Coronavirus (36) Protein subunit COVID-19 vaccine: NVX-CoV2373 developed by Novavax

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

Coronavirus (35) Protein subunit vaccine against COVID-19: an introduction

Coronavirus (35) Protein subunit vaccine to COVID-19: an introduction
Since the rollout of the vaccination against COVID-19 in last December, over 15 million people in the UK have received at least one dose. According to the NHS website, reports of serious side effects, such as allergic reactions, have been very rare. No long-term complications or death caused by vaccination have been reported.¹

So far, I have introduced in my blog three different types of COVID-19 vaccine in different stages of development: inactivated vaccine, non-replicating viral vector vaccine, and mRNA vaccine. Today in this blog post, I am going to introduce to you another type of vaccine for COVID-19: the protein subunit vaccine, also called protein based vaccine or recombinant protein-based vaccine. The information is mainly from the National Institute of Allergy and Infectious Diseases (NIAID) of the US National Institute of Health (NIH) and Centers for Disease Control and Prevention (CDC).^2,3

What is a protein subunit vaccine?
A protein subunit vaccine contains harmless pieces of protein from a viral or bacterial pathogen. These fragments of proteins are identified as the best part of the pathogen to produce a strong and effective immune response. Once vaccinated, the protein subunit triggers the immune system in our body to make T-lymphocytes and antibodies that fight against and remember the protein subunit. Later, when there is infection from the real pathogen, the body can recognize the protein subunit on the pathogen and respond quickly to kill the whole pathogen. For the protein subunit vaccines against COVID-19, most of them are either Spike glycoprotein (S protein) on the surface of the SARS-CoV-2, or the receptor-binding domain (RBD) fragment of a region on the S protein that binds to the receptors of a host cell.^2,3

What are the advantages and disadvantages of protein subunit vaccines?
Since protein subunit vaccines include only the components, but not the entire pathogen, this minimizes the risk of side effects. This is best illustrated using of the pertussis (whooping cough) vaccine, which contains components of purified Bordetella pertussis (B. pertussis, the bacteria that cause whooping cough), in 1996. Since the use of the protein subunit vaccine against B. pertussis, to replace the inactivated, whole-cell pertussis vaccines which have been introduced since the 1940s in the United States, the adverse reactions such as fever and swelling at injection site rarely happen. Moreover, the pertussis vaccines containing only protein subunits of B. pertussis have similar efficacy as the traditional inactivated ones.²

However, the precision has its downsides. The protein subunit vaccines most probably do not contain molecular structures called pathogen-associated molecular patterns, which can be read by immune cells and recognized as danger signals. Moreover, the protein subunit may only trigger antibody-mediated immune responses, but not the complete immune responses. Both of these two factors result in an immune response weaker than using the whole-cell vaccines. In order to overcome the problems, protein base vaccines are usually delivered with adjuvants, agents that enhance the immune system. Additionally, booster doses are often required.⁴

Protein subunit vaccines are made by inserting genetic code for the antigen into living organisms such as bacteria and yeast. The whole manufacturing process requires strict hygiene to avoid contamination with other organisms. This makes them more expensive to produce than chemically-synthesised vaccines, such as mRNA or DNA vaccines. The amount of available protein subunit expands as the bacteria or yeast grows. The final protein subunit vaccine contains the protein subunit extracted and purified from the bacteria or yeast, and other vaccine components such as preservatives to keep it stable, plus adjuvant to enhance the immune response. ⁴

Protein subunit vaccines are classical vaccines which are already in widespread use, such as the protein subunit vaccines to prevent hepatitis B and human papillomavirus (HPV) infections, which have been used since 1986 and the early 1990s respectively.⁴ Therefore the technology in developing and manufacturing protein subunit vaccines should be very mature and reliable by now. Moreover, there is no report of serious incident due to this type of vaccine throughout over 30 years of history, showing they are safe.

Below is a list summarizing the advantages and disadvantages of protein subunit vaccines:⁴
1. The technology is well established. It is a reliable and safe vaccine platform.
2. Suitable for people with compromised immune systems, as no live components are involved in the vaccine. No risk of the vaccine triggering the disease.
3. Relatively stable compared to mRNA and DNA vaccines.
4. Relatively complex and expensive to manufacture compared to the synthesized vaccines.
5. Adjuvants and booster shots may be required.
6. Time needs to spend in determining the best antigen combination.

Thus far, there are 23 protein subunit COVID-19 vaccines in clinical trials (out of a total of 70 COVID-19 vaccines in clinical trials); two of them are in Phase 3 clinical trials.⁵ One is by Novavax and the other is by a biopharmaceutical company in China. In my next blog post I’m going to introduce to you the vaccine by Novavax which had an interim report of the Phase 3 clinical study published at the end of last month.⁶



References
1. Coronavirus (COVID-19) vaccine. NHS website. https://www.nhs.uk/conditions/coronavirus-covid-19/coronavirus-vaccination/coronavirus-vaccine/
2. Vaccine types. Subunit vaccines. NIAID website. https://www.niaid.nih.gov/research/vaccine-types.
3. Understanding how COVID-19 vaccines work. CDC website. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines/how-they-work.html
4. What are protein subunit vaccines and how could they be used against COVID-19? Gavi, The Vaccine Alliance website. https://www.gavi.org/vaccineswork/what-are-protein-subunit-vaccines-and-how-could-they-be-used-against-covid-19
5. Draft landscape and tracker of COVID-19 candidate vaccines. WHO. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
6. Covid-19: Novavax vaccine shows 89% efficacy in UK trials. BBC News, 29 January, 2021. https://www.bbc.co.uk/news/uk-55850352

About Moderna

About Moderna
Moderna, Inc., is an American biotechnology company based in Cambridge, Massachusetts. It has a fully integrated manufacturing plant and clinical development site in Norwood, MA, which opened in 2018.¹ It went public and was listed on NASDAQ in December 2018 and created the largest biotech initial public offering in history on NASDAQ.² Moderna has been ranked in the top ten of Science’s list of top biopharmaceutical industry employers for the past five years.³

The company was founded in 2010 by three scientists, Derrick J. Rossi, Kenneth Chien and Robert Langer, at Harvard Medical School, and by Flagship Ventures.⁴ Since 2011, Moderna has been led by Stéphane Bancel as the company’s CEO. He is a French businessman with pharmaceutical sales and operations experience.

Since the start of the vaccine race in combating COVID-19, Moderna has been well known for its use of messenger RNA (mRNA) as a vaccine. However, when it was initially founded, it mainly focused on the use of modified mRNA technology to reprogram stem cells for therapeutic purposes,¹ which is the research focus of the one of the co-founders, Professor Derrick Rossi.⁵ The company has changed their direction of interest very quickly since then. Nowadays, Moderna uses its mRNA platform to perform drug discovery and drug development, as well as vaccine development.

The products the company is developing
According to Moderna’s website, aside from the vaccine against the novel coronavirus SARS-CoV-2 (mRNA-1273), the company is also developing 10 other vaccine candidates against infections in three main areas.

1.Vaccines against respiratory infections
• Respiratory syncytial virus (RSV) vaccine for older adults (mRNA-1777 and mRNA-1172)
• RSV vaccine for young children (mRNA-1345)
• Human metapneumovirus and parainfluenza virus type 3 (hMPV/PIV3) vaccine (mRNA-1653)
• Novel coronavirus (SARS-CoV-2) vaccine (mRNA-1273)
• Influenza H7N9 (mRNA-1851)
• H10N8 (mRNA1440)
2. Vaccines against infections transmitted from mother to baby
• Cytomegalovirus (CMV) vaccine (mRNA-1647)
• Zika vaccine (mRNA-1893)
3. Vaccines against highly prevalent viral infections
• Epstein-Barr virus (EBV) vaccine (mRNA-1189)
• Chikungunya virus (mRNA-1944)

Of these, Moderna has 7 vaccine candidates, which are against H10N8,⁶ H7N9,⁶ RSV,⁷ Chikungunya virus,⁸ hMPV/PIV3,⁹ and Zika,¹⁰ currently in Phase 1 clinical studies. The company’s CMV vaccine is even currently in a Phase 2 dose-confirmation study.¹¹

As mentioned earlier in this blog post, Moderna also performs drug development. It is now currently developing therapeutics mRNA for immuno-oncology (mRNA-2416 for advanced/ metastatic solid tumours or lymphoma, Phase 1;¹² mRNA-2752 for relapsed/ refractory solid tumours malignancies or lymphoma, Phase 1¹³), for rare diseases (mRNA-3704 for Methylmalonic Acidemia (MMA),Phase 1/2¹⁴; mRNA-3927 for Propionic Acidemia (PA)¹⁵), and for cardiovascular diseases (mRNA AZD-8601, Phase 2)¹⁶, independently or with strategic collaborators.

Besides the public organizations mentioned in my previous blog post, Moderna has established a wide collaboration network with different biopharmaceutical companies (Merck, AstraZenecca, Alexion, et al.) and research institutions.



References
1. Key milestones and advancements in mRNA technology-Moderna. Moderna. https://www.modernatx.com/about-us/modernas-key-milestones-and-advancements
2. Moderna: 5 things to know about the largest biotech to IPO. MarketWatch, Dec. 7, 2018. https://www.marketwatch.com/story/moderna-ipo-5-things-to-know-about-what-could-be-the-largest-biotech-ipo-in-history-2018-12-05
3. Moderna named top employer by Science for sixth consecutive year. Business Wire, October 30, 2020. https://www.businesswire.com/news/home/20201030005447/en/
4. ModeRNA, stealth startup backed by Flagship, unveils new way to make stem cells. Erin Kutz. Xconomy, 4th Oct., 2010.
5. L. Warren, P.D. Manos, T. Ahfeldt, et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell, Volume 7, Issue 5, p.618-630, November 05, 2010.
6. R.A. Feldman, R. Fuhr, I. Smolenov, et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in Phase 1 randomized clinical trials. Vaccine, Volume 37, Issue 25, 31 May 2019, Pages 3326-3334.
7. Moderna announces updates on Respiratory Syncytial virus (RSV) vaccine program. Moderna press release, October 8, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-updates-respiratory-syncytial-virus-rsv/
8. Moderna Announces Positive Phase 1 Results for the First Systemic Messenger RNA Therapeutic Encoding a Secreted Protein (mRNA-1944). Moderna press release, September 12, 2019. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-phase-1-results-first-systemic/
9. Safety and immunogenicity of mRNA-1653, a combined human Metapneumovirus (hMPV) and Parainfluenza Virus Type 3 (PIV3) Vaccine, in healthy adults, and children 12-36 months of age with serologic evidence of prior exposure. ClinicalTrials.gov. ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04144348
10. Safety, tolerability, and immunogenicity of Zika Vaccine mRNA-1893 in healthy flavivirus seropositive and seronegative adults. Moderna press release, August 19, 2019. https://investors.modernatx.com/news-releases/news-release-details/moderna-receives-fda-fast-track-designation-zika-vaccine-mrna/
11. Moderna completes enrollment of Cytomegalovirus (CMV) Vaccine (mRNA-1647) Phase 2 study. Moderna press release, March 3, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-cytomegalovirus-cmv-vaccine-mrna/
12. Dose escalation and efficacy study of mRNA 2416 for intratumoral injection alone and in combination with durvalumab for patients with advanced malignancies. ClinicalTrials.com. https://www.clinicaltrials.gov/ct2/show/NCT03323398?term=Moderna&recrs=ab&rank=2
13. Dose escalation study of mRNA-2752 for intratumoral injection to patients with advanced malignancies. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT03739931?term=mRNA-2752-P101&rank=1
14. Open label study of mRNA-3704 in patients with isolated Methylmalonic Acidemia. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03810690?cond=Methylmalonic+Acidemia
15. "The MaP Study": Mapping the Patient Journey in MMA and PA. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT03484767
16. Entering a new era in vascular and cardiac regeneration research. AstraZeneca. https://www.astrazeneca.com/what-science-can-do/topics/next-generation-therapeutics/entering-a-new-era-in-vascular-and-cardiac-regeneration-research.html

Coronavirus (34) mRNA vaccine candidate for COVID-19: mRNA-1273 (part b)

Coronavirus (34) mRNA vaccine candidate for COVID-19: mRNA-1273 (part b)
The Moderna COVID-19 vaccine was approved by the UK government on 8th January, 2021. It is the third vaccine against COVID-19 approved to be used in the UK.¹ Guidance from the UK government to health professionals in the use of mRNA-1273 gives us ideas of the details in the use of this vaccine, the safety issues and to whom the vaccine can be given.²

Administration of the COVID-19 Vaccine Moderna
According to the guidance, only people of age 18 years and older are allowed to receive the Moderna vaccine. The injection should be administered intramuscularly, ideally using the deltoid muscle of the upper arm. The vaccination is a two-dose programme, with the doses administered 1 month (28 days) apart.

The vaccine can be shipped and stored for up to 6 months at -20ºC, and then remain stable once thawed for 30 days if refrigerated at between 2ºC and 8ºC. Each vial of vaccine contains 10 doses. Once each vial is thawed and ready to be used, the health professional will withdraw only 0.5ml of vaccine from the vial for injection.

The vaccine is normally white to off-white in colour, and may contain white or translucent product-related particulates. At the time of injection, you can help to check the vaccine by visually inspecting if there is any other particulate matter and/or discolouration. The vaccine should not be used if either of these conditions exist.

Safety issues
From clinical trial studies, it was found that the administration of the vaccine could cause pain at the injection site, fatigue, headache, myalgia (muscle aches or pain), arthralgia (joint pain), chills, nausea/vomiting, axillary swelling/tenderness, fever, swelling at the injection site, and erythema (skin redness) at the injection site. After the two doses of vaccination, the most common solicited adverse reactions included “injection site pain (88.2%), erythema (8.6%), swelling (12.2%), and ipsilateral lymphadenopathy (14.2%)”. Most of these reactions were mild to moderate. However, there was a higher occurrence of severe reactions after the second injection. Most of local reactions occurred within the first day or two after injection and then disappeared.

As events of anaphylaxis (severe, whole-body allergic reactions) have been reported, the guidance suggests health professionals should keep an eye on the patient for at least 15 minutes after vaccination. The guidance also suggests appropriate medical treatment and supervision to manage immediate allergic reactions be readily available in case of an acute anaphylactic reaction following administration of the COVID-19 Vaccine Moderna. Therefore, don’t panic if you suddenly experience an anaphylactic reaction immediately after injection: the vaccination centre should be ready to manage the situation. However, a second dose of the Moderna vaccine would not be given to you if you experienced severe allergic reactions after the first dose.

Precautions
According to the guidance, the following people will not be administered the Moderna COVID-19 Vaccine:
1. Children under 18 years of age;
2. People with severe allergic history;
3. Pregnant women. There is insufficient data to inform vaccine-associated risks in pregnancy. “Administration of COVID-19 Vaccine Moderna in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and foetus”;
4. Women during breast-feeding. Data is not available to assess the effects of the Moderna vaccine on the breastfed infant or on milk production/excretion.

The guidance also suggests that health professionals should postpone the vaccination if individuals experience a severe febrile illness or severe acute infection. The jab can be provided to these individuals only when the acute illness has improved.

The guidance also says that “efficacy, safety and immunogenicity have not been assessed in immunocompromised individuals, including those receiving immunosuppressant therapy. The efficacy of COVID-19 Vaccine Moderna may be less in these individuals.” If you are an immunocompromised person, who is also receiving immunosuppressive therapy, you should be bear in mind that you may have a diminished response to the Moderna vaccine, which means the protection you could get from the vaccination would be less than that of other people.

​ The efficacy of the Moderna vaccine is about 94%. Therefore, we have to understand that even if we have been vaccinated with one or two shots of the vaccine, the vaccination does not guarantee full protection. In any case, we should bear in mind that we have to wait at least 14 days after the second dose in order to get the maximum protection from the vaccination.

“The duration of protection afforded by the vaccine is unknown at present.” We may lose protection against the SARS-CoV-2 a certain period of time after the vaccination course. It is important to follow instructions from the government even after the whole nation’s vaccination scheme is completed.



References
1. Moderna becomes third Covid vaccine approved in the UK. By Michelle Roberts. BBC news. 8 January, 2021. https://www.bbc.co.uk/news/health-55586410
2. Regulatory approval of COVID-19 Vaccine Moderna. Regulation 174 Information for UK healthcare professionals. 8th January, 2021. https://www.gov.uk/government/publications/regulatory-approval-of-covid-19-vaccine-moderna

Coronavirus (33) mRNA vaccine candidate for COVID-19: mRNA-1273 (part a)

Coronavirus (33) mRNA vaccine candidate for COVID-19: mRNA 1273 (part a)
2. mRNA-1273 vaccine by Moderna
The mRNA vaccine, mRNA-1273, is also called COVID-19 Vaccine Moderna. The vaccine was issued an emergency use authorization by the US Food and Drug Administration for the prevention of COVID-19 on 18th December, 2020. It was the second vaccine approved to be used against COVID-19 in the US.¹ It was also the second mRNA vaccine ever approved to be used in the world. Under the emergency use authorization, individuals 18 years of age or older are allowed to be vaccinated with this mRNA vaccine.

According to the press release from Moderna, approximately 20 million doses will be delivered to the government by the end of December, 2020. The company expects to have between 100 million and 125 million doses available globally in the first quarter of 2021, with 85-100 million of those available in the US.¹ Moderna’s European production capacity is achieved with its strategic manufacturing partner Lonza of Switzerland, and ROVI of Spain for fill-finish services.

The mRNA-1273 is a lipid-nanoparticle (LNP) encapsulated mRNA vaccine expressing the SARS-CoV-2 spike glycoprotein with a transmembrane anchor. The mRNA sequence is modified so that the conformation of the expressed glycoprotein remains stable once it is produced.² The increase in the conformation stability of the expressed glycoprotein triggers production of antibodies with a higher level of specificity. The lipid-nanoparticle capsule of the vaccine composed of four lipids was formulated in a fixed ratio of mRNA and lipid, but the exact ratio is not mentioned.²

The development of the mRNA-1273
It took only 11 months for Moderna, a 10-year biotech startup, to develop the vaccine and finally get the authorization for its use. A major reason for this is the collaboration of the company with various public organizations. The company obtained scientific leadership and clinical trial support from the National Institute of Health (NIH) and the National Institute of Allergy and Infectious Disease (NIAID), and financial support from the Coalition for Epidemic Preparedness Innovations (CEPI) and from the Biomedical Advanced Research and Development Authority (BARDA).¹ The collective effort of private-public partnerships in dealing with the global health crisis is nicely illustrated in this case.

As soon as the SARS-CoV-2 genetic sequence was determined in January 2020, the mRNA-1273 with modified mRNA sequence was then designed and developed by Moderna and the Vaccine Research Center at the NIAID, a part of the NIH.³ In February, NIAID helped to conduct Investigational New Drug (IND)-enabling studies to evaluate potential toxicity risks of the mRNA vaccine prior to human studies.³ Results from a non-human primate preclinical viral challenge study evaluating the vaccine were published in late July.⁴

A Phase 1 study led by NIAID began in mid-March.⁵ Results from the first and the second interim analysis of the Phase 1 study were separately published in mid-July and September respectively.^2,6 Then, on 3rd December, a letter to the editor in The New England Journal of Medicine reported that participants in the Phase 1 study of the Moderna COVID-19 Vaccine still have high levels of neutralizing antibodies 119 days after first vaccination, i.e. 90 days after second vaccination.⁷

The Phase 2 study of the vaccine in the US started on 29th May, and enrolment completed on 8th July.^8,9 This was a placebo-controlled, dose-confirmation study evaluating the safety, reactogenicity* and immunogenicity** of two doses of mRNA-1273 given 28 days apart. Each participant received either a placebo, a 50μg or a 100μg dose at both shots.

The Phase 3 trial of the vaccine, the Coronavirus Efficacy (COVE), was launched in late July 2020. It was a randomized 1:1 placebo-controlled study testing the vaccine at the 100µg dose level in 30,000 participants ages 18 and older in the US. Forty-two percent of total participants in the Phase 3 COVE study were in medically high-risk groups: people aged over 65 and people with chronic diseases such as diabetes, severe obesity and cardiac disease. And although the trial was conducted in America, the study included more than 11,000 participants from diverse communities such as Hispanic or Latin, and Black or African American. The enrolment of Phase 3 COVE Study was completed on 22nd October, 2020.¹⁰ According to the primary efficacy analysis report of the Phase 3 study of 196 cases on the 30th November, the vaccine efficacy against COVID-19 was 94.1%; vaccine efficacy against severe COVID-19 was 100%. The results also suggests a broadly consistent safety and efficacy profile across all evaluated subgroups.

All participants in the COVE study will be continued to be monitored for two years (the duration of the study) to assess long-term protection and safety. Safety data continue to accrue, and the study continues to be monitored by an independent Data Safety Monitoring Board (DSMB) appointed by the NIH.¹



* Reactogenicity refers to reactions (side effects) that occur soon after vaccination, These include both local reactions (such as injection site pain, tenderness, erythema), and systemic reactions (such as fever, headache, myalgia).
* Immunogenecity refers to the ability of human body to provoke an immune response after vaccination.



References
1. Moderna announces FDA authorization of Moderna COVID-19 Vaccine in US. Moderna press release, Dec. 18, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-fda-authorization-moderna-covid-19-vaccine-us/
2. L.A. Jackson, E.J. Anderson, N.G. Rouphael, et al. An mRNA vaccine against SARS-CoV-2 — preliminary report. N. Engl. J. Med., 2020; 383:1920-1931. DOI: 10.1056/NEJMoa2022483.
3. Moderna announces funding award from CEPI to accelerate development of messenger RNA (mRNA) vaccine against novel coronavirus. Moderna press release, Jan. 23, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-funding-award-cepi-accelerate-development
4. K.S. Corbett, B. Flynn, K.E. Foulds, et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med., 2020; 383:1544-1555.
5. Moderna announces first participant dosed in NIH-led phase 1 study of mRNA vaccine (mRNA-1273) against novel coronavirus. Moderna press release, March 16, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participant-dosed-nih-led-phase-1-study
6. E.J. Anderson, N.G. Rouphael, A.T. Widge, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med., 2020; 383:2427-2438. DOI: 10.1056/NEJMoa2028436
7. A.T. Widge, N.G. Rouphael, L.A. Jackson, et al. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N Engl J Med 2021; 384:80-82. DOI: 10.1056/NEJMc2032195
8. Moderna announces first participants in each age cohort dosed in phase 2 study of mRNA Vaccine (mRNA-1273) against novel coronavirus. Moderna press release, May 29, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-first-participants-each-age-cohort-dosed-phase
9. Moderna completes enrolment of phase 2 study of its mRNA vaccine against COVID-19 (mRNA-1273). Moderna press release, July 8, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-phase-2-study-its-mrna-vaccine
10. Moderna completes enrollment of phase 3 COVE study of mRNA vaccine against COVID-19 (mRNA-1273). Moderna press release, October 22, 2020. https://investors.modernatx.com/news-releases/news-release-details/moderna-completes-enrollment-phase-3-cove-study-mrna-vaccine

Coronavirus (32) mRNA vaccine candidate for COVID-19: BNT162b2 (part b)

Coronavirus (32) mRNA vaccine candidate for COVID-19: BNT162b2 (part b)
After learning about the world's first vaccine approved for use against COVID-19, you may be interested to know more about the two companies, Pfizer Inc. and BioNTech SE, which developed the vaccine. Let us have a look at these two companies in this blog post.

Pfizer Inc.
Pfizer Inc. is one of the world's biggest biopharmaceutical companies and is based in New York. It was established in 1849. The company was started by German-American cousins Charles Pfizer and Charles Erhart in Brooklyn. It started as a manufacturer of fine chemicals. As the company expanded, the headquarters moved to Manhattan in 1868. Later it opened a separate warehouse in Chicago in 1882. An article on the BBC's website thoroughly describes the expansion history of the company from the early days.^1,2

After over 150 years of development, the company is now operating in 180 countries employing 96,000 people. It develops and produces medicines across all therapeutic areas. The research headquarters are in Groton, Connecticut.^2,3

In 2004, Pfizer was added to the Dow Jones stock index, which tracks the 30 large, publicly listed companies trading on the New York Stock Exchange and on NASDAQ.² It had a market value of almost 230 billion dollars on 11th December 2020. Based on the total revenues from the first two quarters of 2020, Pfizer was the world's fifth largest pharmaceutical company, down from the second in 2017.⁴

Pfizer also expanded by acquiring several other pharmaceutical companies. One of these was Warner-Lambert, the original maker of the cholesterol-lowering medicine Lipitor. Since the merger of Warner-Lambert with Pfizer in 2000, Lipitor has contributed billions of revenue and continues to generate roughly US$2 billion per year in sales for Pfizer.⁵

The first pharmaceutical product of the company was santonin, which cured an intestinal parasite common in the 19th century. The drug was a great success as it was given an almond-toffee flavouring to mask its bitterness so that people were more willing to use it for treatment.¹ The company was also known as the world’s first and top producer of vitamin C when they started to mass produce this using a fermentation-free method in 1936. It was also the first company in the world to produce penicillin at a large scale, which was in great demand during World War II.¹ Nowadays, Pfizer's well known products include Advil (Ibuprofen, a non-steroidal anti-inflammatory pain reliever), Lyrica (cholesteral medication), Xanax (psychoactive medicine) and Zoloft (an anti-depressant).³

Despite its successes, the pharmaceutical industry giant has also seen its share of lawsuits and scandals. These included the Protonix case, saying Pfizer failed to warn about the risk of kidney damage; the Prempro lawsuits regarding the onset of breast cancer after using Prempro; the Chantix lawsuits claiming they caused suicidal thoughts and severe psychological disorders; the Depo-Testosterone lawsuits regarding the cause of strokes, blood clots and heart attacks; the Effexor lawsuits which claimed birth defects; the Zoloft lawsuits which also claimed the drug caused birth defects; the Eliquis lawsuits claiming severe bleeding; and the Lipitor lawsuits claiming the development of Type 2 diabetes.³ Some of these lawsuits were dismissed by the court, while others were settled by paying out large sums of money.³

BioNTech SE
This is a biotech company founded in Mainz in Germany in 2008 by a couple, Ugur Sahin and Ozlem Tureci, who are descendants of Turkish immigrants.⁶ Sahin is the CEO of BioNTech, while Tureci, who was a doctor before, is the firm’s chief medical officer. Before starting BioNTech, they set up another biotech company, called Ganymad Pharmaceuticals, focused on immunotherapeutic cancer drugs. That company was sold to Astellas, a Japanese company, for up to 1.3 billion euros in late 2016.⁶

BioNTech, with its North American headquarters in Cambridge, Massachusetts, was publicly traded on the Nasdaq Global Select Market in October 2019. The company was able to generate total gross proceeds of 150 million dollars from that IPO.⁷

A main focus of BioNTech is the use of mRNA as therapeutic strategy. The company has more than a decade of experience in developing their mRNA platforms. Not long after the establishment of the company, they published their first research paper on vaccination of mRNA in preclinical animal models, in 2010.⁸ In more recent years, they put a lot of effort in developing and improving stability of the mRNA and the delivery methods for their therapeutic mRNA platforms.^9-11 Their preclinical studies on the use of mRNA in immunotherapy were at the forefront of the medical research field and are of great value. The results were published in high-ranked peer-reviewed papers, indicating their work is highly recognized by the scientists of the field.^11-14

BioNTech has established a broad set of relationships with multiple global pharmaceutical collaborators, including Eli Lilly and Company, Genmab, Sanofi, Bayer Animal Health, Genentech (a member of the Roche Group), Genevant, Fosun Pharma, and Pfizer. The collaboration with Pfizer started from 2018 when the two companies together developed mRNA vaccines for prevention of influenza.⁶



References
1. Our history. A Journey through Time: How Pfizer has transformed itself and changed the world. Pfizer website in Thai. https://www.pfizer.co.th/en/about-us/%E0%B8%9B%E0%B8%A3%E0%B8%B0%E0%B8%A7%E0%B8%B1%E0%B8%95%E0%B8%B4%E0%B8%84%E0%B8%A7%E0%B8%B2%E0%B8%A1%E0%B9%80%E0%B8%9B%E0%B9%87%E0%B8%99%E0%B8%A1%E0%B8%B2
2. Pfizer: The making of a global drugs giant. BBC Business, 13 May 2014. https://www.bbc.co.uk/news/business-27309851
3. Drugwatch. https://www.drugwatch.com/manufacturers/pfizer/
4. 10 of the largest pharmaceutical companies by revenue. By Samantha McGrail. Pharma News Intelligence, 16th Oct, 2020. https://pharmanewsintel.com/news/10-of-the-largest-pharmaceutical-companies-by-revenue
5. Lipitor is still churning out billions of dollars. By Bob Herman. Axios, Oct 30, 2019. https://www.axios.com/lipitor-pfizer-drug-patent-sales-2019-6937cdfb-47f1-46bc-8cf0-39e6b88e235e.html
6. What you need to know about BioNTech — the European company behind Pfizer’s Covid-19 vaccine. By Ryan Browne. CNBC Health and Science, Nov 11, 2020. https://www.cnbc.com/2020/11/11/biontech-the-european-company-behind-pfizers-covid-19-vaccine.html
7. Germany's BioNTech raises $150 million in smaller-than-planned U.S. IPO amid market volatility. By Rebecca Spalding and Joshua Franklin. Reuters, 9th October, 2019. https://www.reuters.com/article/us-biontech-ipo-idUSKBN1WO29B
8. S. Kreiter, A. Selmi, M. Diken, et al. 2010. Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity.Cancer Res., Nov 15; 70(22): 9031-9040
9. J. Kowalska, A. Wypijewska del Nogal, Z.M. Darzynkiewicz, et al. 2014. Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutic relevant cap-dependent process. Nucleic Acids Res. 42(16): 10245-10264.
10. L.M. Kranz, M. Diken, H. Haas, et al. 2016. Systemic RNA delivery to dendritic cells exploits antiviral defense for cancer immunotherapy. Nature. Jun 1; 534(7607): 396-401.
11. S. Grabbe, H. Haas, M. Diken, et al. 2016. Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma. Nanomedicine (Lond). Oct; 11(20): 2723-2734.
12. N. Pardi, M.J. Hogan, R.S. Pelc, et al. 2017. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature. Mar 9; 543(7644): 248-251.
13. C.R. Stadler, H. Bähr-Mahmud, L. Celik L, et al. 2017. Elimination of large tumors in mice by mRNA-encoded bispecific antibodies. Nature Medicine Jul; 23(7): 815-817.
14. U. Sahin U, E. Derhovanessian, M. Miller, et al. 2017. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. Jul 13; 547(7662): 222-226.

Coronavirus (31) mRNA vaccine candidate for COVID-19: BNT162b2 (part a)

Coronavirus (31) mRNA vaccine candidate for COVID-19: BNT162b2 (part a)
Continued from my last blog post.
1. BNT162b2 by Pfizer Inc. and BioNTech SE
BNT162b2 was the first COVID-19 vaccine in the world to achieve authorization. The UK regulator, Medicine and Healthcare products Regulatory Agency (MHRA), authorized emergency supply of COVID-19 mRNA vaccine under Regulation 174 on 2nd December.¹ And today, the U.S. Food and Drug Administration (FDA) also granted an Emergency Use Authorization (EUA) to permit the emergency use of the vaccine in individuals that are 16 years old and over.²

The UK has ordered 40 million doses of the vaccine, which is enough to vaccinate 20 million people. The first batch of the mRNA vaccine arrived in the UK on 3rd December from Belgium. By the end of this year, the UK government expects to have 800,000 vaccine doses arrived. The vaccination started on 8th December. According to a suggestion from the Joint Committee on Vaccination and Immunisation (JCVI), the first batch should be given to NHS hospital staff and patients. Care home residents and care home staff are prioritised for vaccination next.³

The vaccination of BNT162b2 is a two-dose regimen, 21 days apart, and administered intramuscularly (injected into a muscle). The vaccine comes in concentrated form and remains stable for 6 months at -80°C to -60°C. Once a vaccine vial is taken out from the freezer and thawed, it will be diluted with sodium chloride 9 mg/mL (0.9%) solution. The diluted, ready to use vaccine should be stored between 2°C and 25°C and used within 6 hours after dilution. Before injection, you can have a look with the nurse to check if the vaccine appears as an off-white solution with no particulates visible. The vaccine cannot be used if particulates or discolouration are present.⁴

You should bear in mind that the protection is not fully effective until at least 7 days after the second dose of the vaccine. Even you are vaccinated, the 94%-95% of efficacy of the vaccine BNT162b2 means that you are not entirely safe from COVID-19. Vaccination with the mRNA vaccine may not protect all recipients.^4-6

It is important to note that the following peoples are not suitable to be vaccinated with BNT162b2:⁴
1. Children under 16 years of age. The safety and efficacy of the vaccine in this age group has not yet been established;
2. Pregnant women. Animal reproductive toxicity studies have not been completed. The vaccine, therefore, is not recommended during pregnancy;
3. Women during breast-feeding. It is unknown whether the mRNA vaccine is excreted in human milk. There may be a risk to newborns and infants;
4. Individuals receiving anti-coagulant therapy, and ones with bleeding disorder. Anti-coagulant therapy and bleeding disorder would contraindicate an intramuscular injection;
5. People with a history of significant allergic reactions. There were reports of allergic reaction shortly after the injection in two NHS workers who have a history of serious allergies and carry adrenaline pens around with them.⁷ MHRA advised that people with a history of significant allergic reactions should not have the mRNA vaccination.⁴

Moreover, it should be bourne in mind that if you are of childbearing age, you should avoid pregnancy for at least 2 months after the second shot. And if you are currently suffering from acute severe febrile illness, the administration of the mRNA vaccine should be postponed.⁴

The development of BNT162b2
The vaccine was first developed by BioNTech. Pfizer later joined (in March) to accelerate the development programme, which initially included 4 vaccine candidates. Three vaccine candidates represent a different combination of mRNA format, either a uridine containing mRNA or nucleoside modified mRNA, and target antigen: either the larger spike sequence of SARS-CoV-2 or the smaller optimized receptor binding domain (RBD) from the spike protein. The fourth vaccine candidate contains self-amplifying mRNA. Each mRNA format is combined with a lipid-nanoparticle (LNP) formulation.^8,9

The pre-clinical studies on the four mRNA vaccine candidates was completed in Germany in April.⁹ Two vaccine candidates, BNT162b1 and BNT162b2, induced high viral antigen specific CD4+ and CD8+T cell responses, and high levels of neutralizing antibody in various animal species. They offered protective effects in Rhesus macaques from SARS-CoV-2 infection. The study result on the vaccine candidate BNT162b2 was available to the public in September.¹⁰

The first clinical trial of the vaccine candidates started on 23rd April in Germany (NCT04380701; EudraCT: 2020-001038-36) and later in the US (NCT04368728; C4591001).¹¹ The initial clinical trial included dose range studies, aiming to determine the optimal dose for the mRNA vaccine candidates, as well as to evaluate the safety and immunogenicity of the vaccines. Pfizer took care of clinical trials in the US and other countries other than Germany, while BioNTech conducted its own trials in Germany.

Among the four mRNA vaccine candidates, BNT162b1, a lipid-nanoparticle (LNP)-formulated nucleoside-modified mRNA that encodes the SARS-CoV-2 receptor binding domain (RBD) from the spike protein, and BNT162b2, a LNP-formulated nucleoside-modified mRNA that encodes the spike glycoprotein of SARS-CoV-2, were chosen to be evaluated in the phase 1/2 clincial trials. Both vaccine candidates demonstrated a manageable tolerability at dose levels that elicited robust immune responses. However, BNT162b2 was found to have a milder reactogenicity profile. Based on the preclinical and clinical data obtained in phase 1/2 studies, BNT162b2 was chosen to enter into phase 2/3 study at a 30µg dose level in a 2 dose regimen.^12-14

The information published in November shows that BNT162b2 is now in phase 3 clinical trials in the US, Germany, Argentina, Brazil, South Africa, and Turkey. A pharmaceutical company from China, Fosun Pharma, jointly conducted phase 2 clinical trials in Jiangsu, China with BioNTech in November.¹⁵

Safety results
The safety of BNT162b2 was evaluated in participants 16 years of age and older in two clinical studies. Study EudraCT: 2020-001038-36 enrolled 60 participants in Germany aged between 18 and 55. Study C4591001 enrolled approximately 44,000 participants of aged 12 or older, in the US, Turkey, South Africa, and South America.

In a group of age 16 and above in Study C4591001, a total of 21,720 participants received at least one dose of BNT162b, and 21,728 participants received a placebo. Out of these, at the time of the analysis, 19,067 participants (9531 who received BNT162b2 and 9536 who received the placebo) were evaluated for safety, two months after the second dose. The first interim report of the phase 3 study was published in November.^5,6

The most frequent adverse reactions in participants aged 16 years and older were pain at the injection site (>80%), fatigue (>60%), headache (>50%), myalgia (>30%), chills (>30%), arthralgia (>20%) and pyrexia (>10%). The reactions were usually mild or moderate in intensity and resolved within a few days after vaccination.⁴

There was no pause of study in the clinical trials for the mRNA vaccine BNT162b2, and no report of hospitalization or death after the vaccination in the clinical trials.

Pre-order agreement
Since the mRNA vaccine candidates entered the clinical trial, Pfizer and BioNTech have signed supply agreements with different countries to deliver millions of doses of the vaccine if approved. The companies signed agreements in July to deliver up to 600 million doses of their vaccine for COVID-19 to the US (enough for 2 per person for nearly the whole population), and 120 million doses to Japan.^16,17 In August, the companies signed agreements to provide the mRNA vaccine to Canada.¹⁸ The European Union also signed a contract in November with the two companies to provide the EU with 200 million doses of the mRNA-based vaccine.¹⁹ Today, BioNTech announced an agreement to supply Mainland China with an initial 100 million doses of their mRNA-based vaccine candidate.¹⁵ According to the press release from Pfizer, they have the goal of manufacturing globally up to 50 million doses by the end of 2020 and approximately 1.3 billion doses by the end of 2021.⁶

BioNTech received an up-front payment of $185 million, including an equity investment of approximately $113 million, from Pfizer, upon the collaboration to develop an mRNA vaccine with BioNTech. The company will be eligible to receive further payments of up to $563 million for a potential total consideration of $748 million.⁸



References
1. Decision: Regulatory approval of Pfizer/BioNTech vaccine for COVID-19. Gov.UK news release, 2nd Dec., 2020. https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19
2. FDA takes key action in fight against COVID-19 by issuing emergency use authorization for first COVID-19 vaccine. FDA news release, 11th Dec., 2020. https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19
3. Covid-19: UK 'confident' of having 800,000 vaccine doses by next week. BBC news, 6th Dec., 2020. https://www.bbc.co.uk/news/uk-55184849
4. Information for healthcare professionals on Pfizer/BioNTech COVID-19 vaccine. MHRA website, 10th Dec., 2020. https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/information-for-healthcare-professionals-on-pfizerbiontech-covid-19-vaccine
5. Pfizer and BioNTech announce vaccine candidate against COVID-19 achieved success in first interim analysis from phase 3 study. Pfizer press release, 9th Nov., 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against
6. Pfizer and BioNTech conclude phase 3 study of COVID-19 vaccine candidate, meeting all primary efficacy endpoints. Pfizer press release, 18th Nov., 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-conclude-phase-3-study-covid-19-vaccine
7. Covid-19 vaccine: Allergy warning over new jab. By Nick Triggle and Rachel Schraer. BBC News, 9th Nov., 2020. https://www.bbc.co.uk/news/health-55244122
8. Pfizer and BioNTech to co-develop potential COVID-19 vaccine. Pfizer press release, 17th March, 2020. https://www.pfizer.co.uk/pfizer-and-biontech-co-develop-potential-covid-19-vaccine/
9. BioNTech and Pfizer announce regulatory approval from German authority Paul-Ehrlich-Institut to commence first clinical trial of COVID-19 vaccine candidates. Pfizer press release, 22nd April, 2020. https://www.pfizer.com/news/press-release/press-release-detail/biontech_and_pfizer_announce_regulatory_approval_from_german_authority_paul_ehrlich_institut_to_commence_first_clinical_trial_of_covid_19_vaccine_candidates
10. A.B. Vogel, I. Kanevsky, Y. Che, et al. A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. BioRxiv, Sept. 08, 2020. doi: https://doi.org/10.1101/2020.09.08.280818
11. BioNTech and Pfizer announce completion of dosing for first cohort of phase 1/2 trial of COVID-19 vaccine candidates in Germany. Pfizer press release, 29th April, 2020. https://www.pfizer.com/news/press-release/press-release-detail/biontech-and-pfizer-announce-completion-dosing-first-cohort
12. U. Sahin, A. Muik, E. Derhovanessian, et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature, 2020;586, 594–599.
13. E.E. Walsh, R.W. Frenck, A.R. Falsey, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N. Engl. J. Med., 2020 Dec 17;383(25):2439-2450. doi: 10.1056/NEJMoa2027906. Epub 2020 Oct 14.
14. Pfizer and BioNTech choose lead mRNA vaccine candidate against COVID-19 and commence pivotal phase 2/3 global study. Pfizer press release, 27th July, 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-choose-lead-mrna-vaccine-candidate-0
15. BioNTech and Fosun Pharma to supply China with mRNA-based COVID-19 vaccine. BioNTech press release, 16th Dec., 2020. https://investors.biontech.de/news-releases/news-release-details/biontech-and-fosun-pharma-receive-approval-commence-covid-19/
16. Pfizer and BioNTech announce an agreement with U.S. Government for up to 600 million doses of mRNA-based vaccine candidate against SARS-CoV-2. Pfizer press release, 22nd July, 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-agreement-us-government-600
17. Pfizer and BioNTech to supply Japan with 120 million doses of their BNT162 mRNA-based vaccine candidate. Pfizer press release, 31st July, 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-supply-japan-120-million-doses-their
18. Pfizer and BioNTech to supply Canada with their BNT162 mRNA-based vaccine candidate. Pfizer press release, 5th August, 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-supply-canada-their-bnt162-mrna-based
19. Pfizer and BioNTech reach an agreement to supply the EU with 200 million doses of their BNT162b2 mRNA-based vaccine candidate against SARS-CoV-2. Pfizer press release, 11th Nov., 2020. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-reach-agreement-supply-eu-200-million