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Key Insights into Overcoming mRNA Process Challenges

The varying impurity profiles of mRNA from the IVT step calls on options in purification technologies that would allow process development scientists to…

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As the COVID-19 pandemic began to wreak havoc on the world in 2020, the biopharmaceutical industry started working tirelessly to develop a vaccine to stop this global threat. Emerging from this effort were the vaccines by Moderna and Pfizer-BioNTech using messenger RNA, or mRNA. Originally targeting primarily therapeutic cancer vaccines, mRNA has had a slow uptake in the industry until now due to challenges with distribution, specificity, and stability within the body. In an industry averse to change, these limitations have left mRNA brewing on the back burner of innovation for decades.

However, advances in science and an upheaval of focus and resources dedicated to mRNA R&D during the response to the COVID-19 outbreak have catapulted it into the spotlight as a disruptive technology that could change the future of medicine. The scientific community still faces hurdles, though, when it comes to efficient and effective process development of mRNA vaccines and therapies. Realizing the potential of mRNA requires focus on key areas and strategies that could help alleviate the bottlenecks in this growing market segment, ultimately leading to a transformative breakthrough in patient care.

Growing Interest In mRNA Capabilities

Although many people did not know about mRNA until it ushered us toward a return to normalcy during the COVID-19 pandemic, researchers have been studying the capabilities of RNA-based vaccines and therapeutics for almost 30 years. The potential of mRNA was first discovered by Hungarian scientist Katalin Kariko in the 1990s1; yet, advancing it beyond an idea proved difficult, due to the body’s natural immune response to synthetic RNA. Kariko, along with immunologist Drew Weissman, eventually overcame this hurdle by incorporating modified nucleosides into mRNA, laying the foundation for its use in the vaccines later developed for COVID-19.1

The expected growth of the mRNA market signals the success of the Moderna and Pfizer-BioNTech vaccines as only the beginning of a new era in the biopharmaceutical industry. In 2019—just before the COVID-19 outbreak—the mRNA vaccines and therapeutics market was valued at almost $600 million.2 Now, recent reports show this number could be as high as $2,911.9 million by 2026,2 with 155 therapies based on mRNA already in today’s clinical pipeline.3

There are three parameters driving interest in mRNA:

  1. Safety. mRNA vaccines do not involve infectious elements like many conventional vaccines. mRNA is also degraded rapidly after injection by normal cellular processes.

2. Speed. It is produced more rapidly by cell-free processes than other biologics and is readily standardized and scaled up, improving responsiveness to large emerging outbreaks.

3. Efficacy. It induces expression of specific antigens that give rise to both humoral (antibodies) and cell-mediated immunity (T cells), which results in efficient and effective immune response.

Dr. Jing Zhu, associate director of mRNA development at GeneLeap Biotech, says the success of the Moderna and Pfizer-BioNTech vaccines drove significant changes in his company’s plans for the future. “Last year, GeneLeap Biotech had three areas of focus when it came to developing the vaccines and therapies in our pipeline: AAV [adeno-associated virus], oligonucleotides, and mRNA,” he explains. “But because of the success with the COVID-19 vaccines, we strategically shifted our main efforts to mRNA. Not only does it have the power to do things traditional modalities do not, but the development timelines and investment needed for mRNA are much less than other biologics.”

The impact of mRNA’s success in 2020 was also felt at the Centre for Process Innovation (CPI), a part of the UK government’s High Value Manufacturing network which has an objective of providing process development support and manufacturing expertise to the biopharma industry. Over the last year, CPI was a key part of the UK government response to support rapid vaccine development against COVID-19. As such it lead the work stream to develop scalable manufacturing solutions for Imperial College London’s saRNA (an mRNA type) vaccine candidate and was awarded £5 million early in 2021 to support the development of a COVID-19 variant mRNA vaccine library in the U.K.4,5 “Prior to the pandemic, CPI was studying lipid nanoparticles and also working with other companies and organizations to develop cell-free expression platforms, which prepositioned us for what we’re doing now,” says Dr. John Liddell, chief technologist at CPI. “The attraction of mRNA as a vaccine is that it’s highly potent, and you can generate a lot of vaccine product from small volumes without requiring a large manufacturing footprint. It also offers a high transcription yield and reaction through enzymatic synthesis, allowing you to achieve four or five grams per liter within a few hours. These advantages mean that a company with access to the necessary capabilities and raw materials to produce a new mRNA vaccine could do so in a matter of weeks, while other approaches will take significantly longer.”

Overall, the characteristics of mRNA make it ideal for rapid response to infectious disease as well as for precision, i.e., personalized, medicine, a growing focus in a changing biopharma landscape—but only if the industry can overcome existing mRNA process development challenges.

Where Do We Go From Here?

The implications of what mRNA could achieve for modern medicine are far reaching; yet, advancing its capabilities means establishing a development toolbox that is fit for purpose, rather than relying on legacy methods designed for monoclonal antibodies (mAb) or other gene therapies. And while some aspects of mRNA seem simplified, the reality is that, technically, everything is new. “Compared to protein products, RNA is far more sensitive to degradation – by several orders of magnitude. It is very prone to RNase [ribonuclease] degradation,” explains Dr. Liddell. “RNase activity is ubiquitous and will destroy all of your products before you even know they’ve been destroyed. Therefore, we have to eliminate RNase activity during development and manufacture of mRNA-based products, which is very different from working with proteins. mRNA has the making of a platformable process, similar to what we have at the moment with mAbs. In that case, this has arisen from the advantage of having 20+ years of knowledge accumulated in that space, whereas with mRNA, there is still much to learn.”

Many of the challenges associated with the development and manufacture of mRNA are reminiscent of the early days of mAbs, when the industry struggled to overcome low titer and poor purification yields, leading to costly and inefficient commercial manufacturing. A focused effort to overcome those production challenges resulted in mAbs becoming the fastest growing class of biopharmaceutical products.6 A critical factor in driving mRNA forward is likely to be achieving consistency in process development of mRNA-based products. “The processes used for mRNA today have all been created by independent developers, each of which applied their own skills and knowledge,” says Dr. Liddell. “It should be that the same methods used to make a COVID vaccine are the same ones used for an influenza vaccine, which thus requires standardization across a range of areas.”  One of the main challenges in mRNA process development and scale-up is the lack of dedicated equipment and consumables fit for the relatively small volumes and large size of the mRNA compared to traditional recombinant proteins. There is also a lack of experience and knowledge of scaling up mRNA processes as well as associated perceived regulatory uncertainties.

A Closer Look At mRNA Process Development Challenges

A more detailed examination of mRNA process development (Figure 1) uncovers several areas for improvement across multiple steps.

Plasmids

An integral raw material for mRNA-based therapies and vaccines is plasmid DNA (pDNA), which acts as a template for the mRNA. Yet, pDNA is also used for the production of viral vector-based therapies—another growing area of biopharma. This has led to a significant strain on GMP-quality pDNA supply. CPI has been fortunate to secure long-standing agreements with companies that make pDNA, but emerging companies like GeneLeap Biotech struggle to get the attention they need in an increasingly competitive environment. However, Dr. Liddell highlights a possible solution, “For DNA template production, there are a number of alternative cell-free technologies to generating pDNA, such as rolling circle DNA amplification approaches, which seem very promising for reducing process timelines and improving product quality,” he explains. “There has been a lot of pressure on plasmid manufacture, particularly to GMP, to support gene therapy and mRNA applications. Hence with these supply chain issues alternative approaches such as rolling circle amplification may see their use accelerated.”

In Vitro Transcription

After pDNA is manufactured in an E.coli-based fermentation process, it is harvested, linearized, purified, and used as templates for the enzymatic in vitro transcription (IVT) process, yielding the desired mRNA molecule. IVT is currently the cost-driving step in mRNA process development. “IVT is what generates the product, but it is a highly complex step. It requires the careful addition of a number of diverse components in addition to the DNA template, such as enzymes and nucleotides to synthesize the mRNA,” explains Dr. Liddell. “You also need a capping reagent that will be added to the five-prime end of the mRNA. Design of Experiments approaches are typically used for process optimization of these different components to optimize yield and quality. Currently, reactions are batch based, but alternate reactor designs could be devised to reduce inventory of expensive raw materials, eventually even moving to a continuous reaction scheme. This may be harder to develop, but it could make a big difference in overall productivity.”

Dr. Zhu says the need for additional optimization has led to issues and costs in GeneLeap Biotech’s work with mRNA. “We have found that each vendor’s T7 RNA polymerase has a different ‘flavor,’ which means we will optimize one IVT system using the T7 from one vendor but then have to optimize again if we switch to a different one. That is why sustainable supply from a reliable vendor is critical for us.” Equipment fit for the unique characteristics of mRNA is also essential. “For the upstream, we need equipment that is designed for cell-free expression platforms,” adds Dr. Zhu. “We can use some of the functionality on the bioreactors available now, but they are missing some important functions we need, like certain inline monitoring, which will help with scale-up by monitoring the different parameters that vary with mRNA models.”

Purification

Compounding raw material variability challenges is the impurity profile of mRNA molecules that can vary with each project, requiring different purification steps from case to case. “mRNA is a very large molecule—30 to 50 nanometers—which is way beyond the size of proteins and comparable to viral vectors. That means they do not interact well with conventional chromatography resins, where you will likely get only surface adsorption,” explains Dr. Liddell.

The varying impurity profiles of mRNA from the IVT step calls on options in purification technologies that would allow process development scientists to mix and match media based on the specific characteristics of the molecule. Dr. Zhu points to an internal case where GeneLeap Biotech used the Oligo dT purification platform for mRNA. “For some of our projects, the mRNA we worked on was very clean, with a purity profile higher than 90% after the IVT. Therefore, we applied TFF [tangential flow filtration] or SEC [size exclusion chromatography] to remove the small amount of remaining impurities,” he explains. “For other projects, the impurity profile was more complex and finding a common purification platform has been more difficult than we anticipated. Oligo dT mediated purification often works fine. For some mRNA variants, though, we found very strong double-stranded RNA product impurities, which required a specific polishing step to separate. That is why a mix-and-match approach based on the impurity profile would be ideal to form the final process. More adapted purification solutions for mRNA, such as Cytiva’s fiber-based Fibro chromatography, could also offer a potential alternative to help facilitate purification of mRNA in the future.”

Additional considerations must also be made based on whether the mRNA is conventional or self-amplifying, with the latter having a much bigger structure that creates additional challenges in the purification step. “mRNA can be made using the four conventional nucleotides as well as modified mRNA, where you are using base analogs to increase the half-life, which typically means swapping out uridine for pseudo-uridine,” says Dr. Liddell. “For self-amplifying mRNA, you are using sequences derived from certain viruses to generate what is called a replicon, constructed from four non-structural proteins coded by the saRNA, which then makes copies of the transgene protein that the RNA is coding for.8 It’s quite cunning technology but is at an earlier stage of development.”

Encapsulation

Another critical step in mRNA processing is encapsulation using lipid nanoparticles. The specialized lipids used for mRNA provide a delivery system that protects the nucleic acid from degradation as the drug makes its way through the patient’s body. Prior to encapsulation, the lipids must all first be dissolved in an organic solvent, which is typically ethanol. Because ethanol is highly flammable, facilities must be properly equipped to ensure safe use of those types of materials, such as using flame-proof equipment.

If a company does not have these capabilities in-house, they may look to an outsourcing partner for encapsulation services; however, this could be challenging due to the limited number of CDMOs with experience in this area. There is also a significant number of patents in this area, leading to a complex intellectual property landscape. Dr. Liddell says the lipids used for mRNA today were originally developed to deliver small interfering RNA (siRNA) therapies. There may be better LNP formulations or alternative delivery technologies that might improve conditions required for storage stability, which is another challenge for mRNA products.

Storage

Due to the sensitivity of mRNA, an ultra-cold chain is necessary to deliver COVID-19 vaccines across the world. Paving a way toward a future with mRNA by addressing limitations during process development, though, could help minimize mRNA’s temperature requirements. “The low temperature needed to stabilize mRNA comes from the rough edges arising from rapid development and deployment,” explains Dr. Liddell. “We had to move very quickly for COVID, so people used what was available, but I really think there’s ample scope for improvement by selecting appropriate additives and excipients to achieve storage stability at higher temperatures. In addition to alternate lipid and excipient formulations, we may be able to utilize other formulation technologies, such as lyophilization to achieve better stability.”

The Future Of mRNA Beyond COVID

While the COVID-19 pandemic took so much from us—most importantly, over 3.8 million lives globally7—the white knight of mRNA that offers eligible vaccine recipients with invaluable protection will likely open the door to new opportunities to improve patient care; however, gaps in knowledge could slow progress in not only development but also regulatory approval. Both Drs. Liddell and Zhu agree that we will likely see continued focus on using mRNA for vaccines, such as replacing the egg-based production methods for vaccines, and even oncology applications, but we must address these process development issues and more to make the possibilities of mRNA a reality. Wherever the industry does go from here, though, is possible only through collaboration, communication, and a concerted effort to pave the way for the exciting future of mRNA.

Click here to learn more about equipment and solutions for efficient mRNA production.

 

References

  1. Garde, Damian. (November 10, 2020). StatNews. The story of mRNA: How a once-dismissed idea became a leading technology in the COVID vaccine race. 

2. PR Newswire. (April 5, 2021). mRNA Vaccines and Therapeutic Market Size is Projected To Reach USD 2911.9 Million 2026, Says Brandessence Market Research. 

3. Roots Analysis. (January 2021). mRNA Therapeutics and Vaccines Market, 2020-2030. 

4. Centre for Process Innovation. (April 2020). CPI joins national taskforce to develop COVID-19 vaccine. 

5. Genetic Engineering & Biotechnology News. (June 2020). U.K. Government-Backed Centre for Process Innovation (CPI) Scaling Up Imperial’s Coronavirus Vaccine. 

6. Ecker, Dawn M., et. al. (October 2020). The Therapeutic Monoclonal Antibody Product Market. 

7. WHO Coronavirus Dashboard. (June 2021). 

8. Blakney A et al. (Vaccines, Jan 2021). An Update on Self-Amplifying mRNA Vaccine Development DOI: 10.3390/vaccines9020097

 

To learn more about this topic, view this GEN eBook mRNA Vaccines: A New Era of Biotherapeutic Development

The post Key Insights into Overcoming mRNA Process Challenges appeared first on GEN - Genetic Engineering and Biotechnology News.

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‘Excess Mortality Skyrocketed’: Tucker Carlson and Dr. Pierre Kory Unpack ‘Criminal’ COVID Response

‘Excess Mortality Skyrocketed’: Tucker Carlson and Dr. Pierre Kory Unpack ‘Criminal’ COVID Response

As the global pandemic unfolded, government-funded…

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March 14, 2024

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'Excess Mortality Skyrocketed': Tucker Carlson and Dr. Pierre Kory Unpack 'Criminal' COVID Response

As the global pandemic unfolded, government-funded experimental vaccines were hastily developed for a virus which primarily killed the old and fat (and those with other obvious comorbidities), and an aggressive, global campaign to coerce billions into injecting them ensued.

Then there were the lockdowns - with some countries (New Zealand, for example) building internment camps for those who tested positive for Covid-19, and others such as China welding entire apartment buildings shut to trap people inside.

It was an egregious and unnecessary response to a virus that, while highly virulent, was survivable by the vast majority of the general population.

Oh, and the vaccines, which governments are still pushing, didn't work as advertised to the point where health officials changed the definition of "vaccine" multiple times.

Tucker Carlson recently sat down with Dr. Pierre Kory, a critical care specialist and vocal critic of vaccines. The two had a wide-ranging discussion, which included vaccine safety and efficacy, excess mortality, demographic impacts of the virus, big pharma, and the professional price Kory has paid for speaking out.

Keep reading below, or if you have roughly 50 minutes, watch it in its entirety for free on X:

"Do we have any real sense of what the cost, the physical cost to the country and world has been of those vaccines?" Carlson asked, kicking off the interview.

"I do think we have some understanding of the cost. I mean, I think, you know, you're aware of the work of of Ed Dowd, who's put together a team and looked, analytically at a lot of the epidemiologic data," Kory replied. "I mean, time with that vaccination rollout is when all of the numbers started going sideways, the excess mortality started to skyrocket."

When asked "what kind of death toll are we looking at?", Kory responded "...in 2023 alone, in the first nine months, we had what's called an excess mortality of 158,000 Americans," adding "But this is in 2023. I mean, we've  had Omicron now for two years, which is a mild variant. Not that many go to the hospital."

'Safe and Effective'

Tucker also asked Kory why the people who claimed the vaccine were "safe and effective" aren't being held criminally liable for abetting the "killing of all these Americans," to which Kory replied: "It’s my kind of belief, looking back, that [safe and effective] was a predetermined conclusion. There was no data to support that, but it was agreed upon that it would be presented as safe and effective."

Carlson and Kory then discussed the different segments of the population that experienced vaccine side effects, with Kory noting an "explosion in dying in the youngest and healthiest sectors of society," adding "And why did the employed fare far worse than those that weren't? And this particularly white collar, white collar, more than gray collar, more than blue collar."

Kory also said that Big Pharma is 'terrified' of Vitamin D because it "threatens the disease model." As journalist The Vigilant Fox notes on X, "Vitamin D showed about a 60% effectiveness against the incidence of COVID-19 in randomized control trials," and "showed about 40-50% effectiveness in reducing the incidence of COVID-19 in observational studies."

Professional costs

Kory - while risking professional suicide by speaking out, has undoubtedly helped save countless lives by advocating for alternate treatments such as Ivermectin.

Kory shared his own experiences of job loss and censorship, highlighting the challenges of advocating for a more nuanced understanding of vaccine safety in an environment often resistant to dissenting voices.

"I wrote a book called The War on Ivermectin and the the genesis of that book," he said, adding "Not only is my expertise on Ivermectin and my vast clinical experience, but and I tell the story before, but I got an email, during this journey from a guy named William B Grant, who's a professor out in California, and he wrote to me this email just one day, my life was going totally sideways because our protocols focused on Ivermectin. I was using a lot in my practice, as were tens of thousands of doctors around the world, to really good benefits. And I was getting attacked, hit jobs in the media, and he wrote me this email on and he said, Dear Dr. Kory, what they're doing to Ivermectin, they've been doing to vitamin D for decades..."

"And it's got five tactics. And these are the five tactics that all industries employ when science emerges, that's inconvenient to their interests. And so I'm just going to give you an example. Ivermectin science was extremely inconvenient to the interests of the pharmaceutical industrial complex. I mean, it threatened the vaccine campaign. It threatened vaccine hesitancy, which was public enemy number one. We know that, that everything, all the propaganda censorship was literally going after something called vaccine hesitancy."

Money makes the world go 'round

Carlson then hit on perhaps the most devious aspect of the relationship between drug companies and the medical establishment, and how special interests completely taint science to the point where public distrust of institutions has spiked in recent years.

"I think all of it starts at the level the medical journals," said Kory. "Because once you have something established in the medical journals as a, let's say, a proven fact or a generally accepted consensus, consensus comes out of the journals."

"I have dozens of rejection letters from investigators around the world who did good trials on ivermectin, tried to publish it. No thank you, no thank you, no thank you. And then the ones that do get in all purportedly prove that ivermectin didn't work," Kory continued.

"So and then when you look at the ones that actually got in and this is where like probably my biggest estrangement and why I don't recognize science and don't trust it anymore, is the trials that flew to publication in the top journals in the world were so brazenly manipulated and corrupted in the design and conduct in, many of us wrote about it. But they flew to publication, and then every time they were published, you saw these huge PR campaigns in the media. New York Times, Boston Globe, L.A. times, ivermectin doesn't work. Latest high quality, rigorous study says. I'm sitting here in my office watching these lies just ripple throughout the media sphere based on fraudulent studies published in the top journals. And that's that's that has changed. Now that's why I say I'm estranged and I don't know what to trust anymore."

Vaccine Injuries

Carlson asked Kory about his clinical experience with vaccine injuries.

"So how this is how I divide, this is just kind of my perception of vaccine injury is that when I use the term vaccine injury, I'm usually referring to what I call a single organ problem, like pericarditis, myocarditis, stroke, something like that. An autoimmune disease," he replied.

"What I specialize in my practice, is I treat patients with what we call a long Covid long vaxx. It's the same disease, just different triggers, right? One is triggered by Covid, the other one is triggered by the spike protein from the vaccine. Much more common is long vax. The only real differences between the two conditions is that the vaccinated are, on average, sicker and more disabled than the long Covids, with some pretty prominent exceptions to that."

Watch the entire interview above, and you can support Tucker Carlson's endeavors by joining the Tucker Carlson Network here...

Tyler Durden Thu, 03/14/2024 - 16:20

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Delta Air Lines adds a new route travelers have been asking for

The new Delta seasonal flight to the popular destination will run daily on a Boeing 767-300.

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March 14, 2024

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Those who have tried to book a flight from North America to Europe in the summer of 2023 know just how high travel demand to the continent has spiked.

At 2.93 billion, visitors to the countries making up the European Union had finally reached pre-pandemic levels last year while North Americans in particular were booking trips to both large metropolises such as Paris and Milan as well as smaller cities growing increasingly popular among tourists.

Related: A popular European city is introducing the highest 'tourist tax' yet

As a result, U.S.-based airlines have been re-evaluating their networks to add more direct routes to smaller European destinations that most travelers would have previously needed to reach by train or transfer flight with a local airline.

The new flight will take place on a Boeing 767-300.

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Delta Air Lines: ‘Glad to offer customers increased choice…’

By the end of March, Delta Air Lines  (DAL)  will be restarting its route between New York’s JFK and Marco Polo International Airport in Venice as well as launching two new flights to Venice from Atlanta. One will start running this month while the other will be added during peak demand in the summer.

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“As one of the most beautiful cities in the world, Venice is hugely popular with U.S. travelers, and our flights bring valuable tourism and trade opportunities to the city and the region as well as unrivalled opportunities for Venetians looking to explore destinations across the Americas,” Delta’s SVP for Europe Matteo Curcio said in a statement. “We’re glad to offer customers increased choice this summer with flights from New York and additional service from Atlanta.”

The JFK-Venice flight will run on a Boeing 767-300  (BA)  and have 216 seats including higher classes such as Delta One, Delta Premium Select and Delta Comfort Plus.

Delta offers these features on the new flight

Both the New York and Atlanta flights are seasonal routes that will be pulled out of service in October. Both will run daily while the first route will depart New York at 8:55 p.m. and arrive in Venice at 10:15 a.m. local time on the way there, while leaving Venice at 12:15 p.m. to arrive at JFK at 5:05 p.m. on the way back.

According to Delta, this will bring its service to 17 flights from different U.S. cities to Venice during the peak summer period. As with most Delta flights at this point, passengers in all fare classes will have access to free Wi-Fi during the flight.

Those flying in Delta’s highest class or with access through airline status or a credit card will also be able to use the new Delta lounge that is part of the airline’s $12 billion terminal renovation and is slated to open to travelers in the coming months. The space will take up more than 40,000 square feet and have an outdoor terrace.

“Delta One customers can stretch out in a lie-flat seat and enjoy premium amenities like plush bedding made from recycled plastic bottles, more beverage options, and a seasonal chef-curated four-course meal,” Delta said of the new route. “[…] All customers can enjoy a wide selection of in-flight entertainment options and stay connected with Wi-Fi and enjoy free mobile messaging.”

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Shakira’s net worth

After 12 albums, a tax evasion case, and now a towering bronze idol sculpted in her image, how much is Shakira worth more than 4 decades into her care…

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March 14, 2024

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Shakira’s considerable net worth is no surprise, given her massive popularity in Latin America, the U.S., and elsewhere. 

In fact, the belly-dancing contralto queen is the second-wealthiest Latin-America-born pop singer of all time after Gloria Estefan. (Interestingly, Estefan actually helped a young Shakira translate her breakout album “Laundry Service” into English, hugely propelling her stateside success.)

Since releasing her first record at age 13, Shakira has spent decades recording albums in both Spanish and English and performing all over the world. Over the course of her 40+ year career, she helped thrust Latin pop music into the American mainstream, paving the way for the subsequent success of massively popular modern acts like Karol G and Bad Bunny.

In late 2023, a 21-foot-tall bronze sculpture of Shakira, the barefoot belly dancer of Barranquilla, was unveiled at the city's waterfront. The statue was commissioned by the city's former mayor and other leadership.

Photo by STR/AFP via Getty Images

In December 2023, a 21-foot-tall beachside bronze statue of the “Hips Don’t Lie” singer was unveiled in her Colombian hometown of Barranquilla, making her a permanent fixture in the city’s skyline and cementing her legacy as one of Latin America’s most influential entertainers.

After 12 albums, a plethora of film and television appearances, a highly publicized tax evasion case, and now a towering bronze idol sculpted in her image, how much is Shakira worth? What does her income look like? And how does she spend her money?

Related: Dwayne 'The Rock' Johnson's net worth: How the new TKO Board Member built his wealth from $7

How much is Shakira worth?

In late 2023, Spanish sports and lifestyle publication Marca reported Shakira’s net worth at $400 million, citing Forbes as the figure’s source (although Forbes’ profile page for Shakira does not list a net worth — and didn’t when that article was published).

Most other sources list the singer’s wealth at an estimated $300 million, and almost all of these point to Celebrity Net Worth — a popular but dubious celebrity wealth estimation site — as the source for the figure.

A $300 million net worth would make Shakira the third-richest Latina pop star after Gloria Estefan ($500 million) and Jennifer Lopez ($400 million), and the second-richest Latin-America-born pop singer after Estefan (JLo is Puerto Rican but was born in New York).

Shakira’s income: How much does she make annually?

Entertainers like Shakira don’t have predictable paychecks like ordinary salaried professionals. Instead, annual take-home earnings vary quite a bit depending on each year’s album sales, royalties, film and television appearances, streaming revenue, and other sources of income. As one might expect, Shakira’s earnings have fluctuated quite a bit over the years.

From June 2018 to June 2019, for instance, Shakira was the 10th highest-earning female musician, grossing $35 million, according to Forbes. This wasn’t her first time gracing the top 10, though — back in 2012, she also landed the #10 spot, bringing in $20 million, according to Billboard.

In 2023, Billboard listed Shakira as the 16th-highest-grossing Latin artist of all time.

Shakira performed alongside producer Bizarrap during the 2023 Latin Grammy Awards Gala in Seville.

Photo By Maria Jose Lopez/Europa Press via Getty Images

How much does Shakira make from her concerts and tours?

A large part of Shakira’s wealth comes from her world tours, during which she sometimes sells out massive stadiums and arenas full of passionate fans eager to see her dance and sing live.

According to a 2020 report by Pollstar, she sold over 2.7 million tickets across 190 shows that grossed over $189 million between 2000 and 2020. This landed her the 19th spot on a list of female musicians ranked by touring revenue during that period. In 2023, Billboard reported a more modest touring revenue figure of $108.1 million across 120 shows.

In 2003, Shakira reportedly generated over $4 million from a single show on Valentine’s Day at Foro Sol in Mexico City. 15 years later, in 2018, Shakira grossed around $76.5 million from her El Dorado World Tour, according to Touring Data.

Related: RuPaul's net worth: Everything to know about the cultural icon and force behind 'Drag Race'

How much has Shakira made from her album sales?

According to a 2023 profile in Variety, Shakira has sold over 100 million records throughout her career. “Laundry Service,” the pop icon’s fifth studio album, was her most successful, selling over 13 million copies worldwide, according to TheRichest.

Exactly how much money Shakira has taken home from her album sales is unclear, but in 2008, it was widely reported that she signed a 10-year contract with LiveNation to the tune of between $70 and $100 million to release her subsequent albums and manage her tours.

Shakira and JLo co-headlined the 2020 Super Bowl Halftime Show in Florida.

Photo by Kevin Winter/Getty Images)

How much did Shakira make from her Super Bowl and World Cup performances?

Shakira co-wrote one of her biggest hits, “Waka Waka (This Time for Africa),” after FIFA selected her to create the official anthem for the 2010 World Cup in South Africa. She performed the song, along with several of her existing fan-favorite tracks, during the event’s opening ceremonies. TheThings reported in 2023 that the song generated $1.4 million in revenue, citing Popnable for the figure.

A decade later, 2020’s Superbowl halftime show featured Shakira and Jennifer Lopez as co-headliners with guest performances by Bad Bunny and J Balvin. The 14-minute performance was widely praised as a high-energy celebration of Latin music and dance, but as is typical for Super Bowl shows, neither Shakira nor JLo was compensated beyond expenses and production costs.

The exposure value that comes with performing in the Super Bowl Halftime Show, though, is significant. It is typically the most-watched television event in the U.S. each year, and in 2020, a 30-second Super Bowl ad spot cost between $5 and $6 million.

How much did Shakira make as a coach on “The Voice?”

Shakira served as a team coach on the popular singing competition program “The Voice” during the show’s fourth and sixth seasons. On the show, celebrity musicians coach up-and-coming amateurs in a team-based competition that eventually results in a single winner. In 2012, The Hollywood Reporter wrote that Shakira’s salary as a coach on “The Voice” was $12 million.

Related: John Cena's net worth: The wrestler-turned-actor's investments, businesses, and more

How does Shakira spend her money?

Shakira doesn’t just make a lot of money — she spends it, too. Like many wealthy entertainers, she’s purchased her share of luxuries, but Barranquilla’s barefoot belly dancer is also a prolific philanthropist, having donated tens of millions to charitable causes throughout her career.

Private island

Back in 2006, she teamed up with Roger Waters of Pink Floyd fame and Spanish singer Alejandro Sanz to purchase Bonds Cay, a 550-acre island in the Bahamas, which was listed for $16 million at the time.

Along with her two partners in the purchase, Shakira planned to develop the island to feature housing, hotels, and an artists’ retreat designed to host a revolving cast of artists-in-residence. This plan didn’t come to fruition, though, and as of this article’s last update, the island was once again for sale on Vladi Private Islands.

Real estate and vehicles

Like most wealthy celebs, Shakira’s portfolio of high-end playthings also features an array of luxury properties and vehicles, including a home in Barcelona, a villa in Cyprus, a Miami mansion, and a rotating cast of Mercedes-Benz vehicles.

Philanthropy and charity

Shakira doesn’t just spend her massive wealth on herself; the “Queen of Latin Music” is also a dedicated philanthropist and regularly donates portions of her earnings to the Fundación Pies Descalzos, or “Barefoot Foundation,” a charity she founded in 1997 to “improve the education and social development of children in Colombia, which has suffered decades of conflict.” The foundation focuses on providing meals for children and building and improving educational infrastructure in Shakira’s hometown of Barranquilla as well as four other Colombian communities.

In addition to her efforts with the Fundación Pies Descalzos, Shakira has made a number of other notable donations over the years. In 2007, she diverted a whopping $40 million of her wealth to help rebuild community infrastructure in Peru and Nicaragua in the wake of a devastating 8.0 magnitude earthquake. Later, during the COVID-19 pandemic in 2020, Shakira donated a large supply of N95 masks for healthcare workers and ventilators for hospital patients to her hometown of Barranquilla.

Back in 2010, the UN honored Shakira with a medal to recognize her dedication to social justice, at which time the Director General of the International Labour Organization described her as a “true ambassador for children and young people.”

On November 20, 2023 (which was supposed to be her first day of trial), Shakira reached a deal with the prosecution that resulted in a three-year suspended sentence and around $8 million in fines.

Photo by Adria Puig/Anadolu via Getty Images

Shakira’s tax fraud scandal: How much did she pay?

In 2018, prosecutors in Spain initiated a tax evasion case against Shakira, alleging she lived primarily in Spain from 2012 to 2014 and therefore failed to pay around $14.4 million in taxes to the Spanish government. Spanish law requires anyone who is “domiciled” (i.e., living primarily) in Spain for more than half of the year to pay income taxes.

During the period in question, Shakira listed the Bahamas as her primary residence but did spend some time in Spain, as she was dating Gerard Piqué, a professional footballer and Spanish citizen. The couple’s first son, Milan, was also born in Barcelona during this period. 

Shakira maintained that she spent far fewer than 183 days per year in Spain during each of the years in question. In an interview with Elle Magazine, the pop star opined that “Spanish tax authorities saw that I was dating a Spanish citizen and started to salivate. It's clear they wanted to go after that money no matter what."

Prosecutors in the case sought a fine of almost $26 million and a possible eight-year prison stint, but in November of 2023, Shakira took a deal to close the case, accepting a fine of around $8 million and a three-year suspended sentence to avoid going to trial. In reference to her decision to take the deal, Shakira stated, "While I was determined to defend my innocence in a trial that my lawyers were confident would have ruled in my favour [had the trial proceeded], I have made the decision to finally resolve this matter with the best interest of my kids at heart who do not want to see their mom sacrifice her personal well-being in this fight."

How much did the Shakira statue in Barranquilla cost?

In late 2023, a 21-foot-tall bronze likeness of Shakira was unveiled on a waterfront promenade in Barranquilla. The city’s then-mayor, Jaime Pumarejo, commissioned Colombian sculptor Yino Márquez to create the statue of the city’s treasured pop icon, along with a sculpture of the city’s coat of arms.

According to the New York Times, the two sculptures cost the city the equivalent of around $180,000. A plaque at the statue’s base reads, “A heart that composes, hips that don’t lie, an unmatched talent, a voice that moves the masses and bare feet that march for the good of children and humanity.” 

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