Pandemics and Epidemiology (COVID-19, monkeypox, etc.)

As Moderna and the partnership of Pfizer and BioNTech struggle to respond to huge demand for their messenger RNA (mRNA) COVID-19 vaccines, suppliers of the specialty lipids needed to deliver the vaccines are scrambling to keep up, and one new firm is entering the business.

Lipids are an unsung component in the two mRNA-based shots, the only vaccines to be approved so far in the US. Naked mRNA quickly degrades in the body, and can trigger an unwanted immune reaction. To get the genetic material to its target cells, vaccine developers combine it with a mixture of several sophisticated lipids to form lipid nanoparticles, or LNPs.

Very few companies in the world supply these custom lipids in significant quantities and to the standards needed for vaccine production. On Feb. 5, one of them, the German firm Merck KGaA, announced that it will “significantly accelerate the supply of urgently needed lipids” for BioNTech to use in producing the Pfizer-BioNTech vaccine.

Merck said it has been “working hard” in recent weeks to expand its lipid capacity by further improving production technologies and implementing new process steps. It expects to increase lipid shipments toward the end of 2021. Although Pfizer is so far the main producer of the partners’ vaccine, BioNTech is starting to make it in a facility in Marburg, Germany, that it recently acquired from Novartis.

And on Feb. 11, Evonik Industries said it will begin lipid production at two sites in Germany, also as part of a partnership with BioNTech. The chemical company, a newcomer to large-scale specialty lipid manufacturing, expects to be making commercial quantities as early as the second half of 2021.

Other companies are likewise rapidly scaling up. Croda, a British specialty chemical firm, is increasing production in Alabama at its subsidiary Avanti Polar Lipids to supply Pfizer. And the German pharmaceutical services firm CordenPharma has been investing in Switzerland, France, and Colorado, to supply lipids for Moderna’s vaccine under an agreement announced in May.

mRNA vaccine producers use a package of 4 lipids to formulate their LNPs: An ionizable cationic lipid that encapsulates the negatively charged mRNA; a PEGylated lipid that helps control particle life and size; distearoylphosphatidylcholine (DSPC), a phospholipid that helps form the structure of the LNP; and cholesterol, which also contributes to structure.

The cationic lipid is the most important of the four, and the most complex to produce. Matthieu Giraud, global director of CordenPharma’s peptides, lipids, and carbohydrates business, says the synthesis requires about 10 steps and several product isolations. A complete manufacturing campaign is measured in months.

To meet soaring demand for this and the other lipids, CordenPharma executives realized they needed to supplement their primary lipids site in Switzerland and start production at a facility in Chenôve, France. The firm also transferred lipid purification to its facility in Boulder, Colorado, which is home to its largest purification column, and is usually used for peptides. And it embarked on process-optimization projects at each site, Giraud says.

In addition, the company firmed up its raw material supply chain, ensuring it has dual sourcing for all key raw materials. And it enlisted the help of a sister company, WeylChem, to produce some raw materials internally. In all, CordenPharma went through multiple waves of hiring, investment, and expansion as Moderna’s lipid requirements increased since last May, Giraud says.

These projects are just now beginning to bear fruit. “We started this month to kick off the next level that’s expected by Moderna,” Giraud says. Overall, CordenPharma has increased its lipid production for Moderna more than 50-fold, he adds, and more increases are possible depending on the vaccine firm’s future needs.

Although Evonik is new to lipid production, it has been formulating LNPs since 2016 when it acquired the Canadian firm Transferra Nanosciences. It can produce encapsulated mRNA there for the early phases of clinical testing and make commercial quantities at its site in Birmingham, Alabama. Last year the company entered the cholesterol business with the purchase of Wilshire Technologies.

Now, says Stefan Randl, vice president of R&D for Evonik’s health-care business, Evonik will add production at plants in Hanau and Dossenheim, Germany, for the two most important lipids needed to make LNPs: cationic and PEGylated lipids. The fourth lipid, DSPC, is less critical, Randl says, and can be purchased from other firms.

Both Giraud and Randl say the efforts by their companies to meet the lipid needs of their vaccine customers have been unprecedented.

Giraud says CordenPharma brought together a team of more than 50 employees across multiple locations. “We really have now a good concept to meet demand from Moderna,” he says. And CordenPharma is prepared to supply other COVID-19 vaccine developers that require lipid-based delivery systems.

Similarly, Randl sees his firm’s investment extending beyond vaccines to serve developers of next-generation mRNA-based medicines such as cancer immunotherapies, gene-editing therapeutics, and protein-replacement therapy. “We really believe this mRNA trend is there to last,” he says.

Acuitas Therapeutics, a tiny biotechnology firm in Vancouver, B.C., has just 30 employees and leases its labs from the University of British Columbia. The company doesn’t even have a sign on its building. Until last year, it outsourced production of only small volumes of lipid nanoparticles, fat droplets used to deliver RNA into cells, for research and a single approved treatment for a rare disease.

But now, one of Acuitas’s discoveries has become a precious commodity. A proprietary molecule called an ionizable cationic lipid is a crucial piece of the mRNA vaccine made by Pfizer and its German partner BioNTech, and it is in urgent demand for production of billions of vaccine doses worldwide.

Scaling up production of formerly niche substances such as lipid nanoparticles for a global vaccine drive has been among the most complex challenges facing the Biden administration as it aims to ramp up the frustratingly slow provision of shots across the country, according to interviews with company officials and outside scientists and government reports.

On Jan. 21, the new president’s second day in office, the Biden administration issued a report that cited shortages of lipid nanoparticles among “urgent gaps” in the vaccine supply chain.

“It’s on a scale that hasn’t been done before,” said Pieter Cullis, the Canadian scientist and Acuitas chairman who is considered a godfather of lipid nanoparticle technology.

Although companies are steadily increasing the flow of vaccine doses to states, deliveries have seriously lagged behind earlier government projections. The production problems — which the companies have declined to discuss in any detail — underlie the difficulty of the quest for vaccine shots by elderly U.S. residents in states that have prioritized this population for immunization.

The federal government has committed about $16 billion to vaccine development and manufacturing since last year. Operation Warp Speed, the government’s vaccine effort launched under President Donald Trump, vowed last spring that 300 million doses of vaccine would be ready by the beginning of 2021.

That goal was downgraded by early December to a promise of 40 million doses by Jan. 1, enough for 20 million people to be immunized under the two-shot regimen. But by Dec. 30, only 12.4 million doses had been shipped, according to a recent report by the U.S. Government Accountability Office.

As of Thursday, according to data disclosed by the Centers for Disease Control and Prevention, Pfizer and Moderna had delivered 72.5 million doses combined. That represents only 36 percent of the 200 million doses that Moderna and Pfizer have pledged to deliver by March 31, just six weeks away.

Pfizer said in response to questions that it has made unspecified changes to its facilities and manufacturing that will allow it to double vaccine output. It said it will produce 2 billion doses by the end of the year. It makes its vaccine in Kalamazoo, Mich., and Belgium.

In late December, as part of a deal to obtain additional doses, the Trump administration agreed to use the Defense Production Act to help Pfizer gain access to more lipids, people familiar with the discussions have told The Washington Post.

And the federal government continues to use its authority under the rarely used Korean War-era law to direct domestic suppliers of lipids to prioritize Pfizer’s orders, according to a senior administration official who spoke on the condition of anonymity to discuss sensitive policy matters.

“The scale-up of the raw material supply chain took longer than expected,” Pfizer spokeswoman Amy Rose said in an emailed statement.

“Scaling up a vaccine at this pace is unprecedented, and we have made significant progress as we have ramped up the first-ever commercial scale production of an mRNA vaccine,” she said, referring to messenger RNA technology.

Moderna did not respond to a request for comment. The company, which makes the only other mRNA vaccine authorized by the U.S. Food and Drug Administration, invented its own ionizable lipid and also has been racing to build production capacity.

Many other bottlenecks have plagued the manufacturing of vaccines for the novel coronavirus, which causes covid-19. Companies have had to build equipment from scratch, including machines that shoot two streams of solution — one containing mRNA and one containing lipids — into a high-speed collision to fuse the nanoparticles and encapsulate the genetic payload. The Biden administration said this month that it was using the DPA to help Pfizer procure more specialized industrial machines for the next step, filtering ethanol out of the lipid mixture.

The vaccine makers are also experiencing a lack of machine capacity to fill vaccine vials. The Pfizer-BioNTech team has struck agreements with two other drug giants, Sanofi and Novartis, in Europe for “fill-finish” services, the process of putting vaccine doses into vials and preparing them for shipment.

The idea of using lipid nanoparticles to cocoon a genetic payload for release into human cells had been pursued by researchers at the University of British Columbia since the mid-1990s.

Its first approved use was in 2018 for a drug called Onpattro, which is made by the biotech firm Alnylam. The drug is infused into people with transthyretin-mediated amyloidosis, a rare hereditary disease that affects 50,000 people worldwide.

For the coronavirus vaccine, the lipid nanoparticle releases messenger RNA into a human cell, instructing the cell to make a replica of the coronavirus spike protein. The spike protein then trains the immune system to fight the real virus.

Of the four lipids that make up the protective droplet, the ionizable cationic lipid is the one needed in the highest volume and is subject to restrictive patents held by Acuitas and a few other companies. Its electrical charge changes when it enters a cell, causing the mRNA payload to break free and deliver its instructions.

After working on lipid-based drug delivery systems for so many years, Cullis said in an interview that he has been awed by their sudden success in vaccines that will save countless people from the ravages of the coronavirus pandemic.

“It was a bit of a fringe field as things were starting off,” said Cullis, who is one of the founders of Acuitas. “To see it come into the mainstream like this is completely mind-boggling.”

Problems with the manufacture and delivery of doses were inevitable after the vaccines were developed in record time, he added.

“Some of the hiccups are probably to be expected,” he said. “You can argue that the manufacturing efforts have been largely quite successful.”

Growing pains for the lipid nanoparticle technology have intensified as the government has increased orders for mRNA vaccines. Pfizer and Moderna have now committed to producing 300 million vaccine doses each for the United States by the end of July, in addition to hundreds of millions more for Europe and elsewhere.

The core problem, say executives and scientists, is the accelerated global demand for a technology that had barely reached commercialization as of early last year, a demand surge that has caught suppliers of raw materials unprepared. Explosive demand that began last summer has only intensified as other vaccines in the pipeline that use other methods have hit delays or faltered.

“The biggest difficulty is the lipids to make the lipid nanoparticles,” said Drew Weissman, who pioneered mRNA vaccines at the University of Pennsylvania and is seeing the fruit of his work being used to save millions of lives. He said it is difficult to know the extent of any shortfalls because companies typically do not make such details public.

Kinks in the supply chain could have been foreseen, Weissman said. In retrospect, the government also should have funded the suppliers of raw materials needed to make vaccines — just as it did by providing billions of dollars in advance contracts for the big drug companies that would make the vaccines.

“The pharmaceutical companies should have known that this was going to be a problem, and they should have started last year talking to the lipid companies, talking to the mRNA raw material companies, that they needed to scale up,” Weissman said.

Vaccine companies have released minimal information publicly about how they have used their money to support vaccine manufacturing. The raw materials supply chain also has been shrouded in secrecy relating to proprietary licensing deals and contract manufacturing arrangements.

Acuitas licenses its technology to others and farms out production of its lipids to contract manufacturers.

“The challenge obviously is they needed to ramp up from manufacturing hundreds of grams or kilograms to tons of lipids, so we have worked with them to support that process,” said Acuitas chief executive Thomas Madden, who also is a founder of the company. “There’s never going to be enough.”

Acuitas also is supplying its technology to CureVac, a German company that is developing an mRNA coronavirus vaccine.

ABUJA, Nigeria — Ghana became the first country to receive a delivery of coronavirus doses from the global effort to boost vaccine access after a plane landed Wednesday with 600,000 AstraZeneca shots.

The immunization help arrives days after President Biden pledged $4 billion to the multilateral pact known as Covax, breaking with the Trump administration’s shunning of the World Health Organization-backed mission.

The West African country of 31 million was selected as the first recipient after sending a rollout plan to Covax proving its health-care teams and cold chain equipment were ready to support a quick distribution.

The Ivory Coast and other countries in the region are expected to soon receive similar Covax shipments.

The doses touching down in the capital, Accra, come from the Serum Institute of India, the world’s largest vaccine manufacturer.

Boxes of vaccines left Mumbai on Tuesday for Dubai, where a logistics crew picked up hundreds of thousands of syringes, before hurtling toward Africa’s west coast.

“In the days ahead, front line workers will begin to receive vaccines, and the next phase in the fight against this disease can begin — the ramping up of the largest immunization campaign in history,” Henrietta Fore, the executive director of the United Nations Children’s Fund, said in a statement.

Ghana kicked off its rollout months behind wealthier nations, highlighting the deep disparities of shot distribution as the pandemic throttles life around the globe.

Covax projects that it will deliver 2.3 billion doses by the year’s end — most of which will go to poorer countries, free of charge. High-income nations, however, have already snapped up twice that amount, according to a Duke University tracker.

“So far, 210 million doses of vaccine have been administered globally — but half of those are in just two countries,” WHO head Tedros Adhanom Ghebreyesus said Tuesday in Geneva. “More than 200 countries are yet to administer a single dose.”

Covax organizers have faced a long battle to secure funding, particularly after Trump opted out of participating — a decision informed by his feud with the WHO.

The African Union is pushing to inoculate 60 percent of the continent’s 1.3 billion people over the next three years, but soaring global demand — coupled with the weaker buying power of poorer nations — have delayed this objective.

The body said it has obtained 670 million doses of AstraZeneca, Pfizer and Johnson & Johnson vaccines for 54 countries. Several countries, meanwhile, are negotiating vaccine packages with China and Russia. Most still rely on the Covax support.

Health officials warn that uneven access to vaccines will prolong the pandemic, spawning variants that are harder to tame.

The South African variant, which is far more transmissible, has been detected in Ghana and several other nations, fueling devastating second waves across the continent.

“There is so much stress now with the second strain of this disease,” said Rebecca Kumah, a nurse who treats covid-19 patients on the night shift in Accra. “The fight is still on. As health-care workers in the line of duty, the vaccines are a great relief.”

By Wednesday, Ghana had recorded more than 80,700 coronavirus cases and 580 deaths.

Workers at the Accra airport rushed to load the Covax doses into trucks bound for communities across the country.

Ghana plans to first protect the vulnerable: health-care personnel, the elderly and those with medical conditions that increase their risk of serious illness. The first shots will be administered early next week.

The nation imposed tight restrictions after the pandemic hit, sealing its land borders and airspace, and increased pay for doctors and nurses.

More than 300,000 community health workers have received vaccine distribution training in the coronavirus era, health officials said.

The goal is to vaccinate 20 million people, Kwame Amponsa-Akyianu, Ghana’s program manager for immunization, told reporters earlier this month.

It’s unclear how long that effort could take.

“There is hope in sight,” said Juliette M. Tuakli, a public health physician and pediatrician in Accra. “People have underestimated the enormous mental health toll covid has taken on everyone. We never thought we’d be dealing with this a year-plus later.”