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

Coronavirus (30) mRNA vaccine for COVID-19: an introduction

Coronavirus (30) mRNA vaccine for COVID-19: an introduction
The UK's Medicines and Healthcare Products Regulatory Agency (MHRA) announced on 2nd November that they have granted authorisation for temporary supply of COVID-19 mRNA vaccine BNT162b2, from Pfizer and BioNTech, for active immunization of individuals aged 16 years old and over.¹ This is the first vaccine receiving approval to be used for COVID-19 prevention in the UK. It is one of the mRNA vaccines which had entered Phase 3 according to the WHO's data.² In this blog post, I am going to introduce you the mRNA vaccines.

What is an mRNA vaccine?
Conventional vaccines work by injecting either a dead form of the pathogen (for inactivated vaccines), or a weakened form of it (for live attenuated vaccines), into the body to trigger the production of antibodies against the pathogen. You may wonder how the pathogen can trigger the immune system. A portion of the pathogen called the antigen binds to B-cell surfaces and stimulates these B cells to divide and mature into a group of identical cells, called specific antibodies, that can recognize the antigen. Therefore the antigen, the portion of the new infectious agent—but not the whole infectious agent—initiates our immunity to recognize the pathogen and respond to it. Once the immunity against the pathogen is built, our immune system can respond quickly next time the same pathogen invades.

Based on this understanding of how human immunity against pathogens works, scientists recently developed the mRNA vaccine, which produces only an antigen that inititates specific antibody production and not the rest of the pathogen.³ According to Pfizer's website introducing mRNA vaccines, "mRNA vaccines work by introducing into the body a messenger RNA (mRNA) sequence that contains the genetic instructions for the vaccinated person’s own cells to produce the vaccine antigens and generate an immune response."⁴

The mRNA sequence for the mRNA vaccines are synthetic oligonucleotides*. Since mRNA is not very stable, the genetic materials include modified nucleosides to prevent degradation.⁵ Moreover, mRNA is highly vulnerable to degradation by enzymes, called extracellular RNases, in our body. Therefore, mRNAs of the mRNA vaccines are usually encapsulated within lipids or polymeric nanoparticles to protect the mRNAs and to enable entry of the mRNA into cells. These carrier systems are designed to protect mRNA from enzymes' degradation and also allow rapid uptake of the mRNA by human cells.^3,6 Recent technology innovations, especially in nanotechnology, enables the synthesis of mRNA molecules with higher stability and the encapsulation of mRNA molecules in nanoparticles for efficient delivery of mRNA into target cells.⁵

Additionally, in order to provoke a stronger immune response, a booster shot is usually added after the first shot of the mRNA vaccine. The two mRNA vaccine candidates for COVID-19 that have entered phase 3 clinical trials both require 2 doses.

Advantages of mRNA vaccines over conventional vaccines
1. Faster and cheaper to produce: The process of producing mRNA is inexpensive, and could be standardised and scaled easily. This allows quick responses to large outbreaks and epidemics.³
2. Higher efficacy: There is no viral vector to carry mRNA, therefore the anti-vector immunity, which could decrease the efficacy of the vaccine, is avoided. Additionally, as there is no fear of anti-vector immunity, mRNA vaccines can be administered repeatedly.³
3. Safer: mRNA vaccine does not contain any viral component, neither inactivated disease-causing organisms or proteins made by pathogen. Thus there is no potential risk of infection or insertional mutagenesis. Moreover, mRNA is degraded by normal cellular processes, and its in vivo half-life can be regulated through the use of various modifications and delivery methods. The inherent immunogenicity of the mRNA can be down-modulated to further increase the safety profile.³

However, since mRNA vaccine is a new type of vaccine developed by new technology, it has never before been applied clinically. It is now too early to say the vaccine is totally safe. Long-term follow-up over many years on the people who have used mRNA vaccines is necessary to find out if there are any long-term side effects of this type of vaccine.

Both of the mRNA vaccine candidates for COVID-19 contain genetic codes for the Spike glycoprotein of SARS-CoV-2. My next two blog posts will take a closer look at the two mRNA vaccine candidates.



*Synthesized oligonucleotides are short fragments of nucleic acids with defined chemical structure manufactured by biotech companies. The technique of synthesizing oligonucleotides is very useful, as it provides a convenient and inexpensive way to produce custom-made fragments of nucleic acids with desired sequences.



References
1. Decision: Regulatory approval of Pfizer/ BioNTech vaccine for COVID-19. Gov.UK’s news release, 2nd Dec, 2020. https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19
2. Draft landscape of COVID-19 candidate vaccines. World Health Orgainzation. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
3. N. Pardi, M.J. Hogan, F.W. Porter, et al. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 2018 Apr; 17(4):261-279.
4. Behind the science: what is an mRNA vaccine? Pfizer's website. https://www.pfizer.co.uk/behind-science-what-mrna-vaccine
5. K. Kariko, H. Muramatsu, F.A. Welsh, et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther., 2008, 16(11), 1833–1840.
6. How nanotechnology helps mRNA Covid-19 vaccines work. By Elizabeth Cooney. STAT Biotech, 1st Dec., 2020. https://www.statnews.com/2020/12/01/how-nanotechnology-helps-mrna-covid19-vaccines-work/