Rare side effects cast cloud over vaccines much of the world desperately needs

But the stunning success of those novel mRNA vaccines, which have been delivered mostly to the United States and Europe, has overshadowed the story in the rest of the world: Vaccines developed by AstraZeneca and Johnson & Johnson — which are expected to be mainstays of global supply — remain scarce.

The pause in use of the Johnson & Johnson vaccine recommended by the United States on Tuesday deepened questions about the potential for causing rare blood clots and mirrored clotting concerns associated with the use of AstraZeneca’s vaccine in Europe. Both of the vaccines are based on older viral vector technology. AstraZeneca’s vaccine has not been authorized in the United States.

The Pfizer and Moderna vaccines were rolled out quicker, and early supplies were snapped up by the United States and other wealthy countries using advance purchase contracts.

AstraZeneca and Johnson & Johnson have said they are developing their vaccines to sell at cost and have worked to establish global manufacturing networks to create billions of doses for the whole planet. They also do not require the extreme cold storage that is needed for the Pfizer and Moderna vaccines, and they have been priced far lower — as little as $2.15 per shot for AstraZeneca and no more than $10 a dose for Johnson & Johnson.

“With the mRNA-based vaccines being predominantly available in high-income countries, the AstraZeneca and J&J vaccines are especially important for low- and middle-income countries, including across Africa and in India,” said Krishna Udayakumar, a professor of medicine and director of the Duke Global Health Innovation Center.

“For most populations in most countries, the benefits of both of these vaccines significantly outweigh the risks,” he said, calling them “major drivers of global access.”

AstraZeneca has made the largest promises globally of any vaccine company, saying it will produce more than 3 billion doses in 2021. Johnson & Johnson has said it will make 1 billion doses this year. Both have also pledged to sell hundreds of millions of doses through Covax, a procurement program for developing nations affiliated with the World Health Organization.

But nothing near those levels has been produced so far, and safety questions are escalating amid severe supply shortages. Vaccine companies have collectively pledged to produce more than 10 billion doses in 2021. But they have delivered only about 900 million as of last week with fewer than nine months remaining in the year, according to data from science analytics company Airfinity.

“Ramp-up is going to have to be extremely significant to be able to reach their goals,” said Airfinity senior analyst Matt Linley. “To be honest, I don’t think that anyone will reach their targets.”

Many countries are not expected to receive substantial immunization coverage until 2023. The WHO said last week that just 2 percent of 690 million shots administered globally were in Africa. Dozens of countries worldwide have less than 1 percent of their populations fully vaccinated.

Not vaccinating other countries will widen the gap between wealthy and developing countries, leading to more disease and deaths. Leaving unvaccinated populations in much of Asia, Africa and South America also will open the door to coronavirus variants that could ultimately make their way back to the United States.

The United States has been taking steps intended to build a large domestic surplus of vaccines in the second half of 2021. That excess of hundreds of millions of doses is seen as an opportunity to export shots to nations that need them the most. The United States is on track to produce 200 million doses of vaccine a month by the fourth quarter, Udayakumar said.

“If you look across the board at U.S. manufacturing, we’re ramping up way beyond what domestic needs are, which is good because global needs are significantly higher and largely unmet,” he said. “Over the second half of the year, I expect the United States to become the largest exporter of vaccines globally.”

In addition to safety concerns, manufacturing problems could continue to stand in the way of those goals, however.

Shortages of raw ingredients, lengthy manufacturing schedules, the difficulty of brewing vaccines from new recipes, and the challenges of transferring technology between companies are some of the biggest reasons specialists and industry sources cite for the lack of vaccine delivery on a global scale.

Both AstraZeneca and Johnson & Johnson have suffered serious production setbacks in the United States after an ingredients mix-up at Emergent BioSolutions in Baltimore last month. While that breakdown isn’t likely to dramatically alter the United States’ vaccination trajectory, it could have effects overseas.

The problem extended a two-month delay in Food and Drug Administration certification of Emergent to manufacture Johnson & Johnson vaccine, which has forced the company to turn to imports from Europe to fulfill the first orders of the 100 million doses it contracted to deliver to the United States. That supply crunch could ease once the FDA certifies the Emergent plant.

The United States has provided 4 million doses of the AstraZeneca vaccine to Mexico and Canada, technically as a loan. But how long such exports could continue is unclear. The U.S. government has now removed AstraZeneca from the Emergent plant and is hunting for a new manufacturing partner for the company, causing further delays in production of the 300 million shots AstraZeneca pledged to deliver to the United States. AstraZeneca has not said how long supplies could be delayed with the latest setback, but specialists say it takes four to 10 months to ramp up manufacturing vaccine in a new facility.

The United States has pumped nearly $20 billion into vaccine development and advance purchase contracts.

World leaders also are counting on the arrival of a vaccine from a Maryland biotech company, Novavax, to help inoculate hundreds of millions of people. But it has yet to be approved in the United States; it may win approval in the United Kingdom this month. The company said it has been forced to push its target for full-scale production until October because of a shortage of the single-use plastic bags used to grow batches of raw vaccine, Reuters reported Tuesday.

The Duke Global Health Center estimates that AstraZeneca and Novavax will be the largest suppliers of vaccine through Covax. Johnson & Johnson also has agreed to supply Covax, as well as a purchasing group for African countries, for a total of 900 million doses for disadvantaged nations.

The Biden administration has said it recognizes the need for American leadership to vaccinate the planet. Secretary of State Antony Blinken last week promised “an unprecedented global operation, involving logistics, financing, supply chain management, manufacturing and coordinating with community health workers who handle the vital last mile of health care delivery.”

AstraZeneca’s vaccine may not even be needed in the United States, but researchers see its 300 million in U.S. pledges as a potential key piece of the solution if the Biden administration begins exports as part of its stronger global leadership role. The United States also brokered a deal for Merck to produce the Johnson & Johnson vaccine later this year. Neither company has disclosed volume targets, but it is expected to provide a substantial boost.

Drug companies traditionally treat supply chains and orders as proprietary information. In the pandemic, they have provided only broad goals. They have declined to answer questions from The Washington Post about various manufacturing details.

Pfizer has a tightly controlled, centralized system, with raw substance manufacturing conducted by its own plants in the United States and a plant operated by its partner BioNTech in Germany, according to data compiled by the International Federation of Pharmaceutical Manufacturers and Associations. Sanofi and Novartis are helping Pfizer-BioNTech with later steps of finishing the drug product and filling vials.

Moderna has a single contract manufacturing partner, Lonza, with plants in New Hampshire and Switzerland.

AstraZeneca has the largest global network of contract manufacturing partners, with agreements with local manufacturers to produce raw vaccine substance in China, Thailand, India, Australia, Europe, Argentina and Mexico, as well as the Emergent factory in the United States, according to industry data.

“AstraZeneca has typically not been a vaccine producer before this … and because of that, they have had to make these agreements with other companies to facilitate the production of their vaccine,” said Airfinity’s Linley.

That leaves AstraZeneca more vulnerable to the sort of tech-transfer problems and manufacturing mishaps that are common with reproducing a recipe for a vaccine at numerous locations, with different management teams and scientists at each facility, Linley said.

Experts in vaccine production say each batch of vaccine requires dozens of steps to go perfectly.

AstraZeneca and Johnson & Johnson problems at Emergent were “just another indication to the world how hard it is to run vaccine manufacturing facilities,” said Kristopher Howard, a consultant who is managing director of NRL Enterprise Solutions and former Merck vaccines and biologics operations leader for emerging markets. “Here we have an existing, U.S.-based, FDA-approved manufacturer of vaccines having human errors and a quality system that didn’t immediately catch the issue.”