Vaccines Are Here

With more than 200 vaccines in development, the coronavirus disease 2019 (COVID-19) vaccine landscape is rapidly evolving.¹

As of press time, there were 6 vaccines in development as part of Operation Warp Speed (OWS) that are considered front-runners (see Figure).^2,3 The goal of OWS is to produce and deliver 300 million doses of effective and safe COVID-19 vaccines, with initial doses available by January 2021.^2,3 The FDA’s guidance document for Emergency Use Authorization (EUA) for COVID-19 vaccines and the recent advisory committee meeting discuss the importance of efficacy and safety.^4,5 Phase 3 placebo- controlled studies should demonstrate that the COVID-19 vaccine is at least 50% effective as 1 of the criteria for an EUA or FDA approval.^4,5 Pharmacists will play an important role in COVID-19 vaccine education and administration, which makes it critical to stay up to date on the latest clinical information.

Clinical Overview of Top Candidates

Pfizer and BioNTech’s BNT162

This mRNA vaccine has positive phase 1 results and the phase 2/3 clinical trial began in July 2020.⁶ The vaccine was studied as a 2-dose intramuscular (IM) series (doses separated by 21 days) with 0.3 mL for each injection.^7,8 Additionally, there are more than 43,000 study participants enrolled, and 41,135 had received a second dose as of November 13, 2020, in the placebo-controlled trial.^9,10 On December 11, 2020, the FDA granted an EUA to the Pfizer-BioNTech COVID- 19 vaccine to prevent COVID-19 in individuals aged 16 years and older based on the phase 3 final efficacy analysis demonstrating that the vaccine was 95% effective (P <.0001).¹⁰ This is a historic moment, as it is the first COVID-19 vaccine to be granted an EUA in the United States.¹⁰ There were no serious safety concerns observed in clinical trials, and the vaccine was well tolerated.¹⁰ The vaccine is contraindicated in patients with known history of severe allergic reactions, such as anaphylaxis, to any component of the Pfizer vaccine.¹⁰ Appropriate medical treatment such as epinephrine and oxygen should be immediately available to manage acute anaphylactic reactions. A small number of individuals in the United Kingdom and the United States experienced anaphylactic reactions after vaccine administration recently under the EUAs. They were treated and have since recovered, and the FDA is monitoring these allergic reactions.¹⁰ About 43% of the overall and 30% of the US participants have diverse backgrounds, and the study recently included individuals aged 12 years and older, making it the first COVID-19 vaccine trial in the United States to include pediatric patients.¹¹ Cincinnati Children’s Hospital Medical Center has begun the study in pediatric patients.¹¹ Studying children early on before full adult scientific data have been reported has been controversial. However, many experts think it is critical to begin studying children to ensure there are adequate data for this population. The American Academy of Pediatrics in September issued a letter to the FDA and the US Department of Health and Human Services emphasizing the importance of studying COVID-19 vaccines in pediatric patients.

Moderna’s mRNA-1273

Moderna, in collaboration with the National Institute of Allergy and Infectious Diseases, developed mRNA-1273, which uses a genetic platform called messenger RNA (mRNA) that directs the body’s cells to express a virus protein that will hopefully elicit a robust immune response.¹² This was the first COVID-19 vaccine studied in the United States and the phase 1 clinical trial showed positive interim results.^13,14 Immune responses were seen in all study participants in a dose-escalation, open-label trial that included 45 healthy adults aged 18 to 55 years receiving 2 IM vaccinations 28 days apart, with a dose of 25, 100, or 250 μg.¹⁴ Common adverse effects (AEs) included chills, fatigue, headache, myalgia, and pain at the injection site, and 3 (21%) individuals in the 250-μg dose group reported at least 1 serious AE, such as high fever.¹⁴ The trial was expanded to include 40 older adults aged 56 to 70 years and aged 71 years and older, and they received 2 doses of either the 25- or 100-μg dose administered 28 days apart.¹⁵ AEs were mild or moderate, and the 100-μg dose produced higher antibody responses than the 25-μg dose.¹⁵

The phase 3 randomized placebo-controlled COVE study included more than 30,000 participants, with 37% from diverse communities and 42% at high risk of severe COVID-19 (>65 years or high-risk chronic conditions).^16,17 Individuals received 2 doses of the 100-μg IM injection separated by 28 days or placebo.¹⁶ The primary efficacy analysis of the phase 3 trial revealed that the vaccine efficacy was 94.1% against COVID-19 and 100% against severe COVID-19.¹⁷ There were 196 cases of COVID-19 observed, which included 185 in the placebo group versus 11 cases in the vaccine group, and most AEs were mild or moderate.¹⁷ The FDA granted an EUA to the Moderna COVID-19 vaccine on December 18, 2020 for the prevention of COVID-19 in adults as a 2-dose IM series (0.5 mL each) 1 month apart.¹⁷ The vaccine is contraindicated in patients with a known history of severe allergic reactions to any component of the Moderna vaccine, and appropriate medical treatment should be readily available to manage an acute anaphylactic reaction.¹⁷

AstraZeneca’s AZD1222

AstraZeneca and the University of Oxford have developed AZD1222, which uses a replication-deficient chimpanzee viral vector based on a weakened version of an adenovirus that causes infections in chimpanzees and contains the genetic material of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus spike protein.¹⁸ Interim phase 1 and 2 results showed that the vaccine had a robust immune response, and the most common AEs were fatigue, fever, headache, injection site pain and tenderness, and muscle aches.¹⁹ Interim analysis results including data from 4 ongoing blinded, controlled, randomized trials that included more than 11,000 of the more than 23,000 participants showed that the COVID-19 vaccine efficacy was 62.1% in individuals receiving 2 standard doses.²⁰ The vaccine efficacy in individuals who received a low dose followed by a standard dose had a vaccine efficacy of 90%, and the overall vaccine efficacy was 70.4%.20 Further data are needed to determine the discrepancy of the vaccine efficacy.²⁰ Because of a serious AE experienced by a participant, the phase 3 study was paused for a safety review.¹⁸ The FDA reviewed the data and determined it was safe to restart the clinical trial.¹⁸

Johnson & Johnson’s Ad26.COV2.S (Ad26)

The vector-based vaccine demonstrated that a single dose induced a robust immune response and was well tolerated in an interim analysis from an ongoing phase 1/2a clinical study.²¹ The phase 3 ENSEMBLE study is a double-blind, placebo-controlled, randomized trial evaluating a single IM injection with a planned enrollment of up to 60,000 participants.²² One patient experienced a serious AE during the trial, which was temporarily paused to examine the safety data.²³ No evidence was found that the vaccine caused the AE, so the study has been resumed.²³ Novavax’s NVX-CoV2373 The recombinant-subunit-adjuvanted protein vaccine was created using nanoparticle technology.²⁴ Additionally, it demonstrated in the phase 1 portion of an ongoing phase 1/2 trial in healthy adults aged 18 to 59 years that there were no serious AEs, and all participants developed antibody responses.²⁴ Novavax had enrolled 5500 participants as of October 27, 2020, in a phase 3 COVID-19 vaccine trial in the United Kingdom, with an expected enrollment of 15,000 individuals.²⁵ Additionally, the study is expected to begin soon in the United States.25 Study inclusion criteria involve individuals aged 18 to 84 years with a target of at least 25% who are 65 years and older.²⁶ Diverse patient populations and individuals with and without chronic health conditions are included in the study.²⁶ Patients receive 2 IM injections separated by 21 days. Each injection consists of 5 μg of protein antigen, with 50 μg of Matrix-M adjuvant.²⁶ Interim data from the placebo-controlled, randomized trial are expected in the first quarter of 2021.²⁵

Sanofi and GlaxoSmithKline’s recombinant protein-based vaccine

The adjuvanted, recombinant protein-based COVID-19 vaccine is in a phase 1/2 study that began September 3, 2020, and 440 individuals are enrolled in the double-blind, placebo- controlled, randomized clinical trial.²⁷ The phase 1/2 interim results revealed that the immune response from the vaccine was comparable to individuals who recovered from COVID-19 in adults aged 18 to 49.²⁷ However, there was an inadequate response in older adults from the COVID- 19 vaccine so there is a planned phase 2b study with an improved antigen formulation that is expected to begin in February 2021.²⁷

Jennifer Gershman, PharmD, CPh, is a drug information pharmacist and Pharmacy Times^® contributor who resides in South Florida.

REFERENCES

• World Health Organization. Draft landscape of COVID-19 candidate vaccines. December 8, 2020. Accessed December 15, 2020. https:// www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
• US Department of Health & Human Services. Fact sheet: explaining Operation Warp Speed. Updated December 14, 2020. Accessed December 15, 2020. https://www.hhs.gov/coronavirus/explaining-operation- warp-speed/index.html
• Slaoui M, Hepburn M. Developing safe and effective COVID vaccines—Operation Warp Speed’s strategy and approach. N Engl J Med. 2020;383:1701-1703. doi:10.1056/NEJMp2027405
• FDA. Emergency use authorization for vaccines to prevent COVID-19. Updated November 8, 2020. Accessed December 15, 2020. https://www. fda.gov/regulatory-information/search-fda-guidance-documents/emergency- use-authorization-vaccines-prevent-covid-19
• FDA. FDA briefing document: vaccines and related biological products advisory committee meeting. October 22, 2020. Accessed November 1, 2020. https://www.fda.gov/media/142723/download
• Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. 2020;383(25):2439-2450. doi:10.1056/NEJMoa2027906
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• Anderson EJ, Rouphael NG, Widge AT, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med. 2020. doi:10.1056/NEJMoa2028436
• National Institutes of Health. A study to evaluate efficacy, safety, and immunogenicity of mRNA-1273 vaccine in adults aged 18 years and older to prevent COVID-19. Updated October 28, 2020. Accessed November 2, 2020. https://clinicaltrials.gov/ct2/show/study/NCT04470427
• Moderna announces primary efficacy analysis in phase 3 COVE study for its COVID-19 vaccine candidate and filing today with US FDA for emergency use authorization. News release. Moderna. November 30, 2020. Accessed December 12, 2020. https://investors.modernatx.com/ news-releases/news-release-details/moderna-announces-primary-efficacy- analysis-phase-3-cove-study
• FDA. Fact sheet for healthcare providers administering vaccine (vaccination providers). December 18, 2020. Accessed December 18, 2020. https://www.fda.gov/media/144637/download
• Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020;396(10249):467-478. doi:10.1016/S0140-6736(20)31604-4
• Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2020:S0140-6736(20)32661-1. doi:10.1016/ S0140-6736(20)32661-1
• Johnson & Johnson posts interim results from phase 1/2a clinical trial of its Janssen COVID-19 vaccine candidate. Johnson & Johnson. Updated October 4, 2020. Accessed November 4, 2020. https://www.jnj.com/ johnson-johnson-posts-interim-results-from-phase-1-2a-clinical-trialof- its-janssen-covid-19-vaccine-candidate
• A study of Ad26.COV2.S for the prevention of SARS-CoV-2-mediated COVID-19 in adult participants (ENSEMBLE). National Institutes of Health. Updated December 3, 2020. Accessed November 3, 2020. https:// clinicaltrials.gov/ct2/show/NCT04505722
• Johnson & Johnson prepares to resume phase 3 ENSEMBLE trial of its Janssen COVID-19 vaccine candidate in the US. Johnson & Johnson. Updated October 23, 2020. Accessed November 4, 2020. https://www. jnj.com/our-company/johnson-johnson-prepares-to-resume-phase-3- ensemble-trial-of-its-janssen-covid-19-vaccine-candidate-in-the-us
• Keech C, Albert G, Cho I, et al. Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med. 2020;383:2320- 2332. doi:10.1056/NEJMoa2026920
• Novavax provides phase 3 COVID-19 vaccine clinical development update. News release. Novavax Inc.; October 27, 2020: Accessed November 5, 2020. https://ir.novavax.com/news-releases/news-release-details/ novavax-provides-phase-3-covid-19-vaccine-clinical-development
• A phase 3, randomized, observer-blinded, placebo-controlled trial to evaluate the efficacy and safety of SARS-CoV-2 recombinant spike protein nanoparticle vaccine (SARS-CoV-2 RS) with Matrix-M1 adjuvant in adult participants 18-84 years of age in the United Kingdom. Novavax. October 23, 2020. Accessed November 6, 2020. https://www. novavax.com/sites/default/files/2020-11/2019nCoV302Phase3UKVersion2FinalCleanRedacted. pdf
• Sanofi and GSK to support COVAX with 200 million doses of adjuvanted, recombinant protein-based COVID-19 vaccine. News release. Sanofi. October 28, 2020. Accessed November 6, 2020. https://www.sanofi.com/ en/media-room/press-releases/2020/2020-10-28-07-00-00