In late January, I was sitting in a car waiting for my time to be vaccinated in front of Pet-Co-Park COVID-19 Vaccination Super Station. Normally it takes 10~15 years to develop a drug, although Pfizer and Moderna vaccines are available and now I am going to receive it. How could this warp speed development possible? What is the content of this vaccine? You may already know answers but allow me to revisit process.
Moderna/NIH: mRNA-1273
Established in 2010 and based in Cambridge MA, Moderna is a leading company of mRNA vaccine development. SARS-Cov-2 was first identified as the cause of an outbreak of respiratory disease in Wuhan, China in early January 2020. Genomic sequence of SARS-Cov-2 isolates was revealed by collaboration of NIH and Moderna research groups. Within 24 hours of the release of genomic sequences of isolates on 10 January 2020, the 2P (2 proline residue) mutations were substituted into Spike protein residues 986 and 987 to produce prefusion stabilized SARS-Cov-2 S(2P) protein for structural analysis and serological assay development in silico, since Moderna established previously that 2 proline substitutions at the apex of the central helix effectively stabilized other corona virus S proteins such as MERS-COV and SARS-Cov. “Within 5 days of the release of sequence, current good manufacturing practice (cGMP) production of mRNA-LNP (lipid nano-particle) encoding the
SARS-CoV2 S(2P) (mRNA-1273) was initiated in parallel with preclinical evaluation with animal models.”1. “This led to first-in-human phase 1 clinical trial on 16 March 2020, 66 days after the viral sequence was released, and a phase 2 clinical trial 74 days after on 29 May 2020 (ibid).” Expression and antigenicity of the S (P2) antigen delivered by mRNA was confirmed in vitro, and immunogenicity of mRNA-1273 was documented in several mouse strains, before vaccination of the first human patient in March1. mRNA vaccine was faster in terms of manufacturing and produced balanced immunity of Th1 and Th2 avoiding VERNA side effect, compared to protein vaccine in mouse model. NIH, NIAID, and BARDA accelerated the study and production of mRNA-1273. By October 23, 2020, Moderna completed enrollment of the Phase 3 study of mRNA-1273, which included 30,000 participants. mRNA-1273 met its primary efficacy endpoint in the first interim analysis of the Phase 3 trial with a vaccine efficacy of 94.5%2. Out of 196 cases of COVID-19 among 30,000 of trial participants, 185 were in people who received the placebo. And of the 11 vaccinated participants who got COVID-19, none suffered from severe disease. In August 2020, the United States government awarded Moderna $1.5 billion in exchange for 100 million doses, following up in December with a deal of another 100 million doses. In February 2021, the agreed supply rose to 300 million doses. Currently Moderna and Pfizer are the major suppliers of the country wide vaccination3.
BioNTech/Pfizer: BNT162b2
Unlike Moderna, the BioNTech discovery started from efforts of a small team in Germany. On January 12, 2020, Ugur Sahin, CEO of BioNTech, a German company developing cancer medicine, read a publication in Lancet about a new virus that emerged in the Chinese province of Wuhan. He immediately discussed the issue with his management team. A few days later, BioNTech initiated “Project Lightspeed” in order to develop a vaccine against COVID-194. Subsequently, BioNTech selected potential vaccine candidates and conducted preclinical studies. Shortly thereafter, the team initiated GMP production of its vaccine candidates for potential clinical studies in Germany. The technology is similar to that developed by Moderna, relying on mRNA with 2 proline substitution. The vaccine candidate BNT162b2 was tested in vitro, in mice, in Rhesus macaques (Old World Monkey), and against a human serum panel. All results suggested that BNT162b2 raised immunity and protected hosts from infectious SARS-CoV-2 challenges5. In mid-March 2020, BioNTech announced a development and commercialization collaboration with Fosun Pharma, Chinese leading pharmaceutical company. BioNTech and Pfizer signed a letter of intent to develop and commercialize the mRNA-based vaccine against the coronavirus outside of China. The collaboration with Pfizer built on the existing influenza partnership4. On April 22, 2020, the German regulatory authority approved the initiation of the clinical phase 1/2 study of BioNTech’s vaccine program. The vaccine program consisted of four different COVID-19 mRNA vaccine candidates that were included in the dose-finding study. On May 4th, in parallel, the phase1/2 study in the U.S. was initiated. On July 13th two of BioNTech’s four COVID-19 mRNA vaccine candidates received Fast Track designation from the U.S. FDA. In late July, BioNTech and Pfizer signed an agreement with the UK for the supply of 30 million doses of vaccine, with U.S. Department of Health and human Service for the supply of 100 million dose of vaccine and the option to acquire up to an additional 500 million doses. In addition, the two companies signed an agreement with the Japanese Ministry of Health to supply 120 million doses. Following an extensive review of preclinical and clinical data from Phase1/2 clinical trials in late July 2020, Pfizer and BioNTech chose to advance one of the four COVID-19 mRNA vaccine candidates into the global phase 2/3 efficacy and tolerability study, which is BNT162b2. The phase 2/3 study was planned to include more than 30,000 participants and to be conducted at 120 sites across the U.S., Argentina, Brazil, and Germany. This study was later expanded to approximately 44,000 participants and more than 150 sites4. In November 2020, a global phase 3 study enrolled 43,538 participants, 21,720 received 30 mg of BNT162b2 and 21,728 with placebo for two injections, 21 days apart. There were 8 cases of COVID-19 with onset at least seven days after the second dose who received BNT16b2 and 162 cases among those assigned to placebo. BNT162b2 was 95% effective in preventing Covid-19. Among ten cases of severe Covid-19 with onset after the first dose, nine occurred in placebo recipients and 1 in a BNT162b2 recipient6. An Emergency Use Authorization (EUA) request was submitted to FDA on November 20th. Conditional marketing authorizations were submitted to EMA (Europe), UK, Australia, Canada and Japan. Two days later, UK approved temporary emergency use of Pfizer/BioNTech’s vaccine against COVID-19. 11 December U.S. FDA authorized COVID-19 mRNA vaccine for emergency use. At this point, Pfizer/BioNTech preceded Moderna in U.S. Pfizer/BioNTech’s mRNA vaccine was approved for emergency use in Europe on December 21, 20204.
Johnson & Johnson: JNJ-78436735 or Ad26.COV2.S. single dose vaccine
Johnson & Johnson and Janssen Pharmaceutica are developing a coronavirus vaccine in collaboration with Beth Israel Deaconess Medical Center. Johnson & Johnson’s vaccine comes out of decades of research on adenovirus-based vaccines. The DNA coding COVID-19 Spike protein is stored in another virus called Adenovirus 26, but the virus cannot replicate inside host cells nor cause illness. The adenovirus based vaccines are more stable, can be refrigerated for up to three months at 2 – 8 degrees celsius.3 Some other COVID-19 vaccines are also based on adenoviruses, such as the one from University of Oxford and AstraZeneca, developed in UK. In human clinical trials of , Johnson & Johnson’s vaccine with single dose, reported an efficacy rate of 72% in U.S., 66% in Latin America, 57% in South Africa. The lower result in South Africa is likely due to the rise of B.1.351 variant in that country. On February 4, 2021, Johnson & Johnson applied to FDA for Emergency Use Authorization in the US. The FDA’s advisory board will meet on 26 Feb to consider the application. The vaccine could be authorized by early March.
As of February 23, 2021, 28,276,300 cases are reported positive for COVID-19 in the U.S., 502,341 people died from this tragic disease. Over the past week, there have been an average of 66,977 positive cases per day, which shows a decrease of 40% from the average two weeks earlier3. Currently 100 clinical trials of COVID-19 vaccine are under way in the U.S. (Clinicaltrials.gov). It is anticipated that as we progress through 2021, the number of cases will continue to significantly decline.
Written by: Misa S. Anekoji, Ph.D.
Key Words: COVID, Vaccine, mRNA, Moderna, Pfizer, BioNTech, timeline
References
1. “SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness” KS Corbett et al., nature (2020) 586:567-571, August 5. DOI: 10.1038/s41586-020-2622-0
2. https://www.modernatx.com/modernas-work-potential-vaccine-against-covid-19
3. https://www.nytimes.com/interactive/2020/science/coronavirus-vaccine-tracker.html#moderna
5. “A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates” AB Vogel et al., bioRxiv (2020) September 08, DOI:10.1056/NEJMoa2034577
6. “Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine”, FP Polack et al., New England Journal of Medicine (2020) 383:2603-2615, December 31. DOI: 10.1056/NEJMoa2034577