Location:
- Nucleus Network in Herston, Queensland
- Melbourne, Victoria

Participants: 
- 131 healthy adults
- see child node for more details 

Randomized, placebo-control, phase 1-2 trial:
- 5 ug and 25 ug doses with and without Matrix M1 adjuvant
- Phase 1: two intramuscular injections, 21 days apart

Procedure:
- rSARS-CoV-2 and Matrix M1 mixed before injection
- each participant received 2 intramuscular injections of trail vaccine or the placebo in the deltoid muscle

Safety Outcomes: 
- Reactogenicity: track days 0 to 7 and days 21 to 28
- Laboratory values: day 21, and unsolicited adverse events during the first 35 days
- participants also had nasopharyngeal swab testing for SARS-CoV-2 on day 35 or when they reported symptoms
- after each vaccination, participants were observed for at least 30 minutes after

Methods: NVX-CoV2373

Overview:
- vaccine had acceptable safety findings and induced high immune responses 
- safe for all people as seen in the study from 5 months to 85 years old
- acceptable candidate to move into Phase 3

Limitations:
- small sample size of the trial
- lack of ethnic diversity
- age was on the younger side
- follow up was short
- participants were generally in good health

Matrix M1 benefit:
- after the second vaccination, neutralizing antibody response was greater than seen in symptomatic covid patients
- the magnitude of antibody and Tcell response
- induction of functional antibodies
- antigen dose sparing
- the two doses of rSARS-CoV-2 with the added Matrix M1 regimen is the best from this clinical trial

Microneutralization testing:
 - the vaccine worked as seen with the anti-spike IgG and microneutralization
- anti-spike IgG and microneutralization titers levels can be correlated to the severity of the disease

Discussion: NVX-CoV2373 Vaccine

Trial Population:
- 25 received 25ug doses of rSARS-CoV-2
- 29 received 5ug doses of rSARS-CoV-2 + Matrix M1
- 28 received 25ug doses of rSARS-CoV-2 + Matrix M1
- 26 received 25ug doses of rSARS-CoV-2 + Matrix M1 with second vaccination as a single dose placebo
- 23 received a placebo

Safety Outcomes:
- no serious adverse events were reported
- reactogenicity: absent of mild
- only one person had a fever that lasted 1 day

Immunogenicity:
- Day 0: anti-spike IgG GMEUs ranged from 105-116
- Day 21: induced without adjuvant by a factor of at least 10
- Day 28: with adjuvant GMEUs increased by a factor of 8
- Day 35: responses had more than doubled again
- achieved GMFRs that were approx 100x greater than observed with rSARS-CoV-2 alone
- responses in 5ug and 25ug adjuvanted vaccines were similar

Neutralizing antibodies:
- Undetectable before vaccination
- Day 21: GMFRs were approx 5x greater with adjuvant
- Day 35:  second vaccine with adjuvant increased 100x than single vaccination without adjuvant
- Approached level that would be observed in hospitalized patients with COIVD-19

Conclusion: 
- At day 35, ELISE anti-spike IgG GMEUS and neutralizing antibodies induced by 5ug and 25ug adjuvanted vaccines doses were 4-6x greater 
- two dose of 5ug and 25ug with Matrix M1 had similar magnitude response
- strong bias toward Th1 phenotype

Results: NVX-CoV2373 Vaccine

- NVX-CoV2373 is a recombinant nanoparticle vaccine composed of trimetric full-length SARS-CoV2 spike glycoproteins and Matrix M1 adjuvant
- Novavax identified this as its candidate with high immunogenicity and high levels of neutralizing antibodies
- September 24, 2020: Phase 3 clinical trials began in the UK and immunize 10,000 people in the next 4-6 weeks
- January 21, 2021: 22,000 volunteers enrolled worldwide

Santa Clara University

1. mRNA-1273 (moderna)
2. BNT162b2 (pfizer and biontech)
3. adenovirus type-5 (Ad5)-vectored COVID-19 vaccine (Cansino)
4. rAd26-S and rAd5-S (gamaleya)
5. Ad26.COV2.S (johnson & johnson) 
6. ChAdOx1 (Astrazeneca and Oxford)
7. NVX-CoV2373 (novavax)
8. Inactivated COVID-19 Vaccine (Wuhan Institute of Biological Products)
9. BBIBP-CorV Vaccine (Sinopharm)
10. Sinovac
11. INO-4800 (NCT04336410) by Inovio Pharmaceuticals
12. Anhui Zhifei Longcom and the Chinese Academy of Medical Sciences Vaccine
13. BBV152 (Covaxin)

Phase 3 Vaccine Candidates

Description from Literary Review:

NVX-CoV2373 is a recombinant nanoparticle vaccine composed of trimetric full-length SARS-CoV2 spike glycoproteins and Matrix M1 adjuvant. A randomized, placebo-control, phase 1-2 trial was conducted on 131 healthy adults.  It has high immunogenicity and high levels of neutralizing antibodies. On September 24, 2020, phase 3 clinical trials began and immunized 10,000 people in the next 4-6 weeks. This took place at the Nucleus Network in Herston, Queensland and Melbourne, Victoria.
This vaccine candidate is a recombinant nanoparticle vaccine constructed from full-length wild-type SARS-CoV-2 spike glycoprotein. It includes Matrix M1 Which is a saponin based adjuvant made by Novavax. The rSARS-CoV-2 and Matrix M1 parts were mixed just before use. This vaccine is favorable because it can be stored between 2°C and 8°C, allowing for easy preservation and, therefore, distribution (Novavax Initiates Phase 3 Efficacy Trial of COVID-19 Vaccine in the United Kingdom | Novavax Inc. - IR Site, n.d.).
******


NVX-CoV2373 Vaccine by Novavax Inc.

Keech, C., Albert, G., Cho, I., Robertson, A., Reed, P., Neal, S., . . . Glenn, G. M. (2020). Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine. New England Journal of Medicine. doi:10.1056/nejmoa2026920
https://www.nejm.org/doi/full/10.1056/NEJMoa2026920

Phase 1-2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine

Aimed to further assess the immunogencity and safety of Ad5-vectored COVID-19 vaccine in a larger population with only the 5 x 10^10 and 1 x 10^11 viral particles doses after the first-in-human phase 1 trial with CanSino Biologics (Tianjin, China) suggested high-dose vaccine was associated with a higher risk of severe adverse effects. 
- methods
- results
- discussions
- limitations and future work

Study on immunogenicity and safety of Ad5-vectored COVID-19 vaccine in larger population

mRNA-1273 is a candidate vaccine proposed by Moderna. The candidate vaccine is a lipid nanoparticle that contains an encapsulated, nucleoside-modified messenger RNA (mRNA). The mRNA codes for the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation, or the structure it has before it infects a cell. The S glycoprotein is a primary vaccine target as it controls host cell attachment and is needed for viral entry.

mRNA-1273 Vaccine against SARS-CoV-2 Overview

- Ad26.COV2.S is a vaccine candidate designed by Johnson & Johnson.
- It utilizes a non-replicating adenovirus 26 as a vector expressing the stabilized pre-fusion SARS-CoV-2 spike protein.
- It entered Phase 3 clinical testing in late September, becoming the fourth large-scale vaccine in phase 3 in the United States.

******

From our Literary Review:
Johnson & Johnson vaccine candidate is phase 1/2a randomized, double blinded, placebo-controlled clinical study. The purpose of the study was to assess the safety, reactogenicity and immunogenicity of the Ad26.COV2.S. Ad26.COV2.S is a non-replicating adenovirus. The safety and immunogenicity data collected after only a single dose are supportive for further clinical development of Ad26.COV2.S.It is a 26 based vector aiming to express the spike protein of SARS-CoV-2. 


Ad26.COV2.S (Johnson& Johnson) Vaccine Overview

- ChAdOx1  are a desirable platform of vaccine because they are immunogenic in older adults and can be manufactured at large scale
- Vaccines made by combining adenoviral vectors, DNA, and poxviral vectors have been used in an attempt to improve immunogenicity--Emergence of antivector immunity inhibits the potency of a second dose, so homologous adenoviral regimens are typically avoided
- "The ChAdOx1 nCoV-19 vaccine (AZD1222) consists of the replication-deficient simian adenovirus vector ChAdOx1, containing the full-length structural surface glycoprotein (spike protein) of SARS-CoV-2, with a tissue plasminogen activator leader sequence. ChAdOx1 nCoV-19 expresses a codon-optimised coding sequence for the spike  protein (GenBank accession number MN908947)."

ChAdOx1 nCoV-19 vaccine by The University of Oxford

NVX-CoV2373 (Novavax) Vaccine Overview

The study aimed to investigate the safety and immunogenicity of an inactivated whole virus vaccine agains SARS-CoV-2. The results of Phase I and Phase II trials suggest that minimal adverse reactions were observed and that a multiple dose approach is needed. Non-human primate trials have been conducted, but large scale clinical trials in humans are needed to understand the efficacy and the potential for long-term adverse reactions.
- Methods
- Results
- Discussion

Inactivated Whole Virus vaccine by Wuhan Institute of Biological Products

This paper summarized the phase 1 and phase 2 trials of an inactivated vaccine against SAR-CoV-2. The safety and immunogenicity of the vaccine were assessed, including the adverse reactions and long term effects of the vaccine.

- Methods
- Results
- Discussion

BBIBP-CorV Vaccine (Sinopharm)

- Sinovac Vaccine is also known as CoronaVac SARS-CoV-2 Vaccine
- this is an inactivated pathogen it differs from how the other rival vaccine candidates are made using either DNA or RNA
- virus is grown in cultures and then inactivated it
- typically takes longer than other vaccines to develop

- Introduction 
- Methods
- Results
- Conclusion

 Sinovac Vaccine

INO-4800 targets the MERS coronavirus Spike protein. The nucleic acid vaccine by attaching to the receptor-binding site and neutralizing the epitopes. The vaccine has initiated a humoral and T-cell response as well as a spike in antibodies which function via competitive inhibition of the ACE2 receptor which the novel coronavirus also binds to. NCT04336410 is optimized through electroporation.

INO-4800 (NCT04336410) by Inovio Pharmaceuticals

From the Literary Review:

The plant based vaccine, CoVLP, uses trimeric spike glycoproteins from Nicotiana benthamiana to mimic the size and shape of SARS-CoV-2 (Ward et al., 2020). Medicago has had previous success utilizing other plant-based vaccines for the Influenza virus and H1N1, so the company decided to develop a VLP vaccine against SARS-CoV-2 as well (Medicago Begins Phase I Clinical Trials for Its COVID-19 Vaccine Candidate, n.d.). A randomized, partially-blinded, prime-boost, 21 days apart, dose escalation phase 1 study determined that the vaccine was well-tolerated and effective when used with adjuvants. Medicago has been approved by the government of Canada to initiate a phase 2/3 trial, which began on November 12, 2020. At the time of writing, CoVLP  is the only plant-based vaccine in phase 3 trials, offering diversity to the pool of vaccine candidates. This added diversity can allow for alternative prophylactic treatment options for those at risk for adverse reactions to other COVID-19 vaccines (Ward et al., 2020).
******

CoVLP (Medicago) 

- Background
- Methods
- Results
- Conclusion

CoVLP Phase 1 Trial

- The Anhui Zhifei Longcom vaccine is a recombinant subunit vaccine
- June 19, 2020: approved for phase one clinical trials
- October 22, 2020: complete phase two clinical trials
- Entered Phase 3 clinical trials on November 20, 2020

Anhui Zhifei Longcom and the Chinese Academy of Medical Sciences Vaccine

- BBV152 is an inactivated SARS-CoV-2 vaccine in rhesus macaques. Both Phase 1 and Phase 2 were launched in India. The sponsor is Bharat Biotech International Limited and collaborator is Indian Council of Medical Research.
- Study Description
- Study Design
- Arms and Interventions
- Outcome Measures

BBV152 (Covaxin)

From our Literary Review:

With the aid of the Ministry of Health of the Russian Federation, russian researchers developed a vaccine composed of two distinct adenovirus vector components: recombinant adenovirus type 26 (rAd26) and recombinant adenovirus type 5 (rAd5), each of which had been previously tested separately in clinical trials at Johnson and Johnson (USA) and at the CanSino Biological/Beijing Institute of Biotechnology (China), respectively.  The rAd26/rAd5 vaccine was developed and tested in healthy participants in phase 2 clinical trials after confirming the safety of the two individual vector components in phase 1. They ultimately found  that this heterologous vaccine is safe and immunogenic in healthy adults, but that further investigation is still needed to understand its effectiveness.

******
Study on safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19

Investigates the safety and immunogenicity of a heterologous COVID-19 vaccine with two vector components: recombinant adenovirus type 26 (rAd26) and recombinant adenovirus type 5 (rAd5), both of which carry the gene for the SARS-CoV-2 spike glycoprotein S.  This vaccine was developed in two formulations, frozen and lyophilized, and tested in healthy participants after confirming the safety of the two individual vector components in phase 1.  They ultimately find that this heterologous vaccine is safe and immunogenic in healthy adults, but that further investigation is still needed to understand its effectiveness.

- Methods

- Results

- Discussion
  
       
       

rAd26 and rAd5 vector-based Vaccine


- NVX-CoV2373 is a variant of the SARS-CoV-2 spike protein (S) created by mutating
 the furin cleavage site to be resistant to cleavage and using 2-prolines substitutions.

Structure of double mutant NVX-CoV2373 

- Preserving the structural integrity of the protein in stressful environments is important for global distribution.
- pH extremes, prolonged agitation, freeze/thaw cycles, or elevated temperature had no effect on hACE2 receptor binding. Only oxidizing conditions with hydrogen perozide reduced binding by 8-fold
- NVX-Cov2327 had better thermal stability than wild type S protein

Stability of  NVX-CoV2373

- Production of  titer anti-S IgG that is associated with blockade of hACE2 receptor binding, virus neutralization, and protection against SARS-CoV-2 
- T-cell responses including CD4+ and CD8+ T cells, CD4+T and follicular helper T cells (Tfh)

NVX-CoV2372 Targeted Responses

NVX-CoV2373 attained 50% saturation of hACE2 binding at 2-fold lower concentration than the wild type protein and the single-mutated BV2365. Binding was also specific to hACE2.

NVX-CoV2373 Binding Affinity

- Anti-spike immunoglobulin G (IgG) ELISA (Days 0, 7, 21, 28, and 35)
- Wild-type virus microneutralization assay (MN) with an inhibitory concentration of > 99% (MN IC>99) (Days 0, 21, and 35)
- Intracellular cytokine staining of antigen-specific CD4+ T cells (Days 0 and 28).
- Human ACE2 receptor binding inhibition by ELISA 
- peripheral blood mononuclear cells for T-cell responses  

NVX-CoV2373 Immunogenicity Assays

- Generally mild reactogenicity and well tolerated
- After first dosage, the most common side effects were local tenderness and pain while system events were less frequent (headache, fatigue, and myalgia being the most common), but the majority of reported symptoms remained at grade ≤1. 
- After the second dosage, only one participant experienced (mild) fever

NVX-CoV2373 Reactogenicity

- Induced a greater immune response than without the adjuvant: higher levels of neutralizing antibodies and greater T-cell response 
- Dose sparing (induce same level of response with less dosage)

Learn Before

Related

Learn After