By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

SARS-CoV-2 is a novel virus to which humans have no immunity. The primary strategy against the ongoing pandemic is the development of one or more vaccines, which typically takes years to bring to market. However, the U.S. government has created Operation Warp Speed, with a purpose of expediting the development and availability of a vaccine. The goal is to deliver 300 million doses by January 2021.1 There are dozens of vaccine candidates undergoing investigation in human and animal trials.2,3 Only a few have reached Phase III testing.


SARS-CoV-2 derives from a large family of coronaviruses that includes SARS-V, Middle East respiratory syndrome coronavirus (MERS-CoV), and common cold viruses.4 It is an enveloped virus with a lipid membrane derived from the host cell and a single-strand RNA. It is characterized by protruding glycoprotein — spike protein (S) — from the viral membrane, giving it the “halo-like” corona appearance under electron microscopy. The spike (S) protein is comprised of two subunits (S1 and S2), with S1 carrying the receptor binding domain (RBD).5,6 The latter interacts with the angiotensin-converting enzyme receptor 2 (ACE2) host receptor, which facilitates the entry of the virus into the host.

The goal of a vaccine is to elicit an immune response via neutralizing antibodies to the spike (S) glycoprotein, possibly specifically RBD, thus preventing docking of SARS-CoV-2 to ACE2. Only antibodies directed to the spike (S) protein can neutralize the virus.5 The goal is to elicit humoral and cellular immunity by an appropriate antigen.

Vaccine Platforms

There are six primary strategies/platforms to developing a vaccine: whole live-attenuated virus, recombinant viral-vectored, inactivated/killed virus, protein subunit, virus-like particle, and nucleic acid vaccines.6 The five candidate vaccines that are part of Operation Warp Speed in Phase III trials include Janssen, Oxford/AstraZeneca, Moderna, Novavax, and Pfizer/BioNTech using three platforms (Table 1).

Table 1. Candidate Vaccine in Phase III Clinical Trials3,6



Vaccine Platform


Janssen/Johnson & Johnson


Nonreplicating human
adenovirus vector

2 doses IM,
Days 0 and 56


AZD1222/ChAdOx1 nCov19

Nonreplicating chimpanzee
adenovirus vector

Single dose IM



Nucleic acid (messenger RNA)

2 doses IM,
Days 0 and 28



Nucleic acid (messenger RNA)

2 doses IM,
Days 0 and 28



Recombinant SARS-CoV-2
glycoprotein nanoparticle
subunit with adjuvant

Two doses IM,
Days 0 and 21

Janssen (human adenovirus serotype 26) and Oxford (chimpanzee adenovirus) use a nonreplicating adenovirus vector to insert the SARS-CoV-2 S gene into the adenovirus genome. The use of a nonhuman adenovirus may be an advantage because of possible pre-existing immunity to the human adenovirus.6 The Oxford vaccine requires one dose.

The two RNA vaccines differ somewhat in their approach. The Moderna vaccine codes for the full S protein, while Pfizer/BioNTech originally targeted a subunit (RMD) of the S protein.6 However, Pfizer developed both versions and decided to pursue the full S protein after finding similar immunogenicity but lower systemic reactogenicity with the full S protein.7 Both are embedded or encapsulated in lipid-based nanoparticles. The Novavax vaccine is a recombinant antigenic protein derived from the spike protein. These are formulated into “virus-like” nanoparticles. Because of low immunogenicity, an adjuvant (saponin-based Matrix-M) is required to boost immunogenicity. With these different vaccine strategies, it remains to be established in Phase III trials the degree of efficacy, safety, immunogenicity, and reactogenicity among the candidate vaccines.


Johnson & Johnson is planning to enroll up to 60,000 test subjects age ≥ 18 years. Moderna plans to enroll 30,000 subjects age ≥ 18 years, AstraZeneca 30,000 subjects age ≥ 18 years (randomized 2:1 to vaccine and placebo), Pfizer 30,000 subjects ages 16 to 85 years, and Novavax 10,000 subjects ages 18 to 84 years. Generally, these studies are set to run for two years, with plans for interim analysis by data and safety monitoring boards. The vaccine needs to be at least 50% effective (i.e., prevent the infection or decrease disease severity).

Recently, AstraZeneca paused its trial because of a reported case of transverse myelitis, but has since resumed both inside and outside the United States.8,9 Similarly, Janssen/Johnson & Johnson paused its Phase III study when a patient became ill with an “unexplained illness,” although this trial has been allowed to resume, too.9,10 There is political pressure to grant emergency use authorization to one or more vaccines. The FDA’s latest guidance is that data from Phase III studies should include a median follow-up duration of at least two months after completion of the full vaccination regimen.

As vaccine development continues, nine of the largest vaccine manufacturers have pledged they will not submit vaccine candidates for FDA review until their safety and efficacy is shown in large clinical trials.11 This pledge is meant to allay public fears that vaccines may be rushed to market without adequate testing. The CEOs of all the leading vaccine candidates signed the pledge, including Johnson & Johnson, AstraZeneca, Moderna, Pfizer, and Novavax. Until one or more vaccines have been approved and about 60% to 70% of the population have been inoculated to achieve herd immunity, masks, social distancing, and hand hygiene are the most effective techniques to reduce transmission.


  1. U.S. Department of Health & Human Services. Fact sheet: Explaining Operation Warp Speed. Content last reviewed Oct. 28, 2020.
  2. Corum J, Wee SL, Zimmer C. Coronavirus vaccine tracker. The New York Times. Updated Oct. 29, 2020.
  3. World Health Organization. Draft landscape of COVID-19 candidate vaccines. Oct. 19, 2020.
  4. Uddin M, Mustafa F, Rizvi TA, et al. SARS-CoV-2/COVID-19: Viral genomics, epidemiology, vaccines, and therapeutic interventions. Viruses 2020;12:526.
  5. Kaur SP, Gupta V. COVID-19 vaccine: A comprehensive status report. Virus Res 2020;288:198114.
  6. Jeyanathan M, Afkhami S, Smaill F, et al. Immunological considerations for COVID-19 vaccine strategies. Nat Rev Immunol 2020;10:615-632.
  7. Meštrović T. Pfizer/BioNTech COVID-19 vaccine candidate BNT162b2 profiled for large scale clinical trials. News-Medical. Aug. 23, 2020.
  8. Taylor M, Levine D. Exclusive: FDA widens U.S. safety inquiry into AstraZeneca coronavirus vaccine - sources. Reuters. Sept. 30, 2020.
  9. Burton TM, Loftus P. Pivotal studies of Covid-19 vaccines from AstraZeneca, J&J resuming. The Wall Street Journal. Oct. 23, 2020.
  10. Neergaard L. AstraZeneca COVID-19 vaccine study paused after one illness. The Associated Press, Sept. 8, 2020.
  11. Pfizer. Biopharma leaders unite to stand with science. Sept. 8, 2020.