Coronavirus (36) Protein subunit COVID-19 vaccine: NVX-CoV2373 developed by Novavax
A month ago, on 28th February, another COVID-19 vaccine candidate, NVX-CoV2373 (also called Covovax), developed by Novavax, had its interim report, with a 89.3% overall efficacy (95.6% efficacy against the original strain, 85.6% efficacy against the UK variant) established from Phase 3 trials in the UK.1,2 This vaccine also provides significant protection against the variants dominating in South Africa.1 Novavax has since started to seek authorization of NVX-CoV2373 from regulatory agencies, including the US Food and Drug Administration (FDA), the UK Medicines and Healthcare products Regulatory Agency (MHRA), the European Medical Agency (EMA), and Health Canada.3 Let us have a look at the vaccine in this blog post.
If approved, NVX-CoV2373 will be the first protein-based vaccine against COVID-19. The vaccine contains trimeric full-length SARS-CoV-2 spike glycoproteins,# found on the surface of SARS-CoV-2, made using the company’s nanoparticle technology.4 It also contains saponin-based Matrix-M1™ adjuvant,## a substance that helps to enhance the immune response to the vaccine.5
Like other vaccines, NVX-CoV2373 prepares the body to defend itself against the next attack from the SARS-CoV-2 infection. Since it only contains a fragment of the disease-causing virus SARS-CoV-2, it can neither cause COVID-19 nor replicate by itself. In other words, the vaccine is safer as no live components are involved.
According to the protocol of the clinical trials of the vaccine, the vaccination is a two-dose regimen (each with 5 µg trimeric SARS-CoV-2 recombinant S glycoprotein antigen adjuvanted with 50 µg Matrix-M1) injected muscularly, administered 21 days apart.6 The vaccine is stable at 2°C to 8°C and can be stored at room temperature for at least 24 hours. It can be shipped in a ready-to-use liquid formulation. Existing vaccine supply chain channels can be used for its distribution. Thus the cost spent in transportation, distribution, and storage of the vaccine is much lower than those for the mRNA vaccines.
History of development
On 26 February 2020, Novavax announced that it has produced several nanoparticle vaccine candidates for COVID-19.7 In early April, they were able to identify NVX-CoV2373, a SARS-CoV-2 full-length 1273 amino acid spike protein variant with mutations on 2 sites, as the most ideal vaccine candidate. NVX-CoV2373 demonstrates high immunogenicity and triggers high levels of neutralizing antibodies against SARS-CoV-2 in mice and baboons.8,9
Phase 1
The Phase 1 randomized, observer-blinded, placebo-controlled trial included 131 healthy participants aged 18 to 59 years, and was rolled out in Australia at the end of May. The report from the study was posted online at a preprint server in August 2020, and the full peer-reviewed report came out in September.10
The study showed that NVX-CoV2373 was well-tolerated and the reactions in the participants after injection were generally mild. Following the first dose, tenderness and pain were the most frequent local symptoms. Systemic events were individually less frequent, with headache, fatigue and myalgia being reported most commonly. Similar to the other approved vaccines, the second dose caused greater reactions in the participants, although the majority of symptoms were still reported as ≤ Grade 1, which means quite a mild reaction. The symptoms generally disappeared in 2 days.10
Moreover, NVX-CoV2373 elicited neutralizing antibody concentrations greater than those in a pool of COVID-19 patients with clinically significant disease, indicating the high efficacy of the vaccine. The Matrix-M1 adjuvant induced antigen-specific polyfunctional CD4+ T-cell responses that were reflected in IFN-γ, IL-2, and TNF-α production on spike protein stimulation.10
Phase 1/2
The Phase 2 portion of the Phase 1/2 clinical trial to evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 began in August in both the United States and Australia.11 The trial expanded on the age range of the Phase 1 portion by including older adults of 60-84 years of age, as approximately 50 percent of the trial population.
In addition, a Phase 2b clinical trial, which enrolled over 4400 participants, to assess efficacy of the vaccine, began in South Africa in August.12 The study covered September through mid-January, the period when the SARS-CoV-2 variant was widely circulated in South Africa. In fact, the variant accounted for 92.6% of the symptomatic COVID-19 events detected in the study.### Moreover, approximately 1/3 of the enrolled participants demonstrated prior COVID-19 infection by the original COVID-19 strain. Yet, the interim study report announced by Novavax last month still showed a 60% efficacy for the prevention of mild, moderate and severe COVID-19 disease in the 94% of the study population that was HIV-negative. These data provided two important findings:1. The prior infection with COVID-19 may not completely protect against subsequent infection by the variant widely circulated in South Africa; 2. Vaccination with NVX-CoV2373 provided significant protection against the variant dominating in South Africa.1
Phase 3
A Phase 3 efficacy trial was started in the UK in late September, 2020.13 This trial enrolled more than 15,000 participants aged between 18 and 84 years inclusive, including 27% over 65.1 As mentioned in the first paragraph of this blog post, the first interim analysis results came out last month and showed an overall vaccine efficacy of 89.3%, based on 62 cases of COVID-19 being found among the participants (56 cases were observed in the placebo group while 6 cases were observed in the NVX-CoV2373 group). Of these 62 cases, 61 were mild or moderate; only 1 was severe and was in placebo group.1
At the time the study was initiated in the UK, a variant strain of SARS-CoV-2 was increasingly prevalent, with over 50% of the PCR-confirmed symptomatic cases: 32 variant, 24 non-variant, 6 unknown. When splitting the efficacy based on the strains of the SARS-CoV-2 being detected, from 56 of the 62 cases, the vaccine efficacy was found to be 95.6% against the original COVID-19 strain and 85.6% against the variant strain.1
Phase 3 efficacy trial of COVID-19, PREVENT-19 (the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial for COVID-19), was also initiated later in December, in the United States and Mexico.14 A few days ago, Novavax announced the complete enrolment of 30,000 participants, which included Latin (20%), African American (13%), native American (6%), Asian American (5%), and older adults (65 years and older, 13%).15 The result from the study should provide a better view on the safety and efficacy of the drugs on different ethnicities.
Supply agreements with countries
NVX-CoV2373 is quite a popular protein subunit vaccine. Until now, Novavax has established agreements for the supply of NVX-CoV2373 directly to the US, the UK, Canada, Australia, and Switzerland, and, through partnerships, supply to Japan, South Korea and India.16,17 A purchase agreement with the UK government allowed the UK to buy 60 million doses of NVX-CoV2373. Fujifilm Diosynth Biotechnologies, in its Billingham, Stockton-on-Tees site in the UK, is responsible for manufacturing the antigen component of the vaccine to be provided to the UK.18
#Novavax researchers started with a modified spike gene of SARS-CoV-2. They inserted the gene into a different virus, called a baculovirus, and allowed it to infect moth cells. The infected cells produced spike proteins that spontaneously joined together to form spikes, as they do on the surface of the coronavirus. A similar method of growing and harvesting virus proteins is already used to make licensed vaccines for diseases including influenza and HPV.
##According to the Novavax website, “Novavax’ patented saponin-based Matrix-M adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen-presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune responses.
###A triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa.
References
1. Covid-19: Novavax vaccine shows 89% efficacy in UK trials. BBC news, 29 January, 2021. https://www.bbc.co.uk/news/uk-55850352
2. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
3. Novavax announces start of rolling review by multiple regulatory authorities for COVID-19 vaccine authorization. Novavax press release, Feb 04, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-start-rolling-review-multiple-regulatory
4. Recombinant nanoparticle vaccine technology. Novavax website. novavax.com/our-unique-technology.
5. S.E. Magnusson, A.F. Altenburg, K.L. Bengtsson, et. al. Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice. Immunol Res., 2018 Apr; 66(2):224-233.
6. Current protocol for Phase 3 clinical trial of NVX-CoV2373 in the US and Mexico. novavax.com/resources
7. Novavax advances development of novel COVID-19 vaccine. Novavax press release, Feb 26, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-advances-development-novel-covid-19-vaccine
8. Novavax identifies coronavirus vaccine candidate; Accelerates initiation of first in-human trial to mid-May. Novavax press release, Apr 08, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-identifies-coronavirus-vaccine-candidate-accelerates
9. J.H. Tian, N. Patel, R. Haupt, et. al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nature Communications, 12, Article number: 372 (2021).
10. C. Keech, G. Albert, I. Cho, et al. Phase 1–2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med 2020; 383:2320-2332. DOI: 10.1056/NEJMoa2026920
11. Novavax initiates Phase 2 portion of Phase 1/2 clinical trial of COVID-19 vaccine. Novavax press release, Aug 24, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-2-portion-phase-12-clinical-trial-covid
12. Novavax initiates efficacy trial of COVID-19 vaccine in South Africa. Novavax press release, Aug 17, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-efficacy-trial-covid-19-vaccine-south-africa
13. Novavax initiates Phase 3 efficacy trial of COVID-19 vaccine in the United Kingdom. Novavax press release, Sep 24, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-3-efficacy-trial-covid-19-vaccine-united
14. Novavax announces initiation of PREVENT-19 pivotal Phase 3 efficacy trial of COVID-19 vaccine in the United States and Mexico. Novavax press release, Dec 28, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-initiation-prevent-19-pivotal-phase-3-efficacy
15. Novavax completes enrolment of PREVENT-19, COVID-19 vaccine pivotal Phase 3 trial in the United States and Mexico. Feb. 22, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-completes-enrollment-prevent-19-covid-19-vaccine-pivotal
16. Novavax and Commonwealth of Australia announce agreement in principle for acquisition of Novavax COVID-19 vaccine. Novavax press release, Nov 04, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-commonwealth-australia-announce-agreement-principle
17. Novavax and Government of Switzerland announce agreement in principle to supply COVID-19 vaccine. Novavax press release, Feb 03, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-and-government-switzerland-announce-agreement-principle
18. Novavax and UK government announce collaboration and purchase agreement for Novavax’ COVID-19 vaccine candidate. Novavax press release, Aug 14, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-uk-government-announce-collaboration-and-purchase
A month ago, on 28th February, another COVID-19 vaccine candidate, NVX-CoV2373 (also called Covovax), developed by Novavax, had its interim report, with a 89.3% overall efficacy (95.6% efficacy against the original strain, 85.6% efficacy against the UK variant) established from Phase 3 trials in the UK.1,2 This vaccine also provides significant protection against the variants dominating in South Africa.1 Novavax has since started to seek authorization of NVX-CoV2373 from regulatory agencies, including the US Food and Drug Administration (FDA), the UK Medicines and Healthcare products Regulatory Agency (MHRA), the European Medical Agency (EMA), and Health Canada.3 Let us have a look at the vaccine in this blog post.
If approved, NVX-CoV2373 will be the first protein-based vaccine against COVID-19. The vaccine contains trimeric full-length SARS-CoV-2 spike glycoproteins,# found on the surface of SARS-CoV-2, made using the company’s nanoparticle technology.4 It also contains saponin-based Matrix-M1™ adjuvant,## a substance that helps to enhance the immune response to the vaccine.5
Like other vaccines, NVX-CoV2373 prepares the body to defend itself against the next attack from the SARS-CoV-2 infection. Since it only contains a fragment of the disease-causing virus SARS-CoV-2, it can neither cause COVID-19 nor replicate by itself. In other words, the vaccine is safer as no live components are involved.
According to the protocol of the clinical trials of the vaccine, the vaccination is a two-dose regimen (each with 5 µg trimeric SARS-CoV-2 recombinant S glycoprotein antigen adjuvanted with 50 µg Matrix-M1) injected muscularly, administered 21 days apart.6 The vaccine is stable at 2°C to 8°C and can be stored at room temperature for at least 24 hours. It can be shipped in a ready-to-use liquid formulation. Existing vaccine supply chain channels can be used for its distribution. Thus the cost spent in transportation, distribution, and storage of the vaccine is much lower than those for the mRNA vaccines.
History of development
On 26 February 2020, Novavax announced that it has produced several nanoparticle vaccine candidates for COVID-19.7 In early April, they were able to identify NVX-CoV2373, a SARS-CoV-2 full-length 1273 amino acid spike protein variant with mutations on 2 sites, as the most ideal vaccine candidate. NVX-CoV2373 demonstrates high immunogenicity and triggers high levels of neutralizing antibodies against SARS-CoV-2 in mice and baboons.8,9
Phase 1
The Phase 1 randomized, observer-blinded, placebo-controlled trial included 131 healthy participants aged 18 to 59 years, and was rolled out in Australia at the end of May. The report from the study was posted online at a preprint server in August 2020, and the full peer-reviewed report came out in September.10
The study showed that NVX-CoV2373 was well-tolerated and the reactions in the participants after injection were generally mild. Following the first dose, tenderness and pain were the most frequent local symptoms. Systemic events were individually less frequent, with headache, fatigue and myalgia being reported most commonly. Similar to the other approved vaccines, the second dose caused greater reactions in the participants, although the majority of symptoms were still reported as ≤ Grade 1, which means quite a mild reaction. The symptoms generally disappeared in 2 days.10
Moreover, NVX-CoV2373 elicited neutralizing antibody concentrations greater than those in a pool of COVID-19 patients with clinically significant disease, indicating the high efficacy of the vaccine. The Matrix-M1 adjuvant induced antigen-specific polyfunctional CD4+ T-cell responses that were reflected in IFN-γ, IL-2, and TNF-α production on spike protein stimulation.10
Phase 1/2
The Phase 2 portion of the Phase 1/2 clinical trial to evaluate the safety, immunogenicity, and efficacy of NVX-CoV2373 began in August in both the United States and Australia.11 The trial expanded on the age range of the Phase 1 portion by including older adults of 60-84 years of age, as approximately 50 percent of the trial population.
In addition, a Phase 2b clinical trial, which enrolled over 4400 participants, to assess efficacy of the vaccine, began in South Africa in August.12 The study covered September through mid-January, the period when the SARS-CoV-2 variant was widely circulated in South Africa. In fact, the variant accounted for 92.6% of the symptomatic COVID-19 events detected in the study.### Moreover, approximately 1/3 of the enrolled participants demonstrated prior COVID-19 infection by the original COVID-19 strain. Yet, the interim study report announced by Novavax last month still showed a 60% efficacy for the prevention of mild, moderate and severe COVID-19 disease in the 94% of the study population that was HIV-negative. These data provided two important findings:1. The prior infection with COVID-19 may not completely protect against subsequent infection by the variant widely circulated in South Africa; 2. Vaccination with NVX-CoV2373 provided significant protection against the variant dominating in South Africa.1
Phase 3
A Phase 3 efficacy trial was started in the UK in late September, 2020.13 This trial enrolled more than 15,000 participants aged between 18 and 84 years inclusive, including 27% over 65.1 As mentioned in the first paragraph of this blog post, the first interim analysis results came out last month and showed an overall vaccine efficacy of 89.3%, based on 62 cases of COVID-19 being found among the participants (56 cases were observed in the placebo group while 6 cases were observed in the NVX-CoV2373 group). Of these 62 cases, 61 were mild or moderate; only 1 was severe and was in placebo group.1
At the time the study was initiated in the UK, a variant strain of SARS-CoV-2 was increasingly prevalent, with over 50% of the PCR-confirmed symptomatic cases: 32 variant, 24 non-variant, 6 unknown. When splitting the efficacy based on the strains of the SARS-CoV-2 being detected, from 56 of the 62 cases, the vaccine efficacy was found to be 95.6% against the original COVID-19 strain and 85.6% against the variant strain.1
Phase 3 efficacy trial of COVID-19, PREVENT-19 (the PRE-fusion protein subunit Vaccine Efficacy Novavax Trial for COVID-19), was also initiated later in December, in the United States and Mexico.14 A few days ago, Novavax announced the complete enrolment of 30,000 participants, which included Latin (20%), African American (13%), native American (6%), Asian American (5%), and older adults (65 years and older, 13%).15 The result from the study should provide a better view on the safety and efficacy of the drugs on different ethnicities.
Supply agreements with countries
NVX-CoV2373 is quite a popular protein subunit vaccine. Until now, Novavax has established agreements for the supply of NVX-CoV2373 directly to the US, the UK, Canada, Australia, and Switzerland, and, through partnerships, supply to Japan, South Korea and India.16,17 A purchase agreement with the UK government allowed the UK to buy 60 million doses of NVX-CoV2373. Fujifilm Diosynth Biotechnologies, in its Billingham, Stockton-on-Tees site in the UK, is responsible for manufacturing the antigen component of the vaccine to be provided to the UK.18
#Novavax researchers started with a modified spike gene of SARS-CoV-2. They inserted the gene into a different virus, called a baculovirus, and allowed it to infect moth cells. The infected cells produced spike proteins that spontaneously joined together to form spikes, as they do on the surface of the coronavirus. A similar method of growing and harvesting virus proteins is already used to make licensed vaccines for diseases including influenza and HPV.
##According to the Novavax website, “Novavax’ patented saponin-based Matrix-M adjuvant has demonstrated a potent and well-tolerated effect by stimulating the entry of antigen-presenting cells into the injection site and enhancing antigen presentation in local lymph nodes, boosting immune responses.
###A triple mutant variant, which contains three critical mutations in the receptor binding domain (RBD) and multiple mutations outside the RBD, was widely circulating in South Africa.
References
1. Covid-19: Novavax vaccine shows 89% efficacy in UK trials. BBC news, 29 January, 2021. https://www.bbc.co.uk/news/uk-55850352
2. Novavax COVID-19 vaccine demonstrates 89.3% efficacy in UK Phase 3 trial. Novavax press release, Jan 28, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3
3. Novavax announces start of rolling review by multiple regulatory authorities for COVID-19 vaccine authorization. Novavax press release, Feb 04, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-start-rolling-review-multiple-regulatory
4. Recombinant nanoparticle vaccine technology. Novavax website. novavax.com/our-unique-technology.
5. S.E. Magnusson, A.F. Altenburg, K.L. Bengtsson, et. al. Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice. Immunol Res., 2018 Apr; 66(2):224-233.
6. Current protocol for Phase 3 clinical trial of NVX-CoV2373 in the US and Mexico. novavax.com/resources
7. Novavax advances development of novel COVID-19 vaccine. Novavax press release, Feb 26, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-advances-development-novel-covid-19-vaccine
8. Novavax identifies coronavirus vaccine candidate; Accelerates initiation of first in-human trial to mid-May. Novavax press release, Apr 08, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-identifies-coronavirus-vaccine-candidate-accelerates
9. J.H. Tian, N. Patel, R. Haupt, et. al. SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV2373 immunogenicity in baboons and protection in mice. Nature Communications, 12, Article number: 372 (2021).
10. C. Keech, G. Albert, I. Cho, et al. Phase 1–2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine. N Engl J Med 2020; 383:2320-2332. DOI: 10.1056/NEJMoa2026920
11. Novavax initiates Phase 2 portion of Phase 1/2 clinical trial of COVID-19 vaccine. Novavax press release, Aug 24, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-2-portion-phase-12-clinical-trial-covid
12. Novavax initiates efficacy trial of COVID-19 vaccine in South Africa. Novavax press release, Aug 17, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-efficacy-trial-covid-19-vaccine-south-africa
13. Novavax initiates Phase 3 efficacy trial of COVID-19 vaccine in the United Kingdom. Novavax press release, Sep 24, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-initiates-phase-3-efficacy-trial-covid-19-vaccine-united
14. Novavax announces initiation of PREVENT-19 pivotal Phase 3 efficacy trial of COVID-19 vaccine in the United States and Mexico. Novavax press release, Dec 28, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-announces-initiation-prevent-19-pivotal-phase-3-efficacy
15. Novavax completes enrolment of PREVENT-19, COVID-19 vaccine pivotal Phase 3 trial in the United States and Mexico. Feb. 22, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-completes-enrollment-prevent-19-covid-19-vaccine-pivotal
16. Novavax and Commonwealth of Australia announce agreement in principle for acquisition of Novavax COVID-19 vaccine. Novavax press release, Nov 04, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-commonwealth-australia-announce-agreement-principle
17. Novavax and Government of Switzerland announce agreement in principle to supply COVID-19 vaccine. Novavax press release, Feb 03, 2021. https://ir.novavax.com/news-releases/news-release-details/novavax-and-government-switzerland-announce-agreement-principle
18. Novavax and UK government announce collaboration and purchase agreement for Novavax’ COVID-19 vaccine candidate. Novavax press release, Aug 14, 2020. https://ir.novavax.com/news-releases/news-release-details/novavax-and-uk-government-announce-collaboration-and-purchase
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