adverse events reports were identified as possible cases of severe allergic reaction to the vaccine. However, health officials considered only 10 cases to be anaphylaxis and reported that anaphylaxis occurred at a rate of 2.5 cases per million doses of Moderna COVID-19 vaccine administered.
Deaths following Moderna’s COVID-19 vaccination were also reported. On Jan. 5, 2021, baseball Hall of Famer Hank Aaron was administered the Moderna vaccine in an event that appeared to encourage others, especially African-Americans, to receive the vaccine. Seventeen days later, on January 22, 2021, Aaron died. Health officials have denied that the COVID-19 vaccine played a role in his death, and reported that his death post-vaccine was purely coincidental.
A study published in November 2021 in the New England Journal of Medicine that examined the Phase 3 clinical trials noted that there were 17 deaths in vaccine group and 16 deaths in the placebo group. Additionally, study authors reported that one COVID-19 related death occurred among Moderna vaccine recipients and three COVID-19 related deaths occurred among placebo recipients.
Moderna mRNA COVID-19 Monovalent Booster Doses
In early April 2021, Moderna CEO Stéphane Bancel reported that a third vaccine dose would be needed within one year. In an interview with Business Insider, Bancel stated that “I hope this summer to get the vaccine authorized for a boost so that we can help people getting boosted before the fall, so that we all have a normal fall and not a fall and winter like we just saw in the last 6 months.” Moderna officials reported that the vaccine was 90 percent effective six months after the second vaccine dose.
On July 8, 2021, the CDC and FDA announced that booster doses of COVID-19 vaccines were not required but they, along with the National Institutes of Health (NIH), were actively engaged “in a science-based, rigorous process to consider whether or when a booster might be necessary.”
According to a pre-peer review study conducted by researchers from the Mayo Clinic and nference, a data analytics company, by July 2021, the Moderna COVID-19 vaccine was reported to be only 76 percent effective. This study was conducted during a time when approximately 70 percent of the case were reported as being of the Delta variant.
One month later, the FDA authorized use of a third dose of the Moderna COVID-19 vaccine in persons with immunosuppressive conditions. These individuals were recommended to receive a three dose primary series of a 100mcg dose of the vaccine.
On August 18, 2021, Health and Human Services (HHS) announced a plan to begin administration of COVID-19 mRNA booster doses beginning the week of September 20, 2021, with public health officials recommending the third dose be given eight months after second COVID-19 dose. Leading health officials, however, reported that review of the application to support use of a third Moderna vaccine dose would likely not be completed prior to the White House’s September 20, 2021 timeline. According to health officials, data submitted by Moderna to the FDA as of September 1, 2021 was inadequate to support the recommendation.
The FDA authorized a 50mcg booster dose, or half dose, of the Moderna COVID-19 vaccine on October 20, 2021, to be given six months following administration of the second vaccine dose. One day later, the CDC approved use of the booster dose in all persons 65 years of age and older, in persons 18 and older at risk for severe COVID-19 disease, and in persons 18 and older who live or work in a setting that puts them at an increased risk of exposure to SARS-CoV-2.
A first booster dose of mRNA COVID-19 vaccine was authorized by the FDA and recommended by the CDC for use in all persons 18 years and older who were previously vaccinated with two doses of an mRNA vaccine (Pfizer-BioNTech or Moderna) on November 19, 2021. The booster dose was initially recommended at least six months following receipt of the second mRNA COVID-19 vaccine dose. On January 7, 2022, the interval between the second vaccine dose and the booster dose was shortened to five months.
On March 29, 2022, a second booster dose was authorized by the FDA and recommended for all persons 50 years and older, to be given at least four months after the first booster dose. Immunocompromised individuals who received a 3- dose primary series and a single booster dose were also recommended to receive a second booster dose, at least four months after the initial booster dose.
The FDA issued an EUA to Moderna in June 2022 for use of a 100mcg mRNA COVID-19 vaccine for use in adolescents aged 12 through 17 years. Additionally, the FDA also authorized use of a 50mcg mRNA COVID-19 vaccine dose in children 6 through 11 years of age and a 25mcg vaccine dose in infants and young children aged 6 months through 5 years. One day later, the CDC recommended use of the Moderna vaccine in infants and young children. On June 24, 2022, the CDC approved use of the vaccine in children and adolescents aged 6 through 17 years.
According to the FDA, the efficacy of two 25 microgram doses (one quarter of the adult dose) of the Moderna COVID vaccine given about a month apart to children six months to five years old, who had not been previously infected with SARS-CoV-2, was 50.6 percent in preventing symptomatic COVID-19 in a six to 23-month-old age group and 36.8 percent effective in a two to five year old age group. The FDA also reported that two 50 mcg doses (one half of the adult dose) in children six through 11 years and two 100mcg doses in teenagers aged 12 through 17 years induced an immune response similar to adults who received the Moderna COVID-19 mRNA vaccine.
On August 31, 2022, the FDA withdrew the EUA for the original monovalent booster dose for adults 18 and older when it authorized a single booster dose of a bivalent Moderna mRNA COVID-19 vaccine containing the original Wuhan strain and the Omicron variant BA.4/BA.5. The FDA revoked the EUA for the Moderna monovalent booster dose for all persons six years of age and older on October 12, 2022 when it granted an EUA to Moderna for a bivalent mRNA COVID-19 vaccine in individuals six years and older.
Moderna COVID-19 mRNA Vaccine Approval
On January 31, 2022, the FDA licensed and granted EUA status to Spikevax COVID-19 vaccine, an mRNA vaccine developed by Moderna, for use in persons 18 years of age and older. The FDA also stated that use of Spikevax and the experimental Moderna mRNA COVID-19 vaccine are interchangeable due to having the same formulation. The CDC’s ACIP voted on February 4, 2022 to recommend the use of this vaccine for all persons 18 years and older.
Spikevax received approval by the FDA based on the Phase 3 trial of vaccine efficacy data collected between July 27, 2020 and March 26, 2021, or when the participant decided that they no longer wanted to be blinded. On average, the median follow-up in the blinded placebo-controlled study was four months following dose two. The Phase 3 study involving 30,415 individuals 18 years and older, with half receiving 2 doses of the vaccine, and half receiving 2 doses of a saline placebo.
According to the data provided by Moderna to the FDA to support approval for the Spikevax vaccine, there were 55 cases of COVID-19, with two cases classified as serious among the vaccine recipients and 744 cases of COVID-19 with 106 classified as serious in the placebo group during the blinded study period. The vaccine efficacy of Spikevax was reported to be 93.2 percent during this time period.
There were, however, a total of 32 deaths reported during the blinded Phase 3 clinical trial, with 16 occurring among vaccine recipients and 16 among those who received the placebo. One COVID-19 death was reported among vaccine recipients and three COVID-19 deaths were reported in the placebo group. The remaining deaths that occurred during the clinical trial were reported as being unrelated to vaccination. In the open-label phase of the trial, by May 4, 2021, there were 12 deaths reported. Eight deaths occurred among individuals who received the Moderna vaccine and three deaths occurred among persons who initially received the placebo but chose to receive the Moderna vaccine when offered. Only one death occurred in the placebo group. All deaths, however, were reported as being unrelated to vaccination by clinical trial investigators.
The vaccine was not evaluated for its effectiveness against the Omicron variant, even though this variant was the predominant circulating strain at the time of FDA approval.
Moderna COVID-19 Bivalent Booster Doses
On August 31, 2022, the FDA issued an EUA to Moderna for a bivalent mRNA COVID-19 vaccine to be given as a single dose in persons 18 years and older. This dose was recommended at least two months following receipt of the primary series or booster dose. The FDA authorized use of the Moderna bivalent mRNA COVID-19 vaccine in all persons six years and older on October 12, 2022. Bivalent booster doses were authorized despite a lack of clinical data in humans to support the safety or effectiveness of the product.
In December 2022, the FDA authorized use of the Moderna bivalent mRNA COVID-19 for use in infants and children age six months through five years, to be administered at least two months after completion of the primary COVID-19 vaccine series or most recent booster dose. No clinical studies of this vaccine were conducted prior to the FDA authorization. One day later, the CDC Director recommended use of the vaccine in this population without a recommendation or vote from ACIP.
Discontinuation of Moderna Monovalent COVID-19 vaccines
On April 18, 2023, the FDA announced changes to the COVID-19 vaccination schedule to allow bivalent COVID-19 vaccines to be administered for all doses for individuals six months of age and older and that the monovalent COVID-19 vaccines would no longer be authorized for use in the U.S. The FDA reported that most individuals who had not yet received any COVID-19 vaccines could receive a single dose of COVID-19 bivalent vaccine instead of multiple doses of the monovalent vaccine. Children six months of age through five years were recommended to receive two doses of the Moderna bivalent COVID-19 vaccine.
The FDA reported that their decision was based on the original clinical trial data to support use of the Moderna monovalent COVID-19 vaccine in individuals six months of age and older and from the results of an “investigational” bivalent COVID-19 vaccine (original strain and Omicron BA.1) in adults aged 18 years and older. Additionally, the FDA also reported that the decision also included a review of immune response data that demonstrated that 145 individuals aged six and older with a past history of COVID-19 illness who received a single dose of the Moderna Bivalent COVID-19 vaccine had comparable immune responses to 1,376 individuals aged six and older without a prior history of COVID-19 illness and who received 2 doses of the Moderna COVID-19 monovalent vaccine.
The FDA also stated that the data collected from the Moderna monovalent COVID-19 vaccine and the investigational bivalent COVID-19 vaccine (original strain and Omicron BA.1) was relevant to Moderna’s Bivalent COVID-19 vaccine “because these vaccines are manufactured using the same process.”
Moderna Vaccine Contamination Concerns
In late August 2021, Japanese health officials announced that it had suspended the use of 1.63 million Moderna mRNA vaccine doses after contaminants were noted in certain vials. These contaminants were reported to be stainless steel particles that were attributed to the manufacturing process. Company officials from Moderna along with representatives from Takeda Pharmaceuticals, the company that distributed the vaccine for use in Japan, reported that they did not believe that the stainless-steel contaminants would cause adverse health problems. Company officials reported that the particles were likely caused by friction between metal in the machinery used to place the stoppers on the vaccine vials.
Three deaths following receipt of the contaminated vaccines have been reported by Japanese health officials as of September 2021. The deaths, however, were considered coincidental and unrelated to vaccination.
On September 7, 2021, Japan stopped use of the Moderna vaccine and announced plans to begin use of the Novavax COVID-19 vaccine.
In April 2022, Moderna recalled 764,900 vaccine doses in Europe after contaminants were found in a vial. The vaccine maker did not reveal what contaminants were found but reported that the recall was issued out of “an abundance of caution.”
Profits from Moderna COVID-19 Vaccines
Sales of the Moderna COVID-19 vaccine were expected to earn the company approximately $19.2 B in 2021. In 2022, Moderna reported $18.4B in sales from its COVID-19 vaccine and sales in 2023 are projected to reach $5B.
