I readThe MessengerbyPeter LoftusonSep 23rd, 2024

How Moderna, a little-known startup managed to develop the COVID-19 vaccines only second to Pfizer, approved by FDA, scaled up the manufactures, and delivered millions vaccine per day?

Moderna’s seemingly over-night success is 10 year’s hard work, cultivated with billions dollars from venture capital and tax payers.

Early days

Dr. Drew Weissman and Dr. Katalin Karikó developed the stealth mRNA to bypass the immune reaction in 1997. It opened the new era of messenger RNA, aka mRNA research. They were granted the Nobel Prize in Physiology or Medicine in 2013 for this pioneering work. The scientists can encode the gene information in the mRNA, and instructed the host cells to generate the desired protein. Then the immune system would recognize the protein pattern, and generate the antigen to defend the virus infections. In 2010, Dr. Derrick Rossi publish a journal in Cell Stem Cell about using modified mRNA to turn mature cells into immature cells. Ryan Dietz reached out, and introduced Timothy Springer to consider to commercialize this invention. They invited Robert Langer from MIT, Kenneth Chien from Harvard Medical School, and Flagship Venture, a VC specialized in biotech to found Moderna in 2010.

Stephan Bancel was chosen as CEO by Flagship’s chief Noubar Afeyan. He Joined the broad of directors in March 2011, and became executive chairman in July, and officially took the reign in late 2011.

Feed the beast

According to this book, it seemed that the founders had little influence of the steering the company other than research breakthrough, Bancel was on the driving seat to continuously update the process and the organization. Stephen Hoge, a McKinsey partner was hired in 2012 as senior VP of corporation development, then president in 2015.Tony de Fougerolles, the first chief scientific officer joined in 2011. He also proposed to use lipid nanoparticles to form a package to deliver RNA.

It was no surprise that the tension between Bancel and Rossi started in August 2011 about the transparency of the research. Bancel insisted keeping the discrepancy of the progress, and raced with clock. Rossi eventually stepped down as the board director in 2013.

Moderna had no product to sell in its first 10 years. Bancel negotiated strategical partnership, investment continuously to feed the beast. AstraZeneca agreed to pay $240m upfront for exclusive rights to mRNA-based drugs on March 2023. This is a quite common practice for BigPharm to invest on the biotech startup to secure the future income stream while the current patent-protected cash cow could still feed the company.

By the end of 2013, Moderna had amassed $415m through financing and partnership. It was still not enough amid the intensive competition. Bancel invited Lorence Kim to join the company as CFO on April 2014 for another round of investing.

The $50m deal with Merck shifted Moderna’s strategy from treatment to vaccine. The company was valued as $3 billion with $500m investment.

Dilema of vaccine

The development of vaccine is like a bet to the fashion trend: will this epidemic disease come back next year or they will fade out to obscurity. Like the Zika virus, it had outbreaks in America between 2015 and 2016, then the infection plummeted since Aug, 2017.

Moderna mitigated the risk with its “stopwatch drill” practice to develop vaccine in 60 days with mRNA technology. They had 8 vaccines in development and decided to pivot to COVID-19 vaccine in Jan 2020.

On January 11, 2020, the genetic sequence of COVID virus was posted on GenBank. The virus was characterized the spike protein for binding to the host cells. Kizzmekia Corbett and Moderna scientists agreed on a vaccine design focusing on the spike protein on January 13. On Feb 17, Moderna had manufactured about 500 vials of vaccine, named mRNA-1273.

The phase-I study was operated in Seattle due to its recent outbreak. The study was managed by Kaiser, supervised by Dr. Lisa Jackson. Neal Browning, a Microsoft Engineer was among the first four in the rollout on March 16, 2020. On May 9, 2020, Barney Graham, the deputy director of NIAID’s vaccine-research center, received the phase 1 results, only four months after the sequence of virus was made available.

Warp speed

The Trump Administration also launched Operation Warp Sped, aka OWS, to facilitate and accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics. The boarder director Moncef Slaoui picked two companies in each category:

• Protein-based vaccines with Novavax and Sanofi.
• Viral-vector vaccine, using adenovirus to carry DNA instruction to trigger the immune response to fight coronavirus. Johnson & Johnson, and AstraZaneca.
• mDNA, Moderna, and Pfizer partnered with BioNTech.

He also divested more than $10m worthy of Moderna stock and options, and promised to donate the related financial gain to a cancer research center since his appointment to resolve the scrutiny of interest conflicts.

Other government agencies also chimed in. US Biomedical Advanced Research and Development Authority, BARDA has provided $450 million to Johnson & Johnson, $30 million to Sanofi, also pledged up to 483.3m funding to Moderna.

OWS led the phase-3 trial to have an overarching overview of the vaccine effectiveness across the board. The feds wanted 30,000 adults in each vaccine trial, including the control group and test group. They are staggered as: Moderna on July, AZ on August, J&J on September, followed by Novavax and Sanofi. Pfizer opted-out and ran its own trial on July.

Moderna hesitated to participate the OWS-led phase-3 trial in the fear of slowing down the development, and was pushed back hard, and eventually was conciliatory due to the half billion public funding. Shortly after the phase-3 trial on July 27, 2020, Moderna notched $472 million from BARDA which brings Moderna’s total federal funding to $955 million.

The OWS also requested Moderna to slow down the recruitment of phase-3 trial for better coverage on the minority groups. It costed extra weeks to complete the trial in October instead of the planned September. On the other fronts, AZ paused the trial in UK after unexplained neurological illness, and the US trial would not restart until late October. J&J’s study subjects experienced a rare blood-clotting disorder, and the trial was resumed in late October. This effectively left the two-horse racing for mRNA vaccines tournament.

The trial was supervised by Data Safety and Monitoring Board, aka DSMB, chaired by Richard Whitley. They could make a call on the first 151 confirmed cases for the effectiveness of vaccine.Though there were two-month window for side-effect observation. Moderna’s efficiency was disclosed on Nov 9, 94.5%, slightly higher than Pfizer’s 90%.

Then the FDA scheduled December 17th, 2020 to hold a virtual meeting of the Vaccines and Related Biological Products Advisory Committee, or VRBPAC, to determine whether to grant Madonna emergency-use authorization. The three-week notice was ridiculously fast compared to 6 to 10 months in general. After marathon debate, FDA officially approved Moderna’s vaccine with vote 20-0 on Dec 18, 2020. A week ago, FDA cleared the Pfizer/BioNTech vaccine for anyone sixteen and older with 17-4 votes.

Scale up

General Gustave Perna, the head of operations for Operation Warp Speed, oversaw the distribution, 5.9 million doses of Moderna vaccine would be distributed for the first week of availability. Due to the easier storage and handling requirements, Moderna vaccines reached 3,400 sites compared of 100 of Pfizer’s.

The logistics were more challenging than expected, by the start of 2021, only 15.4 million doses were distributed, about 4.5 million doses have been administrated to people. It was just 5% of Warp Speed’s goal of delivering 300 million by Jan 2021. Moderna kept scaling up the manufacture capacity and turned out 40 million doses a month by March, 2021; while year ago, the company could only manufactured hundred thousands a year.

By the Memorial Day, the average daily case count plunged 88 percent. The vaccine might save up to 139,000 lives according to one analysis. By the end of Sept 2021, more than 148 million doses of Moderna were injected into people in US, fully vaccinated more than 66 million.

By mid June 2021, 55% US adults were fully vaccinated, but the distributed highly disproportional, for example 62% adults in Vermont were vaccines, while in Alabama, the ratio was only 30%. About 70 million people held out.

The COVID virus mutated over the time, with beta, delta, and omicron variants. Moderna developed a new vaccine named mRNA-1213.351 to cope with variants, and also suggested booster shots.

Controversy

Vaccines were not free: US government agreed to pay $1.95 billion to secure 100 million doses of Pfizer/BioNTech vaccine, aka $19.50 per dose. J&J disclosed the cost is $10 per dose. Moderna priced for $15.25 per dose for 100 million doses; with the federal funding taken into account, the US taxpayers paid $25 per dose. Moderna booked $1.7 billion in revenue on Q1 2021, with $1.2 million profit, and projected $19 billion in sales of vaccines of 2021. People challenged pharmaceutical companies whether it is ethical to profit from the pandemic.

People also criticized that Moderna deprioritize the supply of developing countries. Oxfam urged Moderna’s vaccine to

be a people’s vaccine, patent-free, mass produced, distributed fairly, and made available of free of charge, to every individual on the planet.

On May, 2021, Braiden administration sided with the global access advocates; and supported a temporary waiver of IP protection of COVID-19 vaccine to allow developing countries to make the shots. Then Moderna committed to supply 500 million doses to Covas for distribution to the developing countries.

Closing thoughts

As a Chinese working abroad, I paid close attention to the outbreak of COVID in Dec, 2019. It was devastating to see the loss of so many families. We tried to keep the social distance, work/study from home. The field trip, homecoming parties, and even graduation ceremonies were cancelled. The pandemic left scars of us, especially the young generation.

Thanks for the scientists to bring the hope, the light of tunnel to us.