Vaccines in Late-Stage Development

The following vaccines are in, or have completed, phase 3 clinical trials in the United States.

On December 18, 2020, the US Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for the mRNA-1273 SARS-CoV-2 vaccine in individuals 18 years and older, after its Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to recommend (20 yes, 0 no, 1 abstention) the EUA on December 17.

On December 11, 2020, the FDA granted EUA for the BNT-162b2 SARS-CoV-2 vaccine in patients 16 years and older on December 11, 2020, after its VRBPAC voted to recommend (17 yes, 4 no, 1 abstention) the EUA on December 10.

Table 2. Vaccines in Late-Stage Development

BNT-162b2

Overview

  • Genetic-code vaccine
  • Storage and shipping requirements: Frozen; ultra-cold storage of -70ºC
  • Requires reconstitution
  • Once thawed, stable while refrigerated for up to 5 days
  • Room temperature stability: 2 hours
  • Dose: 2 intramuscular injections in deltoid muscle 21 days apart

BNT-152b2 (Pfizer) is a nucleoside-modified messenger RNA (modRNA) vaccine that encodes an optimized SARS-CoV-2 receptor-binding domain (RBD) antigen.

The ongoing multinational phase 3 trial included 43,548 participants 16 years and older who were randomly assigned to receive vaccine or placebo by injection; 43,448 participants received vaccine or placebo (vaccine group, 21,720; placebo group, 21,728). Approximately 42% of global participants and 30% of US participants were of racially and ethnically diverse backgrounds, and 41% of global and 45% of US participants were 56-85 years of age.

Vaccine efficacy was 95%, and no serious safety concerns were observed. The only grade 3 adverse event with a frequency of greater than 2% was fatigue at 3.8%; headache occurred in 2% of participants. Short-term mild-to-moderate pain at the injection site was the most commonly reported reaction, and severe pain occurred in less than 1% of participants across all age groups. [9]

mRNA-1273

Overview

  • Genetic-code vaccine
  • Dose: 2 injections 28days apart
  • No dilution required
  • Shipping and long-term storage: Frozen (-20°C) for 6 months
  • After thawing: Standard refrigerator temperatures (2-8°C) for 30 days
  • Room temperature: Up to 12 hours

The mRNA-1273 vaccine (Moderna) encodes the S-2P antigen. The US phase 3 trial (COVE) launched on July 27, 2020. The trial was conducted in cooperation with the National Institute of Allergy and Infectious Diseases and included more than 30,000 participants who received 2 100-µg doses or matched placebo on days 1 and 29. The primary efficacy analysis was released November 30, 2020.

The COVE study (n = 30,420) included Americans 65 years and older (24.8%), younger individuals with high-risk chronic diseases (16.7%), individuals who identify as Hispanic or Latinx (20.5%), and individuals who identify as Black or African American (10.4%). [13]

Immunogenicity data at 90 days after the second vaccination was evaluated in 34 participants in the phase 3 trial. [10] A phase 2/3 trial in adolescents 12-17 years begun in December 2020 is expected to enroll 3,000 participants.

AZD-1222

Overview

  • Viral vector vaccine
  • Phase 3 trial was temporarily put on hold globally on September 6, 2020 after a study participant in the United Kingdom was diagnosed with transverse myelitis. After FDA review in the United States, [14]  phase 3 trials resumed there on October 23, 2020.
  • Storage: Refrigeration
  • Dose: 2 injections 28-days apart

AZD-1222 (ChAdOx1 nCoV-19; AstraZeneca) is a replication-deficient chimpanzee adenoviral vector vaccine containing the surface glycoprotein antigen (spike protein) gene. This vaccine primes the immune system by eliciting antibodies to attack the SARS-CoV-2 virus if it later infects the body. Owing to the testing of a different coronavirus vaccine last year, development for AZD-1222 was faster than that of other viral vector vaccines.

Results of an interim analysis of the phase 3 clinical trial in the United Kingdom, Brazil, and South Africa are as follows:

One dosing regimen (n = 2741) showed vaccine efficacy of 90% when given as a half dose, followed by a full dose at least 1 month later. Another dosing regimen (n = 8895) showed 62% efficacy when given as 2 full doses at least 1 month apart. The combined analysis from both dosing regimens (N = 11,636) resulted in an average efficacy of 70.4%. All results were statistically significant (p< .0001). [15] The phase 3 efficacy trial in the United States is ongoing. Concerns about the clinical trial implementation and data analysis have emerged because the half-dose regimen was not in the approved study design. [16, 17] These concerns will be addressed by regulatory agencies and await publication of the trial data.

Ad26.COV2.S

Overview

  • Viral vector vaccine
  • Storage: Refrigeration
  • Dose: 1 injection

The phase 3 trial (ENSEMBLE) for adenovirus serotype 26 (Ad26) recombinant vector-based vaccine (JNJ-78436735; Johnson & Johnson) was launched in September 2020 with a goal of 60,000 participants in the United States, South Africa, and South America. In December 2020, the goal was revised to 40,000 participants. Because of the high prevalence of virus in the United States, researchers will be able to reach conclusions with a smaller trial.

The vaccine uses Janssen’s AdVac technology, which enhances vaccine stability (ie, 2 years at -20ºC and at least 3 months at 2-8ºC). This makes the vaccine candidate compatible with standard vaccine distribution channels and new infrastructure would not be required for distribution to people who need it. [18]  A second phase 3 trial (EMSEMBLE 2) to observe effects of 2 doses of the vaccine in up to 30,000 participants worldwide was announced on November 15, 2020.

NVX-CoV2373

Overview

  • Subunit vaccine
  • Dose: 2 injections, 21 days apart

NVX-CoV2373 (Novavax) is engineered using recombinant nanoparticle technology from SARS-CoV-2 genetic sequence to generate an antigen derived from the coronavirus spike protein. This is combined with an adjuvant (Matrix-M). Results of preclinical studies showed that it binds efficiently with human receptors targeted by the virus.

Phase 1/2 trials were initiated in May 2020. Phase 1 data in healthy adults showed that the adjuvanted vaccine induced neutralization titers that exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19. [12] 

The phase 3 trial in the United Kingdom has completed enrollment of 15,000 participants, including more than 25% who were older than 65 years. Researchers conducting the US and Mexico phase 3 trial, which started in December 2020, plan to enroll up to 30,000 participants.

 

Updated: Dec 31, 2020 
  • Author: David J Cennimo, MD, FAAP, FACP, AAHIVS;

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