What is the history of COVID-19 vaccine use in America?

For the past two decades, coronavirus vaccine research has been hampered by one consistent vaccine adverse outcome in particular - paradoxical immune enhancement (antibody disease enhancement). This outcome has not only been observed in SARS-CoV-1 and MERS-CoV vaccines, but also with vaccines using formalin-inactivation for measles (this vaccine was withdrawn in 1967) and respiratory syncytial virus (RSV) vaccines. Disease enhancement has also been observed with the live tetravalent dengue vaccine, Dengvaxia.  

Vaccine induced disease enhancement occurs when the vaccine primes detrimental T cell response or antibodies in the recipient and increases the risk for infection or severe disease. This means that a vaccinated person may seem fine until they contract the illness, but the excess non-neutralizing antibodies not only fail to protect the person from infection but actually make it easier for the virus to infect cells and cause damage and, as a result, the disease is much more severe than it would have otherwise been.   

By mid-March and early April 2020, the WHO, National Institutes of Health  universities,  and global pharmaceutical corporations  had announced development of more than 50 experimental COVID-19 vaccines.   

Responding to the call by public health officials to lockdown the U.S. with in-home quarantines, Congress passed the CARES Act signed into law on March 27, 2020 that would cost American taxpayers over two trillion dollars. This federal legislation included $27 billion for development of COVID-19 vaccines, drug therapies and purchase of pandemic medical supplies. The legislation, however, did not include a cap placed on how much money drug companies could charge and profits they could make on the COVID-19 vaccines and drug therapies they develop with the use of money from the government. 

On March 30, 2020, the HHS Assistant Secretary of Preparedness and Response announced that the government was taking steps to “speed the development and manufacturing of vaccines to prevent COVID-19.”  

The Biomedical Advanced Research and Development Authority (BARDA) was created by Congress in 2006 under the Pandemic and All Hazards Preparedness Act,  legislation that has given billions of dollars to DHHS since then to develop “bioterrorism” and pandemic influenza vaccines.  That federal legislation also removed all civil liability from pharmaceutical companies for injuries and deaths caused by vaccines and drugs manufactured in response to declared public health emergencies, such as pandemics. 

Johnson & Johnson issued a press release on March 30, 2020, stating that BARDA had awarded Janssen Pharmaceutical Companies $1 billion to establish new U.S. vaccine manufacturing capabilities and additional production capacity outside the U.S to produce a global supply of more than 1 billion doses of the COVID-19 vaccine. 

According to a March 30, 2020 Reuters report, Moderna, Inc. “also signed a deal with the Biomedical Advanced Research and Development Authority (BARDA), part of the U.S. Department of Health and Human Services. The arrangements were part of the federal government’s effort to encourage drugmakers to be able to produce massive amounts of COVID-19 vaccines even before any are proven to work.” 

In May 2020, former President Donald Trump formally announced the framework and leadership of “Operation Warp Speed”, a private-public partnership aimed at making a COVID-19 vaccine available to the public by January of 2021. Trump appointed venture capitalist and former Chairman of Global Research and Development and Chairman of Global Vaccines at GlaxoSmithKline Dr. Moncef Slaoui as chief advisor on vaccine development. General Gustave F. Perna, the U.S. army’s four-star general responsible for global supply chain and materiel and installation readiness for the U.S. Army, was selected as chief operating officer and charged with COVID-19 vaccine distribution. 

On June 30, 2020, the U.S. Food and Drug Administration (FDA) announced that a COVID-19 vaccine would only receive approval if it were at least 50 percent more effective than a placebo at either preventing infection or reducing illness severity. 

The FDA released its guidance for industry regarding EUA approval for COVID-19 vaccines on October 6, 2020, and stated that they would be requiring that at least half of all Phase 3 clinical trial participants be followed for at least two months following administration of the second vaccine dose. The FDA also requested that vaccine makers submit information on a minimum of five cases of severe COVID-19 disease among individuals who received the placebo. 

Under EUA authority, the FDA Commissioner may permit “unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN (CBRN = chemical, biological, radiological, nuclear) threat agents when there are no adequate, approved, and available alternatives.” 

On October 22, 2020, the FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) met to discuss COVID-19 vaccine safety and efficacy, and included groups representing ethnic and racial minorities.  VRBPAC is comprised of non-FDA “experts” whose charge is to provide “advice to the Agency regarding the safety and efficacy of the vaccine for the proposed indication.” 

Safety concerns dominated much of the meeting and several committee members expressed worry that the median two-month safety monitoring period appeared to be “arbitrary”. Additionally, if EUA approval was granted, there was concern that placebo control groups and blinding of the Phase 3 trials would be halted immediately and additional vital data would be lost. 

A presentation on vaccine hesitancy by the Reagan-Udall Foundation for the Food and Drug Administration, a nonprofit established by Congress to advance the FDA’s overall mission, reported on the public’s concern over the speed of vaccine development and their overall distrust of the healthcare system and of government. Several committee members stated that allowing a COVID-19 vaccine to be approved under EUA would only increase vaccine safety concerns. 

Concerns that minority populations were under-represented in clinical trials were discussed, however, Dr. Doran Fink of the FDA's Office of Vaccines Research and Review stated that while under-representation was not ideal, this would not cause the vaccine to be restricted for use in this demographic.  Vaccine hesitancy among racial and ethnic minorities was also highlighted and attributed to past historical experiments that have resulted in mistrust of government and health officials. 

COVID-19 vaccine efficacy discussions included a presentation by Dr. Hilary Marston, of the National Institutes of Health, who recommended that the FDA require at least a 60 percent efficacy rate for any approved COVID-19 vaccine. 

Several committee members expressed concern that the FDA had allowed vaccine manufacturers to use broad definitions of COVID-19 disease as their primary endpoint criteria. Concerns included the potential that a vaccine that showed protection against mild disease could be licensed even though the product did not reduce hospitalizations or deaths. 

VRBPAC Committee members also did not unanimously support the idea of allowing data from adult vaccine trials to be used to measure vaccine efficacy for children. VRBPAC Chair, Dr. Arnold Monto cautioned that due to differing immune responses and the potential risk of Multisystem Inflammatory Syndrome in Children (MIS-C), standard bridging of data may be inappropriate. 

Additional VRBPAC meetings for each vaccine candidate approval or EUA was promised by the FDA, however, the FDA would not be required to follow any of the recommendations made by their federal committee. 

Drug companies and government agencies racing to be the first to license a COVID-19 vaccine, began using different technology platforms to create experimental vaccines: inactivated virus, attenuated virus, recombinant protein subunit, virus-like particle, DNA, RNA and replicating and non-replicating viral vector.  Traditional viral vaccines contain attenuated or inactivated viruses or protein subunits in addition to adjuvants, such as aluminum, to stimulate an immune response that produces artificial immunity. For the past two decades, researchers have been experimenting with new technology platforms, notably ones that introduce foreign DNA and RNA directly into the body’s cells for the purpose of developing experimental vaccines for SARS, MERS, HIV and other diseases. 

Gene-based vaccines, which include DNA and mRNA types, encode for a specific viral protein from a pathogen - such as the spike protein for the SARS-CoV-2 virus. The genetic encoding instructs cells in the vaccine recipient to produce antigens that stimulate the immune system to produce antibodies specific to the antigen, without the recipient becoming infected by the pathogen that causes the disease. Compared to traditional vaccines, nucleic acid (genetic) vaccines are inexpensive and easier to manufacture because they consist only of DNA or RNA, which is taken up and translated into protein by host cells.   

Messenger RNA (mRNA) vaccines inject human cells with mRNA, usually within lipid nanoparticles, to stimulate cells in the body to become manufacturers of viral proteins.    In March 2020, a virologist at Imperial College London told Chemistry World that one advantage of using mRNA technology to make vaccines for humans is that, “Rather than generating proteins in a manufacturing plant and purifying them, you are getting the muscle to do the job and make the protein itself.” 

While traditional vaccines typically work with a person’s acquired immune system (immunity gained from exposure to pathogens), COVID-19 mRNA vaccines also have the potential to trigger an immune response from a person’s innate immune system, or the immunity we are born with. However, there are many unknowns, such as length of immunity provided by COVID-19 mRNA vaccines, whether or not the correct viral proteins have been chosen, and the frequency and severity of vaccine reactions and disease enhancement. 

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. 

Another experimental mRNA COVID-19 vaccine developed in a partnership between U.S. based pharmaceutical giant Pfizer, and German drug maker BioNTech, began human trials in late April 2020 in Germany. In early May 2020, Phase 1 and Phase 2 clinical U.S. trials evaluated the safety, tolerability, immunogenicity and potential efficacy of four different SARS-CoV-2 mRNA vaccine candidates using a two-dose or single-dose schedule, at up to three different dose levels and in three age groups (18 to 55 years old, 65 to 85 years old and 18 to 85 years old). 

Trial participants were expected to receive one of four vaccine candidates—BNT162a1, BNT162b1, BNT162b2, BNT162c2 or a placebo. Each vaccine candidate represented a different mRNA formulation and target antigen. Albert Bourla, CEO of Pfizer, stated that if one or two variations of the vaccine candidates appeared successful, human trials would expand to include thousands of participants by September 2020 with plans to deliver millions of vaccine doses by October 2020.  

The Phase 1/2 trials involved 45 healthy adults between the ages of 18 and 55 years and over 50 percent of participants experienced adverse reactions. Two participants suffered severe reactions. A Grade 3 fever of over 101.3°F two days after vaccination was experienced by one adult and sleep disturbance one day after vaccination was experienced by another. 

On July 27, 2020, Pfizer and BioNTech announced the beginning of Phase 2/3 global trials (except China) of their BNT162b2 vaccine candidate. This experimental vaccine was a 30µg level dose administered in a 2-dose regimen. Company officials reported that trials would include up to 30,000 adults between 18 and 85 years of age and if successful, they would pursue regulatory approval of some form by October 2020. If approved, their plan was to supply up to 100 million doses globally by the end of 2020, and 1.3 billion doses by the end of 2021. 

In mid-September, Pfizer and BioNTech reported that they had submitted an amended plan to the FDA to increase the number of trial participants to 44,000 and permit inclusion of individuals with chronic and stable Hepatitis B, Hepatitis C, and HIV as well as adolescents as young as 16 years of age.  They also noted that trial participants were reporting mild-to-moderate adverse reactions which included headache, fatigue, chills, and muscle pain. Fevers, including high fevers, were also reported. Pfizer’s head of vaccine research and development stated that the data was being monitored by an independent monitoring committee that "has access to unblinded data so they would notify us if they have any safety concerns and have not done so to date." 

Pfizer-BioNTech COVID-19 Vaccine EUA

On November 9, 2020, Pfizer-BioNTech issued a press release reporting that their experimental COVID-19 vaccine had an efficacy rate of over 90 percent “at 7 days after the second dose” in trial participants who had no prior history of SARS-CoV-2 infection.  It was, however, not yet known how long vaccine-acquired immunity from the Pfizer-BioNTech vaccine would persist. 

In data submitted to the FDA, Pfizer-BioNTech reported that 170 cases of laboratory confirmed SARS-CoV-2 infections had occurred in clinical trial participants, with eight reported in the vaccine group, and 162 in the placebo group. However, clinical data also reported a category of disease referred to as “suspected COVID-19” illness. This category involved persons who had symptoms of COVID-19 but were not laboratory confirmed. In the Pfizer study, 3,410 cases of suspected COVID-19 illness were reported, with 1,594 occurring in the vaccine group, and 1,816 in the placebo arm. 

In a published editorial, associate editor of the British Medical Journal (BMJ), Dr. Peter Doshi, questioned Pfizer-BioNTech’s efficacy data: 

“With 20 times more suspected than confirmed cases, this category of disease cannot be ignored simply because there was no positive PCR test result. Indeed this makes it all the more urgent to understand. A rough estimate of vaccine efficacy against developing covid-19 symptoms, with or without a positive PCR test result, would be a relative risk reduction of 19% (see footnote)—far below the 50% effectiveness threshold for authorization set by regulators. Even after removing cases occurring within 7 days of vaccination (409 on Pfizer’s vaccine vs. 287 on placebo), which should include the majority of symptoms due to short-term vaccine reactogenicity, vaccine efficacy remains low: 29% (see footnote).”

(Footnote - Calculations in this article are as follows: 19% = 1 – (8+1594)/(162+1816); 29% = 1 – (8 + 1594 – 409)/(162 + 1816 – 287). I ignored denominators as they are similar between groups.) 

Doshi also noted that clinical trials were not designed to determine whether the COVID-19 vaccine could stop transmission of the SARS-CoV-2 virus, and that evaluation of the impact of the vaccine on the reduction of hospitalizations and deaths should be performed. Clinical trial data also revealed that eight people who previously tested positive for SARS-CoV-2 were found to have confirmed, symptomatic COVID-19 illness post-vaccination. This included one person in the vaccine arm, and seven in the placebo group. These results may indicate that COVID-19 vaccines might not prevent reinfection in previously infected individuals. In addition, Doshi stated that false negative PCR test results would significantly decrease the vaccine’s efficacy, and that “suspected” COVID-19 cases could be due to other viruses. 

There was also insufficient data to support the use of Pfizer-BioNTech’s COVID-19 vaccine in persons who were previously infected with SARS-CoV-2. In clinical trials, there was one case of COVID-19 illness in both the vaccine group and the placebo group in persons who were found to be positive for SARS-CoV-2 at baseline. Based on the limited data of this sub-population provided to the FDA by Pfizer-BioNTech, the vaccine efficacy in this population was reported at -7.1 percent (Confidence Ratio -8309.9, 98.6). 

Pfizer-BioNTech applied for Emergency Use Authorization (EUA) approval from the FDA on November 20, 2020  and received EUA approval on December 11, 2020 for use in persons 16 years of age and older.  While the FDA approved use of the experimental vaccine in 16 and 17-year-old individuals, in clinical trials, only 153 adolescents were enrolled, with 77 receiving the vaccine, and 76 receiving the placebo. 

The experimental vaccine was previously granted EUA status in the U.K. on December 2, 2020  and within days of the vaccine’s initial roll-out, reports of anaphylaxis following vaccination began to surface. This prompted U.K. health officials to issue a warning against administration of the vaccine in persons with a previous history of anaphylaxis to any medicine or food. 

Immediately following the FDA issuance of an EUA for Pfizer-BioNTech’s COVID-19 vaccines, reports of anaphylaxis began to appear in the U.S. media. Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research, suggested that a chemical ingredient called polyethylene glycol (PEG)—a polymer derived from petroleum used as an excipient (a diluting agent) in both the BNT162b2 vaccine and Moderna’s COVID-19 vaccine known as mRNA-1273, was likely responsible for the severe reactions. 

Between December 14 and 23, 2020, 21 cases of anaphylaxis were reported to the federal Vaccine Adverse Events Reporting System (VAERS), with 71 percent occurring within 15 minutes of vaccine administration. Of these cases, 17 reports were in persons with a past history of allergic reaction, including seven who had previously reported a history of anaphylaxis. Public health officials reported that anaphylaxis following Pfizer-BioNTech’s COVID-19 vaccine occurred at a rate of 11.1 cases per million doses administered. 

In addition to reports of anaphylaxis, deaths following Pfizer-BioNTech’s vaccine administration were also reported to VAERS. In January 2021, a 56-year-old obstetrician developed a bleeding disorder within 72 hours of vaccination, and died 16 days later of a stroke. 

In January 2021, health officials in Norway reported that they were investigating the deaths of 23 elderly individuals following vaccination with the Pfizer-BioNTech COVID-19 vaccine. The Norwegian Medicines Agency (NOMA) concluded that in 13 of the 23 deaths, common mRNA vaccine adverse reactions, such as diarrhea, fever, and nausea may have contributed to the deaths in the frail patients.  Deaths following the Pfizer-BioNTech COVID-19 vaccine were also reported in Israel,  Germany,  Portugal and Switzerland. 

A study published in November 2021 in the New England Journal of Medicine on the Phase 3 clinical trials of the Pfizer-BioNTech COVID-19 vaccine reported 15 deaths among vaccine recipients and 14 deaths among those who received the placebo. One death in the vaccine group and two deaths in the placebo group were reported to be related to COVID-19. Non-COVID-19 related deaths in the vaccine group included cardiac arrest, sepsis, septic shock, arteriosclerosis, cardiopulmonary arrest, congestive heart failure, chronic obstructive pulmonary disease, lung cancer, and hypertensive heart disease.   

In mid-December 2020, pharmacists administering the Pfizer-BioNTech COVID-19 vaccine discovered that vials contained six or even seven vaccine doses, instead of five – the amount listed on the product vial. The extra doses were attributed to overfill of the vials and dependent on the type of needle and syringe used to administer the vaccines.  In January 2021, the FDA officially granted Pfizer’s request to update the EUA Fact Sheet to clarify that each vial contained six doses. 

In order for all six vaccine doses to be extracted from the vial, special syringes known as low dead space syringes were required, which were in short supply. The lack of proper syringes caused controversy in Europe in January 2021 when it was revealed that Pfizer would be paid for six vaccine doses of the vaccine even though it would only be possible to extract five doses from the vial. The U.S. government finalized a contract with Pfizer that would permit government officials to track which vaccine shipments came with dead space syringes and which did not. Shipments accompanied by dead space syringes would be counted as having six doses per vial, while those with regular syringes would count as having only five. 

In the spring of 2021, Pfizer-BioNTech began testing their product for use in children 12 to 15 years of age.  On April 9, 2021, company officials announced that they had submitted a request to the FDA for approval of the vaccine for use in this population. 

On May 10, 2021, the FDA expanded the EUA granted to Pfizer/BioNTech for use of its experimental mRNA vaccine in children as young as 12 years old  and the CDC’s ACIP voted to approve its use in this population on May 12, 2021. 

The approval for use in adolescents 12 to 15 years was based on a small clinical trial involving 2,260 teens, of which 1,131 received the vaccine and 1,129 received a saline placebo.  According to data provided by the vaccine manufacturer, the vaccine was reported to be 100 percent effective at preventing COVID-19. In the clinical trial, there were no cases of COVID-19 in the vaccine arm and 18 cases in the placebo arm. There were no cases of severe COVID-19 illness or death reported among clinical trial participants. 

Clinical trial data reported the most common adverse events among 12 through 15 year olds to be injection site pain, fatigue, headache, chills, muscle pain, fever, joint pain, injection site swelling and redness, lymph node swelling, and nausea. 

During the clinical trial, nearly 11 percent of 12- to 15-year-olds experienced a severe or Grade 3 vaccine reaction, with one study participant experiencing a Grade 4 reaction of a fever of 40.4°C. Five adolescents who received the Pfizer vaccine experienced a serious adverse event (SAE) during the trial, however, none of these events were considered by clinical trial investigators to be related to vaccination. 

On July 16, 2021, the FDA announced that it had accepted the Biologics License Application (BLA) from Pfizer requesting full licensure and had granted a priority review of the application.   In early August 2021, the FDA announced that it was aiming to fully approve the Pfizer-BioNTech COVID-19 vaccine by Labor Day. 

Pfizer-BioNTech COVID-19 Vaccine Approval

On August 23, 2021 the FDA licensed and granted EUA status to Comirnaty COVID-19 vaccine, an mRNA vaccine developed BioNTech, for use in persons 16 years of age and older.  The FDA also stated that use of Comirnaty and the experimental Pfizer-BioNTech mRNA COVID-19 vaccine were interchangeable due to having the same formulation.   The FDA, however, also stated that the Pfizer-BioNTech experimental vaccine and the BLA approved Comirnaty were legally distinct, but did not disclose how and why the two vaccines were legally distinct.    

Following FDA approval, the CDC’s ACIP recommended use of the 2-dose vaccine series in persons 16 years of age and older. 

When a product receives a priority review designation by the FDA, the decision to take action on the application is usually done within 6 months.  In the case of the Pfizer – BioNTech vaccine, the decision to grant full approval was completed in less than four months. 

Prior to granting approval of Comirnaty, the FDA declined to hold a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting  despite previously stating that they were “committed to use an advisory committee composed of independent experts to ensure deliberations about authorization or licensure are transparent for the public.”  In the Summary Basis for Regulatory Action Document published to support approval of Comirnaty, the FDA reported that it “did not refer this application to the VRBPAC because our review of the information submitted to this BLA did not raise concerns or controversial issues that would have benefited from an advisory committee discussion.” 

In June 2021, a group comprised of international scientists, clinicians, and patient advocate organizations formally submitted a Citizen Petition with the FDA and requested that the regulatory agency delay full approval of COVID-19 vaccines. In their petition, the Coalition Advocating for Adequately Licensed Medicines (CAALM) appealed to the agency to slow down the approval process to ensure that the scientific data was thoroughly assessed. In their petition, the group detailed safety and efficacy criteria that the FDA needed to provide prior to full licensure. These included: 

• Completion of a minimum follow-up for at least two years of individuals who participated in the clinical trials, including trials that are no longer placebo controlled;
• Ensuring that evidence is clear that the benefits of vaccination outweigh the risks in specific populations such as in persons with previous SARS-CoV-2 infection, pregnant women, nursing women, infants, children, adolescents as well as in older adults, persons with immunosuppressive disorders, blood disorders, and those with cancer;
• Requiring a complete safety review of the spike proteins being produced by the body after vaccination, as well as the spike proteins’ full distribution within the body, the pharmacokinetics, and tissue specific toxicity;
• Completion of vaccine distribution studies at the injection site and the impact of the mRNA technologies in the tissues of the body;
• A complete assessment and review of all severe adverse events and deaths reported to VAERS and other global vaccine safety monitoring systems following COVID-19 vaccination;
• Full assessment of the safety of the vaccine in persons receiving more than two vaccine doses;
• Include experts in gene therapy and delivery in VRBPAC meetings due to the significant differences between gene-based vaccines and traditional vaccines;
• Ensure that individuals involved in reviewing clinical data submitted to support full approval are free of conflicts of interest with vaccine makers.

The FDA, however, disregarded the request made by the petitioners, and granted full approval of the Pfizer-BioNTech mRNA COVID-19 vaccine in persons 16 years of age and older without addressing the concerns expressed by CAALM.  

On August 23, 2021, Dr. Peter Doshi, Senior Editor of the British Medical Journal (BMJ), expressed concerns regarding the FDA approval in a reference article published in the BMJ Opinion. In his article, Doshi noted that approval of the vaccine was based on a data cut-off date of March 13, 2021, and did not adequately address the concerns of waning vaccine immunity or the efficacy of the vaccine against the Delta variant, which was circulating during this time. 

Doshi noted that the Pfizer data showed that from two months to just less than four months following vaccination, observed vaccine efficacy (VE) had decreased from 96 percent to 90 percent and further decreased to 84 percent from four months to the end date of the data cut off (March 13, 2021). He also noted that the Delta variant likely had little impact on decreased VE as most of the data was collected in the U.S. (77 percent of trial participants were U.S. residents) where Delta was not yet circulating.  

Data from Israel, which nearly exclusively administered the Pfizer-BioNTech COVID-19 vaccine, reported a VE of only 64 percent in early July 2021.   By late July 2021, the VE had dropped to 39 percent.  

Additionally, data submitted to the FDA on efficacy involved only seven percent of clinical trial participants who remained blinded up to six months post receipt of the second vaccine dose. By the March 13, 2021 cut off, 93 percent of clinical trial participants had received the vaccine because company officials had begun offering the placebo group vaccination beginning in December of 2020. Doshi noted that no data was submitted to the FDA on VE past 6 months following vaccination, which was the time frame that the Israeli data had reported the vaccine to have a VE of only 39 percent. 

Many in the medical community have stated that the clinical trials demonstrated the vaccine to be effective against severe COVID-19 illness and would reduce the number of hospitalizations and deaths. Doshi, however, noted that the clinical trials were not designed to study severe disease, that company officials did not report the number of hospitalizations, and that there were no COVID-19 related deaths. In this study, there was one reported case of severe COVID-19 disease in the vaccine group and 30 in the placebo group, but the study did not indicate the number of COVID-19 hospitalizations. There was also a total of three COVID-19 related deaths, one in the vaccine group and two in the placebo group.  

Following FDA approval, ACIP voted to recommend the 2-dose vaccine series for use in all persons 16 years of age and older.  In July 2022, the FDA licensed Comirnaty for use in persons 12 years of age and older. 

Full data that the FDA relied upon to license the Pfizer-BioNTech COVID-19 vaccine is currently under review by independent scientists. The non-profit Public Health and Medical Professional for Transparency, a group comprised of medical and public health professionals, journalists, and scientists, filed suit to have the full data released within 108 days, by March 3, 2022, which was the same time frame that the FDA took to fully license the vaccine. The FDA, however, proposed a plan to release the data on a rolling basis, providing 500 pages per month.  

In early January 2022, a court ordered the FDA to release 55,000 pages of data each month. 

Pfizer-BioNTech mRNA COVID-19 Vaccine in Children

On October 29, 2021, the FDA authorized the use of a 10mcg dose of Pfizer-BioNTech COVID-19 mRNA vaccine in children 5 through 11 years of age. The vaccine was authorized to be administered intramuscularly as a two-dose series, three weeks apart.  The CDC’s ACIP voted to approve use of the vaccine in all children 5 through 11 years on November 2, 2021. 

The authorization of the Pfizer-BioNTech vaccine in children 5 through 11 years was based on two cohort studies involving 3,100 children who received the vaccine, and 1,538 children who received a placebo. Only 1,444 vaccine recipients, those involved in the cohort 1 study, were monitored for safety and effectiveness for at least two months after the second vaccine dose. Data from children enrolled in the cohort 2 study was limited to only 2.4 weeks following the second vaccine dose. 

The FDA reported that the Pfizer-BioNTech 10-mcg vaccine was 90.7 percent effective at preventing infection. In clinical trials, three children who received the vaccine and 16 children who received the placebo developed COVID-19. No severe cases or deaths occurred among any children who developed COVID-19 infection. The FDA also reported that the immune responses to the 10-mcg vaccine in children 5 through 11 years were comparable to those from individuals 16 through 25 years who received the 30-mcg vaccine dose. 

A pre-print study pending peer review on the effectiveness of the Pfizer-BioNTech vaccine in children 5 – 11 years completed in New York State in December 2021 and January 2022 reported a decline in vaccine effectiveness from 65 percent to 12 percent by 28-34 days. 

Pfizer-BioNTech mRNA COVID-19 Vaccine in Infants and Young Children

The FDA issued an EUA to Pfizer-BioNTech for a 3mcg mRNA COVID-19 vaccine for use in infants and young children aged 6 months through 4 years on June 17, 2022.  The vaccine, which was authorized as a three-dose series, with a three week interval between the first and second dose, and a two month interval between the second and third dose.   Although Pfizer reported 80 percent efficacy after the third dose in children under five, the numbers of children evaluated were so tiny that the FDA staff simply commented in its June 15 briefing paper for VRBPAC that, “In these FDA analyses, the immune response to the vaccine for both age groups of children was comparable to the immune response of the older participants.” 

One day later, the vaccine was recommended for use in this population by the CDC, and the recommendation included use of the vaccine in infants and young children with a history of prior COVID-19 infection.  Authorization of the vaccine was made despite a lack of evidence to show that the vaccine was capable of stopping infection or transmission of the SARS-CoV-2 virus. 

Pfizer-BioNTech Monovalent mRNA COVID-19 Booster doses

On February 25, 2021, Pfizer-BioNTech company officials announced that they had begun evaluating the safety and effectiveness of a third dose of COVID-19 vaccine. The study was aimed at learning more on the effects of a booster dose for currently circulating and newly emerging SARS-CoV-2 variants. Specifically, Phase 1 clinical trial participants would be offered a 30µg booster dose of the current vaccine six to 12 months after completing the two-dose vaccine series. 

Additionally, Pfizer-BioNTech reported that they were in discussions with the FDA and the European Medicines Agency regarding plans for a clinical study of variant specific vaccine, including a vaccine targeting the South African B.1.351 (Beta) variant. 

In early March 2021, a small exploratory study out of New York University’s Grossman School of Medicine found that persons already recovered from SARS-CoV-2 virus infection receiving one dose of the vaccine produced more neutralizing antibodies to defend against future SARS-CoV-2 infection in comparison to persons who have not been infected with the SARS-CoV-2 virus and who had received two doses of the vaccine. 

In the spring of 2021, Pfizer CEO Albert Bourla reported that a third vaccine dose would likely be needed within 12 months, and annual shots might also be necessary.  Pfizer also reported that studies had shown the vaccine to be 93.1 percent effective six months after the second dose was administered. 

In late June 2021, Israeli health officials reported the Pfizer-BioNTech COVID-19 vaccine to be 64 percent effective against the SARS-CoV-2 variant B.1.617 (Delta).  By late July 2021, the vaccine’s effectiveness against the Delta variant in Israel had decreased to only 39 percent. 

The FDA and CDC announced in July 2021 that they were not recommending booster doses, but reported that they were monitoring data. The federal agencies also stated that they “are prepared for booster doses if and when the science demonstrates that they are needed.”  One month later, however, the FDA authorized use of a third dose of the Pfizer-BioNTech COVID-19 vaccine in immunocompromised individuals. 

Pfizer-BioNTech announced on August 16, 2021 that it had submitted data to the FDA to support the use of a COVID-19 booster dose. According to the press release issued by Pfizer, administration of a third COVID-19 vaccine dose produced higher levels of neutralizing antibody titers against the original SARS-CoV-2 virus as well as the Beta and Delta variants, in comparison to levels elicited following receipt of the 2-dose series. Company officials also reported that administration of a booster dose produced neutralizing antibody titers for variants that were equivalent to the wild type. 

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. Public health officials stated that they would be recommending that the third dose be administered eight months after receipt of the second COVID-19 booster dose. 

Not all public health officials agreed with the booster dose recommendation. Following the White House’s announcement on booster doses, two senior FDA vaccine officials announced their resignations. Their decision to leave the agency was reported to be related to the White House’s announcement on booster doses ahead of the FDA’s completion of review on the data to support this recommendation. 

On September 13, 2021, the Lancet published a report authored by 18 scientists, including several from the World Health Organization and the FDA, against a broad recommendation of mRNA booster doses in the general population. The authors expressed concerns that the introduction of booster doses too soon or too frequently could result in serious immune-related adverse events and may deter acceptance of the use of COVID-19 and other vaccines. While the authors reported that certain populations, such as those with immunosuppressive conditions, may benefit from a booster dose, they indicated that ensuring a primary vaccine series in previously unvaccinated individuals would save more lives than boosting previously vaccinated populations. 

On September 17, 2021, the FDA’s VRBPAC voted to authorize use of a third booster dose of the Pfizer-BioNTech mRNA COVID-19 vaccine under EUA in persons 65 years of age and older as well as those who were at high risk of severe illness. The booster dose for this population was recommended to be given six months following administration of the second dose. 

The FDA amended the Pfizer-BioNTech EUA on September 22, 2021 and authorized a booster dose in all persons 65 years and older, in individuals 50 through 64 years at high risk for COVID-19, and in persons 18 through 64 “whose frequent institutional or occupational exposure to SARS-CoV-2 puts them at high risk of serious complications of COVID-19 including severe COVID-19.” 

While the CDC’s ACIP voted on September 23, 2021 to recommend booster doses in all persons 65 and older, in persons 50 through 64 years with pre-existing health conditions that put them at increased risk from COVID-19 infection, and in persons 18 through 49 who were at risk of infection due to pre-existing health conditions if the individual believes that they need one, they voted against recommending a booster dose for all persons 18 through 64 years whose living or employment situation placed them at high risk for COVID-19 infection. CDC Director Dr. Rochelle Walensky, however, overruled ACIP and issued a recommendation for a booster dose of Pfizer-BioNTech COVID-19 vaccine in all persons 18 and older who work or live in high-risk settings. 

A Pfizer funded study published in the Lancet on October 4, 2021 reported that after six months, the vaccine was only 47 percent effective at preventing infection. Study authors, however, reported the vaccine to be 93 percent effective against COVID-19 hospitalization. The declining effectiveness of the vaccine was blamed on vaccine waning rather than on the variants. 

A study published in the New England Journal of Medicine in late October 2021 found that vaccine immunity waned within months of receipt of the second vaccine dose among all age groups. This study was based on data collected in an Israeli database between July 11 and July 31, 2021, for all Israeli residents who were vaccinated prior to June 2021. 

A retrospective study out of Sweden published in October 2021 found that the Pfizer-BioNTech vaccine progressively waned from a high of 92 percent effectiveness at 15 to 30 days post vaccination with the second vaccine dose, to 47 percent between day 121 and day 180. After day 211, no effectiveness from the vaccine could be detected. 

A booster dose of mRNA COVID-19 vaccine was authorized by the FDA and recommended by the CDC’s ACIP 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, to be given at least six months following receipt of the second mRNA COVID-19 vaccine dose.    In early January 2022, public health officials shortened the interval of the booster dose recommendation to five months.  A fourth vaccine dose was also authorized in immunocompromised populations, to be administered at least three months following administration of a third dose. 

On December 9, 2021, the FDA authorized a booster dose of Pfizer-BioNTech vaccine for 16- and 17-year-olds. The authorization in this population was based on data examining the immune responses of 200 individuals between the ages of 18 and 55 years who received a third Pfizer-BioNTech mRNA vaccine about 6 months following their second dose. According to the FDA, the immune response of the third dose was compared to the immune response examined one month following the second dose in the same individuals, and the results showed a boost in antibody levels. 

The FDA also reported that the data they reviewed indicated a lower risk of myocarditis following the third vaccine dose when compared to the second dose.    A risk-benefit assessment completed by Pfizer-BioNTech was also reviewed by the FDA and was reported to support the booster dose recommendation in this population.  That day, the booster dose was recommended for use by CDC Director Rochelle Walensky, without a review of the data by ACIP to support use of the additional dose in this population.  In early January 2022, public health officials shortened the interval of the booster dose recommendation in 16 and 17- year olds to five months. 

A booster dose of Pfizer-BioNTech COVID-19 vaccine was authorized for use in 12 through 15-year-olds in early January 2022 by the FDA and CDC, to be administered five months following the second vaccine dose.   

In March 2022, the FDA and CDC authorized a second booster dose for persons 50 years of age and older, to be given at least four months following receipt of the first booster dose. Immunocompromised individuals were recommended to receive a 3-dose primary series of mRNA vaccine, followed by a booster dose at least three months after the third vaccine dose. A second booster dose could also be given at least four months after the first booster dose.   

The FDA and CDC authorized and recommended a booster dose for all children 5 through 11 years in May 2022, to be given at least 5 months after the second dose.  The FDA reported that the EUA for the booster dose was based on data that demonstrated an increase of antibodies post-vaccination in 67 children aged 5 through 11 years who received a booster dose seven to nine months after completion of the two-dose primary series.  

Pfizer-BioNTech mRNA COVID-19 Bivalent Booster Doses

Since the fall of 2020, multiple variants of the SARS-CoV-2 virus have emerged.  U.S. public health officials reported that while the current COVID-19 vaccines appeared to be effective against the variants,   they were in the process of developing guidance to help vaccine manufacturers adapt their products as needed.  

In June 2022, the FDA’s VRBPAC meet to discuss the “future framework” plan for COVID-19 vaccines. This plan, considered similar to the current flu vaccine strategy, would allow for all future reformulations of the COVID-19 vaccine to bypass any additional clinical trials due to their similarity to current vaccines.  The committee voted in favor of adding the Omicron BA.4/5 spike protein to the current vaccine to create a booster dose for use by early to mid-fall 2022. 

One of the committee members who voted against the booster dose reformulation, Dr. Paul Offit, expressed concern over a lack of data to support the recommendation. In an interview, Offit noted:

“There are potentially billions of dollars at stake to transform a vaccine from the ancestral strain to a new bivalent strain including these Omicron-specific boosters, without clear and compelling evidence that it’s actually going to improve the outcome we care about most which is protection against severe disease.”  

On August 31, 2022, the FDA issued an EUA to Pfizer-BioNTech for a bivalent mRNA COVID-19 vaccine to be given as a single dose in persons 12 years and older. This dose was recommended to be given at least two months following receipt of the primary series or booster dose. The FDA also withdrew the EUA for the original monovalent booster dose for persons 12 and older when it authorized a single booster dose of a bivalent Pfizer-BioNTech mRNA COVID-19 vaccine containing the original Wuhan strain and the Omicron variant BA.4/BA.5.  The FDA withdrew the EUA for the Pfizer-BioNTech monovalent booster dose for all persons five years of age and older on October 12, 2022 when it granted an EUA for the bivalent mRNA COVID-19 vaccine in individuals six years and older. 

No human trials of the bivalent mRNA COVID-19 vaccine were completed prior to the FDA issuing the EUA. Instead, the FDA authorized use of the vaccine based on data that showed a boost in immune responses against all Omicron variants in mice. The FDA also reported that the authorization was also based on data provided by the manufacturers on a bivalent COVID-19 vaccine containing the original strain and the Omicron BA.1 strain.   

In December 2022, the FDA authorized use of the bivalent vaccine for use in infants and children six months through four years of age, to be given as a single dose at least two months following completion of the 3-dose primary series. It was also authorized to be given as the third dose of the 3-dose primary series, following two doses of the monovalent COVID-19 vaccine, in infants and children who had not yet received a COVID-19 vaccine.  One day later, the CDC Director recommended use of the vaccine in this population without a recommendation or vote by ACIP. 

Discontinuation of Pfizer-BioNTech 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 were no longer 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 four years were recommended to receive three doses of the Pfizer-BioNTech bivalent COVID-19 vaccine, while children aged five years were only recommended a single dose of the Pfizer-BioNTech bivalent COVID-19 vaccine. 

The FDA reported that their decision was based on the original clinical trial data to support use of the Pfizer-BioNTech monovalent COVID-19 vaccine in individuals six months of age and older, from the results of an “investigational” bivalent COVID-19 vaccine (original strain and Omicron BA.1) in adults aged 55 years and older, from safety data on the Pfizer-BioNTech bivalent COVID-19 vaccine (original and omicron BA.4/BA.5) in persons 6 months of age and older and from immune response data in infants and children aged 6 months through 4 years of age.   The FDA also reported that use of a single dose of the Pfizer-BioNTech COVID-19 bivalent vaccine was also supported by observational data from England on the effectiveness of a single dose of the Pfizer-BioNTech monovalent vaccine. According to the FDA, 12- to 17-year-olds with a prior history of infection from the Alpha, Delta, or Omicron variant who received a single dose of the Pfizer-BioNTech monovalent COVID-19 vaccine had “increased protection” from symptomatic COVID-19 infection than those without a prior infection history. 

Again, the FDA reported that the clinical data pertaining to the Pfizer-BioNTech monovalent COVID-19 vaccine and the investigational Pfizer-BioNTech COVID-19 bivalent vaccine (original and Omicron BA.1) were relevant to the Pfizer-BioNTech COVID-19 bivalent vaccine “because these vaccines are manufactured using the same process.”  

Pfizer-BioNTech mRNA COVID-19 Vaccine Profits

Pfizer’s COVID-19 vaccines generated $36.8B in sales in 2021, and $37.8B in 2022. The company reported earnings of $100.3B in 2022, but announced it was expecting a 64 percent decrease in profits in 2023. This decrease was anticipated despite plans to increase the price of each dose of its Comirnaty vaccine to between $110 and $130 dollars. Earnings from the Pfizer COVID-19 vaccine in 2023 are expected to be at $14.4B. 

Pfizer-BioNTech mRNA COVID-19 Vaccine Contamination Concerns

In early September 2021, Japanese health officials reported that “floating matter” had been found in five unused vials of COVID-19 vaccines belonging to the same vaccine lot. Vaccines from the same lot continued to be administered after being visually inspected. Pfizer company officials responded by stating that the material was probably undissolved vaccine ingredients and would not impact the safety or efficacy of the product. Additionally, Pfizer also reported that by early September 2021, floating matter had been reported in at least 95 vials. 

Pfizer-BioNTech mRNA COVID-19 Vaccine Clinical Trial Data Integrity Issues

On November 2, 2021, the British Medical Journal published an investigational report on concerns related to the Phase 3 clinical trials of the Pfizer-BioNTech. From information provided by a whistleblower involved in the clinical trials, many concerning practices occurred at one of the Pfizer-BioNTech trial sites. Concerns included:

• Clinical trial participants were not adequately monitored by staff post-vaccination
• Protocol deviations were not reported
• Improper vaccine storage
• Lack of timely follow-up of individuals who experienced adverse reactions
• Mislabeling of laboratory specimens
• Targeting of staff who reported concerns

Brook Jackson, the whistleblower who reported concerns directly to the FDA, was reportedly terminated by the research company contracted to conduct the clinical trials. Despite receiving a complaint from Jackson regarding concerns associated with the clinical trial, the FDA failed to conduct a follow-up investigation. Two additional individuals employed with Ventavia, the same research company contracted with conducting the trials, have reportedly collaborated Jackson’s account of the situation. 

In May 2021, Israeli health officials reported a possible link between the Pfizer COVID-19 vaccine and myocarditis after reporting that 62 cases had been reported following vaccination. Of these cases, 56 had occurred following the second shot, and most had involved persons 30 years of age and younger. A Pfizer spokesperson, however, stated that a causal link had not been established and that they had not observed a higher rate of myocarditis post-vaccination than what would have been expected in the overall population. 

On May 17, 2021, the ACIP’s COVID-19 Vaccine Safety Technical (VaST) Work Group met and reviewed information on myocarditis following mRNA vaccines. VaST reported that most of the cases had occurred in teens and young adults, and more cases had occurred in males. Additionally, there were more cases reported after the second vaccine dose, and most occurred on average within four days of vaccination. Members of VaST reported that few cases had been reported but that information on myocarditis following COVID-19 vaccination should be given to vaccine providers. 

Reports of myocarditis and pericarditis following mRNA vaccines continued to increase and on June 11, 2021, the CDC scheduled an emergency ACIP meeting for June 18, 2021 to discuss the higher-than-expected number of cases. A total of 301 cases following Moderna vaccination and 488 cases following Pfizer vaccination had been reported at the time the meeting was scheduled. 

The meeting, however, was postponed due to the newly created Juneteenth National Independence Day holiday, with the CDC announcing that it would discuss concerns the following week at the regularly scheduled June ACIP meeting.  By the June 23, 2021 meeting, CDC officials reported that through June 11, 2021, 1,226 cases of myocarditis/pericarditis had been reported to VAERS, with 791 occurring after Pfizer vaccination and 435 after Moderna vaccination. Most cases had been reported in males, and most had occurred following the second dose. 

In the data presented during the June 23, 2021 ACIP meeting, the CDC reported that in females between the age of 12 and 17 years, after the second dose, the case rate of myocarditis/ pericarditis was 9.1 per million doses administered. In males 12 to 17 years of age, however, the reported rate after the second vaccine dose was 66.7 per million doses. Cases among females 18 to 24 years old after dose two were reported at 5.5 per million, while after dose two, males of the same age range were affected at a rate of 56.3 per million doses. Most cases of myocarditis/pericarditis resulted in hospitalization, and while most were reported as being resolved, the long-term health outcomes were reported to be unknown.   

The CDC, however, declined to pause use or make changes to the vaccine recommendations, as they reported the benefits to vaccination outweighed the risk. Additionally, they stated that persons with a history of myocarditis and pericarditis could still receive an mRNA vaccine and persons who developed pericarditis after the first mRNA vaccine dose could receive the second dose after symptoms resolved. The CDC also advised that individuals who developed myocarditis after the first dose could consider receiving a second dose under certain circumstances. No data to support this recommendation was provided. 

A study of myocarditis after mRNA vaccines on members of the military found a higher-than-expected number of cases following vaccination.  Additional studies have also associated mRNA vaccines with heart inflammation, with researchers reporting the need for further investigation.     

A population-based cohort study published in the British Medical Journal in December 2021 found that the Moderna COVID-19 vaccine was four times more likely to cause heart inflammation than the Pfizer vaccine.  A study published in Nature Medicine in December 2021 reported that men under the age of 40 were more likely to develop myocarditis following Moderna vaccination than following SARS-CoV-2 infection. 

In late February 2022, the CDC stated that the interval time between the first and second dose of mRNA vaccine could be extended to eight weeks. The increase in interval time was based on data suggesting that an increase in interval time might decrease the risk of heart inflammation, especially among males 12 through 39 years.   

When the mRNA COVID-19 vaccines were initially authorized, they were recommended to be given intramuscularly (IM) in a two-dose series. Doses of the Pfizer-BioNTech vaccine were recommended to be administered 21 days apart, while doses of the Moderna vaccine were to be given 28 days apart. In early January 2021, following reports in the media of alternative vaccine schedules which included giving a single vaccine dose, giving half doses, and using vaccine brands interchangeably, the FDA issued a press release to emphasize the need for clinicians to follow the authorized EUA dosing schedules. Agency officials reported that without clinical data to support alternative dosing schedules, the public could be put at risk and this might ultimately undermine efforts to protect people against COVID-19. 

In contrast, U.K. health officials announced in early January 2021 that it was prioritizing first dose administration to as many people as possible, and delaying the booster dose until more vaccines became available.   

Studies on the use of different combinations of COVID-19 vaccines were initiated by the University of Oxford and included the evaluation of the safety and effectiveness of using a different COVID-19 vaccine as the second vaccine dose. Vaccines involved in the clinical trials included Pfizer-BioNTech, Moderna, AstraZeneca, and Novavax. 

According to a study published in The Lancet on May 12, 2021, adults 50 years and older who received a mixed dose combination of the Pfizer-BioNTech vaccine and the AstraZeneca COVID-19 vaccine experienced more mild and moderate side effects than those administered only one type of vaccine. Systemic reactions, especially fever, were significantly higher after the second vaccine dose in persons who received the AstraZeneca vaccine followed by a dose of the Pfizer-BioNTech vaccine when compared to persons who received two doses of the Pfizer-BioNTech vaccine. There were also more reports of joint and muscle pain, chills, malaise, fatigue, and headache after the second vaccine dose in person who received a mixed dose schedule. 

On October 20, 2021, the FDA authorized use of a “mix and match” booster dose for all available COVID-19 vaccines. According to the FDA, the known and potential benefits of a single boost of a different vaccine outweighed the known and potential risks.   At the time of this recommendation, there was limited safety and effectiveness data to support the mixed-use vaccine schedule. 

In March 2020, Janssen/Johnson & Johnson announced that it had expanded its partnership with BARDA to reach its goal of providing one billion COVID-19 vaccine doses. Company officials reported that human trials of an experimental COVID-19 vaccine utilizing its AdVac® and PER.C6® technologies would likely begin in September 2020.  The AdVac technology uses an adaptation of human Adenovirus 26 to transport the genetic code of the SARS-CoV-2 spike protein into the body to trigger an immune response.    PER.C6 are proprietary cells owned by Janssen Pharmaceutical that were developed in 1985 from retinal cells of an 18-week-old aborted fetus. 

The Janssen/Johnson & Johnson experimental COVID-19 vaccine entered Phase 2 trials in Spain in mid-September 2020.  Clinical trials, however, were halted on October 12, 2020 after a participant developed an “unexplained illness.”  Sources familiar with the event reported that a male in his 20’s had a stroke after receiving the experimental vaccine.  Clinical trials in the U.S resumed in late October 2020. 

On January 29, 2021, company officials reported that overall, their COVID-19 vaccine was 66 percent effective at preventing moderate to severe symptoms, 85 percent effective at severe illness, and 100 percent effective at preventing COVID-19-related hospitalizations and deaths. 

Janssen/Johnson & Johnson COVID-19 Vaccine EUA

On February 27, 2021, the FDA issued an EUA for Janssen/Johnson & Johnson’s experimental vaccine for use in persons 18 years of age and older.  In clinical trials, the vaccine was reported to be 67 percent effective in preventing moderate to severe COVID-19 occurring at least 14 days after vaccination and 66 percent effective in preventing moderate to severe COVID-19 occurring at least 28 days after vaccination.  The vaccine, however, was reported to be only 42 percent effective in persons over the age of 60 with underlying health conditions. 

Common side effects reported after vaccine administration with the Janssen/Johnson & Johnson COVID-19 vaccine in clinical trials included injection site pain, headache, fatigue, myalgia, nausea, fever, injection site redness and swelling. 

Serious adverse events reported after vaccine administration included severe pain in the injected arm, hives, hypersensitivity, deep vein thrombosis, pulmonary embolism, transverse sinus thrombosis, severe generalized weakness with fever and headache, tinnitus (ringing or buzzing noises in the ears) and seizures. 

On April 13, 2021, the FDA and CDC paused use of the vaccine after serious blood clots were reported in women between the ages of 18 and 49.  By April 23, 2021, 15 cases and 3 deaths had been associated with the rare blood clot disorder, now referred to by health officials as thrombosis with thrombocytopenia syndrome (TTS). All cases were reported in women, with two occurring in women over 50 years of age. The CDC’s ACIP voted to resume full use of the vaccine in all persons 18 years of age and older on April 23, 2021, by a vote of 10 to 4 (with one voting member abstaining due to a conflict of interest). Those who voted against the recommendation expressed concern regarding the lack of warning on the risk of TTS in women under 50 years of age.   

On April 23, 2021, the FDA updated the Janssen/Johnson & Johnson’s COVID-19 Fact Sheet and acknowledged that: 

“Reports of adverse events following use of the Janssen COVID-19 Vaccine under emergency use authorization suggest an increased risk of thrombosis involving the cerebral venous sinuses and other sites (including but not limited to the large blood vessels of the abdomen and the veins of the lower extremities) combined with thrombocytopenia and with onset of symptoms approximately one to two weeks after vaccination. Most cases of thrombosis with thrombocytopenia reported following the Janssen COVID-19 Vaccine have occurred in females ages 18 through 49 years; some have been fatal. The clinical course of these events shares features with autoimmune heparin-induced thrombocytopenia. In individuals with suspected thrombosis with thrombocytopenia following the Janssen COVID-19 Vaccine, the use of heparin may be harmful and alternative treatments may be needed. Consultation with hematology specialists is strongly recommended.”

By May 7, 2021, there had been 28 cases of TTS and 3 deaths confirmed by the CDC to be related to the Johnson & Johnson/Janssen COVID-19 vaccine. TTS was also reported in men and in women between 50 and 60 years of age, in addition to women between the ages of 18 and 49 years.  According to the CDC, TTS occurred at a rate of 1 case per 250,000 doses of the vaccine. 

On December 16, 2021, the CDC gave a preferential recommendation for mRNA COVID-19 vaccines in lieu of the Johnson & Johnson/Janssen COVID-19 vaccine due to the risk of TTS.  According to the CDC, use of the Johnson & Johnson/Janssen vaccine was advised to be limited to persons who were unable to or unwilling to receive an mRNA COVID-19 vaccine, or when no other vaccine option was available. 

A study conducted by the Mayo Clinic and published in the Journal of the American Medical Association in November 2021 found that individuals who received the Janssen/Johnson & Johnson COVID-19 vaccine were 3.7 times more likely to develop cerebral venous sinus thrombosis (CVST) in comparison to the rates prior to the pandemic. Women were over five times more likely to develop CVST after vaccination when compared to pre-pandemic rates of the condition, with the highest rates in women 40-49 years of age, followed by women 30-39 years. Most cases of CVST were reported within 15 days of vaccination. Researchers did not have an answer on why women were more susceptible; however, autoantibody production or other risk factors that place a woman at increased risk of CVST were thought to play a role. 

On July 12, 2021, the FDA announced that it would be issuing a warning that the Johnson & Johnson/Janssen COVID-19 vaccine could trigger Guillain-Barré syndrome (GBS). By July 2021, health officials reported 100 cases of GBS following vaccination, with 95 considered serious and requiring hospitalization, and this data included one death. According to the FDA: 

"Although the available evidence suggests an association between the Janssen vaccine and increased risk of GBS, it is insufficient to establish a causal relationship….Importantly, the FDA has evaluated the available information for the Janssen COVID-19 Vaccine and continues to find the known and potential benefits clearly outweigh the known and potential risks."

Per the CDC, rates of GBS within 21 days following the Johnson & Johnson/ Janssen COVID-19 vaccine were 21 times higher than after the Moderna or Pfizer/BioNTech mRNA COVID-19 vaccines. After 42 days following vaccination with the Johnson & Johnson/ Janssen COVID-19 vaccines, rates were 11 times higher than after the available mRNA COVID-19 vaccines. 

In early September 2021, the European Medicines Agency reported that its Pharmacovigilance Risk Assessment Committee (PRAC) was investigating a link between the Johnson & Johnson/Janssen COVID-19 vaccine and venous thromboembolism (blood clots in the veins). According to PRAC, in the initial clinical trials of the vaccine, a higher rate of venous thromboembolism was noted in the vaccine group when compared to the placebo group. Additional data collected from two larger clinical trials were expected to be submitted to PRAC in advance of vaccine marketing authorization, to determine whether the condition was linked to vaccination.   

The FDA updated the Johnson & Johnson/Janssen COVID-19 Vaccine Fact Sheet for Health Care Providers Administrating Vaccine on January 11, 2022 with information regarding the serious risk of immune thrombocytopenia (ITP) within 42 days of vaccination. ITP is a blood disorder that can cause excessive bruising and bleeding due to very low levels of platelets. 

Johnson & Johnson/Janssen COVID-19 Vaccine Production Concerns

On March 31, 2021, The New York Times reported that vaccine ingredients were mixed up by employees at an Emergent BioSolutions plant in Baltimore, resulting in up to 15 million ruined Johnson & Johnson vaccine doses. The mistake, which was determined by federal investigators to be the result of “human error”, was caught before any doses were released for distribution. The Baltimore plant was enlisted by the federal government in 2020 to manufacture vaccines developed by both Johnson & Johnson and AstraZeneca. While these vaccines use similar technologies, their ingredients and manufacturing processes are not interchangeable. According to The New York Times, in February 2021, one or more workers erred in the production process and this error was not discovered by Johnson & Johnson quality control checks for several days. 

This was not the first time that the Emergent BioSolutions Baltimore plant had been cited for errors. In April 2020, an FDA investigator had discovered that employees at the plant lacked adequate training, that testing protocols were not being followed, that records were not properly secured, and that policies to ensure that mix-ups or contaminations would not occur were found to be inadequate. Despite these safety issues, the plant was awarded $628 million by the U.S. government and also secured deals worth more than $740 million with AstraZeneca and Johnson & Johnson to manufacture COVID-19 vaccines for both companies at the Baltimore site. 

On April 20, 2021, the FDA cited the Baltimore Emergent BioSolutions plant for multiple quality control and sanitary issues, including their failure to adequately review and investigate the events that resulted in the manufacturing of 15 million botched Johnson & Johnson vaccine doses. Additionally, the FDA reported that they were not confident that previously released batches of the vaccines were not subject to cross-contamination. Unsanitary conditions at the plant included chipping paint from the walls in the hallways surrounding the manufacturing rooms, “brown residue” on walls, “black residue” and debris on the floor, and congested work areas. Plant employees were noted to be carrying unsealed bags containing medical waste and even “throwing unsealed bags of special medical waste into the service elevator accessing the warehouse corridor.” 

In November 2021, Emergent BioSolutions reported that it was no longer manufacturing COVID-19 vaccines for the U.S. Government. The decision to end the contract was related to manufacturing concerns at the Baltimore plant. The Baltimore facility, however, was reportedly continuing the manufacturing of the Janssen/ Johnson & Johnson COVID-19 vaccine for global distribution. The company’s actions during the pandemic were subjected to a congressional investigation and was reportedly involved in a lawsuit pertaining to concerns of insider trading among company executives. 

Johnson & Johnson/Janssen Booster Doses

A booster dose of Janssen/Johnson & Johnson vaccine was authorized by the FDA on October 20, 2021, for all individuals 18 years and older and was permitted to be administered at least two months following administration of the first dose.  The CDC, however, recommended mRNA COVID-19 vaccines over the Johnson & Johnson/Janssen COVID-19 vaccine due to the risk of TTS.  Immunocompromised individuals who received two doses of the Johnson & Johnson/Janssen COVID-19 vaccine were recommended to receive a third COVID-19 vaccine at least two months after the second vaccine dose. 

On September 1, 2022, the CDC voted to recommend use of either the Moderna or Pfizer-BioNTech booster dose in all persons 18 years and older who previously received the Johnson & Johnson/Janssen COVID-19 vaccine. This booster dose was recommended at least two months after the primary or latest booster dose. 

FDA revocation of the Johnson & Johnson/Janssen COVID-19 vaccine EUA

On June 1, 2023, the FDA revoked the EUA for Johnson & Johnson/Janssen COVID-19 vaccine. According to the FDA, Janssen BioTech had requested the voluntary withdrawal of its COVID-19 vaccine due to lack of demand for new lots of the vaccine, the expiration of last vaccine lots purchased by the U.S. federal government, and the decision by company officials to decline to update the vaccine to target new and emerging COVID-19 strains. 

Johnson & Johnson/Janssen COVID-19 Vaccine Profits

In January of 2022, Johnson & Johnson reported earnings of $2.4B from its COVID-19 vaccine in 2021. The company, however, reported weaker than expected earnings in 2022 and announced that it would no longer be including the vaccine’s revenue expectations in their projections. 

Maryland-based Novavax Inc, a biotechnology company which, prior to its COVID-19 vaccine, had never successfully delivered a product to market,  developed an experimental vaccine using recombinant nanoparticle technology. Referred to as a protein subunit vaccine,  NVX‑CoV2373 contains Novavax’s patented saponin-based Matrix-M™ adjuvant designed to enhance the immune response and stimulate high levels of neutralizing antibodies. 

Matrix-M1 contains nm (nanometers) of nanoparticles composed of Quillaja saponins, phospholipid and cholesterol. Quillaja saponins are chemical compounds extracted from the soapbox tree and are used as emulsifiers in food additives and beverages. 

Phase 1/2 clinical trials involved 131 participants, with 83 administered the NVX-CoV2373 vaccine containing the Matrix-M1 adjuvant to help stimulate an immune response to produce a strong antibody response.  Of the remaining trial participants, 25 were given the NVX-CoV2373 vaccine without the Matrix-M1 adjuvant and 23 participants were given a placebo of sterile 0.9 percent normal saline. Participant received two intramuscular injections in the deltoid muscle administered three weeks apart. 

According to the results of the clinical trial, two of the 83 participants (one each in groups D and E) suffered “severe adverse events” (fatigue, headache, and malaise) after the first dose. Two participants—one each in groups A and E—had “reactogenicity events” (malaise, fatigue, and tenderness). Following administration of the second dose, one participant in group D had a “severe local event” (tenderness) and eight participants—one or two in each group—had “severe systemic events.” The most common of these severe systemic events were fatigue and joint pain. One participant in group D developed a fever greater than 100 °F. 

Phase 3 clinical trials of NVX-CoV2373 began in the United Kingdom in late September 2020. This trial, a randomized, placebo-controlled, observer-blinded trial, was expected to enroll up to 10,000 volunteers. Half of the volunteers would be administered two intramuscular doses of the experimental vaccine candidate 21 days apart, while the remaining participants would receive a placebo. 

On November 9, 2020, Novavax received “fast track” status from the U.S. Food and Drug Administration. This designation permitted the company to submit clinical data to the FDA when it became available rather than waiting for all results to be collected. 

In late January 2021, company officials reported that the experimental vaccine was 89.3 percent effective at protecting individuals from illness. This data was based on interim results of late-stage clinical trials conducted in the U.K. The vaccine, however, was found to be only 49.4 percent effective in South African clinical trials, where the B.1.351(Beta) variant was most predominant. 

By February 2021 Novavax had secured a memorandum of understanding with Canada  and Takeda Pharmaceutical Company Ltd.  (Japan) to produce the vaccine, while the European Medicines Agency (EMA) started their rolling reviews of the experimental vaccine.  As Phase 3 trials continued in the United States and the United Kingdom, Novavax had secured advance commitments and purchase agreements totally over 1.2 billion doses of NVX-CoV2373 with GAVI, The Vaccine Alliance (formerly the Global Alliance for Vaccines and Immunization);  Switzerland;  Australia;  New Zealand;  and Canada. 

On March 1, 2021, Novavax released pre-peer reviewed research results on their experimental NVX-CoV2373 vaccine. The Phase 2 component of their Phase 1/2 trial was a randomized placebo-controlled trial to identify dosing regimen for the vaccine.

Vaccine arms of about 250 participants received one or two intramuscular doses at 5-μg or 25-μg or placebo, 21 days apart. Subsequent to randomization, 45 percent of participants were 50 to 84 years of age, and side effects were reported as mild and lasted about three days, with intensification after the second dose with the higher dosage of the vaccine.

The lower dose antibody response was reported as 100 percent for all age groups with neutralizing antibody rates exceeding those present in convalescent sera. The study concluded by stating that the two-dose regimen at the lower dose of 5-μg was suited for young and old alike and was highly protective. 

In September 2021, Novavax company officials announced that it was initiating a Phase 1/2 study of a combination COVID-19-seasonal flu vaccine. The clinical trial would combine the Novavax recombinant protein-based NVX-CoV2373 COVID-19 vaccine with their NanoFlu™ vaccine candidates and patented saponin-based Matrix-M™ adjuvant in a single vaccine product.

Clinical trials would involve 640 healthy Australians between 50 and 70 years of age. Trial participants, however, must have previously been infected with SARS-CoV-2 or been vaccinated with an approved COVID-19 vaccine at least eight weeks prior to enrollment in the vaccine trial. Participants would be randomized to different cohorts to evaluate the safety and efficacy of different vaccine formulations and doses. Participants in the study were scheduled to receive two vaccine doses, spaced 56 days apart. 

In June 2022, the FDA’s Vaccine and Related Biologics Products Advisory Committee (VRBPAC) voted to recommend issuing Novavax an EUA for its COVID-19 vaccine for adults. VRBPAC made this recommendation despite the risks of myocarditis and pericarditis associated with the vaccine, as well as a lack of data on the effectiveness of the vaccine against the Omicron COVID-19 strain, the predominant variant in circulation at the time of the review. The FDA stated that the issuance of EUA would depend on an evaluation of Novavax’s manufacturing process. On June 3, 2022, Novavax had notified the FDA of a change to the manufacturing process of its COVID-19 vaccine. 

The FDA issued Novavax an EUA for its COVID-19 vaccine on July 13, 2022,  which was followed by a recommendation for use by the CDC. Novavax was authorized for use as a two-dose primary series in adults 18 years and older who had not previous received a COVID-19 vaccine.  According to the FDA, the vaccine was reported to be 90.4 percent effective at preventing mild, moderate, or severe COVID-19 illness. In persons 65 years and older, the vaccine was reported to be 78.6 percent effective. Clinical trials, however, were conducted prior to the emergence of the Delta and Omicron variants, and information on the vaccine’s effectiveness against these strains was not known.  In August 2022, the FDA expanded use of the vaccine in persons 12 years of age and older. 

In September 2022, the CDC recommended that individuals who received the Novavax COVID-19 vaccine series get a booster dose of an mRNA bivalent COVID-19 vaccine (either Moderna or Pfizer-BioNTech) at least two months following the second vaccine dose.  A booster dose of Novavax vaccine in persons 18 years and older who were unable to receive an mRNA COVID-19 vaccine, or in adults 18 years and older who would otherwise not receive a COVID-19 vaccine was authorized for use by the FDA on October 19, 2022. This booster dose was recommended to be given at least six months after completion of the primary COVID-19 vaccine series or most recent vaccine dose. 

In February 2021, the CDC stated that currently available mRNA COVID-19 vaccines would likely offer fully vaccinated individuals at least three months of vaccine-acquired immunity. In their quarantine guidance released on February 11, 2021, the CDC stated that fully vaccinated people (those who had received two doses of COVID-19 vaccine) who were exposed to SARS-CoV-2 through close contact would not be required to quarantine as long as vaccination had occurred within three months and they remained asymptomatic. 

However, in March 2021 the CDC’s website stated that it was not unknown how effective, or for what length of time the experimental COVID-19 vaccines would provide immunity against COVID 19 illness. The website also reported that it was also not known how effective the vaccine would be in mediating the severity of illness, should the vaccine fail to prevent COVID-19. 

On April 27, 2021, fully vaccinated individuals were still being told that they must stay at least 6 feet apart from others; wear masks in certain outdoor crowded public settings and indoor public settings; and when in gatherings with unvaccinated individuals. Vaccinated individuals were also being told to take precautions when visiting unvaccinated individuals who were at an increased risk for severe COVID-19 disease and to be vigilant about symptoms and get tested when they occur. The CDC, however, stated that vaccinated individuals could travel domestically and internationally without quarantining, and that pre- and post- travel testing was not required, unless the international destination required it. Persons entering the U.S., however, were still required to show a negative COVID-19 test result before boarding a flight and testing was still advised 3-5 days following international travel. 

In May 2021, the CDC announced that fully vaccinated individuals could resume activities without masking or physically distancing, except where required by law, workplace or local requirements. Additionally, they could travel domestically without testing or self-quarantine, and travel internationally without testing unless their destination required it, and would not be required to self-quarantine on return. Vaccinated persons exposed to someone with SARS-CoV-2 were also advised that they would not need to self-quarantine or test unless symptomatic. 

Since emergency use of the experimental COVID-19 vaccines was authorized by the FDA in December 2020, there have been multiple reports of fully vaccinated individuals testing positive for SARS-CoV-2.            

In early 2021, the CDC began reporting cases, hospitalizations, and deaths among fully vaccinated individuals. By April 30, 2021, the CDC reported 10,262 cases, 995 hospitalizations, and 160 deaths among persons who had been fully vaccinated, with the CDC acknowledging that the actually number of breakthrough cases were likely much higher due to the passive and voluntary system of reporting. 

In late April 2021, the CDC announced that it was only going to be reporting the number of breakthrough cases that resulted in hospitalization and death “to help maximize the quality of the data collected on cases of greatest clinical and public health importance.”  As a result, the public would not be made aware of the actual number of reported breakthrough cases occurring fully vaccinated individuals.

On July 27, 2021, the CDC issued a health alert and reported that fully vaccinated individuals could still become infected and be capable of transmitting the virus to others. Public health officials reported that the SARS-CoV-2 variants currently circulating in the U.S., especially the Delta variant, were highly transmissible and increasing the rate of infections. The CDC also recommended that all persons, including fully vaccinated individuals, wear masks in public indoor spaces in communities with high or substantial transmission rates. 

While this health alert reported that most COVID-19 cases, hospitalizations, and deaths were occurring in unvaccinated individuals,  data released from an outbreak in Massachusetts reported that 74 percent of cases had occurred in fully vaccinated individuals. Additionally, four of the five hospitalizations reported during this study occurred in fully vaccinated individuals. 

A study published in Science using data from the U.S. Veterans Health Administration published in early November 2021 reported that after six months, the effectiveness of all three available COVID-19 vaccines had significantly waned. The Moderna COVID-19 vaccine effectiveness decreased from an 89.2 percent effectiveness in March 2021 to a 58 percent effectiveness by September 2021. The Pfizer-BioNTech COVID-19 vaccine was reported to have decreased in effectiveness from 86.9 percent in March 2021 to 43.3 percent by September 2021. The Janssen/Johnson & Johnson COVID-19 vaccine decreased from an effectiveness of 86.4 percent in March 2021 to only a 13.1 percent effectiveness by September 2021. 

In the summer of 2023, the Informed Consent Action Network (ICAN), a non-profit dedicated to eradicating man-made disease, obtained FDA email communications pertaining to the effectiveness of COVID-19 vaccines in the first half of 2021 through a Freedom of Information Act (FOIA) request. These emails revealed that health regulators were aware that a data analysis compiled on 20 million Medicare beneficiaries had found that COVID-19 vaccine effectiveness waned rapidly within 5-6 months post vaccination for both infection and hospitalization in persons 65 years and older. The emails also reported that health officials knew that similar trends were emerging in the data among seniors who were 3-4 months post-vaccination.  

This data, however, was not revealed to the public during the August 2021 ACIP and September 2021 VRBPAC meetings convened to review and make recommendations on COVID-19 vaccine booster doses. Instead, data from the CDC’s COVID-NET, which showed the vaccine effectiveness against hospitalization to be 80 percent during the delta variant surge, was presented. Additional data, including studies on the Pfizer vaccine effectiveness in Israel, which showed the vaccine to be between 39 and 84 percent effective against infection and between 75 and 95 percent against hospitalization were also presented in lieu of the Medicare data analysis. 

Efficacy of the original COVID-19 mRNA vaccines

In February 2021, a study questioning the efficacy of COVID-19 vaccines expressed concerns regarding the absence of data on absolute risk reduction in the Pfizer-BioNTech and Moderna COVID-19 vaccine clinical trials. 

According to this study, the Pfizer-BioNTech COVID-19 vaccine showed an absolute risk reduction of 0.7 percent (95% CI 0.59% to 0.83%) and the study author, Ronald Brown, reported that 142 people (95% CI 122 to 170) would need to be vaccinated to prevent one case of COVID-19. The Moderna COVID-19 vaccine showed an absolute risk reduction of 1.1 percent (95% CI 0.97% to 1.32%) and 88 individuals (95% CI 76 to 104) would need to be vaccinated to prevent one COVID-19 case.

Brown concluded by noting that:

“A critical appraisal of phase III clinical trial data for the Pfizer/BioNTech vaccine BNT162b2 and Moderna vaccine mRNA-1273 shows that absolute risk reduction measures are very much lower than the reported relative risk reduction measures. Yet, the manufacturers failed to report absolute risk reduction measures in publicly released documents. As well, the U.S FDA Advisory Committee (VRBPAC) did not follow FDA published guidelines for communicating risks and benefits to the public, and the committee failed to report absolute risk reduction measures in authorizing the BNT162b2 and mRNA-1273 vaccines for emergency use. Such examples of outcome reporting bias mislead and distort the public’s interpretation of COVID-19 mRNA vaccine efficacy and violate the ethical and legal obligations of informed consent.”

The B.1.1.529 variant (Omicron), which was initially identified in early November 2021 in South Africa, was labeled a Variant of Concern by WHO on November 26, 2021. According to WHO, the variant was concerning because it contained a significant number of mutations  and might evade vaccine-acquired immunity.

A study from Denmark completed in late 2021 noted that fully vaccinated individuals were at greater risk of COVID-19 infection than unvaccinated, and those who received a booster dose were at an even greater risk of infection from the Omicron variant of COVID-19. 

In January 2022, a paper completed in Canada studied the data from person 18 years of age and older who had a PCR test for SARS-CoV-2 between November 22 and December 19, 2021. The study, which excluded long-term care residents and individuals who had received only one COVID-19 vaccine dose or who had received their second dose less than 7 days prior to being tested, reported:  

“…receipt of 2 doses of COVID-19 vaccines was not protective against Omicron infection at any point in time, and VE was –38% (95%CI, –61%, –18%) 120-179 days and –42% (95%CI, –69%, –19%) 180-239 days after the second dose. VE against Omicron was 37% (95%CI, 19-50%) ≥7 days after receiving an mRNA vaccine for the third dose. Findings were consistent for any combination of 2 mRNA vaccines and 2 doses of BNT162b2 for the primary series.”

The authors concluded that “two doses of COVID-19 vaccines are unlikely to protect against infection by Omicron. A third dose provides some protection in the immediate term, but substantially less than against Delta.”  

A CDC study published in February 2022 reported that after four months, a third dose of COVID-19 vaccine was significantly less effective at protecting a person against severe COVID-19 illness caused by the Omicron variant. According to this study, the effectiveness of the third dose against hospitalization dropped from 91 percent at two months to only 78 percent at four months. Effectiveness of the booster dose against urgent care or emergency room visits decreased from 87 percent at two months to 66 percent at four months. By five months, the effectiveness was found to be only 37 percent. 

A study published in the New England Journal of Medicine in June 2022 found that two doses of COVID-19 vaccine did not offer any protection against the Omicron variant and could potentially increase a person’s risk of infection. 

An article published in the New England Journal of Medicine in September 2022 found that children who had COVID-19 illness and were subsequently vaccinated with the Pfizer-BioNTech mRNA COVID-19 vaccine were more likely to get COVID-19 illness during the Omicron wave. Children who had not experienced a COVID-19 illness but received a COVID-19 vaccine were also more likely to become infected from the Omicron variant. Children with natural immunity from prior infection and who remained unvaccinated, however, were the least likely to become re-infected. 

A study completed in 2022 found that within 150 days, the effectiveness of the Moderna COVID-19 turned negative against the Omicron BA.2, BA.4, and BA.5 subvariants. Additionally, the study also found that against the Omicron BA.1.12.1, the vaccine turned negative within 91 days. Negative effectiveness means that a vaccinated individual is more likely to contract the virus. The study, which was conducted by researcher from Moderna and Kaiser Permanente, also found that persons who received three vaccine doses were more likely to become infected than those who only received two doses. 

A study published in the CDC’s Morbidity and Mortality Weekly Report (MMWR) in November 2022 reported that the bivalent COVID-19 vaccines were less than 50 percent effective at preventing symptomatic COVID-19 illness. For individuals 65 years and older, the bivalent booster vaccine was reported to be only 32 percent effective in persons who received two primary doses. In those who received two primary doses and a monovalent booster before receipt of the bivalent booster, the effectiveness was only 19 percent. The bivalent vaccine was reported to be only slightly more effective in younger populations, but remained under 50 percent. This CDC sponsored study did not study the effects of the bivalent booster against severe disease, hospitalization, or death. 

Two studies conducted in the U.S. and released in late 2022 found that vaccinated individuals were more likely to develop COVID-19 infections.  One of the studies, found that the likelihood of COVID-19 infection increased with each subsequent dose and that unvaccinated individuals were least likely to become infected with COVID-19. 

An article published on September 30, 2021 in the European Journal of Epidemiology reported that vaccination has had no impact on COVID-19 rates. According to the published data that looked at COVID-19 cases in 68 countries and 2947 U.S. counties reported: 

At the country-level, there appears to be no discernable relationship between percentage of population fully vaccinated and new COVID-19 cases in the last 7 days. In fact, the trend line suggests a marginally positive association such that countries with higher percentage of population fully vaccinated have higher COVID-19 cases per 1 million people.

Study authors recommended that strategies focusing on vaccination as a primary method of mitigating COVID-19 be re-evaluated.

A conducted primarily by Danish researchers and published in April 2023 found that mRNA COVID-19 vaccines have had no impact on reducing all-cause mortality in randomized controlled trials (RCTs). Scientists involved in the research found that mRNA COVID-19 vaccines were only protective against fatal infection, while adenovirus vaccines such as the Janssen/Johnson & Johnson vaccine "were associated with lower overall mortality and lower non-accident, non-COVID-19 mortality." The paper also found that while mRNA COVID-19 vaccines reduced COVID-19 deaths, the vaccine increased cardiovascular deaths, but that the data for either was not statistically significant. 

COVID-19 Vaccines and Mortality Rates

An analysis conducted for The Health 202 in the fall of 2022 reported a higher mortality rate in COVID-19 vaccinated individuals than those who were unvaccinated. According to the study, in August 2022, 58 percent of deaths occurred in individuals who were either vaccinated or vaccinated and boosted. This was an increase from earlier in the year, when an estimated 42 percent of deaths occurred among vaccinated people. 

In June 2023, the FDA’s VRBPAC met and voted to recommend that all COVID-19 vaccines manufactured for use in the United States be updated to target the Omicron XBB strain, with a preference for the XBB.1.5 strain. The FDA advised COVID-19 vaccine manufacturers that they should develop a monovalent COVID-19 vaccine to specifically target the XBB.1.5 strain for use in 2023-2024. 

On September 11, 2023, the FDA approved use of the Pfizer-BioNTech Comirnaty and the Moderna SPIKEVAX 2023-2024 COVID-19 vaccines containing the SARS-CoV-2 Omicron variant XBB.1.5 for use in individuals aged 12 year of age and older. The FDA also authorized use of a 3mcg dose of Pfizer-BioNTech 2023-2024 COVID-19 vaccine for use in children aged 6 months through four years of age, a 10mcg dose of Pfizer-BioNTech 2023-2024 COVID-19 vaccine for use in children aged five through 11 years of age, and a 25 mcg dose of Moderna 2023-2024 COVID-19 vaccine for use in children aged 6 months through 11 years of age.  One day later, the CDC recommended use of the vaccines for all persons six months of age and older. 

Approval for the vaccines manufactured and distributed by Pfizer-BioNTech was based on safety and efficacy data from clinical trials completed for COVID-19 vaccines containing the original SARS-CoV-2 virus and on trials of an experimental COVID-19 vaccine containing the original SARS-CoV-2 and Omicron variant BA.1.   

No human clinical trials were conducted on the Pfizer-BioNTech 2023-2024 COVID-19 vaccines prior to the September 11, 2023 FDA approval and authorizations. Pfizer-BioNTech company officials, however, reported that the vaccine elicited immune responses when tested on 20 female mice. 

The FDA approved and authorized the Moderna 2023-2024 mRNA COVID-19 vaccines based on safety and efficacy data from clinical trials completed on the COVID-19 vaccines containing the original SARS-CoV-2 virus and on trials of an experimental COVID-19 vaccine containing the original SARS-CoV-2 and Omicron variant BA.1.   

Additionally, Moderna conducted a clinical trial involving 101 individuals previously vaccinated with 3 doses of the original monovalent COVID-19 vaccine and one dose of bivalent COVID-19 vaccine. Fifty adult participants received a 50 mcg dose of a monovalent COVID-19 vaccine containing the SARS-CoV-2 Omicron variant XBB.1.5 and fifty-one participants received a dose of a bivalent COVID-19 vaccine containing 25mcg of SARS-CoV-2 Omicron XBB.1.5 variant and 25mcg of Omicron BA.4/BA.5.

According to the data published by company officials, fifteen days after receipt of the vaccine, individuals who received the monovalent COVID-19 vaccine containing SARS-CoV-2 Omicron variant XBB.1.5 had higher antibody response against the original SARS-CoV-2 virus, and the Omicron XBB.1.5 and Omicron XBB.1.16 variant than those who received the experimental bivalent booster. Most clinical trial participants reported both localized and system adverse reactions following vaccination. Researchers reported that no serious adverse events or deaths occurred among trial participants, however, data was limited to only 20-22 days post vaccination. 

The FDA issued an EUA to Novavax for its adjuvanted COVID-19 vaccine containing spike protein from the Omicron XBB.1.5 variant of SARS-CoV-2 on October 3, 2023.  No clinical trials of this vaccine were conducted prior to FDA authorization. Instead, federal regulators stated that the authorization of this updated vaccine was based on safety and effectiveness data from the original Novavax COVID-19 vaccine clinical trials and an experimental monovalent and bivalent Novavax vaccine, along with post-marketing data. The FDA justified the use of data from different vaccine products by stating that “the data accrued with these Novavax COVID-19 vaccines are relevant to Novavax COVID-19 Vaccine, Adjuvanted (2023-2024 Formula) as the vaccines are manufactured using a similar process.” 

No human trials were conducted on the Novavax COVID-19 vaccine targeting Omicron XBB.1.5. Novavax company officials, however, reported that this vaccine produced “robust neutralizing responses against XBB subvariants” in rhesus macaques. 

The FDA revoked the EUA for the original Novavax COVID-19 vaccine when it authorized use of the Novavax COVID-19 vaccine containing the Omicron XBB.1.5 variant. 

AstraZeneca-University of Oxford COVID-19 vaccine

A vaccine development team from the University of Oxford in the United Kingdom endeavored to make an experimental COVID-19 vaccine candidate by the end of the summer of 2020. On April 23, 2020, human trials of the ChAdOx1 nCoV-19 experimental vaccine using a replication-deficient chimpanzee viral vector based on a weakened version of a common cold virus (adenovirus) that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein began. 

The University of Oxford reported that the initial clinical trials of ChAdOx1 nCoV-19 would involve 800 individuals. Half would receive the experimental vaccine while the other half would serve as the control group and receive a meningitis vaccine (MenACWY). 

Preliminary results of the AstraZeneca’s Phase 1 and Phase 2 trials were published in July 2020 in The Lancet.  This study involved 1,077 healthy adults between 18 and 55 years of age who were randomly given either the ChAdOx1 nCoV-19 vaccine (AZD1222) or the meningococcal conjugate (MenACWY) vaccine. Systemic and local reactions were reported to be more common in the trial group given the experimental COVID-19 vaccine, and a selection of participants from both groups received prophylactic paracetamol (acetaminophen) before vaccinations were administered.

In April 2020, Oxford University partnered with AstraZeneca to develop, manufacture, and distribute the ChAdOx1 nCoV-19 vaccine (now referred to as AZD1222) and U.S. Phase 3 clinical trials began in late August 2020. Their goal was to enroll 30,000 vaccine participants through 62 sites. On September 8, 2020, the pharmaceutical company announced that it was putting the trial on hold after a female participant in the U.K. developed transverse myelitis, a rare but serious neurological disorder, which causes inflammation of the spinal cord.  This was the second time that AZD1222 vaccine trials were placed on hold. In July 2020, trials were paused after a woman developed multiple sclerosis; however, company officials reported that her diagnosis was not related to vaccination. 

While clinical trials resumed quickly in several countries including Great Britain, Japan, South Africa, India,  and Canada,   trials in the U.S. remained on hold until October 23, 2020.  

On October 1, 2020, the European Medicines Agency (EMA) stated that it had started reviewing AstraZeneca’s COVID-19 clinical trial data in real time, and anticipated that following approval, all adults in Britain could receive at least one vaccine dose within 6 months. 

At the January 27, 2021 advisory committee meeting of the U.S. Centers for Disease Control (CDC), company officials from AstraZeneca reported that across the four studies, serious adverse events occurred in 168 participants, with 79 occurring among persons who received the experimental COVID-19 vaccine, and 89 among persons who received either the MenACWY vaccine or saline control. In total, 175 serious adverse events were reported; however, only four events were considered as possibly related to vaccination by clinical trial investigators. Company officials also reported that most solicited adverse events were mild to moderate and the majority resolved within a few days of vaccination. 

The European Union approved the vaccine for use in individuals 18 years and older on January 29, 2021, despite limited data to support its effectiveness in adults over the age 55 years. The University of Oxford and AstraZeneca’s COVID-19 vaccine was estimated to have an efficacy of about 60 percent. 

Health officials in South Africa halted use of the AstraZeneca COVID-19 vaccine after it was found to be less than 25 percent effective against the B.1.351 variant, the most common SARS-CoV-2 virus variant circulating in South Africa at the time. 

On March 12, 2021, CNN reported that while AstraZeneca, and UK and European regulators stated there was no evidence of this experimental COVID-19 vaccine causing blot clots, a number of countries suspended use of the vaccine. These countries included Denmark, Norway, Iceland, and Thailand. Other countries, including Austria and Italy chose instead to suspend specific batches of the vaccine, while Spain delayed rollout of the AstraZeneca vaccine. 

The World Health Organization (WHO) issued a statement on March 19, 2021 stating that their Global Advisory Committee on Vaccine Safety reviewed data on the vaccine in relation to blood clots and low platelets after vaccination and concluded that the rates of these events were fewer than when they occur naturally in the generalized population. The WHO added that these events would continue to be monitored. 

Soon thereafter, Canadian health officials joined France and limited the vaccine’s use in persons under 55 years of age, stating “From what is known at this time, there is substantial uncertainty about the benefit of providing AstraZeneca COVID-19 vaccine to adults under 55 years of age,” and had requested a new risk analysis on the vaccine’s risks and benefits broken down by age and gender.  On March 30, 2021, Germany limited the vaccine’s use to persons over the age of 60. 

On April 7, 2021, the European Medicines Agency (EMA) safety committee (PRAC) concluded that “unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca).” In their report, PRAC reminded health care professionals and vaccine recipients to be aware of the possibility of “blood clots combined with low levels of blood platelets occurring within 2 weeks of vaccination.” PRAC reported that the blood clots occurred in the abdomen (splanchnic vein thrombosis), brain (cerebral venous sinus thrombosis or CVST), and arteries, in conjunction with low levels of blood platelets and at times with bleeding. 

According to PRAC, “One plausible explanation for the combination of blood clots and low blood platelets is an immune response, leading to a condition similar to one seen sometimes in patients treated with heparin (heparin induced thrombocytopenia, HIT).” New studies and revised protocols to ongoing clinical trials have been requested by safety officials. 

In the spring of 2021, German researchers described what they believed to be the two-step mechanism responsible for the serious clotting reaction following the AstraZeneca COVID-19 vaccine. According to the scientists, the first step involved the activation of blood platelets when they came into contact with the adenovirus outer shell and the proteins from the cells where the vaccine grows. When this occurred in large numbers, a signal would activate B-cells that then would produce an enormous number of antibodies against the platelet factor 4 protein, which is what assists to coordinate blood clotting. The body then believes that it is responding to a huge number of pathogens in the body, and causes antibodies to bind to the platelets, pull in white blood cells, and cause a systemic disruption. The second step involved the calcium-binder and stabilizer, EDTA, that is an ingredient in the AstraZeneca vaccine. EDTA reportedly causes the blood vessel walls to open up and permit entry of the protein and platelet complexes to begin circulation in the blood stream and triggers the syndrome. 

While many cases of the serious blood clotting disorder were reported to have occurred in women, lead author Dr. Andreas Greinacher reported that this disorder was not specific to one gender. Greinacher noted that since most health-care workers were women and part of the initial group of people to receive the vaccine, the tendency for cases to be reported among females was significantly higher. 

An in-depth review of 24 cases of splanchnic vein thrombosis and 62 cases of cerebral venous sinus thrombosis reported to the EU drug safety database, EudraVigilance, as of March 22, 2021 was completed by the committee. Of these cases, 18 were reported as fatal. The committee, however, continued to recommend the vaccine, stating that “The reported combination of blood clots and low blood platelets is very rare, and the overall benefits of the vaccine in preventing COVID-19 outweigh the risks of side effects.” 

Vaccine use has resumed in many countries; however, some countries have restricted use of the product to persons over the age of 60 or 65 years of age.  In April 2021, Danish health officials announced that it was halting use of the vaccine after studies had noted that blood clots occurred at a rate of one in 40,000 people. 

By April 22, 2021, more than 220 cases of blood clots in conjunction with low platelets had been reported by European regulators following AstraZeneca vaccination. 

The AstraZeneca COVID-19 vaccine was also linked to Guillain-Barré Syndrome (GBS), a serious neurological disorder where the body’s immune system attacks the peripheral nervous system, and result in muscle weakness, paralysis, and even death. On September 8, 2021, the EMA stated that GBS should be listed as a potential adverse event following vaccination. According to the EMA, by July 31, 2021, 833 cases of GBS had been reported after AstraZeneca COVID-19 vaccination. 

In July 2021, AstraZeneca announced plans to seek full approval of the vaccine, rather than a fast-tracked status, in U.S.  However, in November 2022, AstraZeneca company officials announced that it had withdrawn its application for approval with the FDA, citing the ample availability of COVID-19 vaccines and the decreasing demand for the product. 

Inovio Pharmaceuticals INO-4800 DNA experimental vaccine

In early April 2020, Inovio pharmaceuticals began Phase 1 clinical trials of its experimental COVID-19 DNA vaccine, INO-4800. Inovio’s COVID-19 vaccine research had been funded by a $9 million grant from the Norway-based Coalition for Epidemic Preparedness Innovations (CEPI) and a $5 million grant from the Bill and Melinda Gates Foundation. It also has a partnership with Philadelphia’s Wistar Institute and Beijing Advaccine Biotechnology Co. in China to develop the vaccine in addition to a $11.9 million contract with the U.S. Department of Defense to provide the experimental DNA coronavirus vaccine potential use in military personnel. 

Inovio’s INO-4800 vaccine injects a small piece of circular DNA, called a plasmid (pGX9501), that encodes for the entire length of the Spike glycoprotein of SARS-CoV-2  to provoke the vaccine recipient’s cells into producing antibodies. The biggest challenge for DNA/RNA vaccines is getting patients’ cells to accept the introduced genetic material. Currently, the most effective technique appears to be electroporation, which is the delivering short pulses of electrical current to the patient to open cell pores and allow the plasmids to enter. This vaccine, unlike many of its counterparts, is stable at room temperature for over a year.    

On June 30, 2020, Inovio Pharmaceutical announced positive results from its Phase 1 clinical trials. Participants received either a 1.0mg or 2.0mg dose administered using INOVIO's CELLECTRA® 2000 device. According to company officials, all 10 reported adverse events were considered Grade 1 and involved localized injection site redness. 

INOVIO’s CELLECTRA® 2000 electroporation device delivers short pulses of electrical current to the patient in addition to the vaccine. The electricity creates temporary pores in a patient’s cell membranes and this process enables the DNA/RNA to enter.    The device is also associated with higher rates of injection site pain in comparison to standard injections.

In late September 2020, the U.S. Food and Drug Administration (FDA) placed the INO-4800 experimental vaccine trials on partial hold and requested more information on the clinical trials and the device used to deliver the vaccine. 

INOVIO announced in November 2020 that their INNOVATE Phase 2/3 randomized, blinded, placebo-controlled safety and efficacy trial would be funded by the U.S. Department of Defense and by December of 2020, the company had published Phase 1 clinical trial data suggesting that the vaccine generated both humoral (neutralizing antibodies) and/or cellular responses in CD4 and CD8 T cells. 

In October 2022, INOVIO company officials announced that it had discontinued trials of INO-4800 in the U.S. Trials of the vaccine candidate, however, were continuing in China through its partnership with Advaccine. 

Convidicea. CanSino Biologics, Inc. of Tianjin, China, in partnership with China’s Academy of Military Medical Sciences’ Institute of Biotechnology, also began development of a COVID-19 vaccine, Convidicea (Ad5-nCoV), that employs a chimpanzee adenovirus vector using the HEK293 cell lines derived from tissue of an aborted fetus. Phase 1 clinical trials of the CanSino vaccine enrolled 108 participants, where 87 of whom (81 percent) experienced at least one adverse reaction within seven days of vaccination. The most common reactions included headache, pain, fever, and fatigue. 

By December of 2020, Convidicea clinical trials had been launched in Saudi Arabia,  Moscow,  Mexico,  and Chile,  with advanced purchase agreements totaling 35 million doses. 

Pakistan and Mexico approved Convidicea under emergency prior to approval by any international health organizations and completion of Phase 3 trials in early 2021.   

CoronaVac. Beijing-based Sinovac Biotech Ltd began Phase 3 trials in July of CoronaVac, an inactivated coronavirus vaccine utilizing traditional vaccine manufacturing processes. To develop its vaccine, Sinovac obtained SARS-CoV-2 virus from patients globally, cultured and grew the virus in vero cells, which are derived from monkey kidneys. The virus was then inactivated with beta-propiolactone, a chemical derived from formaldehyde, and prepared and bottled as a vaccine. 

In September 2020, reports indicated that health officials in China had already begun administering experimental COVID-19 vaccines under their emergency use laws to their citizens prior to completion of Phase 3 clinical trials. Frontline healthcare workers, public officials, border security personnel, persons considered high-risk for COVID-19 infection as well as pharmaceutical company officials and their families were first to be given the experimental vaccines. Persons receiving the vaccines were required to sign a “nondisclosure agreement” which would prevent them from sharing any details to the media. 

On November 9, 2020, CoronaVac Phase 3 clinical trials were halted in Brazil due to a death that occurred in a vaccine trial recipient. Two days later, clinical trials resumed, and the death was reported as a suicide that was not related to vaccination. 

In December 2020, CoronaVac was reported to be 50.65 percent effective against COVID-19 illness in Brazil among health care workers 18 years of age and older. Company officials reported the vaccine to be 91.25 percent effective in clinical trials conducted in Turkey; however, this data was based on a preliminary analysis of only 29 cases. The Indonesia trial reported a vaccine effectiveness of 65.3 percent. China approved the vaccine for use by the general public in early February 2021.  By March 2021, CoronaVac became available for use in Tunisia, the Philippines, Mexico, Malaysia, Turkey, Indonesia,  and Brazil. 

In June 2021, China authorized CoronaVac vaccine for children between the age of 3 and 17 years.  By July 2021, company officials announced that a non-peer reviewed study found that the use of a third vaccine dose invoked a strong immune response and that adverse events were lower than those seen following the initial 2-dose series.

A study published in the Lancet reported an increased risk of Bell’s Palsy following CoronaVac vaccine but that the benefits of vaccination outweighed the risk. 

A COVID-19 vaccine using viral vector technology, Sputnik V, developed in partnership between the Russian research institution, the Gamaleya National Center of Epidemiology and Microbiology, and the Russian Direct Investment Fund, received approval for widespread use by Russian authorities in early August 2020. Sputnik V uses two different strains of adenovirus and requires a second vaccine dose after 21 days to boost the immune response. The Lancet published data on the vaccine’s Phase 1/2 trials on September 4, 2020. Concerns about the lack of transparency related to pre-licensing clinical trial results had been expressed by some in the scientific community. 

On February 2, 2021, interim results from the Sputnik V (Gam-COVID-Vac) Phase 3 trials were published in The Lancet, which reported the vaccine to be 91.6 percent effective at 21 days following administration of the first vaccine dose (on the day that dose 2 was administered). Clinical trials of this vaccine included healthy adults 18 years of age and older who were negative for SARS-CoV-2 at baseline. Seventy serious adverse events were reported among 68 trial participants across both the vaccine group and the control group; however, trial investigators declared that none were related to vaccination. Four deaths occurred during the Phase 3 trials, three in vaccine recipients and one in the placebo group. No deaths were considered to be related to vaccination. Researchers report that the durability of vaccine acquired immunity is not known and it is not known whether the vaccine can halt transmission of SARS-CoV-2. 

In early February 2021, Russian vaccine developers reported that they were in discussions with China’s CanSino Biologics to study whether the second dose of the Sputnik V vaccine could be replaced with the COVID-19 vaccine manufactured by the Chinese vaccine maker. Vaccine researchers are looking to find out if combining COVID-19 vaccines made by different pharmaceutical companies could still offer adequate vaccine acquired immunity, or even better protection against the emerging virus variants. 

By March 2021, Sputnik V vaccine distribution agreements spanned more than 50 countries. On June 17, 2021, company officials reported that a booster dose targeting the Delta variant would soon be available. 

Sputnik V vaccine is approved for use in over 70 countries worldwide.