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

On December 17, 2020, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted to recommend (20 yes, 0 no, 1 abstention) Emergency Use Authorization (EUA) for the mRNA-1273 vaccine for the prevention of COVID-19 in individuals 18 years and older. The agency released its briefing document for the vaccine on December 15, which was “largely positive”Medscape Medical News reported.

The FDA is expected to announce a decision about the EUA soon.

The FDA granted Emergency Use Authorization (EUA) for the BNT-162b2 SARS-CoV-2 vaccine in patients 16 years and older on December 11, 2020. A day earlier, the VRBPAC voted to recommend (17 yes, 4 no, 1 abstention) the EUA. 

Phase 1a of vaccine distribution is expected to focus on healthcare workers and residents of long-term care facilities. The Advisory Committee on Immunization Practices has published guidelines on the ethical principles for the initial allocation for this scarce resource. [8]  


Table 2. Vaccines in Late-Stage Development (Open Table in a new window)

Vaccine

Clinical Trials

Results

Regulatory Status

BNT-162b2

(2 injections)

Phase 3 trial ongoing in those 16 y and older

In mid-October 2020, FDA allowed Pfizer to expand phase 3 trial to adolescents 12 y and older.

Primary efficacy analysis:

  • 95% effective against clinically evident COVID-19 infection 28 days after first dose across all subgroups
    [9]  
  • Well tolerated across all populations
    [9]
  • 170 confirmed cases (placebo group, 162; vaccine group, 8) Ten severe cases after first dose (placebo group, 9; vaccine group, 1)
    [9]
  • Efficacy consistent across age, gender, race, and ethnicity demographics
    [9]
  • Not evaluated for asymptomatic infection/carriage
    [9]

First approved in United Kingdom on December 2, 2020

Approved in early December 2020 by Bahrain and Canada

FDA gave Emergency Use Authorization on December 11, 2020.

mRNA-1273

(2 injections)

US Phase 3 trial (COVE) ongoing

Phase 2/3 trial began in adolescents 12-17 y in December 2020

Primary efficacy analysis:

  • Efficacy rate 94.1%

  • 196 confirmed cases (placebo group, 185; vaccine group, 11)

  • Only severe illness was in placebo group

  • 90 d after second dose (30 participants): high levels of binding and neutralizing antibodies that fell but remained elevated

FDA’s VRBPAC will meet on December 17, 2020 to vote on EUA

AZA-1222

(2 injections)

Phase 3 trials resumed on October 23, 2020 after being paused globally on September 6.

Interim analysis of phase 3 clinical trial in United Kingdom, Brazil, and South Africa:

  • Efficacy 90%, depending on dosage regimen. Average efficacy of 70.4% in combined analysis of 2 dosing regimens.

  • 131 COVID-19 cases: From 21 d after first dose, 10 hospitalizations, all in placebo group (2 classified as severe; 1 death)

Phase 3

Ad26.COV2.S

(1 injection)

Phase 3 trial (ENSEMBLE) ongoing

Second phase 3 trial (EMSEMBLE 2) announced November 15, 2020 to study effects of 2 doses

Rolling Biologics License Application submitted in Canada and Europe on December 1, 2020.

NVX-CoV2373

Phase 3 trial in UK concluded enrollment at end of November 2020.

The US phase 3 trial begins in late 2020.

  • Phase 1 data in showed the adjuvanted vaccine induced neutralization titers in healthy volunteers that exceeded responses in convalescent serum from mostly symptomatic patients with COVID-19.
    [12]   

Phase 3

BNT-162b2 

Overview

  • Genetic-code vaccine

  • Storage and shipping requirements: Frozen; ultra-cold storage of -70ºC

  • Requires reconstitution

  • Once thawed, stable refrigerated for up to 5 days

  • Room temperature stability: 2 hours

  • Dose: 2 IM injections in deltoid muscle 21 days apart

This 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 greater than 2% in frequency 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 28-days 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

This vaccine 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 over 30,000 participants who received two 100-mcg doses on days 1 and 29 or matched placebo. The primary efficacy analysis was released November 30, 2020.

The COVE study included Americans 65 years and older; younger individuals with high-risk chronic diseases; participants who identify as Hispanic or Latinx; and those who identify as Black or African American. [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 aged 12-17y begun in December 2020 intends to enroll 3,000 participants.

AZD-1222

Overview

AZD-1222 (ChAdOx1 nCoV-19) 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 other viral vector vaccines.

Results of an interim analysis of the phase 3 clinical trial in the United Kingdom, Brazil, and South Africa One dosing regimen (n = 2,741) showed vaccine efficacy of 90% when given as a half dose, followed by a full dose at least 1 month apart. Another dosing regimen (n = 8,895) 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< 0.0001). [15] The phase 3 efficacy trial in the United States is ongoing. Concerns about the clinical trial implementation and data analysis have emerged as the half-dose regimen was not in the approved study design. [16, 17] These 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) was launched in September 2020 with a goal of 60,000 participants in the United States, South Africa, and South America. In December 2020, this was revised to require 40,000 participants, owing to the high prevalence of virus in the US, researchers will be able to reach conclusions with a smaller trial.

The vaccine uses Janssen’s AdVac technology, which assists vaccine stability (ie, 2 years at -20 degrees Celsius and at least 3 months at 2-8 degrees Celsius). This makes the vaccine candidate compatible with standard vaccine distribution channels and would not require new infrastructure to get it to the 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

NVX-CoV2373 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). Preclinical studies found it binds efficiently with human receptors targeted by the virus.

Phase 1/2 trials initiated in May 2020. Phase 1 data in healthy adults showed 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 UK has completed enrollment of 15,000 participants, including more than 25% who were older than 65 years. The US phase 3 trial starting in late 2020 plans to enroll up to 30,000 participants.



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