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CMAAO Coronavirus Facts and Myth Buster: COVID-19 Vaccines (Part 2)

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Dr KK Aggarwal    04 January 2021

With input from Dr Monica Vasudev

Vaccines in Late-Stage Development

Vaccines that are in, or have completed, phase 3 clinical trials in the United States are mentioned below.

On December 18, 2020, the US FDA granted EUA for the mRNA-1273 SARS-CoV-2 vaccine in individuals aged 18 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 of age and above, after its VRBPAC voted to recommend (17 yes, 4 no, 1 abstention) the EUA on December 10. 

Table 1. Vaccines in Late-Stage Development

 

Vaccine

Trials

Findings

Regulatory Status

BNT-162b2

(2 injections)

Phase 3 trial ongoing in individuals 16 y and above

In mid-October 2020, company allowed by FDA to expand phase 3 trial to adolescents 12 years and older.

Primary efficacy analysis:

·        95% effective against clinically evident COVID-19 infection 28 d after 1st dose across all subgroups   

·        Well tolerated across all populations 

·        170 confirmed cases (placebo group, 162; vaccine group, 8) 10 severe cases after 1st dose (placebo group, 9; vaccine group, 1) 

·        Efficacy consistent across age, sex, race, and ethnicity 

·        Not evaluated for asymptomatic infection/carriage

First approved in United Kingdom on December 2, 2020

Approved in early December 2020 by Bahrain and Canada

Emergency use authorized  by FDA on December 11, 2020.

mRNA-1273

(2 injections)

Ongoing US phase 3 trial (COVE)

Phase 2/3 trial began in adolescents 12-17 years of age in December 2020

Primary efficacy analysis:

·        Efficacy rate 94.1%

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

·        Only severe illness (30 cases) was in placebo group, including 1 death 

·        90 d after 2nd dose (30 participants): high levels of binding and neutralizing antibodies that declined but remained elevated

·        Well tolerated 

Emergency use authorization

by FDA on December 18, 2020.

AZA-1222

(2 injections)

Phase 3 trials resumed on October 23, 2020 after being halted worldwide on September 6, 2020.

·        Participant in United Kingdom diagnosed with transverse myelitis, causing a temporary hold on trial.

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

·        Efficacy 90%, depending on dosage; average efficacy of 70.4% in combined analysis of 2 dosing regimens.

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

Approved in United Kingdom on December 29, 2020.

Phase 3 in United States.

Ad26.COV2.S

(1 injection)

Phase 3 trial (ENSEMBLE) ongoing

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

·        Phase 1/2a study: antibodies to SARS-CoV-2 seen after a single injection

·        99% were positive for neutralizing antibodies against SARS-CoV-2 at day 29: strong T-cell responses and a T H1 response noted  

Rolling biologics license application submitted in Canada and Europe on December 1, 2020.

NVX-CoV2373

Phase 3 trial in United Kingdom concluded enrolment at November-end.

US and Mexico phase 3 trial began in December 2020.

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

Phase 3

 

BNT-162b2 

  • This is a genetic-code vaccine; Storage and shipping requirements: Frozen; ultra-cold storage of -70ºC; Requires reconstitution; Once thawed, it is stable while refrigerated for up to 5 days; Room temperature stability: 2 hours; Dose: 2 intramuscular 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 enroled 43,548 participants 16 years of age and above, randomized to receive vaccine or placebo injection; 43,448 participants received vaccine or placebo (vaccine group, 21,720; placebo group, 21,728). Nearly 42% of global participants and 30% of US participants had racially and ethnically diverse backgrounds, and 41% of global and 45% of US participants were 56-85 years of age.

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

 

mRNA-1273

  • This is a genetic-code vaccine; Dose: 2 injections 28 days apart; No dilution required; Shipping and long-term storage: Frozen (-20°C) for 6 months; Once thawed: 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) was started on July 27, 2020, conducted in association with the National Institute of Allergy and Infectious Diseases. It included more than 30,000 participants who were given 2 100-µg doses or matched placebo on days 1 and 29. The primary efficacy analysis was released on November 30, 2020.

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

Immunogenicity data at 90 days after the second vaccination was assessed in 34 participants in the phase 3 trial.  A phase 2/3 trial in adolescents 12-17 years was started in December, 2020 and is expected to enrol 3,000 participants.

 

AZD-1222

  • This is a viral vector vaccine,
  • Phase 3 trial was temporarily halted worldwide on September 6, 2020 after a study participant in the United Kingdom was diagnosed with transverse myelitis. Following FDA review in the United States,  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 that contains the surface glycoprotein antigen (spike protein) gene. This vaccine primes the immune system by eliciting antibodies that attack the SARS-CoV-2 virus if it later infects the body. Because of the testing of a different coronavirus vaccine last year, development for AZD-1222 was faster in comparison with 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. The second dosing regimen (n = 8895) showed a 62% efficacy when given as 2 full doses at least 1 month apart. The combined analysis from both dosing regimens (N = 11,636) yielded an average efficacy of 70.4%. All results were statistically significant (p< .0001). The phase 3 efficacy trial in the United States is going on. There are concerns about the clinical trial implementation and data analysis since the half-dose regimen was not in the approved study design.  These concerns will be addressed by regulatory agencies and await publication of the trial data.

 

Ad26.COV2.S

  • 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 initiated in September, 2020 with the aim of 60,000 participants in the United States, South Africa, and South America. In December, the goal was revised to 40,000 participants. Because of the high prevalence of virus in the United States, researchers are expected to reach conclusions with a smaller trial.

The vaccine makes use of Janssen’s AdVac technology, which improves vaccine stability (2 years at -20ºC and at least 3 months at 2-8ºC), thus making the vaccine candidate compatible with standard vaccine distribution channels and new infrastructure would not be needed for distribution.  A second phase 3 trial (EMSEMBLE 2) to assess the effects of 2 doses of the vaccine in up to 30,000 participants globally 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 produce an antigen derived from the coronavirus spike protein. This is combined with an adjuvant (Matrix-M). Preclinical studies suggest that it binds efficiently with human receptors targeted by the virus.

Phase 1/2 trials were started 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.    

The phase 3 trial in the United Kingdom has completed enrolment of 15,000 participants, including over 25% older than 65 years. The US and Mexico phase 3 trial, which started in December 2020, plans to enrol up to 30,000 participants.

[Source: Medscape; Reproduced for educational purposes]

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA

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