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What is COVID-19 vaccine?


covid-19

Coronaviruses are a group of diverse, single-stranded, enveloped RNA viruses that cause a wide range of respiratory, gastrointestinal and neurologic illnesses with varying severity in animals and humans. Most coronaviruses, including those causing the common cold, are not associated with significant mortality, with the exception of Severe Acute Respiratory Syndrome (SARS), which emerged in China in 2002, the coronavirus causing Middle East Respiratory Syndrome (MERS), which was identified in Jordan and Saudi Arabia in 2012,1 and SARS-CoV-2, new novel coronavirus, which was initially identified in Wuhan City, in the Hubei province of China.2 In the U.S., there are no FDA-licensed vaccines targeting SARS, MERS or any of the four common coronaviruses.

Immediately after the January 30, 2020 WHO declaration that a novel coronavirus outbreak in China posed a “public health emergency of international concern,” the Gates Foundation3 and World Health Organization (WHO)4 issued press releases informing the world that experimental coronavirus vaccines already in development would be put on a fast track to licensure for global use.

In May 2020, Former President Donald Trump announced the rollout of Operation Warp Speed, a plan to develop, manufacture, and distribute millions of COVID-19 vaccine doses by the end of 2020.5 According to the National Institute of Allergy and Infectious Diseases (NIAID):

“Operation Warp Speed is a partnership among several federal government agencies to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics, including the specific goal of delivering 300 million doses of a safe, effective vaccine for COVID-19 by January 2021.

Notably, Operation Warp Speed will manufacture promising candidate vaccines at an industrial scale before efficacy and safety are confirmed through Phase III trials. Doing so will significantly shorten the timeline for distribution as compared to traditional vaccine development, should the trials succeed.” 6

New ways to make vaccines including new technologies and production platforms quickly became favored over the older traditional ways to make vaccines in the COVID-19 vaccine race.7 8 

Traditional vaccines contain attenuated (live) or inactivated (killed) viruses or bacteria or selected proteins, as well as adjuvants, such as aluminum, to stimulate an immune response that produces artificial immunity. For example, older viral vaccines for smallpox and measles vaccine contain live attenuated viruses; injectable influenza vaccines contain inactivated viruses; the recombinant hepatitis B virus vaccine is a protein subunit vaccine, while the newer human papillomavirus (HPV) virus vaccine contains virus-like particles.9

For the past two decades, researchers have been experimenting with gene-based technology platforms, notably ones that introduce foreign DNA and RNA into cells of the body, to develop experimental vaccines for SARS, MERS, HIV and other diseases.10

Pre-licensing Clinical Trial Process

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

Emergency Use Authorization

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 had been 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

Pfizer - BioNTech mRNA COVID-19 Vaccine

On December 11, 2020, the FDA issued an EUA for Pfizer-BioNTech’s experimental messenger RNA (mRNA) COVID-19 Vaccine for use in persons 16 years of age and older.30

According to the Fact Sheet provided by the FDA,31 the 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 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.” 32

The Pfizer-BioNTech COVID-19 Vaccine is recommended to be given intramuscularly (IM) as a two-dose series administered three weeks apart. There is no available data on the interchangeability of the Pfizer-BioNTech COVID-19 Vaccine with other COVID-19 vaccines to complete the two-dose vaccination series. Persons who have received one dose of Pfizer-BioNTech COVID-19 Vaccine should complete the series by receiving a second dose of Pfizer-BioNTech COVID-19 Vaccine.33

The duration of vaccine-acquired immunity from Pfizer-BioNTech’s COVID-19 vaccine is not known. It is also not known whether this vaccine can reduce or stop transmission of the virus. This means that vaccinated individuals may still be capable of transmitting the virus to others.34

There is insufficient data to support the use of Pfizer-BioNTech’s COVID-19 vaccine in persons who are positive for SARS-CoV-2 at the time of vaccination. 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).35

The Pfizer-BioNTech COVID-19 vaccine must be shipped and stored between -80ºC to -60ºC (-112ºF to -76ºF) and protected from light until ready to use.36 However, 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.37 Mishandling of the vaccine during any step of the distribution process may result in an ineffective vaccine product. 38

The CDC reports that after two doses of Pfizer-BioNTech COVID-19 vaccine, efficacy in preventing disease is 95 percent.39 Pfizer-BioNTech reports that the vaccine is just as effective against the U.K.’s B.1.1.7 as the earlier variant of SARS-CoV-2 virus.40 The vaccine, however, appears to be less effective against the South African B.1.351 variant.41 As of April 10, 2021, the B.1.17 variant has been detected in 52 U.S. jurisdictions and B.1.351 in 36 jurisdictions in the U.S.42

Moderna mRNA COVID-19 Vaccine

On December 18, 2020, the FDA issued an EUA for Moderna’s experimental mRNA COVID-19 Vaccine for use in persons 18 years of age and older.43

According to the Fact Sheet provided by the FDA,44 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-19.45

The Moderna COVID-19 Vaccine is recommended to be given as a two-dose series administered 28 days apart. 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 Moderna COVID-19 Vaccine should receive a second dose of Moderna COVID-19 Vaccine to complete the vaccination series.46

The duration of vaccine-acquired immunity from Moderna’s COVID-19 vaccine is not known. It is also not known whether this vaccine can reduce or stop transmission of the virus. This means that vaccinated individuals may still be capable of transmitting the virus to others.47

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.48

The CDC states vaccine efficacy for the Moderna is 94 percent.49 Moderna reports that its COVID-19 vaccine appears to offer vaccine-acquired protection against the U.K’s B.1.1.7 variant. The vaccine, however, had a six-fold reduction against the South African B.1.351 variant when compared to the initial SARS-CoV-2 virus.50 As of April 10, 2021, the B.1.17 variant has been detected in 52 U.S. jurisdictions and B.1.351 in 36 jurisdictions in the U.S.51

Janssen/Johnson & Johnson COVID-19 Viral Vector Vaccine

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.52

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.53

Janssen/Johnson & Johnson’s experimental vaccine, Ad26.COV2.S, is also a non-replicating viral vector vaccine that uses AdVac® and PER.C6® technologies.54 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.55 56 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.57

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.58

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.59

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.60

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.61 The vaccine, however, was reported to be only 42 percent effective in persons over the age of 60 who have underlying health conditions.62 The CDC reported in March 2021 that preliminary data suggests that the vaccine has an overall efficacy of 66 percent.63

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 49.64 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.65 66

Additional COVID-19 Vaccines

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.67 These include several experimental inactivated vaccine candidates by Chinese based pharmaceutical companies.68 69

Globally, over 270 COVID-19 vaccines are under development and as of April 23, 2021, 91 experimental vaccines were in clinical trials.70

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.71 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.”72

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).73

In July 2020, preliminary results of the AstraZeneca’s Phase 1 and Phase 2 trials were published in The Lancet.74 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.75

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.76

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.77

While clinical trials resumed quickly in several countries including Great Britain, Japan, South Africa, India,78 and Canada, 79 trials in the U.S. remained on hold until October 23, 2020. 80

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.81

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,82 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.83

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.84

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. 85

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.86 Health officials in Germany, however, are not recommending 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.87

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 is estimated to have an efficacy of about 60 percent.88

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 variant, which is most common SARS-CoV-2 virus variant circulating in South Africa89 and has been detected in most U.S. states.90

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 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.91

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 are fewer than when they occur naturally in the generalized population. The WHO added and that these events would continue to be monitored.92

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.93 On March 30, 2021, Germany limited its use to persons over the age of 60.94

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.95

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.96

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, continues 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.”97

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. As of April 19, 2021, the vaccine remained suspended in Cameroon, Norway, and Denmark.98 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.99

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.100

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 has 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 for upcoming clinical trials and potential manufacturing of the vaccine for military personnel in the future.101

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-2102  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. At this point, 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. 103 104

On June 30, 2020, Inovio Pharmaceutical announced positive results from its Phase 1 clinical trials. In the initial trial, 40 healthy adults between 18 and 50 years of age were administered two vaccine doses four weeks apart. Participants received either a 1.0mg or 2.0mg dose administered using INOVIO's CELLECTRA® 2000 device – a device that 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.105 106

According to company officials, all 10 reported adverse events were considered Grade 1 and involved localized injection site redness.107

The World Health Organization (WHO) has acknowledged that gaps in scientific knowledge exists regarding DNA vaccines and that their immune responses are not fully understood.108

Some of the outstanding questions about DNA vaccine safety include:109

  • chronic inflammation because the vaccine continually stimulates the immune system to produce antibodies;
  • possible integration of plasmid DNA into the body’s host genome resulting in mutations;
  • problems with DNA replication;
  • triggering of autoimmune responses, and
  • activation of cancer-causing genes.

INOVIO’s CELLECTRA® 2000 electroporation device is also associated with higher rates of injection site pain in comparison to standard injections. A small clinical trial that involved the injection of a sterile solution followed by the use of the CELLECTRA® 2000 device reported mild to moderate injection pain, tenderness, redness and swelling, involuntary muscle contractions and increases in serum creatine phosphokinase (CK). CK is an enzyme found in the brain, heart, skeletal muscle, and other tissues and an increase in levels is indicative of muscle damage in the body.110

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.111 While the Phase 3 clinical trials remain on hold as of December 9, 2020, the FDA has permitted Inovio to proceed with Phase 2 clinical trials. According to Inovio:112

“The Phase 2 segment of the trial is designed to evaluate safety, tolerability and immunogenicity of INO-4800 in a 2-dose regimen (1.0 mg or 2.0 mg), in a three-to-one randomization to receive either INO-4800 or placebo for each dose to confirm the more appropriate dose(s) for each of three age groups with high risks of infection (18-50 years, 51-64 years and 65 years and older) for the subsequent Phase 3 efficacy evaluation. The Phase 3 segment of the INNOVATE trial remains on partial clinical hold until INOVIO satisfactorily resolves the FDA's remaining questions related to the CELLECTRA® 2000 device that will be used to deliver INO-4800 directly into the skin. The company plans to resolve the remaining device questions during the conduct of Phase 2 segment and prior to the start of the Phase 3 segment of the trial.”

Inovio company officials report that they expect to provide regulators with the answers to any questions by the end of the second quarter of 2021. Vaccine trials, however, are progressing in China in partnership with Advaccine Biopharmaceuticals Suzhou Co Ltd.113

In October 2020, it was reported that Inovio’s experimental COVID-19 vaccine neutralized SARS-CoV-2 viruses with the D614G mutation that had become globally dominate.114

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 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.115

Novavax COVID-19 Vaccine

Maryland-based Novavax Inc, a biotechnology company which has never successfully delivered a product to market,116 has developed an experimental vaccine using recombinant nanoparticle technology. Referred to as a protein subunit vaccine,117 NVX‑CoV2373 contains Novavax’s patented saponin-based Matrix-M™ adjuvant designed to enhance the immune response and stimulate high levels of neutralizing antibodies.118

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.119

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. 120 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.121

Trial participants were divided into five group: group A, group B, group C, group D and group E. The 23 participants in group A received two doses of the placebo; 25 participants in group B received 25-μg (microgram) doses of the NVX-CoV2373 vaccine without the Matrix-M1 adjuvant; 29 participants in group C received 5-μg doses of NVX-CoV2373 with Matrix-M1; 28 participants in group D received 25-μg doses of NVX-CoV2373 with Matrix-M1; and 26 participants in group E received a single 25-μg dose of NVX-CoV2373 with Matrix-M1 followed by a single dose of placebo.122

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.123

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.124

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.125

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 variant was most predominant.126

By February 2021 Novavax had secured a memorandum of understanding with Canada127 and Takeda Pharmaceutical Company Ltd.128 (Japan) to produce the vaccine, while the European Medicines Agency (EMA) started their rolling reviews of the experimental vaccine.129 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);130 Switzerland;131  Australia;132 New Zealand;133 and Canada.134

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 and each study arm contained about 250 participants assigned to one of four vaccine groups or placebo. Vaccine arms 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.135

Local adverse reactions after one dose 5-μg regimen included injection site tenderness and pain across all age groups and were more frequent in younger groups 18 to 59 years of age (48 and 59 percent, respectively) than older vaccine participants 60 to 84 years of age (27 and 38 percent, respectively), with one report of a grade 3 adverse event in the low dose group and most systemic adverse events being noted as similar to placebo.136 

Upon receipt of the second dose, reports of injection site tenderness and pain increased across all age groups and lasted a median of two days. Injection site tenderness and pain were reported in vaccine groups as 65 and 76 percent for the lower age group; and 46 and 55 percent for the older group, respectively. The most frequent systemic adverse events reported in both age groups following the second dose of vaccine were fatigue (36 and 43 percent, respectively); muscle pain (31 and 41 percent, respectively); headache (30 and 34 percent, respectively); and malaise (26 and 30 percent, respectively).137

Of unsolicited adverse events reported, one low dose participant discontinued the trial due to urinary incontinence that was felt to be unrelated to the vaccine. Serious adverse events in vaccine recipients included one case of acute colitis (considered vaccine related); one case of atrial fibrillation (unrelated, due to underlying heart disease); one case of vertigo (unrelated); and one case of non-Hodgkin’s lymphoma (unrelated).138  

IMPORTANT NOTE: NVIC encourages you to become fully informed about covid-19 and the covid-19 vaccine by reading all sections in the Table of Contents, which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.

« Return to Vaccines & Diseases Table of Contents

Updated April 28, 2021

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