After billions of dollars and dozens of wartime declarations, why are vaccines still in short supply?

The U.S. government has invested billions of dollars in manufacturing, used a wartime act dozens of times to boost supplies and yet there's still not enough covid vaccine on the way to meet demand — or even the government's own goals for national immunization.

President Joe Biden, in remarks at the National Institutes of Health this month, said the nation is "now on track to have enough supply for 300 million Americans by the end of July." But at the current rate of production, Pfizer and Moderna will miss their targets of providing at least 100 million doses each by the end of March, let alone 200 million more doses each has promised by July.

Moderna would need to more than double its vaccine production rate from January — when it made roughly 19 million doses — to meet its contractual obligations. Pfizer supplied 40 million vaccine doses by Feb. 17. It has roughly six weeks left to deliver the first 120 million doses it has promised.

Biden and officials from the two companies say they are rapidly expanding production capacity. But critics are lining up. They want to know whether the government did enough, fast enough, to guarantee that companies would meet the urgent challenges of the pandemic. As for the manufacturers bolstered by extraordinary sums of taxpayer money, why did they not share technology and know-how sooner, or move more quickly into strategic production partnerships?

Experts say it's complicated, noting that the output of raw materials and assembly lines can't be ratcheted up 10,000-fold at the push of a button — and that the effort thus far has been close to miraculous. They cite bottlenecks in at least three areas: the production of specialty lipids, fatty materials that are a primary component of the Moderna and Pfizer-BioNTech vaccines; the hundreds of millions of glass vials that hold the vaccine; and the sterile automated assembly lines where vaccine moves from bulk containers into vials before shipment.

U.S. officials have run headlong into the limits of the Defense Production Act, a Korean War-era law that allows the federal government to ramp up supplies of critical materials in times of national emergency. The vaccine manufacturing process relies on a complex supply chain, from sourcing raw materials and equipment to designing chemical processes, building production lines and hiring and training workers.

Also, experts note, no one knew which vaccines would prove effective.

"A year ago there was no commercial market for mRNA product. There was scientific research and pharma making small-volume clinical lots. Now we need billions of doses, in the space of a year. That's overloading the supply infrastructure," said Kevin Gilligan, a senior consultant with Biologics Consulting and a former official with the Biomedical Advanced Research and Development Authority, or BARDA, a federal agency created in 2006 to deal with pandemics and bioterrorism.

As of December, the Trump administration through its Operation Warp Speed initiative had obligated nearly $14 billion for vaccine development and manufacturing, including investments to expand U.S. capacity, according to a Government Accountability Office report in January. The administration invoked the Defense Production Act on at least 23 vaccine-related contracts, in part to prioritize the government's contracts over others, according to a KHN review of the federal contracts database, contracts obtained by the nonprofit group Knowledge Ecology International, GAO and government news releases.

They include the December contract that the Department of Health and Human Services signed with Pfizer for another 100 million doses, on top of the initial 100 million it committed to last summer. That contract, worth $1.95 billion, included DPA provisions to give the company priority access to raw materials and spare parts for factories, according to a former administration official.

The DPA has also been used in vaccine contracts with Moderna, Johnson & Johnson and other drug companies for hundreds of millions of doses. On top of that, the law has been invoked for at least 10 contracts with companies making needles or syringes. It's been used to require glass makers Corning and SiO2 Materials Science to prioritize vial production for vaccine production, and in contracts for aspects of manufacturing with companies like Emergent BioSolutions, Fujifilm Diosynth Biotechnologies and Grand River Aseptic Manufacturing.

Operation Warp Speed awarded Emergent BioSolutions $648 million last year to boost the manufacturing capacity it needed to enter agreements with Johnson & Johnson and AstraZeneca — worth at least $615 million and $261 million, respectively — to help make their vaccines. Grand River Aseptic Manufacturing won a $160 million award from BARDA and has contracted with Johnson & Johnson to fill vials and finish packaging of its single-shot covid vaccine, which is expected to get emergency authorization from the Food and Drug Administration as soon as this month but will only have a few million doses available initially.

The Biden administration has expanded its use of the wartime act to prioritize equipment like filling pumps and filtration systems for Pfizer. "We told you that when we heard of a bottleneck on needed equipment, supplies or technology related to vaccine supply, that we would step in and help," Tim Manning, the White House official leading the administration's covid supply efforts, said during a February press briefing.

Yet it can do only so much, according to medical supply chain experts. Prashant Yadav, a senior fellow at the Center for Global Development at Harvard University, said it could take months for the impact of that DPA action to be felt because of the time it takes to procure equipment and get it installed, with each step tightly regulated.

The U.S. is unlikely to get a meaningful bump in capacity "unless we think about co-production deals," in which a drug company agrees to manufacture a competitor's vaccine, said Tinglong Dai, an associate professor at Johns Hopkins University's Carey Business School.

So far, such arrangements have proliferated in Europe — which has less capacity to produce drugs than the United States does. Deals with other major vaccine manufacturers have been less common on the U.S. side of the pond.

"Though we have not partnered with, say, another large pharma for production, we have built strategic partnerships with a number of organizations that have been instrumental to our scaling up and meeting supply and commercialization plans," Moderna spokesperson Ray Jordan said in an email.

Moderna this month said that its manufacturing process would scale up rapidly in the coming weeks, that it would provide the U.S. between 30 million and 35 million doses in February and March and between 40 million and 50 million doses monthly from April to July. The company declined to elaborate on what made the boost possible.

Vaccine manufacturers long ago should have been sharing technology and expertise to boost production in the U.S. and Europe, and especially in developing countries, said James Love, director of Knowledge Ecology International, a nonprofit focused on patent rights.

"We've wasted about a year by not doing some of the obvious things," he said. "The rhetoric is that it's an emergency. But on the scale-up of manufacturing, you just don't see it."

It's not that simple, others say. "There wasn't any excess capacity available in the United States a year ago. Zero," Paul Mango, a former HHS official heavily involved in Operation Warp Speed, said regarding vaccines. "It's getting the equipment. It's quality control. It's getting the employees. People make it sound like this is easy. You can't just push 400 workers and say, go at it."

Each Pfizer-BioNTech or Moderna shot contains billions of lipid nanoparticles, each particle containing four lipids and a strand of the nucleic acid RNA, the five pieces assembled in a way that allows the RNA to enter our cells and create a particle that stimulates the immune system to defend against the covid virus.

The lipids, which are made only in a handful of factories, have been a major supply problem. "No one has ever thought of a scenario where we would use lipid nanoparticle formulation for [billions of] doses," Yadav said. "We have not invented a process for doing lipid nanoparticles at scale."

Two of the lipids in the vaccine, cholesterol and DSCP, have long been used in industry to shape and buffer chemical formulations. A third lipid prevents the particles from clumping together. A fourth enables the lipid shell of the vaccine to fuse with human cells and, once inside the cell, to crack open so the RNA can move to a structure called a ribosome and make proteins that stimulate immunity.

All of these raw materials are produced under regulated conditions — in Massachusetts, Missouri, Colorado and Alabama by companies under license with Moderna, Pfizer or Acuitas Therapeutics, which was co-founded by Pieter Cullis, a University of British Columbia professor who is considered the grandfather of lipid nanoparticle technology.

Before the pandemic, these companies produced meager amounts for use in small clinical trials, laboratory experiments or in one licensed drug, patisiran, which is used to treat a rare genetic disease in about a thousand people worldwide. Now they are producing thousands of kilograms of the stuff, said Stefan Randl, a vice president at Evonik, a lipid maker. Evonik recently announced it would scale up production at two German sites, possibly in the second half of the year, to be used in the Pfizer-BioNTech vaccine. The company last year bought a U.S. lipid manufacturer in Alabama.

"All of a sudden the quantities had to be ramped up a thousand-fold or more," Randl said. "This is the biggest bottleneck."

Several elements of the vaccine, including lipids and enzymes used in making the mRNA, until recently were produced using animal products such as sheep's wool, said Andrew Geall, chief scientific officer at Precision NanoSystems, which designs equipment for mixing the mRNA and lipids. Animal products could cause contamination or disease, even in minute quantities, so manufacturers now use synthetic chemicals.

Luckily, the cosmetic industry — a major user of some of the same lipids used in the vaccines — has been switching from animal products in recent decades, noted Julia Born, an Evonik spokesperson.

Still, only a limited number of companies globally have expertise and facilities to make the lipids, said Thomas Madden, CEO and a co-founder of Acuitas, and they've all struggled to move from quantities produced in a laboratory to industrial-scale production. For instance, he said, hazardous solvents and chemicals used in laboratory procedures need to be avoided in industrial processes, where they could give rise to workplace safety issues.

"This is a hugely complex supply chain," Madden said. "Once you address a bottleneck at one point, you identify the next bottleneck in the process. It's a bit of a game of whack-a-mole."

Although it's not particularly difficult to make the lipids used in vaccines, it takes time to get FDA authorization of a facility that can make them in high quantities, said Cullis, the UBC professor. It would take two to three years to start such a factory from scratch, so instead, Moderna and Pfizer-BioNTech have been hooking up with existing manufacturers and getting them to convert to lipid production, he said.

Another bottleneck is "fill/finish" — getting the finished vaccine into vials or syringes so the shots can be shipped to customers. Vaccine filling lines require extremely high levels of efficiency and sterility, and few companies in the world have this capacity, said Mike Watson, former president of Valera, a Moderna subsidiary. Moderna has hired Catalent, a contract manufacturer that recently experienced delays that slowed the release of some doses, to fill and finish U.S. doses at its facility in Bloomington, Indiana. At least two other companies will do the same for Moderna's vaccine supply abroad.

In January, the French multinational Sanofi — whose own covid vaccine has been delayed by poor performance in producing immunity — agreed to offer its fill/finish line in Germany for the Pfizer-BioNTech vaccine. That line isn't expected to be running until July.

In the U.S., the number of vaccine doses shipped to states has ticked up in recent weeks, partly because Pfizer said its five-dose vials actually provide six shots. Moderna is seeking FDA permission to add up to five doses to its 10-dose vials.

Pfizer has said it is manufacturing raw materials in St. Louis, the active ingredients for the vaccine in Andover, Massachusetts, and filling vials in Kalamazoo, Michigan.

CEO Albert Bourla, with Biden at his side in Kalamazoo on Friday, said the company added lipid production capabilities at plants in Michigan and Connecticut, as well as fill/finish lines in Kansas. He said it has significantly cut the average time it takes to make doses — from 110 days to 60 days.

"Today, during this meeting, the president challenged us to identify additional ways in which his administration could help us potentially accelerate even further the delivery of the full 300 million doses earlier than July," Bourla said. "The challenge is accepted, and we will try to do our best."

This story was produced by KHN, which publishes California Healthline, an editorially independent service of the California Health Care Foundation.

This article was reprinted from khn.org with permission from the Henry J. Kaiser Family Foundation. Kaiser Health News, an editorially independent news service, is a program of the Kaiser Family Foundation, a nonpartisan health care policy research organization unaffiliated with Kaiser Permanente.

Posted in: Healthcare News

Tags: Cell, Cholesterol, Contamination, Coronavirus, Drugs, Genetic, Health and Human Services, Health Care, Immune System, Immunization, Laboratory, Lipids, Manufacturing, Mole, Nanoparticle, Nanoparticles, Nucleic Acid, Pandemic, Pharmaceuticals, Public Health, Research, Ribosome, RNA, Running, Therapeutics, Vaccine, Virus

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COVID-19 vaccine candidate shows potential against SARS-CoV-2 and potential future zoonotic coronaviruses

Over the last two decades, three major outbreaks of highly pathogenic coronaviruses have occurred. The third is the ongoing coronavirus disease 2019 (COVID-19) pandemic that has claimed well over 2.46 million human lives so far, in a little over a year from its onset. Without any targeted, safe and effective antivirals to prevent or treat the infection by the causative pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), population immunity via mass vaccination seems to be the only way out – as complex and expensive as the process is likely to be.

Study: SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys. Image Credit: Numstocker / Shutterstock

Pan-group 2b CoV vaccine

A new study, released on the bioRxiv* preprint server, sheds light on the threat posed by future zoonotic coronaviruses to make similar leaps across species barriers to infect human beings and cause other pandemics. The goal would appear to be a vaccine capable of inducing not limited immunity against SARS-CoV-2 alone, but one that can elicit broadly neutralizing antibody and cellular immune responses against a range of other betaCoVs.

This includes existing SARS-related coronaviruses (SARSr-CoVs) in humans, as well as those that are now circulating in animals.

The first evidence that this could be so came from the observation that SARS-CoV caused the production of cross-neutralizing antibodies against many betacoronaviruses (betaCoVs). This proof-of-concept drove the search for a vaccine that would induce neutralizing antibodies against multiple group 2b Sarbecoviruses.

Cross-neutralizing antibodies

Cross-neutralizing antibodies always target the viral receptor-binding domain (RBD) via a specific epitope. The RBD can be rendered more immunogenic by using a multimeric form. One way to achieve this is by using nanoparticles to mount arrays of RBD proteins, creating a virus-like particle (VLP).

Vaccines have been shown to successfully induce cross-neutralizing antibodies against pseudoviruses expressing CoV antigens in mouse studies. The current study describes a non-human primate (NHP) study that explores the cross-neutralizing ability of a SARS-CoV-2 vaccine based on multimeric SARS-CoV-2 RBD-bearing nanoparticles.

RBD-conjugated nanoparticle vaccine

The RBD-conjugated nanoparticle vaccine comprises 24 RBD protomers on a sortase-ferritin platform for the sake of versatility. This bound not only to the human host cell receptor, the angiotensin-converting enzyme 2 (ACE2), which is thought to be the SARS-CoV-2 entry receptor, but also to potent anti-RBD neutralizing antibodies. These include DH1041, DH1042, DH1043, DH1044, and DH1045.

All these antibodies bind to epitopes within the receptor-binding motif, within the RBD. However, antibodies that bound to epitopes outside the RBD were not able to bind the RBD-bearing nanoparticle. In contrast, it did show binding to the cross-neutralizing antibody DH1047.

This vaccine was assessed by a three-dose regimen, administered at four-week intervals, in a non-human primate (NHP) study. The vaccine was found to result in high plasma levels of antibodies to the SARS-CoV-2 RBD and to the stabilized spike protein.

The antibodies completely blocked the ACE2 binding site on the spike protein after two doses of vaccine and partially blocked the binding of the RBD antibody DH104.

SARS-CoV-2 receptor binding domain (RBD) sortase conjugated nanoparticles (scNPs) elicits extremely high titers of SARS-CoV-2 pseudovirus neutralizing antibodies. a. SARS-CoV-2 RBD nanoparticles were constructed by expressing RBD with a C-terminal sortase A donor sequence (blue and red) and a Helicobacter pylori ferritin nanoparticle with N737 terminal sortase A acceptor sequences (gray) on each subunit (top left). The RBD is shown in blue with the ACE2 binding site in red. The RBD was conjugated to nanoparticles by a sortase A (SrtA) enzyme conjugation reaction (top right). The resultant nanoparticle is modeled on the bottom left. Nine amino acid sortase linker is shown in orange. Two dimensional class averages of negative stain electron microscopy images of actual RBD nanoparticles are shown on the bottom right. b. Antigenicity of RBD nanoparticles determined by biolayer interferometry against a panel of SARS-CoV-2 antibodies and the ACE2 receptor. Antibodies are color-coded based on epitope and function. N-terminal domain (NTD), nonAbs IE, infection enhancing non-neutralizing antibody; nAb, neutralizing antibody; nonAb, non-neutralizing antibody. Mean and standard error from 3 independent experiments are shown. c. Cynomolgus macaque challenge study scheme. Blue arrows indicate 748 RBD-NP immunization timepoints. Intranasal/intratracheal SARS-CoV-2 challenge is indicated at week 10. d. Macaque serum IgG binding determined by ELISA to recombinant SARS-CoV-2 stabilized Spike ectodomain (S-2P), RBD, NTD, and Fusion peptide (FP). Binding titer is shown as area752under-the curve of the log10-transformed curve. Arrows indicate immunization timepoints. e. Plasma antibody blocking of SARS-CoV-2 S-2P binding to ACE2-Fc and RBD neutralizing antibody DH1041. Group mean and standard error are shown. f. Dose-dependent serum neutralization of SARS-COV-2 pseudotyped virus infection of ACE2- expressing 293T cells. Serum was collected after two immunizations. The SARS-CoV-2 pseudovirus spike has an aspartic acid to glycine change at position 614 (D614G). Each curve represents a single macaque. g. Heat map of serum neutralization ID50 and ID80 titers for SARS-COV-2 D614G pseudotyped virus after two immunizations. h. SARS-COV-2 D614G pseudotyped virus serum neutralization kinetics. Each curve represents a single macaque. i. Comparison of serum neutralization ID50 titers from cynomolgus macaques immunized with recombinant protein RBD nanoparticles (blue) or nucleoside-modified mRNA-LNP expressing S- 2P (burgundy) (**P<0.01, Two-tailed Exact Wilcoxon test n = 5). j. Comparison of serum neutralization titers obtained from RBD-scNP-vaccinated macaques (blue) and SARS-CoV-2 infected humans (shades of green). Human samples were stratified based on disease severity as asymptomatic (N=34), symptomatic (n=71), and hospitalized (N=60) (**P<0.01, Two-tailed Wilcoxon test n = 5).

Competitive with the Moderna/Pfizer vaccine for neutralizing antibody titer

When tested against the currently dominant D614G strain of SARS-CoV-2, the RBD-conjugated nanoparticle vaccine induced higher neutralizing antibody titers than another vaccine similar to the Moderna and Pfizer lipid-encapsulated nucleoside-modified mRNA (mRNA-LNP) vaccines that are now being used in the vaccination campaigns against COVID-19.

The measure of antibody titer used here showed an eight-fold increase with the former compared to the latter. The antibody response was also higher with the RBD-nanoparticle vaccine than with natural infection of all grades of severity.

Unaffected by emerging variants

It also showed potent neutralizing activity against the new SARS-CoV-2 variant B.1.1.7, which is rapidly spreading worldwide. This is not only more infective but may be resistant to many RBD-targeting antibodies, as well as more virulent.

While changes in binding affinity of anti-RBD antibody DH1041 to the ACE2 receptor and to the spike protein were observed with different mutations, such as those acquired during mink infection, or those found in the South African or Brazil or UK strains, the cross-neutralizing antibody DH1047 showed unchanged binding to the SARS-CoV-2.

“RBD-scNP (RBD sortase A conjugated nanoparticle) and mRNA-LNP-induced RBD binding antibodies were not sensitive to spike mutations present in neutralization-resistant UK, South Africa or Brazil SARS-CoV-2 variants.”

SARS-CoV-2 spike induces cross-neutralizing antibodies to pre-emergent betaCoVs

SARSr-CoVs still pose a danger of future pandemics to human beings. The researchers, therefore, explored the ability of this vaccine to neutralize other viruses. Similar to the LNP-mRNA vaccines based on the prefusion stabilized spike or the RBD, the RBD-scNP also elicited potent cross-neutralizing antibodies against SARS-CoV and SARSr-bat CoVs (batCoV-WIV-1, and batCoV-SHC014).

The neutralization was most potent against SARS-CoV-2, however. The highest neutralizing antibody titers were observed with RBD-scNP and the least with the RBD-expressing LNP-mRNA vaccine. The high titers may indicate that durable immunity is achieved.  

The RBD-scNP vaccine showed cross-neutralizing activity against batCoV-RaTG13 and pangolin CoV GXP4L spike antigens, in addition to SARS-CoV and SARS-CoV-2. Notably, sera obtained following vaccination with this formulation failed to neutralize the seasonal human CoVs or MERS-CoV, probably because of the difference in RBD among these CoVs, which belong to different groups.

The similarity between the RBD-scNP and DH1047 in terms of cross-neutralizing profile shows that not only do antibodies induced by the former bind near the epitope bound by the latter, but they are not specific to SARS-CoV-2 RBD. In fact, they also block batCoV-SHC01.

Notably, only a third of COVID-19 patients produce antibodies that block DH1047, indicating it is a sub-immunodominant epitope. As such, the RBD-scNP vaccine targets this epitope rather than the immunodominant ACE2 blocking epitope.

Protection against productive infection

The RBD-scNP vaccine was also protective for vaccinated monkeys when challenged with the SARS-CoV-2 virus via the respiratory tract. In all but one of the vaccinated macaques, “RBD-scNP-induced immunity prevented virus replication, and likely provided sterilizing immunity, in the upper and lower respiratory tract.”

What are the implications?

The RBD-scNP platform induced the highest cross-neutralizing antibody titer for group 2b CoVs, and as such, may serve as the basis for a reasonably effective initial broadly neutralizing vaccine against this group – both now, and in the future, if the further zoonotic transmission should occur.

The study also showed that the use of both RBD-scNP and the LNP-spike mRNA vaccines, the latter resembling those which have been recently rolled out, is capable of inducing cross-neutralizing antibodies to the dominant D614G variant and the newer variants of SARS-CoV-2, but at lower titers.

The findings indicate the ability of the SARS-CoV-2 Spike to be included in an RBD-scNP or LNP-mRNA formulation to induce cross-neutralizing antibodies against several SARSr-CoVs. Thus, even the currently used vaccines are likely to prevent future pandemics if immunization is successfully achieved.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
  • Saunders, K. O. et al. (2021). SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys. bioRxiv preprint. doi: https://doi.org/10.1101/2021.02.17.431492. https://www.biorxiv.org/content/10.1101/2021.02.17.431492v1

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Tags: ACE2, Amino Acid, Angiotensin, Angiotensin-Converting Enzyme 2, Antibodies, Antibody, Aspartic Acid, binding affinity, Cell, Conjugation, Coronavirus, Coronavirus Disease COVID-19, Electron, Electron Microscopy, Enzyme, Glycine, heat, Helicobacter pylori, Immunization, MERS-CoV, Microscopy, Nanoparticle, Nanoparticles, Nucleoside, Pandemic, Pathogen, Protein, Pseudovirus, Receptor, Respiratory, SARS, SARS-CoV-2, Severe Acute Respiratory, Severe Acute Respiratory Syndrome, Spike Protein, Syndrome, Vaccine, Virus

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Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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