Continuing Education Activity

Multiple COVID-19 vaccines have received emergency use authorizations (EUA) to prevent severe COVID-19 illness caused by the SARS-CoV-2 virus. They have been instrumental in controlling the severity of this pandemic and improving clinical outcomes. Moreover, a novel approach to vaccination was initiated during this pandemic using mRNA vaccines. This activity reviews the indications, administration, and contraindications for COVID-19 vaccines to allow clinical understanding of these agents and their appropriate use. This activity will also highlight the mechanism of action, adverse event profile, and other key elements of the COVID-19 vaccines in the clinical setting for the interprofessional team members when vaccinating individuals to prevent COVID-19 and its related conditions sequelae.

Objectives:

• Identify the mechanism of action of COVID-19 vaccines.
• Describe indications for COVID-19 vaccines.
• Review the adverse effects of the currently authorized COVID-19 vaccines.
• Outline some interprofessional strategies the healthcare team can employ to optimize SARS-COVID-19 vaccine deployment and improve public health outcomes.

Indications

COVID-19 (coronavirus 2019) vaccines are indicated for the prevention of coronavirus 2019 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus.[1][2][3] The SARS-CoV-2 virus first surfaced in Wuhan, China, in December 2019. The virus was announced as a public health emergency of International Concern on January 30, 2020, by the World Health Organization (WHO).[4] Since then, the lethal virus has spread rapidly, affecting various countries worldwide. On March 11, 2020,  the global COVID-19 occurrence was declared a pandemic by the WHO.[5][6]

The virus's transmission mode is mainly through infected individuals' respiratory droplets.[4] SARS-CoV-2 invades its host cells by binding its viral spike (S) protein - constituted of S1 and S2 spike glycoprotein subunits and located on its surface, to the human angiotensin-converting enzyme 2 (ACE2) receptors expressed on the surface epithelium of various organs and transmembrane protease, serine 2 (TMPRSS2) receptors.[7][8][9]

The COVID-19 disease can have various manifestations, with increased susceptibility in individuals with comorbidities and immunosuppression.[10][4] Individuals with underlying comorbid ailments are reported to have increased ACE2 expression.[11] Although the SARS-CoV-2 virus is predominantly a respiratory illness, extrapulmonary manifestations have been reported. The symptoms may present in two to fourteen days (with a mean of approximately five days) after exposure.[6][10] The individual may be asymptomatic or exhibit mild to severe disease affecting multiple organs. Patients with mild to moderate disease usually present with fever, headache, chills, dry cough, shortness of breath, sore throat, nasal congestion, malaise, myalgia, body aches, nausea, and vomiting.

Organ system manifestations include:

Respiratory

• Mild to severe pneumonia[6]
• Acute respiratory distress syndrome (ARDS)[10]

Central Nervous System

• Meningitis
• Encephalitis
• Encephalopathy
• Cerebrovascular event
• Chemosensory dysfunction (altered taste and smell)[12]

Cardiovascular

• Myocarditis
• Dysrhythmias[13]
• Coronary heart disease
• Cardiomyopathy[14]

Renal

• Acute kidney injury[15][16]

Gastrointestinal

• Moderate to severe diarrhea[17][18]

Currently Available Vaccines 

On December 11, 2020, an emergency use authorization (EUA) was granted by the US Food and Drug Administration (FDA) to the BNT162b2 vaccine to prevent COVID-19 illness with vaccine distribution in the US 48 hours later. Soon after, the second vaccine, mRNA-1273 SARS-CoV-2, was granted emergency use authorization on December 18, 2020.[19][20] Both mRNA vaccines are designated for active immunization to prevent COVID-19 caused by SARS-CoV-2.[1] The third COVID-19 vaccine to receive EUA in the United States was the Ad26.COV2.S on February 27, 2021. The EUA was later revised and limited its use to people 18 years and above who are unable to access the approved COVID-19 vaccines or those choosing to receive the Ad26.COV2.S vaccination. The fourth vaccination to receive EUA was the NVX-CoV2373 vaccine on July 13, 2022.

On August 23, 2021, the FDA approved its first COVID-19 vaccine, the BNT162b2 - COVID-19 Vaccine, mRNA for individuals 12 years and above. The second approval was given on January 31, 2022, to the mRNA-1273 - COVID-19 Vaccine, mRNA in individuals 18 years and above.

FDA Approved

• BNT162b2 - for 12 years of age and above
• mRNA-1273- for 18 years of age and above

FDA Emergency Use Authorization (EUA)

• BNT162b2 
  • For individuals aged 6 months to 4 years, the vaccine has EUA as a three-dose primary series.
  • For individuals aged 5 years and above, the vaccine has EUA as a two-dose primary series.
  • For immunocompromised individuals aged 5 years and older, the vaccine has EUA as a three-dose primary series.
  • A bivalent vaccine formulation to include the original vaccine and Omicron BA.4/BA.5 is now authorized as a booster dose for individuals aged 12 years or older.
• mRNA-1273 
  • For individuals aged 12 to 17 years, the vaccine has EUA as a two-dose primary series.
  • For immunocompromised individuals aged 12 years and older, the vaccine has EUA as a three-dose primary series.
  • For individuals aged 6 months and above, the vaccine has EUA as a two-dose primary series.
  • For immunocompromised individuals aged 6 months and above, the vaccine has EUA for a third primary series dose.
  • A bivalent formulation of this vaccine with Omicron BA.4/BA.5 is authorized as a booster dose for individuals aged 18 years or older.
• Ad26.COV2.S
  • Single-dose primary vaccine in individuals aged 18 years and above.
  • Single dose booster in individuals aged 18 years and above two months following the primary vaccination.
  • The EUA for this vaccine limits its use to individuals who cannot or elect not to use an mRNA vaccine due to the risk of vaccine-induced thrombotic thrombocytopenia.
• NVX-CoV2373
  • It is an adjuvanted recombinant protein vaccine.
  • Authorized for individuals aged 12 years or older as a two-dose primary series.
  • Not authorized to be given as primary series for individuals with immunocompromising conditions.

Vaccine Efficacy

Covid-19 vaccines have been instrumental in curbing the intensity of this pandemic and decreasing the morbidity and mortality of this disease. COVID-19-associated hospitalizations and emergency/urgent care evaluations significantly improved with these vaccines.[21] A study from Israel stated that two doses of BNT162b2 were highly effective in preventing symptomatic and asymptomatic SARS-CoV-2 infections, as well as COVID-19-related hospitalizations, severe disease, and death.[22]

A study from the United States evaluated the efficacy of BNT162b2 and mRNA-1273 vaccines in preventing severe illness for individuals at the highest risk of severe COVID-19 illness (those with advanced age and underlying comorbidities) by comparing their outcomes to unvaccinated individuals. The study stated that vaccine effectiveness 7 or more days after the second dose of the vaccine was 69% in preventing infection and 86% against severe disease/death.[23] They concluded that in an elderly population with a high-comorbidity burden, the vaccine effectiveness was lower than previously projected; however, the efficacy against death was high.

Mechanism of Action

The mRNA class of vaccines' rapid evolution and advancements are from the mRNA capabilities to imitate the antigen structure and expression comparable to those occurring during the SARS-CoV-2 infection.[24] The mRNA class of the vaccine does not pose a risk of infection or insertional mutagenesis. The mRNA eludes the anti-vector immunity permitting repeated vaccinations. The mRNA's ability to produce an undesired immune response within the body can be reduced, and modifications can be arranged to improve the mRNA vaccines' determination.[25]

BNT162b2

BNT162b2 is a nucleoside-modified messenger RNA (mRNA) expressed in lipid nanoparticles (LNP), encoding the spike (S) protein for the SARS-CoV-2 virus - the main site for neutralizing antibodies.[26][27] The lipid particles allow the transfer of the RNA into host cells, resulting in the SARS-CoV-2 S antigens' expression.[24] The immunogenicity and antibody response to SARS-CoV-2 S antigens further confers protection against COVID-19. 

mRNA-1273 

The mRNA-1273 vaccine is comprised of a lipid nanoparticle (LNP) encapsulating nucleoside-modified messenger RNA (mRNA), encoding the perfusion stabilized spike (S) protein of the SARS-CoV-2 virus and an S1-S2 cleavage site, which includes a transmembrane component. The S-2P antigen present on its surface allows entrance into the host cell. This further transfers the RNA into host cells, resulting in the expression of the SARS-CoV-2 S antigens. The immunogenicity and antibody response to SARS-CoV-2 S antigens also confers protection against COVID-19.[27][24]

Ad26.COV2.S

The Ad26.COV2.S exerts its effects by expressing the SARS-CoV-2 S protein to human cells creating an immune response to the SARS-CoV-2 antigen, conferring immunity without dispersal of the virus. Different from the mRNA vaccines (BNT162b2 and mRNA-1273), the Ad26.COV2.S is a recombinant viral vector vaccine. The Ad26.COV2.S recombinant viral vector vaccine bears DNA which forms the S protein of the SARS-CoV-2 virus, once injected into host cells, provide considerable amounts of the S protein antigen. The immune response to the S protein confers immunity by T-cells and B-cell stimulating antibodies to the S protein, similar to SARS-CoV-2 infection.[28]

NVX-CoV2373

This vaccine contains recombinant spike (rS) protein nanoparticles and Matrix-M adjuvant proteins. The rS protein is produced using recombinant DNA technology. Intramuscular injection of the full-length rS protein elicits an immune response to the rS protein, which protects against COVID-19 illness.[29]

Administration

BNT162b2

• For adults and children aged 12 and older: The vaccine is administered intramuscularly (IM) as a series of two doses (0.3 ml each) 3 to 8 weeks apart.
• For children aged 5 to 11: The vaccine is administered intramuscularly as a series of two doses (0.1 ml each) 3 to 8 weeks apart.
• For children six months to four years of age: The first two doses are 3 mcg given 3 to 8 weeks apart. The third dose is usually a 3 mcg of the bivalent vaccine given 8 weeks after the second dose. 
• For immunocompromised patients: The third dose is given at least 28 days after the second dose. 
• The vaccine is distributed as a frozen suspension in a multiple-dose vial containing a volume of 0.45 ml that does not contain a preservative. After dilution with 1.8 ml of 0.9% sodium chloride injection, each vial contains up to 6 dosages of 0.3 ml. Vial labels and cartoons may state that after dilution, a vial contains five doses of 0.3 ml. Each 0.3 ml dose contains 30 mcg of mRNA, expressed in lipid nanoparticles encoding the spike (S) protein for the SARS-CoV-2 virus.

mRNA-1273 

• The vaccine is administered intramuscularly as a series of two doses (100 mcg each) 4 to 8 weeks apart.
• The vaccine is distributed in 0.20 mg/ml white to off-white suspension rendered in vials containing ten doses of 0.5 ml. Each vial dosage carries 100 micrograms of mRNA.
• For immunocompromised patients: The third dose is given at least 28 days after the second dose.
• For children 6 to 11 years of age: 2 IM doses of 50 mcg each given 4 to 8 weeks apart.
• For children six months to five years of age: 2 IM doses of 25 mcg each given 4 to 8 weeks apart.

Ad26.COV2.S

• The vaccine is administered as a single dose of 0.5 mL and authorized for individuals aged 18 years or older who cannot receive or elect not to receive mRNA COVID-19 vaccines.
• An additional dose with an mRNA monovalent vaccine is recommended for immunocompromised individuals.

NVX-CoV2373

• The recommended dose is 2 IM injections of 5 mcg spike protein/50 mcg adjuvant protein for individuals aged 18 years or older, to be given 3 to 8 weeks apart.
• This vaccine is not authorized for individuals with immunocompromising conditions.

Booster Dose

The United States Centers for Disease Control and Prevention (CDC) recommends booster doses for all individuals aged five years and older. The preferred vaccine for booster dosing is a bivalent mRNA COVID-19 vaccine, which contains the original SARS-CoV-2 strain (in the monovalent BNT16b2 and mRNA-1273 vaccines) and the SAR-CoV-2 Omicron BA.4 and BA.5 variant strains.[30] The bivalent booster should be given at least two months after the last COVID-19 vaccine dose. Monovalent mRNA vaccines can no longer be used for booster doses. 

For individuals 18 years or older who have completed a primary series and are unable or unwilling to receive an mRNA vaccine for a booster dose, a single dose of NVX-CoV2373 vaccine can be used if given at least six months after the COVID-19 vaccine.

According to the CDC, COVID-19 vaccines may be coadministered with other vaccines. 

Adverse Effects

BNT162b2

• Injection site tenderness/pain (84.1%)
• Injection site swelling (10.5%)
• Redness at the injection site (9.5%)
• Fever (14.2%)
• Fatigue (62.9%)
• Headache (55.1%)
• Muscle pain (38.3%)
• Chills (31.9%)
• Joint pain (23.6%)
• Nausea (1.1%)
• Malaise (0.5%)
• Lymphadenopathy (0.3%)
• Severe allergic reaction (rare)
• Temporary one-sided facial drooping (rare)[31][3][32]

During clinical trials, four serious adverse events related to the BNT162b2 vaccination were reported. Serious adverse events include lymphadenopathy - localized to the right axillary, paroxysmal ventricular arrhythmia, right lower limb paresthesia, and shoulder injury associated with vaccine injection.[3] Mortality was seen in two BNT162b2 vaccine recipients but was not considered associated with the vaccination, as per investigators. These deaths were deemed to have been from arteriosclerosis and cardiac arrest. Mortality linked to Covid-19 following vaccine administration was not seen.

mRNA-1273

• Injection site tenderness/pain (92.0%)
• Injection site swelling (14.7%)
• Injection site redness (10.0%)
• Fever (15.5%)
• Fatigue (70.0%)
• Headache (64.7%)
• Muscle pain (61.5%)
• Chills (45.4%)
• Joint pain (46.4%)
• Swollen lymph nodes on injection site arm (1.1%)
• Nausea/vomiting (23.0%)
• Hypersensitivity (1.5%)[2]

Serious adverse effects occurred in 1% of recipients of the mRNA-1273 SARS-CoV-2 during the clinical trials. Three cases (<0.1%) of Bell's palsy were also reported during the clinical trials of mRNA-1273 SARS-CoV-2.[2]

Ad26.COV2.S

• Injection site tenderness/pain (33.3-62.4%)
• Injection site swelling (1.1-9.0%)
• Injection site redness (1.1-7.0%)
• headache (18.8-52.7%)
• fatigue (18.8-59.1%)
• myalgia (8.3-47.3%)
• fever (2.1-14.0%)
• nausea (12.3-14.0%)

Adverse reactions varied based on age groups 18 to 59 years old and 60 to 65 and above. Serious adverse effects included Thrombosis with Thrombocytopenia Syndrome (TTS), Immune Thrombocytopenia (ITP), Guillain-Barré Syndrome (GBS), and syncope.

NVX-CoV2373

According to the FDA fact sheet, solicited adverse reactions following the administration of this vaccine include:

• Injection site pain/tenderness (82.2%)
• Fatigue/malaise (62.0%)
• Muscle pain (54.1%)
• Headache (52.9%)
• Joint pain (25.4%)
• Nausea/vomiting (15.6%)
• Injection site redness (7.0%)
• Fever (6.0%)

Myocarditis, pericarditis, hypersensitivity reactions, lymphadenopathy-related reactions, and decreased appetite were also reported in some patients following the administration of this vaccine. 

Contraindications

BNT162b2

The BNT162b2 vaccine is not recommended for individuals with a known history of severe allergic reactions to any vaccine's components.[33] The use of this vaccine in children under the age of 5 is not yet recommended. Pregnant or breastfeeding women must consult a doctor or pharmacist before receiving this vaccine.

mRNA-1273 

The mRNA-1273 SARS-CoV-2 vaccine is not recommended for individuals with a known history of severe allergic reactions to any vaccine's components. Data on its use in pregnancy has not been studied, and its associated risks are yet to be determined. Its uses in individuals under the age of 18 have not yet been analyzed.

Ad26.COV2.S

The Ad26.COV2.S vaccination is not recommended in individuals with a known history of hypersensitivity and anaphylactic-type reactions to any vaccine components, individuals with any vaccine components, and individuals with a history of thrombosis with thrombocytopenia after vaccination.

NVX-CoV2373

According to the FDA fact sheet, this vaccine should not be administered to individuals with a known history of severe allergic reactions to any vaccine component. 

Monitoring

Immunocompromised vaccination recipients may not have a prominent immune response and should be routinely monitored. Recipients of the vaccines should periodically monitor any new and unusual adverse effects and report them to their vaccination provider.

Pregnant women planning to be vaccinated by the mRNA-1273 vaccine are encouraged to register in the pregnancy exposure registry. The registry monitors outcomes in pregnant women exposed to the mRNA-1273 vaccine.

Warnings and Precautions

• The BNT162b2 vaccine postmarketing data showed elevated cardiac inflammatory risk (myocarditis and pericarditis) within seven days of completing the 2-dose series. Males aged 18-24 are most at risk, and males below 40 are at higher risk than females.
• The mRNA-1273 vaccine postmarketing data showed elevated cardiac inflammatory risk (myocarditis and pericarditis) within seven days of completing the 2-dose series. Males aged 12-17 are most at risk, and males below 40 are at higher risk than females.
• Thrombosis with Thrombocytopenia Syndrome (TTS), Immune Thrombocytopenia (ITP), and Guillain-Barré Syndrome (GBS) with the Ad26.COV2.S vaccine has been reported.
• Syncope, altered immunocompetence, and limitations of vaccine effectiveness have also been reported in both mRNA vaccines (BNT162b2,mRNA-1273) and the Ad26.COV2.S vaccine.
• Monitoring for allergic reactions and syncope has been advised by the FDA fact sheet following the administration of NVX-CoV2373 vaccines.
• Given the reports of myocarditis, pericarditis, hypersensitivity reactions, and lymphadenopathy-related reactions following NVX-CoV2373 vaccines, appropriate workup and reporting to the CDC are advised when patients present with signs and symptoms consistent with these complications. 

Enhancing Healthcare Team Outcomes

COVID-19 vaccines are intended to prevent the COVID-19 disease caused by the SARS-CoV- 2 virus. An interprofessional team consisting of clinicians (MDs, DOs, NPs, PAs), nurses, and pharmacists providing a holistic and integrated approach to preventing COVID-19 can help achieve the best possible outcomes for this disease. COVID-19 is a public health emergency that may manifest from mild symptoms to severe multi-system effects in all age groups. Vaccines are the key to limiting severe illness, even as new variants emerge. 

Before receiving the vaccination, healthcare professionals providing the COVID-19 vaccination should thoroughly communicate and educate the vaccination recipients on the information presented in the "Fact Sheet for Recipients and Caregivers" before receiving these vaccinations. The healthcare provider should give a CDC vaccination card to each person receiving the vaccine with a return date to complete the two-dose series.

The healthcare team should inform the recipients on the V-safe information sheet, a smartphone app that identifies possible adverse effects following the COVID-19 vaccination through texting, and a website survey. The provider should also register in the federal COVID-19 vaccination program and report any unusual or severe adverse effects to Vaccine Adverse Event Reporting System (VAERS). The vaccination information must be included in a proper state or local jurisdiction's preferred system, such as the Immunization Information System (IIS), by the healthcare professional providing the vaccine.

The healthcare team should be prepared for immediate allergic reactions and have the equipment and treatment, such as; epinephrine, antihistamines, stethoscopes, and blood pressure cuffs, on hand in case anaphylaxis occurs following vaccine administration. Providers should also be aware of the limited data on vaccines' interchangeability and complete the two-dose series with the same vaccination as the first dose. The healthcare team should also communicate the vaccination's effectiveness and advise that receiving a vaccine does not ensure protection for all recipients.

Interprofessional communication is vital for establishing patient rapport and increasing public health measures to control the spread of the virus and disease within communities. Patients should be counseled on handwashing, wearing a mask, maintaining a distance of 6 feet, and 14-day quarantine after suspected exposure to limit the spread of the virus. Individual, collective, and preventative measures can help stop the further spread of COVID-19. [Level 5]