What is COVID-19 vaccine?

According to the U.S Food and Drug Administration (FDA), pre-licensing clinical trials are generally conducted in three phases. Phase 1 trials are the initial human studies involving a small number of individuals to test for safety and immune response. Phase 2 studies usually enroll a slightly larger number of subjects and focuses on selecting the product’s dosage. The final pre-licensing study, Phase 3, collects data on the experimental product’s effectiveness and safety. The FDA reports that Phase 3 trials typically involve thousands of subjects.¹¹

Double-blind, randomized, placebo-controlled trials (RCTs) are considered the most reliable research method. In these studies, one group of subjects receives the experimental product being tested while the other group receives a placebo designed to appear as similar as possible to the product being studied. Individuals in both groups do not know whether they are receiving the experimental product or the placebo. Additionally, the researchers conducting the trials are also not made aware about which group is receiving which treatment (making it a "double-blind" experiment). This is important, as it prevents the researchers from unconsciously biasing their evaluation of the results or unintentionally tipping off the study participants.¹²

If pre-licensing clinical trials are considered successful, the manufacturer can submit a Biologics License Application (BLA). This application must include safety and efficacy data and contain enough information to allow the FDA review team to decide on whether to approve or deny a vaccine. Once the application is reviewed by the FDA, the manufacturer along with the FDA may present their information to the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC). This committee is comprised of non-FDA scientists, physicians and others whose charge is to provide advice to the FDA on the data provided in a public forum. The FDA, however, has the option to disregard any feedback it receives from VRBPAC.¹³

Typically, it takes several years, if not decades, for pharmaceutical companies to develop, test, and receive approval for a new vaccine. The fastest timeline to date for a vaccine to complete all stages of clinical development, pre-licensing clinical trials and FDA-approval has been four years.¹⁴

On June 30, 2020, the 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 illness or reducing its severity.¹⁵

The FDA released its guidance for industry regarding Emergency Use Authorization (EUA) approval for COVID-19 vaccines on October 6, 2020, and stated that it 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 manufacturers submit information on a minimum of five cases of severe COVID-19 disease among individuals who received the placebo.¹⁶

However, vaccine trial designs have faced criticism and in October of 2020 the British Medical Journal (BMJ) noted that Phase 3 trials for Moderna, Pfizer, AstraZeneca COVID-19 vaccines will not answer basic questions around preventing infection and reducing the likelihood of severe illness.¹⁷

A September 2020 article in Forbes by noted biologist William Haseltine, PhD¹⁸ revealed that COVID-19 vaccine studies by Moderna, Pfizer, AstraZeneca, and Johnson & Johnson intend “to complete interim and primary analyses that at most include 164 participants.” ¹⁹

According to Dr. Haseltine, with an efficacy success requirement of 70 percent, this equates to interim analysis based on the results of infection ranging from 32 (Moderna) vaccine to 77 (Johnson & Johnson) vaccine recipients. Dr. Haseltine concluded by saying that COVID-19 vaccine trials were in essence designed to succeed. The article also contained many of the same concerns noted in the October 2020 BMJ article and added that “vaccines currently under trial will not be the silver bullet” ending the pandemic.²⁰

According to the FDA, vaccine makers may submit an application to have their products approved under an Emergency Use Authorization (EUA). 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.”²¹ To learn more about EUA products and vaccines and consumer rights, visit NVIC’s FAQ on Emergency Use Vaccines (EUA) & Vaccine Injury Compensation.

In December 2020, two experimental messenger RNA COVID-19 vaccines developed and produced by Pfizer - BioNTech and Moderna with NIAID were granted an EUA by the FDA to release the vaccines for use in the U.S.^{22 23} Messenger RNA (mRNA) vaccines are gene based vaccines that involve injecting lipid nanoparticles containing mRNA (genetic code) that enable the vaccine to get past the cell wall, into the intracellular space, then causes the cell’s ribosome to make viral proteins (antigen that stimulate the immune system.)²⁴ In essence, an mRNA vaccine tricks the body into producing the viral proteins to trigger an immune response.²⁵ Messenger RNA vaccines can be produced in the lab using faster and less expensive processes than traditional vaccines.²⁶

On February 27, 2021, the FDA granted an Emergency Use Authorization to Johnson & Johnson and Janssen Pharmaceutical Companies for a non-replicating viral vaccine. This experimental vaccine uses an adaption of human adenovirus 26 (Ad26), which causes common colds, to transport the SARS-CoV-2 spike protein code into the body to trigger an immune response.^{27 28 29}

The FDA issued an Emergency Use Authorization to Novavax for an experimental COVID-19 vaccine using recombinant nanoparticle technology on July 13, 2022.³⁰ Referred to as a protein subunit vaccine,³¹ this vaccine contains Novavax’s patented saponin-based Matrix-M™ adjuvant designed to enhance the immune response and stimulate high levels of neutralizing antibodies.³²

On August 23, 2021 the FDA licensed and granted EUA status to Comirnaty COVID-19 vaccine, an mRNA vaccine developed by BioNTech, for use in persons 16 years of age and older.³³ The FDA also stated that use of Comirnaty and the experimental Pfizer-BioNTech mRNA COVID-19 vaccine are interchangeable due to having the same formulation.^{34 35}  However, the FDA 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 are legally distinct. ^{36 37}  

Following FDA approval of Comirnaty in August 2021, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended use of the 2-dose vaccine series in persons 16 years of age and older.³⁸ The FDA licensed Comirnaty for use in teens 12 through 15 years in July 2022.³⁹

When a product receives a priority review designation by the FDA, the decision to take action on the application is usually done within six months.⁴⁰ In the case of the Pfizer – BioNTech vaccine, the decision to grant full approval was completed in less than four months.⁴¹

Prior to granting approval of Comirnaty, the FDA declined to hold a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting⁴² 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.”⁴³

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.”⁴⁴

The Pfizer-BioNTech mRNA COVID-19 vaccine was initially issued an EUA by the FDA on December 11, 2020 for use in persons 16 years of age and older.⁴⁵ The FDA expanded the EUA to include adolescents 12 and older on May 10, 2021.⁴⁶

According to the Fact Sheet provided by the FDA,⁴⁷ the Comirnaty /Pfizer-BioNTech COVID-19 Vaccine is manufactured and made available as a frozen suspension in vials that contain multiple doses. Each individual vial must be diluted with 1.8 ml of sterile 0.9 percent Sodium Chloride injection, USP, before use.

Each dose contains 30 mcg of a nucleoside-modified messenger RNA (modRNA) that encodes the viral spike (S) glycoprotein of SARS-CoV-2. Additional vaccine ingredients include lipids (0.43 mg (4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg 2[(polyethylene glycol)-2000- N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.2 mg cholesterol), 0.01 mg monobasic potassium phosphate, 0.36 mg sodium chloride, 0.01 mg potassium chloride, 6 mg sucrose, and 0.07 mg dibasic sodium phosphate dihydrate. The 0.9 percent Sodium Chloride Injection, USP adds another 2.16 mg sodium chloride per dose.

This vaccine does not contain a preservative and the vaccine vial stoppers are free of latex.

Additionally, the Comirnaty/Pfizer-BioNTech Fact Sheet states:

“The modRNA in the Pfizer-BioNTech COVID-19 Vaccine is formulated in lipid particles, which enable delivery of the RNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits an immune response to the S antigen, which protects against COVID-19.” ⁴⁸

On December 16, 2021, the FDA approved a change to the ingredients of Pfizer’s Comirnaty vaccine. The ingredient, Tris, is a buffer that, according to the FDA, will permit the vaccine to be more stable at refrigerator temperatures for long periods of time.⁴⁹

The Comirnaty/Pfizer-BioNTech COVID-19 vaccine is recommended to be given intramuscularly (IM) as a two-dose series administered three weeks apart. The CDC also states that the interval time between the first and second dose can 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. Males between the ages of 12 and 39 are considered at highest risk for myocarditis.^{50 51}

There is no available data on the interchangeability of the Comirnaty/Pfizer-BioNTech COVID-19 Vaccine with other COVID-19 vaccines to complete the two-dose vaccination series. Persons who have received one dose of Comirnaty/Pfizer-BioNTech COVID-19 Vaccine should complete the series by receiving a second dose of Comirnaty/Pfizer-BioNTech COVID-19 Vaccine.⁵²

There is no data available on the co-administration of the Comirnaty/Pfizer-BioNTech Vaccine with any other vaccine product.⁵³

The duration of vaccine-acquired immunity from Pfizer-BioNTech’s COVID-19 vaccine is not known.⁵⁴ It is now known that this vaccine is incapable of reducing or stopping transmission of the virus. This means that vaccinated individuals may still be capable of transmitting the virus to others.^{55 56}

There is 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).⁵⁷

The Pfizer-BioNTech COVID-19 vaccine is recommended to be shipped and stored between -80ºC to -60ºC (-112ºF to -76ºF) and protected from light until ready to use.⁵⁸ On February 25, 2021, the FDA announced that frozen undiluted vials of the Pfizer-BioNTech COVID-19 could also be transported and stored at temperatures typically found  in pharmaceutical freezers for up to 14 days.⁵⁹ Temperature storage and shipping guidelines were updated again on May 19, 2021, which permitted undiluted, thawed vaccines to be stored at refrigerator temperatures, 2°C to 8°C (35°F to 46°F), for up to 1 month.⁶⁰

Mishandling of the vaccine during any step of the distribution process may result in an ineffective vaccine product. ⁶¹

Pfizer – BioNTech mRNA COVID-19 Pediatric Vaccine

On October 29, 2021, the FDA authorized use of a 10-mcg dose of Pfizer-BioNTech mRNA COVID-19 vaccine for children 5 through 11 years of age.⁶²

According to the Fact Sheet provided by the FDA,⁶³ each 0.2 ml dose of Pfizer-BioNTech COVID-19 Vaccine contains 10mcg of nucleoside modified messenger RNA (mRNA) that encodes the pre-fusion stabilized Spike glycoprotein (S) of SARS-CoV-2 virus. The multidose vials with orange caps and labels with orange borders must be diluted with 1.3ml of sterile 0.9 percent sodium chloride prior to use.

Each dose also contains a total lipid content of (0.14 mg (4- hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.03 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.06 mg cholesterol), 0.02 mg 2[(polyethylene glycol)-2000- N,N-ditetradecylacetamide,10.3 mg sucrose, 0.02 mg tromethamine, and 0.13 mg tromethamine hydrochloride. The vaccine also contains 0.9mg sodium chloride per dose. The vaccine vial stoppers are free of latex and the vaccine does not contain a preservative.

According to the FDA:⁶⁴

“To provide a vaccine with an improved stability profile, the Pfizer-BioNTech COVID-19 Vaccine for use in children 5-11 years of age uses tromethamine (Tris) buffer instead of the phosphate buffered saline (PBS) as used in the previous formulation and excludes sodium chloride and potassium chloride. The packaged vials for the new formulation are stored frozen at -90°C to - 60°C. The frozen vials may be thawed and stored at refrigerator at 2°C to 8°C for up to 10 weeks.”

The vaccine is recommended to be administered intramuscularly (IM) as a two-dose primary series, three weeks apart. There is no data on the safety or effectiveness of administering the Pfizer-BioNTech vaccine with any other vaccine.

On November 2, 2021, the CDC’s ACIP voted to approve use of the 10mcg dose of the Pfizer-BioNTech COVID-19 vaccine in all children 5 through 11 years of age.⁶⁵ An additional dose of the Pfizer-BioNTech COVID-19 pediatric vaccine was also authorized for use in moderately or severely immunocompromised children, to be administered 28 days after the second vaccine dose.^{66 67} In May 2022, ACIP voted to recommend that all children 5 through 11 years receive a booster dose of COVID-19 vaccine to be administered five months after completion of the 2-dose vaccine series.⁶⁸

Pfizer – BioNTech mRNA COVID-19 Vaccine for Infants and Young Children

On June 17, 2022, the FDA issued an EUA for a 3mcg dose of Pfizer-BioNTech mRNA COVID-19 Vaccine for infants and young children aged 6 months through 4 years of age.⁶⁹

According to the Fact Sheet provided by the FDA,⁷⁰ the vaccine is supplied in a maroon colored capped multi-dose vial and labeled with maroon borders. The frozen vaccine suspension must be diluted with 2.2 mL of sterile 0.9 percent sodium chloride prior to use. Each 0.2 mL dose of the vaccine contains 3mcg of nucleoside modified messenger RNA (mRNA) that encodes the pre-fusion stabilized Spike glycoprotein (S) of SARS-CoV-2 virus.

Each dose also contains the following ingredients: 3.2 mg sucrose, 0.006 mg tromethamine, 0.04 mg tromethamine hydrochloride; lipids (0.04 mg ((4- hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.005 mg 2[(polyethylene glycol)-2000- N,N-ditetradecylacetamide, 0.01 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.02 mg cholesterol). The sterile 0.9 percent sodium chloride diluent adds 1.52 mg of sodium chloride per dose. The vaccine vial stoppers are free of latex and the vaccine does not contain a preservative.⁷¹

The vaccine is recommended to be administered intramuscularly (IM) as a three-dose primary series, with the first two doses administered three weeks apart, followed by a third dose at least 8 weeks after the second dose. There is no data on the safety or effectiveness of administering the Pfizer-BioNTech COVID-19 vaccine with any other vaccine.⁷²

The CDC’s ACIP voted to recommend use of the Pfizer-BioNTech mRNA COVID-19 vaccine for all children 6 months through 4 years of age on June 18, 2022. The recommendation also included infants and young children with a prior history of COVID-19 infection.⁷³

Pfizer-BioNTech Monovalent Booster Doses

Prior to August 31, 2022, the CDC and FDA recommended that all persons 5 years and older receive a booster dose of the primary COVID-19 vaccine, to be administered five months following receipt of the second Pfizer-BioNTech COVID-19 vaccine dose. Individuals 50 years of age and older were also advised to receive a second booster dose, at least four months following receipt of the first booster dose. Additionally, persons with immunosuppressive conditions were recommended to receive an additional vaccine dose.⁷⁴

On August 31, 2022, the FDA revoked the booster dose EUA recommendation for the Pfizer-BioNTech monovalent mRNA COVID-19 vaccine targeting the original Wuhan strain for all persons 12 years of age and older when they authorized use of a bivalent COVID-19 vaccine containing both the original strain and the Omicron variant.⁷⁵ The EUA for the monovalent mRNA COVID-19 vaccine booster dose in children five through 11 years of age was revoked on October 12, 2022 when the FDA authorized use of the Pfizer-BioNTech bivalent mRNA COVID-19 vaccine for use in this population.⁷⁶

Individuals who received a primary series of the Pfizer-BioNTech COVID-19 vaccine may opt to receive a different mRNA COVID-19 vaccine as a booster dose.⁷⁷ There is limited safety and effectiveness data to support the use of a mix and match COVID-19 vaccination schedule.⁷⁸

Pfizer-BioNTech Bivalent Booster Doses

Vaccine in Persons 12 years and Older

The FDA authorized a bivalent Pfizer-BioNTech mRNA COVID-19 vaccine containing the original Wuhan strain and the Omicron variant on August 31, 2022, to be administered as a single booster dose for all persons 12 years and older. This vaccine is recommended to be given two months following the original primary series or any booster dose.⁷⁹

Each 0.3mL dose of the bivalent Pfizer-BioNTech COVID-19 Vaccine contains 15 mcg of a nucleoside-modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of original SARS-CoV-2 Wuhan-Hu-1 strain and 15 mcg of modRNA encoding the S glycoprotein of SARS-CoV-2 Omicron BA.4/BA.5 variant. The S-proteins of the SARS-CoV-2 BA.4 and BA.5 Omicron variant are identical. Each dose contains 30 mcg modRNA. Each 0.3 mL dose of the Bivalent Pfizer-BioNTech COVID-19 Vaccine supplied in single dose and multiple dose vials also contains: 0.05 mg 2[(polyethylene glycol)-2000-N, lipids (0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-

6,1- diyl)bis(2-hexyldecanoate), N-ditetradecylacetamide, 0.09 mg 1,2- distearoyl-sn-glycero-3-phosphocholine, and 0.19 mg cholesterol), 0.4 mg tromethamine hydrochloride, 0.06 mg tromethamine, and 31 mg sucrose. The bivalent Pfizer-BioNTech COVID-19 vaccine does not contain a preservative and the vial stoppers are not made with natural rubber latex.⁸⁰

Vaccine in Children 5 through 11 years

On October 12, 2022, the FDA authorized use of a bivalent Pfizer-BioNTech mRNA COVID-19 vaccine containing both the original Wuhan strain and the Omicron variant for use in children five through 11 years of age. The vaccine is authorized as a single dose to be administered at least two months following completion of the primary series or booster dose.⁸¹

Each 0.2 mL dose of the Pfizer-BioNTech Bivalent COVID-19 Vaccine authorized for children five through 11 years of age contains 5 mcg of a nucleoside-modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of original SARS-CoV-2 Wuhan-Hu-1 strain and 15 mcg of modRNA encoding the S glycoprotein of SARS-CoV-2 Omicron BA.4/BA.5 variant. The S-proteins of the SARS-CoV-2 BA.4 and BA.5 Omicron variant are identical. Each dose contains 10 mcg modRNA.  Each 0.2 mL dose of the Bivalent Pfizer-BioNTech COVID-19 Vaccine supplied in multiple dose vials also contains: lipids (0.14 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2- hexyldecanoate), 0.02 mg 2[(polyethylene glycol)-2000-N,N-ditetradecylacetamide, 0.03 mg 1,2-distearoyl-snglycero-3-phosphocholine, and 0.06 mg cholesterol),  0.02 mg tromethamine,  0.13 mg tromethamine hydrochloride and 10.3 mg sucrose. The diluent (sterile 0.9% Sodium Chloride Injection, USP) adds 0.9 mg sodium chloride per dose. The bivalent Pfizer-BioNTech COVID-19 vaccine does not contain a preservative and the vial stoppers are not made with natural rubber latex.⁸²

Pfizer-BioNTech Vaccine in Infants and Children Age 6 Months through 4 Years

On December 8, 2022, the FDA authorized use of a bivalent Pfizer-BioNTech mRNA COVID-19 vaccine containing both the original Wuhan strain and the Omicron variant for use in infants and children six months through four years of age. This vaccine is authorized as a single dose to be administered at least two months following completion of the 3-dose primary series. It is 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 have not received a COVID-19 vaccine.⁸³ The FDA authorized the use of a booster dose of the bivalent Pfizer-BioNTech mRNA COVID-19 vaccine in infants and children 6 months through 4 years who have completed the 3-dose primary series in March 2023, to be given at least two months following the 3^rd vaccine dose.⁸⁴

Each 0.2 mL dose of the Pfizer-BioNTech Bivalent COVID-19 Vaccine authorized for infants six months through four years of age contains 1.5 mcg of a nucleoside-modified messenger RNA (modRNA) encoding the viral spike (S) glycoprotein of original SARS-CoV-2 Wuhan-Hu-1 strain and 1.5 mcg of modRNA encoding the S glycoprotein of SARS-CoV-2 Omicron BA.4/BA.5 variant. The S-proteins of the SARS-CoV-2 BA.4 and BA.5 Omicron variant are identical. Each dose contains 3 mcg modRNA. Each 0.2 mL dose of the Bivalent Pfizer-BioNTech COVID-19 Vaccine supplied in multiple dose vials also contains: 3.2 mg sucrose, 0.006 mg tromethamine, 0.04 mg tromethamine hydrochloride; lipids (0.04 mg ((4- hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.005 mg 2[(polyethylene glycol)-2000- N,N-ditetradecylacetamide, 0.01 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.02 mg cholesterol). The sterile 0.9 percent sodium chloride diluent adds 1.52 mg of sodium chloride per dose. The vaccine vial stoppers are free of latex and the vaccine does not contain a preservative.⁸⁵

Moderna mRNA COVID-19 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. ⁸⁶

Following FDA approval of Spikevax in January 2022, the CDC’s ACIP recommended use of the vaccine in persons 18 years of age and older.⁸⁷

Prior to granting approval of Spikevax, the FDA declined to hold a Vaccines and Related Biological Products Advisory Committee (VRBPAC) meeting⁸⁸ 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.”⁸⁹

In the Summary Basis for Regulatory Action Document published to support approval of Spikevax, the FDA reported that the most critical issues pertaining to vaccine safety were discussed by VRBPAC during meetings conducted October 2020, December 2020, and October 2021. According to the FDA, the assessment of the information had no impact on the risk/benefit considerations that would prompt the need for VRBPAC’s input on the vaccine’s licensure decision in persons 18 years of age and older.⁹⁰

The Moderna mRNA COVID-19 vaccine was initially issued an EUA by the FDA on December 18, 2020 for use in persons 18 years of age and older.⁹¹

According to the Fact Sheet provided by the FDA,⁹² each 0.5 ml dose of Moderna’s COVID-19 Vaccine contains 100 mcg of nucleoside modified messenger RNA (mRNA) that encodes the pre-fusion stabilized Spike glycoprotein (S) of SARS-CoV-2 virus.

Each dose also contains a total lipid content of 1.93 mg (SM-102, polyethylene glycol [PEG 2000 dimyristoyl glycerol [DMG, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC), 0.31 mg tromethamine, 0.043 mg acetic acid, 1.18 mg tromethamine hydrochloride, 43.5 mg sucrose and 0.12 mg sodium acetate. This vaccine does not contain a preservative and the vaccine vial stoppers are free of latex.

Additionally, the Moderna Fact Sheet states:

“The nucleoside-modified mRNA in the Moderna COVID-19 Vaccine is formulated in lipid particles, which enable delivery of the nucleoside-modified mRNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits an immune response to the S antigen, which protects against COVID-19.”⁹³

Spikevax/Moderna COVID-19 vaccine is recommended to be given as a two-dose series administered 28 days apart. The CDC also states that the interval time between the first and second dose can 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. Males between the ages of 12 and 39 are considered at highest risk for myocarditis.^{94 95}

There is no available data available on the interchangeability of the Moderna COVID-19 vaccine with other COVID-19 vaccines to complete the two-dose vaccination series. Persons who have received one dose of Spikevax/Moderna COVID-19 vaccine should receive a second dose of Spikevax/Moderna COVID-19 Vaccine to complete the vaccination series.^{96 97}

There is no data available on the co-administration of the Spikevax/Moderna mRNA COVID-19 vaccine with any other vaccine product.

The duration of vaccine-acquired immunity from Spikevax/Moderna’s COVID-19 vaccine is not known. The vaccine offers only minimal protection against infection and transmission. This means that vaccinated individuals can still become infected with the virus and spread it on to others.⁹⁸

There is insufficient data on the use of Moderna’s COVID-19 vaccine in persons who are 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.⁹⁹

Moderna COVID-19 Vaccine for Adolescents

On June 17, 2022, the FDA issued an EUA to Moderna for its COVID-19 mRNA vaccine for use in adolescents aged 12 through 17 years of age.¹⁰⁰

According to the Fact Sheet provided by the FDA,¹⁰¹ each 0.5mL dose of Moderna COVID-19 mRNA vaccine contains 100 mcg of nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion stabilized Spike glycoprotein (S) of SARS-CoV-2 virus. This product is contained in a multi-dose vial with a red cap and labelled with a light blue border. Additional ingredients contained in the vaccine include 43.5 mg sucrose, 0.31 mg tromethamine, 1.18 mg tromethamine hydrochloride, 0.043 mg acetic acid, 0.20 mg sodium acetate trihydrate, and a total lipid content of 1.93 mg (SM-102, polyethylene glycol [PEG 2000 dimyristoyl glycerol [DMG, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC).

The vaccine does not contain a preservative and the vaccine vial stopper does not contain natural latex rubber.¹⁰²

The vaccine is recommended to be administered intramuscularly (IM) as a two-dose primary series, administered at least four weeks apart. There is no data on the safety or effectiveness of administering the Moderna COVID-19 vaccine with any other vaccine.¹⁰³

On June 23, 2022, the CDC’s ACIP voted to recommend use of the 100mcg dose of Moderna mRNA COVID-19 vaccine for all adolescents aged 12 through 17 years.¹⁰⁴

Moderna COVID-19 Vaccine for Children

The FDA issued an EUA to Moderna on June 17, 2022 for their mRNA COVID-19 vaccine for use in children ages 6 through 11 years of age.¹⁰⁵

According to the Fact Sheet provided by the FDA,¹⁰⁶ each 0.5mL dose of Moderna COVID-19 mRNA vaccine contains 50 mcg of nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion stabilized Spike glycoprotein (S) of SARS-CoV-2 virus. This product is contained in a multi-dose vial with a dark blue cap and labelled with a teal border. Additional ingredients contained in the vaccine include 43.5 mg sucrose, , 0.25 mg tromethamine, 1.2 mg tromethamine hydrochloride, 0.021 mg acetic acid, 0.10 mg sodium acetate trihydrate, and a total lipid content of 1.01 mg (SM-102, polyethylene glycol [PEG 2000 dimyristoyl glycerol [DMG, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC).

The vaccine does not contain a preservative and the vaccine vial stopper does not contain natural latex rubber.¹⁰⁷

The Moderna COVID-19 mRNA vaccine is recommended to be administered intramuscularly (IM) as a two-dose primary series, administered at least four weeks apart.¹⁰⁸ Children aged 6 through 11 years of age who are considered immunocompromised are recommended to receive a third vaccine dose at least four weeks following the second dose.¹⁰⁹

There is no data on the safety or effectiveness of administering the Moderna COVID-19 vaccine with any other vaccine.¹¹⁰

On June 23, 2022, the CDC’s ACIP voted to recommend use of the 50mcg dose of Moderna mRNA COVID-19 vaccine for all children 6 through 11 years of age.¹¹¹

Moderna COVID-19 Vaccine for Infants and Young Children

On June 17, 2022, the FDA issued an EUA to Moderna for their mRNA COVID-19 vaccine for use in children ages 6 months through 5 years of age. ¹¹²

According to the Fact Sheet provided by the FDA,¹¹³ each 0.25mL dose of Moderna COVID-19 mRNA vaccine contains 25 mcg of nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion stabilized Spike glycoprotein (S) of SARS-CoV-2 virus. This product is contained in a multi-dose vial with a dark blue cap and labelled with a magenta border. Additional ingredients contained in the vaccine include 21.8 mg sucrose, 0.13 mg tromethamine, 0.62 mg tromethamine hydrochloride, 0.011 mg acetic acid, 0.049 mg sodium acetate trihydrate, and a total lipid content of 0.5 mg (SM-102, polyethylene glycol [PEG 2000 dimyristoyl glycerol [DMG, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC).

The vaccine does not contain a preservative and the vaccine vial stopper does not contain natural latex rubber.¹¹⁴

The vaccine is recommended to be administered intramuscularly (IM) as a two-dose primary series, administered at least four weeks apart. ¹¹⁵ Children aged 6 months through five years of age who are considered immunocompromised are recommended to receive a third vaccine dose at least four weeks following the second dose.¹¹⁶ There is no data on the safety or effectiveness of administering the Moderna COVID-19 vaccine with any other vaccine.¹¹⁷

On June 18, 2022, the CDC’s ACIP voted to recommend use of the 25mcg dose of Moderna mRNA COVID-19 vaccine for all children 6 months through 5 years of age. The recommendation also included infants and young children with a prior history of COVID-19 infection.¹¹⁸

Moderna COVID-19 Monovalent Booster Doses

Prior to August 31, 2022, the FDA, under EUA, authorized a 50mcg booster dose, or half dose, of the Moderna COVID-19 vaccine to be given six months following administration of the second vaccine dose.¹¹⁹ This vaccine was approved for use in October 2021 by the CDC 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-2.¹²⁰ This booster dose recommendation was expanded in November 2021 to all persons 18 years and older on November 19, 2021 who were previously vaccinated with two doses of an mRNA vaccine (Pfizer-BioNTech or Moderna). The booster dose was initially recommended at least six months following receipt of the second mRNA COVID-19 vaccine dose.^{121 122} On January 7, 2022, the interval between the second vaccine dose and the booster dose was shortened to five months.¹²³

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.^{124 125}

The FDA withdrew the EUA for the monovalent booster dose on August 31, 2022 for all adults 18 years 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.¹²⁶ On October 12, 2022, the FDA withdrew the EUA for the Moderna monovalent booster dose in children and teens five through 17 years when it authorized a bivalent mRNA COVID-19 vaccine booster dose.¹²⁷

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 is recommended at least two months following receipt of the primary series or booster dose.¹²⁸ The FDA authorized use of the bivalent mRNA COVID-19 vaccine manufactured by Moderna in all persons six years and older on October 12, 2022.¹²⁹

Moderna’s bivalent COVID-19 vaccine is provided as a sterile white to off-white suspension for intramuscular injection. Each 0.5 mL booster dose contains 25 mcg nucleoside-modified messenger RNA (mRNA) encoding the prefusion stabilized Spike glycoprotein (S) of the SARS-CoV-2 Original Wuhan-Hu-1 strain and 25 mcg mRNA encoding the pre-fusion stabilized S-protein of the SARS-CoV-2 Omicron BA.4 and BA.5 variant. The BA.4 and BA.5 S-proteins of the SARS-CoV-2 Omicron variant lineages are identical. Each dose also contains the following ingredients: 0.25 mg tromethamine, 1.2 mg tromethamine hydrochloride, 0.021 mg acetic acid, 0.10 mg sodium acetate trihydrate, a total lipid content of 1.01 mg (SM-102, polyethylene glycol [PEG 2000 dimyristoyl glycerol [DMG, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC), and 43.5 mg sucrose. The bivalent Moderna COVID-19 vaccine does not contain a preservative and the vial stoppers are not made with natural rubber latex.¹³⁰

According to Fact Sheet for the Moderna Bivalent mRNA COVID-19 vaccine, children six through 11 years are recommended to receive a single 0.25mL dose, while individuals 12 years and older are recommended to receive a 0.5mL booster dose.¹³¹

Moderna Bivalent Vaccine in Infants and Children Six Months through Five Years

On December 8, 2022, the FDA issued an EUA to Moderna for a bivalent mRNA COVID-19 vaccine to be given as a single dose in infants and children six months through five years of age, to be given at least two months following completion of the primary series (either Moderna or Pfizer-BioNTech) or most recent booster dose.¹³²

Moderna’s bivalent COVID-19 vaccine for infants and children age six months through five years is provided as a sterile white to off-white suspension for intramuscular injection. Each 0.2 mL booster dose contains 5 mcg nucleoside-modified messenger RNA (mRNA) encoding the prefusion stabilized Spike glycoprotein (S) of the SARS-CoV-2 Original Wuhan-Hu-1 strain and 5 mcg mRNA encoding the pre-fusion stabilized S-protein of the SARS-CoV-2 Omicron BA.4 and BA.5 variant. The BA.4 and BA.5 S-proteins of the SARS-CoV-2 Omicron variant lineages are identical. Each dose also contains the following ingredients: 0.09 mg tromethamine, 0.51 mg tromethamine hydrochloride, 0.0042 mg acetic acid, 0.02 mg sodium acetate trihydrate, a total lipid content of 0.20 mg (SM-102, polyethylene glycol [PEG 2000 dimyristoyl glycerol [DMG, cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC), and 17.4 mg sucrose. The bivalent Moderna COVID-19 vaccine does not contain a preservative and the vial stoppers are not made with natural rubber latex.¹³³

Viral vector vaccines genetically engineer live viruses such as poxviruses and adenoviruses to include the SARS-CoV-2 spike protein code. The engineered viruses are then used as a vector, or delivery method, to get the altered genetic code inside the cell where the cell’s ribosome produces SARS-CoV-2 protein antigen that is recognized by immune system to elicit a protective immune response.¹³⁴

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.¹³⁵ The CDC, however, gave a preferential recommendation to mRNA vaccines on December 16, 2021 due to the risk of TTS following vaccination.¹³⁶ According to the CDC, the Janssen/Johnson & Johnson COVID-19 vaccine should only be used in cases where a person is unable to or unwilling to receive an mRNA vaccine, or in cases where no other option is available.¹³⁷

Janssen/Johnson & Johnson’s experimental vaccine, Ad26.COV2.S, is a non-replicating viral vector vaccine that uses AdVac® and PER.C6® technologies.¹³⁸ 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.^{139 140} PER.C6 are proprietary cells owned by Janssen Pharmaceutical Companies that were developed in 1985 from retinal cells of an 18-week-old aborted fetus.¹⁴¹

Adenoviruses are “non-enveloped, double-stranded DNA viruses” that often cause mild respiratory or gastrointestinal infections like the common cold in humans; however, an adenovirus infection can be serious in persons with a compromised immune system or pre-existing respiratory or cardiac issues.¹⁴²

Several characteristics are considered as advantages to using an adenoviral vector for delivering a vaccine antigen, including the ability to stimulate both an innate (cell-mediated) and humoral (adaptive) immune system response and because adenoviral vectored vaccines are easy to genetically manipulate. Another feature is that the adenovirus itself can trigger the vaccine’s inflammatory immune response. This means that it is not necessary to add an adjuvant to the vaccine to provoke an inflammatory response to stimulates immunity.¹⁴³

Each 0.5 mL dose of the vaccine also contains citric acid monohydrate (0.14 mg), ethanol (2.04 mg), trisodium citrate dihydrate (2.02 mg), 2-hydroxypropyl-β-cyclodextrin (HBCD) (25.50 mg), polysorbate-80 (0.16 mg), and sodium chloride (2.19 mg). Additionally, each dose may also contain residual amounts of host cell DNA host and/or cell proteins. This vaccine does not contain a preservative and the vaccine vial stoppers are free of latex. The vaccine is approved to be administered as a single 0.5mL dose intramuscularly.¹⁴⁴

In clinical trials, the vaccine was 66.9 percent effective in preventing moderate to severe COVID-19 occurring at least 14 days after vaccination and 66.1 percent effective in preventing moderate to severe COVID-19 occurring at least 28 days after vaccination.¹⁴⁵ The vaccine, however, was reported to be only 42 percent effective in persons over the age of 60 who have underlying health conditions.¹⁴⁶

On April 13, 2021, the FDA and CDC paused use of the Janssen/Johnson & Johnson vaccine after serious blood clots were reported in women between the ages of 18 and 49.¹⁴⁷ 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 2 occurring in women over 50 years of age. The CDC’s Advisory Committee on Immunization Practices (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.^{148 149}

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. Additionally, TTS has been reported in men and in women between 50 and 60, in addition to women between 18 and 49 years.¹⁵⁰ According to the CDC, TTS occurs at a rate of 1 case per 250,000 doses.¹⁵¹

On July 13, 2021, Janssen/Johnson & Johnson company officials reported that they were working on modifying their COVID-19 vaccine in an attempt to reduce or eliminate the risk of blood clots.¹⁵²

Additionally, on July 13, 2021, the FDA announced revisions to the Fact Sheet for Healthcare Providers Administering the Johnson & Johnson/Janssen COVID-19 vaccine and the Fact Sheet for Recipients and Caregivers to include information regarding an increased risk of Guillain-Barré Syndrome (GBS) following vaccination. GBS, a serious neurological disorder where the body’s immune system attacks the peripheral nervous system, can cause muscle weakness, paralysis, and even death. According to the press release, the FDA reported 100 cases of GBS following vaccination, with 95 considered serious and requiring hospitalization, and one death. Government health officials noted that there was insufficient evidence to establish a causal relationship between the Johnson & Johnson/Janssen COVID-19 vaccine and GBS, and reported that “the known and potential benefits clearly outweigh the known and potential risks.”¹⁵³

According to the CDC, most cases occurred within two weeks of vaccination and among men, primarily those aged 50 and older.¹⁵⁴

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.¹⁵⁵ According to the CDC, use of the Johnson & Johnson/Janssen vaccine should be limited to persons who are unable to or unwilling to receive an mRNA COVID-19 vaccine, or when no other vaccine option is available.¹⁵⁶ Limited safety and effectiveness data are available for use of a mix and match vaccine schedule.¹⁵⁷

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.¹⁵⁸

Janssen/Johnson & Johnson COVID-19 Booster Doses

Prior to August 31, 2022, health officials recommended that all persons who received a single dose of the Johnson & Johnson/Janssen COVID-19 get a first booster dose of COVID-19 vaccine at least two months after receipt of the first vaccine dose, and a second booster dose at least four months following the first booster dose. A dose of mRNA COVID-19 vaccine was recommended over the Johnson & Johnson/Janssen COVID-19 vaccine.¹⁵⁹

As of March 17, 2023, a single booster dose of a bivalent mRNA COVID-19 vaccine is authorized for all persons who received a primary series of Janssen/Johnson & Johnson COVID-19. The mRNA COVID-19 vaccine is recommended to be administered at least two months following receipt of primary series or booster dose.¹⁶⁰

On July 13, 2022, the FDA issued an EUA to Novavax for its adjuvanted COVID-19 vaccine, for use in adults 18 years and older who have not received a prior dose of COVID-19. The vaccine is authorized as a two-dose primary series, to be administered intramuscularly three weeks apart. ¹⁶¹ The EUA was expanded on August 19, 2022 to include adolescents 12 through 17 years.¹⁶²

Maryland-based Novavax Inc, a biotechnology company which had never successfully delivered a product to market,¹⁶³  developed an experimental vaccine using recombinant nanoparticle technology. Referred to as a protein subunit vaccine,¹⁶⁴ NVX‑CoV2373 contains Novavax’s patented saponin-based Matrix-M™ adjuvant designed to enhance the immune response and stimulate high levels of neutralizing antibodies.¹⁶⁵

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.¹⁶⁶

According to the fact sheet for health care providers administering Novavax COVID-19 vaccine, the vaccine is supplied as a multi-dose vial containing 10 doses of 0.5mL. After the vial is punctured, it must be stored between 36 and 77 degrees Farhenheit and discarded after six hours.¹⁶⁷

Each 0.5 mL dose of the Adjuvanted Novavax COVID-19 Vaccine contains 5 mcg of SARS-CoV-2 recombinant spike protein and 50 mcg Matrix-M adjuvant. The Matrix-M adjuvant is made of Fraction-A (42.5 mcg) and Fraction-C (7.5 mcg) of saponin extracts from the soapbark tree (Quillaja saponaria Molina). The recombinant spike protein is made by recombinant DNA technology in an insect cell line that is derived from cells of the Spodoptera frugiperda species.¹⁶⁸  

Each dose of the Adjuvanted Novavax COVID-19 vaccine also contains the following ingredients: potassium dihydrogen phosphate (3.85 mcg), potassium chloride (2.25 mcg), disodium hydrogen phosphate dihydrate (14.7 mcg), disodium hydrogen phosphate heptahydrate (2.465 mg), cholesterol, phosphatidylcholine, sodium dihydrogen phosphate monohydrate (0.445 mg), sodium chloride (8.766 mg) and polysorbate 80 (0.050 mg), and Water for Injection. The pH is adjusted with either sodium hydroxide or hydrochloric acid. Each 0.5 mL dose of the Novavax vaccine may also contain residual amounts of baculovirus and Sf9 cell proteins (≤ 0.96 mcg), lentil lectin (< 0.025 mcg), methyl-α-D-mannopyranoside (2 mcg), baculovirus and cellular DNA (≤ 0.00016 mcg), Triton X-100 (< 0.025 mcg), simethicone (< 2.19 mcg), and Tergitol (NP9) (< 0.05 mcg). The Adjuvanted Novavax COVID-19 vaccine does not contain preservative and the vial stoppers are not made with natural rubber latex.¹⁶⁹

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 currently circulating Omicron COVID-19 strain. The FDA stated that the issuance of EUA would depend on an evaluation of Novavax’s manufacturing process. On June 3, 2022, Novavax notified the FDA of a change to the manufacturing process of its COVID-19 vaccine.¹⁷⁰

On July 19, 2022, the CDC’s ACIP approved use of Novavax as a primary series for use in persons 18 years and older.¹⁷¹ The FDA expanded the EUA on August 19, 2022, and authorized use of the vaccine in all persons 12 and older.¹⁷²

In September 2022, the CDC recommended that all persons who received a primary series of Novavax COVID-19 vaccine get a booster dose of a bivalent mRNA COVID-19 (Pfizer-BioNTech or Moderna) vaccine at least two months following receipt of the primary series. No data was provided to support the safety or effectiveness of this recommendation.^{173 174} A booster dose of Novavax vaccine in persons 18 years and older who are 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 is recommended to be given at least six months after completion of the primary COVID-19 vaccine series or most recent vaccine dose.¹⁷⁵

Although several COVID-19 vaccine candidates employ unproven vaccine technologies, many COVID-19 vaccines that employ traditional vaccine manufacturing methods are under development and in pre-licensure clinical trials.¹⁷⁶ These include several experimental inactivated vaccine candidates by Chinese based pharmaceutical companies.^{177 178}

Globally, over 380 COVID-19 vaccines are under development and as of March 17, 2023, 183 experimental vaccines were in clinical trials.¹⁷⁹

AstraZeneca-University of Oxford Viral Vector COVID-19 vaccine

A 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. Teaming with AstraZeneca in April of 2020 to develop, manufacture, and distribute the ChAdOx1 nCoV-19 vaccine (now referred to as AZD1222) in the U.S., this COVID-19 vaccine candidate is a non-replicating viral vector vaccine that uses a chimpanzee adenovirus to express the SARS-CoV-2 protein.¹⁸⁰ According to the University of Oxford:

“Genetic material has been added to the ChAdOx1 construct, that is used to make proteins from the COVID-19 virus (SARS-CoV-2) called Spike glycoprotein (S). This protein is usually found on the surface of SARS-CoV-2 and plays an essential role in the infection pathway of the SARS-CoV-2 virus. The SARS-CoV-2 coronavirus uses its spike protein to bind to ACE2 receptors on human cells to gain entry to the cells and cause an infection.”¹⁸¹

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).¹⁸²

In July 2020, preliminary results of the AstraZeneca’s Phase 1 and Phase 2 trials were published in The Lancet.¹⁸³ 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 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.

Headache and fatigue were the most commonly reported systemic reactions. Headaches were reported in the experimental COVID-19 vaccine group by 68 percent of the participants without acetaminophen and 61 percent with acetaminophen and in the MenACWY group by 41 percent of the participants without acetaminophen and 37 percent of the participants with acetaminophen. Fatigue was reported in the experimental COVID-19 vaccine group by 70 percent of the participants, who were not give acetaminophen prior to vaccination, and in the MenACWY group by 48 percent of the participants without acetaminophen. 

Other common systemic adverse reactions reported in the experimental COVID-19 vaccine group included feeling feverish (51 percent), chills (56 percent), muscle ache (60 percent)  and malaise (61 percent). Eighteen percent of participants who did not receive acetaminophen and 16 percent of participants who did reported a temperature of at least 100.4°F. Two percent of patients without acetaminophen reported a temperature of at least 102.2°F. In comparison, less than one percent of individuals receiving MenACWY reported a fever of at least 100.4°F, none of whom were receiving prophylactic acetaminophen. The intensity and severity of systemic and local reactions was highest on the first day after vaccination.¹⁸⁴

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.¹⁸⁵

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.¹⁸⁶

While clinical trials resumed quickly in several countries including Great Britain, Japan, South Africa, India,¹⁸⁷ and Canada, ¹⁸⁸ trials in the U.S. remained on hold until October 23, 2020. ¹⁸⁹

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.¹⁹⁰

Trials in the U.S. involving the University of Oxford and AstraZeneca’s experimental COVID-19 vaccine candidate were put on hold in early September 2020 due to safety concerns. While several countries including Canada, Japan, Brazil, South Africa, and Great Britain continued with clinical trials despite these concerns,¹⁹¹ U.S trials did not resume until October 23, 2020. According to the Wall Street Journal, the FDA did not fault the vaccine for the serious neurological events that occurred in two trial participants, however, they have not yet ruled out a link.¹⁹²

At the January 27, 2021 ACIP meeting, 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. In the COVID-19 vaccine group, one participant experienced a high fever two days following the first vaccine dose that resolved with paracetamol (acetaminophen) treatment on the same day and another participant developed transverse myelitis two weeks after the second vaccine dose. In the control group, one participant developed autoimmune hemolytic anemia ten days after MenACWY, and another participant developed transverse myelitis two months after the first control dose.¹⁹³

AstraZeneca company officials reported that most solicited adverse events were mild to moderate and the majority resolved within a few days of vaccination. The most commonly reported adverse events included injection site tenderness, injection site pain, fatigue, headache, muscle and joint pain, malaise, fever, chills, and nausea. Adverse events were more common after the first vaccine dose. ¹⁹⁴

On January 29, 2021, the European Union approved the vaccine for use in individuals 18 years and older despite limited data to support its effectiveness in adults over the age 55 years. The University of Oxford and AstraZeneca’s experimental COVID-19 vaccine is estimated to have an efficacy of about 60 percent.¹⁹⁵ Health officials in Germany, however, did not recommend use of the vaccine in adults 65 years of age and older after concluding that there was not enough data to determine whether the vaccine was effective in this population.¹⁹⁶

Health officials in South Africa halted use of the AstraZeneca COVID-19 vaccine in February 2021, after it was found to be less than 25 percent effective against the B.1.351 (Beta) variant, which was the most common SARS-CoV-2 virus variant circulating in South Africa at the time.¹⁹⁷

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 blood clots, a number of countries had already suspended use of the vaccine. These countries included Denmark, Norway, Iceland, and Thailand. Other countries, like Austria and Italy chose instead to suspend specific batches of the vaccine, while Spain delayed rollout of the AstraZeneca vaccine.¹⁹⁸ On June 11, 2021, Italy suspended use of the vaccine in persons under 60 years following the death of an 18-year-old female from cerebral hemorrhage 16 days post vaccination.¹⁹⁹

The World Health Organization (WHO) issued a statement on March 19, 2021 stating that their Global Advisory Committee on Vaccine Safety had reviewed the data on the vaccine in relation to blood clots and low platelets after vaccination and concluded that the rates of these events are fewer than when they occur naturally in the generalized population. The WHO added and that these events would continue to be monitored.²⁰⁰

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.²⁰¹ On March 30, 2021, Germany limited its use to persons over the age of 60.²⁰²

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 reports 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.²⁰³

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.²⁰⁴

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.”²⁰⁵

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.²⁰⁶ On April 14, 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.²⁰⁷

On July 13, 2021, AstraZeneca company officials reported that they were working on modifying their COVID-19 vaccine in an attempt to reduce or eliminate the risk of blood clots.²⁰⁸

The AstraZeneca COVID-19 vaccine has also been linked to Guillain-Barré Syndrome (GBS). GBS, a serious neurological disorder where the body’s immune system attacks the peripheral nervous system, can cause 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, as of July 31, 2021, 833 cases of GBS had been reported after AstraZeneca COVID-19 vaccination.²⁰⁹

Inovio Pharmaceuticals INO-4800 DNA Vaccine

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. DNA vaccines deliver pieces of DNA into the nucleus of human cells in ways that result in production of pathogen protein antigens that subsequently, stimulate the immune system to produce antibodies specific to the pathogen’s antigen without becoming infected by the pathogen that can cause the disease. Compared to traditional vaccines, nucleic acid (genetic) vaccines are less inexpensive and easier to manufacture because they consist only of DNA or RNA, which is taken up and translated into protein by host cells.²¹⁰

In early April 2020, Inovio pharmaceuticals began clinical trials of an experimental COVID-19 DNA vaccine in partnership with Philadelphia’s Wistar Institute and Beijing Advaccine Biotechnology Co in China.²¹¹ Inovio’s experimental INO-4800 vaccine injected a small piece of circular DNA to provoke the vaccine recipient’s cells into producing antibodies. Electroporation, which delivered short pulses of electrical genetic current to the patient to open cell pores and allow the plasmids to enter, was required for the effective delivery of the experimental vaccine.^{212 213}

The experimental vaccine, however, was found to be ineffective, and by October 2022, company officials reported that they had halted all efforts to produce a COVID-19 vaccine in the US. The vaccine candidate, however, would continue to be studied by INOVIO’s partner in China, Advaccine.²¹⁴