COVID-19 Vaccines: FDA Approved, EUA, and in the Pipeline

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Clinical testing of COVID-19 vaccine efficacy has led to the first FDA-approved COVID-19 vaccine, Comirnaty.

Genetic variants of SARS-CoV-2 have emerged worldwide. Within the United States, these variants are tracked and classified into categories based on genetic sequencing, laboratory testing, and epidemiological investigations.1 The SARS-CoV-2 Interagency Group—established by the US Department of Health and Human Services to improve coordination between the CDC, FDA, National Institutes of Health, Biomedical Advanced Research and Development Authority, and the Department of Defense—has classified and is monitoring variants currently circulating in the United States into 3 groups: variants of interest, variants of concern, and variants of high consequence (Table 1).1 Variants of interest include Eto, Iota, Kappa, and a currently unnamed variant, whereas Alpha, Beta, Delta, and Gamma are variants of concern. No strains of SARS-CoV-2 have been deemed "variants of high consequence" at this time.1 Data from September 11, 2021, indicate that the highly transmissible Delta variant of SARS-CoV-2 is now responsible for the majority of COVID-19 cases in the United States (98.6%-100%).2

EMERGING SARS-COV-2 VARIANTS AND THE EFFECTIVENESS OF VACCINES

The United States is facing an increased emergence of SARS-CoV-2 variants. Clinical testing of COVID-19 vaccine efficacy has led to the first FDA-approved COVID-19 vaccine, Comirnaty.3

Comirnaty (BNT162b2, Pfizer-BioNTech) COVID-19 Vaccine

The Pfizer-BioNTech, now called Comirnaty, COVID-19 vaccine was first given Emergency Use Authorization (EUA) on December 11, 2020, and as of May 10, 2021, has been approved for patients 12 years and older and has been administered to over 205 million Americans.3,4 On August 23, 2021, Comirnaty became the first FDA-approved COVID-19 vaccine for patients 16 years and older.4 This recommendation came from results of a phase 2/3 ongoing multinational, placebo-controlled, observer-blinded, trial of Comirnaty. Primary end points were efficacy of the vaccine against laboratory-confirmed COVID-19 and safety. A total of 43,548 participants (≥ 16 years) from 152 sites worldwide were randomized 1:1 to receive 2 doses, 21 days apart, of either placebo or Comirnaty (30 μg/dose).5 The primary efficacy end point was achieved in 8 patients in the Comirnaty group (0.04%) and 162 patients in the placebo group (0.88%). This corresponds with the vaccine being 95% effective in preventing COVID-19 (95% CI, 90.3%-97.6%).5

There were more adverse events (AEs) in the Comirnaty group than the placebo group; however, most were mild to moderate in severity and resolved within 1 to 2 days. The most common AEs included fatigue (51%-59%) and headache (39%-52%); severe systemic events after either dose were reported by less than 2% of participants who received Comirnaty.5

Moderna (mRNA-1273, Moderna) COVID-19 Vaccine

The Moderna COVID-19 vaccine was granted EUA on December 18, 2020, for adults 18 and older. On August 12, 2021, the FDA amended that to allow an additional dose for certain individuals who are immunocompromised.6 The phase 3 randomized, observer-blinded, placebo-controlled trial used to grant the vaccine its EUA status enrolled 30,420 volunteers across 99 centers in the United States in a 1:1 ratio to receive either placebo or the Moderna COVID-19 vaccine (100 μg/dose).7 The primary end point was the efficacy of the vaccine in preventing symptomatic COVID-19 illness within 14 days after the second injection. The primary end point was met in 185 participants in the placebo group (56.5 per 1000 person-years; 95% CI, 48.7-65.3) and in 11 participants in the mRNA1273 group (3.3 per 1000 person-years; 95% CI, 1.7- 6.0). This difference yielded a vaccine efficacy of 94.1% (95% CI, 89.3%-96.8%; P < .001). AEs occurred more often in the group who received the Moderna COVID-19 vaccine than the placebo group: injection site pain (84% vs 18%, respectively), fatigue (38% vs 27%), headache (33% vs 27%), and myalgia (23% vs 14%). These AEs lasted for 2 to 3 days. Serious AEs were rare but similar between groups.7

Janssen (Ad26.COV2.S, Johnson & Johnson) COVID-19 Vaccine

The Janssen COVID-19 vaccine is the only single-dose vaccine against COVID-19 that received EUA within the United States.9 Unlike the other COVID-19 vaccines available in the United States, which are messenger RNA (mRNA) vaccines, the Janssen COVID-19 vaccine uses a replication-incompetent recombinant adenovirus vector that expresses the SARS-CoV-2 spike protein, classifying it as a viral-vector vaccine.9,10

In an international, randomized, double-blind, placebo-controlled, phase 3 trial, 19,630 volunteers were randomly assigned to receive a single dose of the Janssen COVID-19 vaccine (5 x 1010 viral particles), and 19,691 volunteers were randomly assigned to receive placebo.11 The primary end points were vaccine efficacy against moderate to severe/critical COVID-19 disease with an onset at least 14 days and 28 days after administration. The 14-day primary end point occurred in 116 (0.59%) patients in the vaccine group and 348 (1.77%) patients in the placebo group, yielding an efficacy rate of 66.9% (adjusted 95% CI, 59.0%-73.4%). The 28-day primary end point was achieved in 66 patients in the vaccine group and 193 cases in the placebo group (95% CI, 55.0-74.8). The efficacy rate increased to 76.7% when only examining severe/critical COVID-19 disease. Similar to the mRNA vaccines, the AEs were more common in the vaccine group than the placebo group, and the incidence of serious AEs was balanced between groups.11

This vaccine received EUA approval on February 26, 2021; however, distribution and administration were paused for 10 days in April 2021 while investigators evaluated the correlation between vaccine administration and the occurrence of vaccine-associated thrombosis with thrombocytopenia syndrome (TTS) in women aged 18 to 49 years.12 As a result, recommendations were revised to advise women between 18 and 50 years of age of the rare risk for blood clots but that the benefits of vaccination outweigh the known and potential risk of infection.13 Another rare AE that has occurred with the Janssen vaccine is Guillain-Barré Syndrome (GBS). In most people in which this occurred, symptoms began within 42 days after receipt of the vaccine.13 The CDC and FDA shared that they will continue to monitor for severe AEs of this vaccine, but still endorse its use for the prevention of COVID-19 infection in appropriate individuals.12

GLOBAL COVID-19 VACCINE CANDIDATES UNDER CONSIDERATION IN THE UNITED STATES

As of September 19, 2021, there are 118 vaccine candidates in clinical trials worldwide: 38 in phase 1, 30 in phase 1/2, 8 in phase 2, 10 in phase 2/3, 24 in phase 3, and 8 in phase 4.14 A summary of the important characteristics of the vaccines in phase 3 and phase 4 development is included in Table 2.14 Of the 32 phase 3/4 vaccine candidates, only the AstraZeneca COVID-19 and Novavax COVID-19 vaccines are potential new candidates for use in the United States. The safety, efficacy, and immunogenicity of these vaccines are being tested in clinical trials and are summarized in this article.

AstraZeneca (ChAdOxI-S, AZD1222, Vaxzevria, COVISHIELD, University of Oxford) COVID-19 Vaccine

AstraZeneca, in collaboration with the University of Oxford, has released their ChAdOx1-S vaccine, called the AstraZeneca COVID-19 vaccine (AZD1222) (used in the United States), Vaxzevria (used in the European Union), and COVISHIELD (used in India), and is under the Emergency Use Listing by the World Health Organization (WHO) in over 100 countries.15,16 This vaccine is based on the ChAdOx1-S (recombinant) structure, which is a single recombinant, replication-deficient chimpanzee adenovirus encoding the S-glycoprotein of the SARS-CoV-2 virus. Similar to the Janssen COVID-19 vaccine, the AstraZeneca COVID-19 vaccine is a viral-vector vaccine.17 It is administered as a 2-dose series with 5 x 1010 viral particles,18 8 to 12 weeks apart, per WHO recommendations.15

The data to support the Emergency Use Listing for the AstraZeneca COVID-19 vaccine come from 4 studies: 1 phase 1/2 study (COV001, UK), 1 phase 2/3 study (COV002, UK), 1 phase 3 study (COV003, Brazil), and 1 double-blind phase 1/2 study (COV005, South Africa). The immunogenicity and safety data for the AstraZeneca COVID-19 vaccine were pooled from all 4 studies, while the efficacy data were pooled from the ongoing COV002 and COV003 trials.18

The primary efficacy end point of the trials was efficacy of the vaccine against virologically confirmed, symptomatic COVID-19. A total of 23,848 participants (≥ 18 years of age) were recruited and vaccinated across all 4 studies. Participants were randomized 1:1 to receive 2 doses, 4 to 12 weeks apart, of either the control product (placebo or Meningococcal ACWY vaccine) or the AstraZeneca COVID- 19 vaccine (low dose: 2.5 x 1010 viral particles; standard dose: 3.5-6.5 x 1010 viral particles). Of the 23,848 participants, only 11,636 met the inclusion criteria for the primary efficacy end point: 5807 received the AstraZeneca COVID-19 vaccine, and 5829 received a control product.19

Among included participants, there were 30 cases of COVID-19 in the group who received either dose of the AstraZeneca COVID-19 vaccine (n = 5807) compared with 101 in the control group (n = 5829), with disease onset being at least 14 days after the second dose for both groups. This corresponds with the vaccine being 70.4% effective in preventing symptomatic COVID-19 disease (95% CI, 54.8%-80.6%).19 Among the participants who received 2 standard doses of the AstraZeneca COVID-19 vaccine, the primary end point was achieved in 27 of 4440 patients in the vaccine group and 71 of 4455 patients in the control group, yielding a vaccine efficacy of 62.1% (95% CI, 41.0%-75.7%). A majority of the included patients were aged 18 to 55 years (86.7% represented in COV002; 89.9% represented in COV003); therefore, extrapolations to other age groups cannot be made at this time. Additional age groups and coexisting conditions are currently being studied.19 As of August 2021, 2 doses of the AstraZeneca vaccine have been shown to be 92% effective against severe disease or hospitalization due to the Delta variant, 86% effective against the Alpha variant, and 82% effective against the Beta and Gamma variants.20

A total of 10 participants were hospitalized due to COVID- 19 disease—defined as confirmed COVID-19 with 1 of the following additional features: temperature of at least 37.8°C, cough, shortness of breath, anosmia, or ageusia—all among participants in the control group. Two of these cases were deemed severe COVID-19, including 1 fatal case. Five of these cases were more than 21 days after the first dose but less than 14 days after the second dose, and the other 5 cases were more than 14 days after the second dose.19

A total of 23,745 participants were included in the main safety subset.19 Both groups had a low incidence of serious AEs (0.7% in the vaccine group vs 0.8% in the control group). Mild to moderate AEs were reported in the initial phase 1/2 trial.21 The most common systemic AEs reported were fatigue (70%) and headache (68%), irrespective of whether participants took adjuvant paracetamol. Local adverse reactions were similar to other COVID-19 vaccines (muscle ache [60%], malaise [61%], chills [56%], feeling feverish [51%]), with the highest severity/intensity of reactions occurring within 24 hours of vaccination.21

In April 2021, concerns were raised about the emergence of a new AE related to administration of the AstraZeneca COVID-19 vaccine, TTS, which resulted in severe blood clotting with low platelets.22 As of July 2021, the WHO reported that the incidence is approximately 1 case per 100,000 vaccinated adults within 3 to 30 days following vaccination, with a slightly higher risk in younger adults compared with older adults. However, further research is needed to confirm additional risk factors for TTS. Another rare AE reported with administration of the AstraZeneca COVID-19 vaccine is GBS; however, a causal relationship with regards to vaccine administration has not been confirmed at this time. The benefits of vaccination to protect against COVID-19 still far outweigh the risks presented from vaccine administration.15

Novavax (NVX-CoV2373) COVID-19 Vaccine

The Novavax COVID-19 vaccine is a protein-based vaccine that combines the SARS-CoV-2 virus S protein with Novavax’s saponin-based Matrix-M adjuvant to enhance the immune response and stimulate high levels of neutralizing antibodies.23 Novavax is submitting data for Emergency Use Listing with the WHO on a rolling basis beginning in August 202124 and is preparing to submit for EUA from the FDA in September 2021.23

The 2019nCoV-302 study was a randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom. A total of 14,039 participants (≥ 18 years of age) were assigned in a 1:1 ratio to receive 2 doses, 21 days apart, of either placebo or the Novavax COVID-19 vaccine (5 μg/dose). The primary efficacy end point of the trial was efficacy of the vaccine against virologically confirmed symptomatic mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.25

COVID-19 infections were reported in 10 participants (n = 7020) in the Novavax COVID-19 vaccine group and 96 participants (n = 7019) in the placebo group, for a vaccine efficacy of 89.7% (95% CI, 80.2%-94.6%). Of the 10 cases reported in the vaccine group, 8 were caused by the Delta variant. Among participants who were at least 65 years of age, vaccine efficacy was 88.9% (95% CI, 12.8%-98.6%), and overall vaccine efficacy at 14 days after the first dose was 83.4% (95% CI, 73.6%-89.5%). Efficacy of the vaccine, while similar amongst age groups, could not be confirmed among different races, as too few non- White participants were enrolled.25

A total of 5 cases of severe COVID-19—defined as confirmed COVID-19 with 1 of the following additional features: clinical signs at rest indicative of severe systemic illness; respiratory failure; evidence of shock; significant acute renal, hepatic, or neurologic dysfunction; admission to an intensive care unit; or death—occurred among participants in the placebo group. All 5 patients also had abnormal vital signs, required supplemental oxygen, and had additional COVID-19–related complications.25

A total of 15,139 participants were included in the safety sub-analysis for unsolicited AEs. There were more treatment-related AEs in the vaccine group than in the placebo group (10.9% vs 4.5%, respectively); however, serious AEs were low in both groups (0.5% in both). The most common systemic AEs were fatigue (19.4%-40.3%), headache (24.5%-40%), and muscle pain (21.4%-40.3%). The most common local AEs reported in the vaccine group included pain (29.3%-51.2%) and tenderness (53.3%- 76.4%) at the injection site. All AEs increased in prevalence after the second vaccine dose. Younger participants were more likely to report pain after the first and second doses than older participants (≤ 65 years).25

A current ongoing phase 3 trial is being conducted in the United States and Mexico (PREVENT-19) and has enrolled a total of 25,457 participants from 119 total sites in a 2:1 ratio to receive either 2 doses, 21 days apart, of the Novavax COVID-19 vaccine (5 μg/dose) or placebo. This trial differs from the first phase 3 trial in that the priority participants are from traditionally under-represented minority groups and populations at high risk for COVID-19 (> 65 years, < 65 years with comorbidities, or those having life circumstances with frequent COVID-19 exposure). The primary end point was the development of virologically confirmed symptomatic mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection.26

There were 77 cases of SARS-CoV-2 infection: 63 (n = 8142) cases in the placebo group and 14 (n = 17,315) cases in the vaccine group for a vaccine efficacy of 90.4% (95% CI, 82.9%-94.6%). Vaccine efficacy was 100% (95% CI, 87%-100%) for moderate or severe COVID- 19 disease; all 4 cases occurred in the placebo group. In the high-risk populations, vaccine efficacy was 91% (95% CI, 83.6%-95%) with 62 cases in the placebo group and 13 cases in the vaccine group. The Novavax COVID- 19 vaccine also demonstrated high efficacy against the COVID-19 variants. In patients with Variants of Concern or Variants of Interest (as defined by the CDC), the vaccine demonstrated an efficacy of 93.2% (95% CI, 83.9%- 97.1%). In other variants, the vaccine demonstrated 100% efficacy (95% CI, 80.8%-100%).26

Preliminary safety data from the PREVENT-19 trial demonstrated a higher incidence of AEs in the vaccine group than the placebo group, namely represented by more tenderness and pain at the injection site and the presence of headache, muscle pain, and fatigue. All AEs increased in prevalence after the second injection.26

LOOKING AHEAD: COVID-19 VACCINE BOOSTERS

As more people become vaccinated against SARS-CoV-2, the question of waning immunity and need for “booster” doses has arisen. On August 12, 2021, the FDA made the decision to modify the EUAs for both the Pfizer-BioNTech and Moderna COVID-19 vaccines to allow for administration of a third dose in certain immunocompromised populations (ie, solid organ transplant recipients or those who have received a diagnosis with a similar immunocompromised state).28 With the FDA approval of Comirnaty on August 23, 2021, they continued authorization of the third dose. Additionally, the ACIP stated that this third (booster) dose can be safely administered at least 28 days after completion of the initial 2-dose series of either mRNA vaccine. There are currently no sufficient data available to determine if an additional dose of the Janssen COVID-19 vaccine is necessary, but the CDC and FDA are investigating this.28

OVERALL CONSIDERATIONS

With this fourth wave of COVID-19 cases, vaccines are the best defense at preventing hospitalizations, death, and viral mutation. In the United States, 3 vaccines are currently available against COVID-19: 2 mRNA vaccines (Pfizer-BioNTech’s Comirnaty and Moderna) and 1 viral-vector vaccine (Janssen [Johnson & Johnson]); however, both the viral-vector AstraZeneca vaccine and the protein-based Novavax vaccine look to be viable options to consider adding to the arsenal for protecting against COVID-19 infection once they are approved in the United States.

Erin M. Johnson and Hannah C. Oliver are PharmD candidates at the University of Mississippi School of Pharmacy in Oxford.

Jamie L. Wagner, PharmD, BCPS, is a clinical associate professor of pharmacy practice at the University of Mississippi School of Pharmacy in Jackson.

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