2023 was an important year for patients with sickle cell disease. Prior to CRISPR, the only cure for the life-long ailment was a bone marrow transplant, which is notoriously dangerous and costly. This month, the FDA approved Vertex’s “Casgevy,” a CRISPR-based therapy for the treatment of sickle cell disease in patients 12 and older. The landmark approval made the therapeutic the first genetically edited therapy to reach the general market.

Casgevy, which also received the greenlight from regulators in the UK for another blood disorder called beta thalassemia, works by being administered in a single-infusion of genetically modified stem cells to a patient. Clinical study participants that took Casgevy were free from symptoms associated with sickle cell disease, like periodic episodes of extreme pain due to blocked blood flow through vessels, for up to a year.

CRISPR, which modifies precise regions of a human’s DNA strands, was once thought to be a far off scientific innovation. Human cells were first modified using CRISPR in clinical trials in China back in 2016. Less than a decade later, these landmark approvals have set the stage for future nods by regulators for other CRISPR-based therapies that can treat things like HIV, cancers and high blood pressure. “Gene therapy holds the promise of delivering more targeted and effective treatments,” Nicole Verdun, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research said in a recent press release.

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CRISPR-based gene editing can be designed as a therapeutic for a number of diseases. A scientist can either delete, disrupt or insert segments of DNA to treat conditions by either targeting specific genes or engineering new cell therapies. The editing process can occur ex vivo (outside the body), in the same way Casgevy does, or in vivo (inside the body). Using CRISPR, sickle cell patients’ blood stem cells are modified in a lab before they are re-infused via a single-dose infusion as part of a hematopoietic transplant.

Neville Sanjana, a core faculty member at the New York Genome Center and associate professor in the Department of Biology at New York University, runs the Sanjana lab, which develops gene therapies for complex diseases like autism and cancer. “One of the really fundamental characteristics of CRISPR is its programmability,” Sanjana told Engadget. While working at the Zhang lab at the Broad Institute of MIT and Harvard, Sanjana says he helped design the “guide RNA” that became the blueprint for Vertex’s Casgevy. “CRISPR screens can be powerful tools for understanding any disease or genetic trait,” Sanjana said. Right now, he said biomedical folks are focused on applying CRISPR-based therapies for really serious inheritable diseases.

While it does “set a precedent” to have these first CRISPR-based gene therapies out there, it could also mean that regulators and the general public will regard future innovations in the space as “less novel,” Katie Hasson, a researcher with the Center for Genetics and Society (CGS) told Engadget. The CGS is a public interest and social justice organization that is focused on making sure gene editing is developed and distributed for good. Hasson explained, it doesn't mean that because one got approved that all other innovative therapies to come after it will not get as much scrutiny.

Beyond therapeutics, gene editing has very broad applications for the discovery and understanding of diseases. Scientists can use CRISPR to explore the origins of things like cancer and pave paths for therapeutics and incurable diagnoses, but that's not all there is to it. Scientists still need to conduct “considerable experimental research” when it comes to bringing an actual therapeutic to fruition, Sanjana said. “When we focus on therapeutic activity at a particular site in the genome, we need to make sure that there will not be any unintended consequences in other parts of the genome.”

Still, the spotlight will always shine a brighter light on the flashy developments of CRISPR from a therapeutic standpoint. Currently, a new gene editing method is being developed to target specific cells in a process called “cancer shredding“ for difficult-to-treat brain cancer. Scientists have even discovered a pathway to engineer bacteria to discover tumorous cells. However, there are barriers to using CRISPR in clinical practice due to the lack of “safe delivery systems to target the tissues and cells.”

“Maybe by curing one disease, you might give them a different disease — especially if you think of cancer. We call that a secondary malignancy,” Sanjana said. While there is strong reason for concern, one cure creating a pathway for other diseases or cancers is not unique to CRISPR. For example, CAR T cell therapy, which uses an entirely different approach to cell-based gene therapy and is not reflective of CRISPR, is a lifesaving cancer treatment that the FDA discovered can, in certain situations, cause cancer.

“We definitely don't want any unintended consequences. There are bits of the genome that if you edit them by mistake, it's probably no big deal but then there are other genes that are vitally important,” Sanjana said. Direct assessment of “off-target effects” or events in which a gene edit incorrectly edits another point on a DNA strand in vivo is challenging.

The FDA recommends that after a clinical trials’ period of investigatory study looking at the efficacy of a gene editing-based therapy, there needs to be a 15-year long term follow up after product administration. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said that the agency’s approval of Casgevy follows “rigorous evaluations of the scientific and clinical data.” Right now, researchers are focused on improving the precision and accuracy of gene editing and having the proper follow up is absolutely well merited, Sanjana explained. “The process right now is a careful one.”

Hasson believes that the 15-year recommendation is a good start. “I know that there is a big problem overall with pharmaceutical companies actually following through and doing those long term post-market studies.”

That’s where new approaches come into play. Base editing, a CRISPR-derived genome editing method that makes targeted changes to DNA sequences, has been around since 2016. Drugs that use base editing have already made headway in the scientific community. Verve Therapeutics developed a gene edited therapy that can lower cholesterol in patients with a single infusion. At higher doses, Verve said the treatment has the potential to reduce proteins associated with bad cholesterol for 2.5 years. Base editing, like CRISPR, has many potential applications for treatment and discovery. For example, base editing could repair a gene mutation that causes childhood blindness. Researchers at Weill Cornell Medicine also found base editing could help understand what genetic changes influence a patient’s response to cancer therapies.

Base editors use CRISPR to bring another functional element to a specific place in the genome. “But it doesn't matter whether it's CRISPR cutting or base editing… any time you're modifying DNA…you would want to know what the off target effects are and you can bet that the FDA wants to know that too. You're going to need to collect data using standard models like cell culture, or animal models to show there are zero or near zero off-target impacts,” Sanjana said.

CRISPR-based therapies already show high therapeutic potential for conditions beyond sickle cell disease. From blood based treatments, to edited allogeneic immune cells for cancers, there are a number of human clinical trials underway or expected to start next year. Trials for gene-edited therapies that target certain cells for cancer and autoimmune diseases are expected to begin in 2024.

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It won't be until 2025 before we get a better understanding of how Excision BioTherapeutics’ CRISPR-based therapy works to treat HIV. The application of gene editing as a therapeutic for Alzhiemer’s is still in the early stages, with mice at the forefront of research. Similarly, University College London researchers proved that CRISPR has promise as a potential therapeutic for treatment-resistant forms of childhood epilepsy. In a recent study, a gene edited therapy developed in the lab was shown to reduce seizures in mice.

But the clinical process of getting CRISPR to safely and effectively work as it's intended isn’t the only hurdle. The pricing of CRISPR and related therapies in general will be a huge barrier to access. The Innovative Genomics Institute (IGI), a research group that hopes to advance ethical use of these gene editing in medicine, estimates that the average CRISPR-based therapy can cost between $500,000 and $2 million per patient. The IGI has built out an “Affordability Task Force” to tackle the issue of expanding access to these novel therapies. Vertex’s sickle cell treatment costs a cool $2.2 million per treatment, before hospital costs. David Altshuler, the chief scientific officer at Vertex, told MIT Tech Review that wants to innovate the delivery of the therapeutic and make it more accessible to patients. “I think the goal will be achieved sooner by finding another modality, like a pill that can be distributed much more effectively,” Altshuler said.

“Access is a huge issue and it's a huge equity issue,” the CGS’ Hasson told Engadget. “I think we would also like to look at equity here even more broadly. It's not just about who gets access to the medication once it comes on the market but really how can we prioritize equity in the research that's leading to these treatments.” The US already does a poor job of providing equitable healthcare access as it is, Hasson explained, which is why it's important for organizations like CGS to pose roundtable discussions about implementing guardrails that value ethical considerations. “If you support people having access to healthcare, it should encompass these cutting edge treatments as well.”

In a landmark decision, the FDA greenlit two new drugs for the treatment of sickle cell disease in patients 12 and older, one of which —Vertex’s drug Casgevy — is the first approved use of genome editing technology CRISPR in the US. Bluebird Bio’s Lyfgenia also is a cell-based gene therapy, however, it uses a different gene modification technique to deliver tweaked stem cells to the patient.

Both approvals cultivate new pathways for the treatment of sickle cell disease, which is an inherited blood disorder that is characterized by red blood cells that can’t properly carry oxygen, which leads to painful vaso-occlusive crises (VOCs) and organ damage. The disease is particularly common among African Americans and, to a lesser extent, among Hispanic Americans. Bone marrow transplants are currently the only cure for sickle cell disease, but they require well-matched donors and often involve complications.

While both drug approvals use gene editing techniques, Casgevy’s CRISPR/Cas9 genome editing works by cutting out or splicing in DNA in select areas. Patients first have blood drawn so that their own stem cells can be isolated and edited with CRISPR. They then undergo a form of chemotherapy to remove some bone marrow cells, so the edited stem cells can be transplanted back in a single infusion.

Both drug approvals are based on studies that evaluated the effectiveness and safety of the novel therapies in clinical patients. With Casgevy, study participants reported that they did not experience “severe VOCs” for at least 12 consecutive months during the 24-month follow-up. Similarly, patients on Lyfgenia did not experience a “pain crisis” for six to 18 months after the therapy.

The FDA's decision comes shortly after UK regulators, as well as the National Health Regulatory Authority in Bahrain both approved Vertex’s Casgevy. The approval for a CRISPR-based treatment creates opportunity for further innovation in the gene editing space — for treatments ranging from cancers to heart diseases to Alzheimer’s. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited,” Nicole Verdun, director of the Office of Therapeutic Products at the FDA’s Center for Biologics Evaluation and Research said. Casgevy is still currently under review by the European Medicines Agency.

In a trial run by Verve Therapeutics, a Cambridge–based biotech company, researchers discovered that a single infusion of a gene-editing treatment called VERVE-101 was able to reduce cholesterol levels in patients. This treatment was tested in individuals with hereditary conditions that made them susceptible to developing clogged arteries and heart attacks. Scientists were able to use CRISPR editing techniques to tweak liver gene cells. The researchers “turned off” a cholesterol-raising gene called PCSK9, which is found in the liver, in order to lower LDL-C — sometimes called "bad" cholesterol — which causes plaque to build up in arteries in the first place.

PCSK9 was lowered by as much as 84 percent in the cohorts that received higher infusion rates of the treatment. At those higher treatment doses, Verve scientists said that the reduction of those LDL-C-related proteins lasted 2.5 years in previous studies on primates.

Verve Therapeutics

From a clinical standpoint, this gene editing therapy has the potential to disrupt the current standard treatment for high cholesterol. The current go-to's include prescription statins and PCSK9 inhibitors, but they require strict adherence and can have bad side effects like muscle pain and memory loss.

CRISPR, while seemingly miraculous, is a long way from replacing daily medications though. According to Nature, two of the 10 participants in the study suffered from a “cardiovascular event” that coincided with the infusion. Verve says one was not related to the treatment at all and the second was “potentially related to treatment due to proximity to dosing.” The use of a gene-editing technology will always carry some risk because the edits could occur elsewhere in the genome.

Before a single infusion therapy for high cholesterol can reach consumers, the FDA mandates that the treatment will need to be studied for up to 15 years. Verve recently received FDA clearance for an Investigational New Drug Application for VERVE-101, meaning that the company can begin to conduct trials in the US. The current trials in New Zealand and the United Kingdom will look for willing clinical trial participants to expand the study.

CVS Health is launching a new subsidiary unit, Cordavis, that will collaborate with drug manufacturers to produce biosimilar products, or medications that are near identical to an already approved and existing drug. This unit will commercialize and co-produce FDA-approved biosimilar products to U.S. markets, which will likely have a trickle-down effect on the way consumers buy drugs by increasing competition and driving down prices.

This subsidiary will not reinvent the wheel with new drugs. All the biosimilar products produced will be highly similar to an already approved biologic medicine but will still undergo testing and approvals to ensure they are highly comparable in terms of safety, efficacy and quality. If generic drugs are the Kirkland brand of medication — an identical product made cheaper through the expiration of a patent — biosimilars are more like Amazon Basics: less expensive, legally distinct but functionally the same as what they imitate. CVS claims that Cordavis will "help ensure consistent long-term supply of affordable biosimilars" when it officially debuts at the beginning of 2024.

The first confirmed offering from Cordavis in the near future is Hyrimo, a biosimilar of the drug Humira. Humira is an injectable drug that is used to treat a range of diseases, including Crohn's and rheumatoid arthritis in adults. The drug is a popular prescription that generated its maker AbbVie net revenues of $3.5 billion in global sales in the second quarter of 2023. It has a list price of nearly $7,000 a month, making it a prime drug worth diluting in the competitive pharmaceutical landscape. Cordavis says its biosimilar for Humira will list under a new private label and will be 80 percent cheaper than the current list price of the drug. This early offering gives just a snapshot of the kind of influence Cordavis can have on disruption in the drug manufacturing space.

Biogen and Sage Therapeutics' collaboration to develop Zurzuvae has proved fruitful. The FDA approved the oral pill specifically for the treatment of postpartum depression (PPD), making it the first of its kind in a class of antidepressants intended specifically for new mothers. According to research by the CDC, one in eight women will experience symptoms of postpartum depression. Symptoms of PPD can occur quite intensely after birth and can be dangerous because it can interfere with a new mother’s ability to function. The long-awaited approval comes thanks to two randomized, double-blind studies that proved the efficacy of the drug.

A key hallmark of Zurzuvae is that the medication is expected to work within just a few days and is meant to be taken for up to two weeks. Before this once-daily oral pilll, the most common treatment plan for PPD required an IV injection. That meant administration by a healthcare provider in a hospital or healthcare facility was necessary. With this approval, Zurzuvae will be able to expand access and reach to more women on their way out of hospitals.

The catch is the drug can impact a patient's ability to drive and cause extreme drowsiness. Additionally, the warning label for the drug highlights that, like most antidepressants, the drug can cause an increased risk for suicidal ideation. To top it off, Zurzuvae may also cause fetal harm. Patients on the drug should use contraception while taking the pill and for one week after taking Zurzuvae.

Japanese drugmaker Eisai and US-based Biogen have been working together on advancing research in the space of Alzheimer’s for nearly a decade. Finally, the FDA, granted the fruits of that labor, Leqembi, its blessing for intravenous use. This marks the first approved treatment that can slow the progression of Alzheimer’s.

Leqembi received a preliminary approval in January that allowed it to be used in a limited capacity. That approval was conditioned on the two drug makers conducting a confirmatory study to verify the drug's clinical benefit.

Though Leqembi slows Alzihmer’s progression, it is not a cure. Instead, it addresses the underlying biology that spurs Alzheimer's advancement. The drug works by reducing amyloid plaques, or "misfolded" proteins that form in the brain of a person with Alzheimer's.

Leqembi isn’t the only drug targeting beta-amyloid plaque buildup to treat Alzheimer's. Aduhelm received approval under the accelerated pathway in 2021, but it’s still not fully FDA-approved. But what sets Leqembi apart from its predecessor is that the drug demonstrated actual clinical benefit in addition to simply reducing the buildup of the AD-inducing proteins.

Besides needing a medical prescription, taking the drug will require professional administration in a hospital or infusion center every two weeks. The company, though it may not be its sole responsibility, recognizes its need to boost accessibility. In a public statement, Christopher Viehbacher, the CEO of Biogen, said the company’s main focus now is to work with Eisai to make Leqembi “accessible to eligible patients as soon as possible.”

The drug’s hefty price tag of $26,500 will unfortunately make it inaccessible to most. Current rules mean that it’s unlikely to be covered by Medicare. According to the Alzheimer's Association, those on Medicaid only should be able to get coverage of the FDA-approved drug in most cases. But, even if Medicaid does cover it, patients would be responsible for a 20 percent copay – or about $5,300. Experts predict the total cost of Leqembi treatment can run upward of $90,000 a year, if you take infusions and laboratory tests into account.

An expensive treatment program is something to consider for the one in nine Americans who are over the age of 65 that have Alzheimer’s dementia. That number is expected to grow as the nation’s aging population continues to grow. The number of Americans 65 and older is projected to climb from 58 million in 2021 to 88 million by 2050. This has led to an increased focus on treatments and diagnostics for Alzheimer’s, like blood tests that can detect the disease.

After 38 years as the head of the National Institute of Allergy and Infectious Diseases, Dr. Anthony Fauci announced on Monday that he will be stepping down from his role in December. Appointed to the position in 1984 by then-president Ronald Reagan, Fauci has personally overseen the federal government’s response to some of the 20th century’s deadliest infectious diseases — from tuberculosis and COVID to SARS and MERS.

But, as he told The Guardian in 2020, “my career and my identity has really been defined by HIV.” The prevention and treatment of HIV has been a prioritized area of research for the NIAID since 1986, and one that Dr. Fauci has devoted much of his public service to. The current state of AIDS research and response in America is thanks in no small part to his continued efforts in the field.

The NIAID is one of 27 specialized institutes and centers that make up the National Institutes of Health (NIH), which in turn reports to the Department of Health and Human Services. The NIH overall serves as the federal government’s premiere health research program. The NIAID operates within that bureaucratic framework, conducting and supporting “basic and applied research to better understand, treat, and ultimately prevent infectious, immunologic, and allergic diseases,” per its mission statement. That includes everything from working to mitigate effects of the annual influenza strain and alleviate asthma in urban youth to leading the development of an effective vaccine against COVID-19. The technology behind that vaccine is now being adapted for use against HIV and malaria as well.

Working at the forefront of immunoregulation research in the early 1980s, Fauci developed treatments for a class of otherwise-fatal inflammatory diseases including polyarteritis nodosa, granulomatosis with polyangiitis (formerly Wegener's granulomatosis) and lymphomatoid granulomatosis. The results of those studies helped lay the groundwork for today’s research by the NIAID’s Laboratory of Immunoregulation. That research includes cellular and molecular mechanisms of HIV immunopathogenesis and the treatment of immune-mediated diseases. Combining the institute’s nearly four decades of HIV/AIDS research with cutting edge genomic technology has brought us not one, but three potentially viable AIDS vaccines, all of which are currently in clinical trials.

“Finding an HIV vaccine has proven to be a daunting scientific challenge,” Dr. Fauci said in a March NIAID release. “With the success of safe and highly effective COVID-19 vaccines, we have an exciting opportunity to learn whether mRNA technology can achieve similar results against HIV infection.”

The active, hands-on approach we see in response to the AIDS epidemic today is a far cry from that of the Reagan administration at the start of the crisis in 1983, which initially met the issue with silence. That is, outside of the time Larry Speakes, Reagan's press secretary, called it “the gay plague.”

Fauci’s initial efforts during the AIDS epidemic did more harm than good. In 1983, he published The Acquired Immune Deficiency Syndrome: The Ever-Broadening Clinical Spectrum in which he warned of “the possibility that routine close contact, as within a family household, can spread the disease.” We know now that this is not at all how HIV works, but at the time — despite the study urging caution until more evidence was gathered — it set off a moral panic in the media. The study was subsequently picked up by right-wing organizations and used as a political cudgel blaming the LGBTQIA+ community for the disease.

Reagan himself didn’t publicly mention the crisis until 1985, three years after it was officially identified by the CDC (and, coincidentally, a month after he admitted his involvement in the Iran-Contra Scandal). Social stigma around the disease made funding for basic health research nearly impossible to acquire, and was exacerbated by Reagan’s repeated budget cuts to the NIH and CDC.

"The inadequate funding to date has seriously restricted our work and has presumably deepened the invasion of this disease into the American population," a CDC staffer wrote in an April, 1983 memo to then-Assistant Director, Dr. Walter Dowdle. "In addition, the time wasted pursuing money from Washington has cast an air of despair over AIDS workers throughout the country."

Even after his appointment as Chief Medical Officer — one who was determined to treat the AIDS crisis with its deserved gravity — Fauci faced pushback from the LGBTQIA+ community, who demanded greater action from the government in response to the crisis and sought to accelerate the glacial pace of drug trials at the time.

By 1990, the community’s patience had reached a breaking point, resulting in ACT UP’s (AIDS Coalition to Unleash Power) attempt to storm the NIH in protest. “One of the things that people in ACT UP said is that we are the people who are experiencing this novel disease, and we are the experts, not just the scientists and doctors,” Garance Ruta, executive director of GEN magazine and an ACT UP member at the protest, told The Washington Post in 2020.

“I was trying to get them into all the planning meetings for the clinical trials,” Fauci told WaPo, in response. “I felt very strongly that we needed to get them into the planning process because they weren’t always right, but they had very, very good input.”

Over the last 30 years, the NIH has helped lead development of numerous antiretroviral therapies. Azidothymidine (AZT), the first drug discovered to inhibit HIV’s replication without damaging cells, was initially developed by the NIH as an anti-cancer drug in the 1960s. Its use as an antiretroviral, approved by the FDA in 1987, helped to establish the AIDS Clinical Trials Group (ACTG), which further accelerated research into nucleoside reverse transcriptase inhibitors (NRTIs, the class of drug to which AZT belongs). NIAID-funded studies in the 1990s helped establish combination therapies, which combine multiple medications for a synergistic effect, and explored a newly-identified class of drug, non-nucleoside reverse transcriptase inhibitors or NNRTIs.

NIAID

Today, nearly three dozen antiretroviral drugs are available, many of them combined into fixed-dose tablets. In the 1990s, people living with AIDS would be expected to take up to 20 individual pills at set schedules throughout the day. The average lifespan for someone infected with the disease was roughly a year. Today, assuming you’re lucky enough to live in the developed world, AIDS has become a chronic condition to be controlled with a single daily pill. For the 20 million people living with AIDS but without access to modern treatment, it remains a death sentence.

The state of medical research technology has also evolved, even if the nation’s prevailing notions of fairness and equality haven't improved much in the intervening years since Reagan held power. Advances in laboratory standardization and automation have rapidly reduced development cycles and the occurrence of outlier results. The monotonous tasks that were once performed by lab assistants are now handled by robotic arms equipped with pipette arrays.

Disease prevention and diagnosis efforts have been augmented in recent years with artificial intelligence and machine learning algorithms. They’ve also found use in helping to stem the spread of HIV and improve access to both retrovirals and PReP with applications including, “ML with smartphone-collected and social media data to promote real-time HIV risk reduction, virtual reality tools to facilitate HIV serostatus disclosure, and chatbots for HIV education,” argue Drs. Julia Marcus and Whitney Sewell, of Harvard and UMass Amherst, respectively.

And just as Dr Fauci is, quite specifically, not retiring — “I want to use what I have learned as NIAID Director to continue to advance science and public health and to inspire and mentor the next generation of scientific leaders as they help prepare the world to face future infectious disease threats,” he noted in Monday’s announcement — the work of the NIAID is far from complete. Even as we slowly conquer existing scourges like COVID and HIV, re-emerging threats like Monkeypox (not to mention ancient killers like Polio) will continue to appear on our quickly warming planet.

The national news cycle may have largely moved on from coverage of the COVID-19 pandemic — despite, as of this writing, infections being on the rise and more than 300 deaths tallied daily from the disease. But that certainly doesn't diminish the unprecedented international response effort and warp speed development of effective vaccines. 

In The Messenger: Moderna, the Vaccine, and the Business Gamble That Changed the World, veteran Wall Street Journal reporter Peter Loftus takes readers through the harrowing days of 2020 as the virus raged across the globe and biotech startup Moderna raced to create a vaccine to halt the viral rampage. The excerpt below takes place in early 2021, as the company works to adapt its treatments to slow the surging Delta variant's spread.

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Reprinted by permission of Harvard Business Review Press. Excerpted from The Messenger: Moderna, the Vaccine, and the Business Gamble That Changed the World by Peter Loftus. Copyright 2022 Peter Loftus. All rights reserved.

Delta

Viruses of all types frequently change. They mutate as they jump from person to person. The coronavirus was no different. Throughout the pandemic, health officials tracked variants of the SARS CoV-2 virus first found in Wuhan, China, as those variants arose. None seemed a big concern, until one was flagged in the United Kingdom in December 2020, right as Moderna’s vaccine neared approval. This UK variant appeared to be as much as 70 percent more transmissible. It was given the name the Alpha variant.

Alpha reinforced the possibility that the virus could mutate enough to become resistant to vaccines and treatments that were designed to target the earlier, predominant strain. Or it could fizzle out. But variants would keep coming. Shortly after Alpha, researchers identified another variant circulating in South Africa. Beta.

In late December—just a few days after the United States authorized its vaccine — Moderna issued a statement that it was confident the vaccine would be effective at inducing the necessary immune response against variants. The original vaccine targeted the full length of the spike protein of the coronavirus, and the new variants appeared to have mutations in the spike protein that represented less than a 1 percent difference from the original.

“So, from what we’ve seen so far, the variants being described do not alter the ability of neutralizing antibodies elicited by vaccination to neutralize the virus,” Tal Zaks said during a virtual appearance at the all-important J.P. Morgan Healthcare Conference in January 2021. “My definition of when to get worried is either when we see real clinical data that suggest that people who’ve either been sick or have been immunized are now getting infected at significant rates with the new variants.”

Even if the vaccine proved less effective against a new variant, Moderna could use its mRNA technology to quickly tweak the design of its Covid-19 vaccine, to better target a variant of the virus, Zaks said. After all, the company and its federal health partners had already demonstrated the year before how quickly they could design, manufacture, and test a new vaccine.

Still, Moderna needed to run a series of tests to see if its original vaccine offered the same high level of protection against variants as it showed in the big Phase 3 clinical trial.

Moderna collaborated again with researchers from NIAID including Barney Graham and Kizzmekia Corbett. They analyzed blood samples taken from eight people who were vaccinated with Moderna’s shot in the Phase 1 trial back in early 2020. They essentially mixed these blood samples with the coronavirus variants, engineered so they copied the mutations of the variants but couldn’t replicate and pose a threat to lab researchers. Researchers then analyzed whether the vaccine-induced antibodies present in the human blood samples could effectively neutralize the virus variants.

The results were mixed. They suggested the vaccine worked as well against the UK Alpha variant as against the original strain of the coronavirus. That was good news. Even if the UK variant spread more easily than the original virus, Moderna’s vaccine could probably mute its effects.

But the Beta variant first identified in South Africa seemed to pose a problem. The vaccine-induced antibodies had a significantly reduced neutralization effect on this strain in the lab tests. “Oh shit,” Bancel said when Stephen Hoge showed him the data. It wouldn’t be the last time. Moderna’s leaders saw the data on a Friday in late January 2021 and spent the weekend discussing it. They hoped that a modified, variant- targeted vaccine wouldn’t be needed, and that Moderna’s original vaccine would suffice, even if it had a reduced neutralizing effect. But Moderna didn’t want to be caught flat-footed if a variant-specific booster was needed.

They decided by the next Monday it was time to take action. They would develop a new version of the vaccine, one that more closely matched the mutations seen in the strain that circulated in South Africa, and which could potentially be given as a booster shot to better protect people who had gotten the original vaccine.

“It really highlights the fact that we need to continue to stay vigilant,” Moderna’s president, Stephen Hoge, said. “This virus is evolving, it’s changing its stripes. And we need to keep testing the new variants, and make sure the vaccine works against them.”

Moderna repeated the steps it took a year earlier: it quickly designed a new variant vaccine and manufactured an initial batch for human testing, shipping it to NIAID in late February, a year to the day after it had shipped the original batch of the original vaccine. The new batch was called mRNA-1273.351, appending the “351” because researchers initially called the variant seen in South Africa “B.1.351.”

“Moderna is going to keep chasing the variants until the pandemic is under control,” Bancel said that day.

Moderna also developed other plans to test. It would try a third dose of its original vaccine, given several months after the second dose, to see if that booster shot would protect against variants. It would also develop a combined vaccine that targeted both the original strain and the Beta strain.

Once again, volunteers stepped up to test these various approaches. Neal Browning, the Microsoft engineer who was the second person to get Moderna’s vaccine, showed up once again to volunteer. In the intervening year, he had gotten married, in a small outdoor ceremony to minimize Covid risk. Now he received a third dose of the Moderna vaccine. He felt tenderness at the injection site and a low-grade fever and chills, but the symptoms went away after several hours. He continued to visit the research site to give blood samples to be analyzed for immune responses.

By early May, Moderna had some answers. It gave booster shots — either the original vaccine or the Beta variant – targeting vaccine — to people about six to eight months after they had been vaccinated with two doses of the original vaccine. The company found that in the new analysis, both types of booster shots increased neutralizing antibodies against the Beta variant. And they increased antibodies against a related variant that had been detected in Brazil. But the newer version of the vaccine that targeted Beta induced a stronger immune response against the Beta variant than the booster shot of Moderna’s original vaccine.

At the time, Moderna’s plan was to continue testing the different booster approaches, with an eye toward possibly getting government approval to sell the booster shot that specifically targeted the Beta variant. But it didn’t seem particularly urgent. The existing mass vaccination campaign was making good progress at the time.

Then, with the virus on the retreat in the United States, scientists discovered a new variant driving an alarming surge in India. This variant had already jumped to other countries, including the United States. Initially, it was code-named B.1.617.2. It was even more contagious than the Alpha variant and there were fears that it could evade vaccines. This was the Delta variant.

The previous winter the hope provided by vaccines was juxtaposed with the deadliest virus surge in the United States. Again, in early summer 2021, the lifting of mask mandates and reopening of public life was bringing great hope and a sense of relief. And again, this would be juxtaposed with public-health officials sounding the alarm about the Delta variant. It could become the dominant strain of the virus in the United States, they said. The best way to stop its spread, officials said, was to get more people vaccinated, with any of the three vaccines available.

By mid-June, about 55 percent of the US adult population was fully vaccinated, which was good but still left many people exposed to the new Delta variant that spread much more easily than earlier strains. And there were clear geographic vulnerabilities. The Northeast United States had higher vaccination rates than the national average, particularly in some New England states, like Vermont with its 62 percent vaccination rate. But in the South the numbers were much lower in states like Alabama, where only 30 percent were fully vaccinated.

The high proportions of unvaccinated people in those places would serve as a breeding ground for Delta. And the more the variant spread, the more it could mutate into more variants.

By late July, the effects of an ill-fated combination — stubbornly low vaccination rates in some regions, the winding down of masking and distancing, and a rapidly spreading Delta strain—were clearer. Infections, hospitalizations, and deaths were climbing again, especially in open states like Florida, which suffered one of the highest rates of Covid-19 hospitalizations, and low-vaccinated states.

Doctors and nurses who thought they had put the worst of the pandemic behind them were once again scrambling to treat severely ill Covid-19 patients in intensive-care units. By the end of August, the United States was averaging about fifteen hundred Covid-19 deaths a day, versus fewer than two hundred in early July. Nearly all of the patients who ended up in the ICU were unvaccinated.

Some vaccinated people were beginning to test positive for Covid-19, too — commonly called “breakthrough” cases—and a few progressed to severe cases. The vaccines, after all, weren’t 100 percent effective in the clinical trials, either. A small percentage of vaccinated people in the studies got sick with Covid. But it was becoming clear that the vaccines weren’t entirely blocking transmission of the virus or stopping asymptomatic infections, as initially hoped.

Vaccinated people were better protected than unvaccinated people, even when Delta took over. In states like Massachusetts, less than 1 percent of fully vaccinated people in the state had tested positive for Covid-19 by the fall of 2021. Other analysis showed that people who weren’t fully vaccinated were nearly five times more likely to get infected, ten times more likely to be hospitalized and eleven times more likely to die from Covid than fully vaccinated people.

But Delta reminded people, or made them understand for the first time, that the vaccines weren’t bullet-proof. New indoor mask mandates were imposed, including at schools, where educators just weeks earlier had been eager for the first normal back-to-school season in two years. No vaccine was yet authorized for children under twelve (both Moderna and Pfizer were studying that population), raising concerns that Delta would spread rapidly among them as they gathered in classrooms.

By the end of the summer, people wondered if the pandemic would ever end. Some started talking about the coronavirus as endemic, not a pandemic.

And a big slice of America was still saying “No thanks” to the vaccine.

A Food and Drug Administration official said COVID-19 vaccine makers won't need to carry out fresh clinical trials to receive approval for booster shots they're updating for newer Omicron variants. Dr. Peter Marks, who runs the FDA's Center for Biologics Evaluation and Research, told Reuters the agency will use data from trials for vaccines that target BA.1 — the Omicron variant that caused a huge surge in infections last winter — as well as manufacturing data to assess the vaccines. Safety data and preclinical data from animal studies may also be used. 

This week, the FDA asked vaccine manufacturers to modify booster shots to target the Omicron BA.4 and BA.5 variants in addition to the original strain of the virus. The agency hopes the updated boosters will be ready by the fall. "It's going to be really critical as we move into this fall where we've seen this evolution into BA.4/5, where we could see further evolution, to try to get as many people boosted as we can," Marks said.

The Centers for Disease Control and Prevention says BA.1 isn't circulating in the US anymore, but BA.4 and BA.5 now account for over 52 percent of COVID-19 infections in the country. Combined, they made up just 0.5 percent of cases in the US at the end of April.

Pfizer and Moderna this week released clinical trial data which suggests versions of their shots that target BA.1 offered a stronger immune response than the initial COVID-19 vaccines. Those boosters did not perform quite as well against BA.4 and BA.5. However, the data showed that the immune response was still robust.

The Food and Drug Administration has asked COVID-19 vaccine makers to update booster shots to tackle newer omicron variants that are on the rise. It says the manufacturers should add a spike protein component to shots to target the omicron BA.4 and BA.5 variants in addition to the original strain.

An "overwhelming majority" of the FDA's advisory committee voted this week in favor of updating shots with an omicron component, in the hopes of starting to use those modified boosters in the fall. The advisory is only for booster shots and not primary inoculations.

Vaccine makers are essentially playing whack-a-mole with the various strains of COVID-19. Pfizer and Moderna have created versions of their vaccines that target BA.1, the omicron variant that caused a significant upswing in COVID-19 cases during the winter.

However, that strain isn't circulating in the US anymore, according to the Centers for Disease Control and Prevention. Earlier this week, the CDC said BA.4 and BA.5 now account for over 52 percent of COVID-19 infections in the US. That figure is expected to rise in the coming weeks.

As CNBC notes, Pfizer and Moderna released clinical trial data this week showing that the current omicron shots performed better against BA.1 than the original versions of their vaccines in terms of offering a stronger immune response. While the immune response against BA.4 and BA.5 was still said to be robust, the omicron inoculations were less effective against those strains. It's unclear how long it will take vaccine makers to develop shots that take aim at BA.4 and BA.5.

"Vaccine manufacturers have already reported data from clinical trials with modified vaccines containing an omicron BA.1 component and we have advised them that they should submit these data to the FDA for our evaluation prior to any potential authorization of a modified vaccine containing an omicron BA.4/5 component," the FDA said. "Manufacturers will also be asked to begin clinical trials with modified vaccines containing an omicron BA.4/5 component, as these data will be of use as the pandemic further evolves."