‘Super-antibodies’ could curb COVID-19 and help avert future pandemics

 Companies are designing next-generation antibodies modeled on those taken from unique individuals whose immune systems can neutralize any COVID-19 variant—and related coronaviruses, too.

The US Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) in late May to sotrovimab, providing a new therapeutic weapon in the fight against SARS-CoV-2—and future coronaviruses with pandemic potential.

According to analysts and researchers alike, so-called super-antibodies such as sotrovimab should have an edge over first-generation monoclonal antibody (mAb) therapies for COVID-19 because of their broad neutralization capacity in the face of emerging virus variants. “Physicians aren’t going to sequence what version of the virus people have, so they’ll go for the antibodies that have the higher barrier to resistance or the ones that work on [known] variants,” says Phil Nadeau, an analyst at Cowen.

The antibody therapy from Vir Biotechnology and GlaxoSmithKline, a recombinant human immunoglobulin G1 mAb, is now the third mAb-based treatment marketed for individuals with mild-to-moderate COVID-19 who are at high risk for progression to severe disease. (Eli Lilly and Regeneron each have a two-mAb cocktail with EUAs for the same indication.) And although sales opportunities should diminish for all these products as vaccination rates increase worldwide, Nadeau anticipates there will be a sustained market for COVID-19 mAbs to help treat individuals who, for medical reasons, can’t mount an appropriate immune response to vaccination or, for whatever reason, elect not to get the shot.

According to his models, sotrovimab should capture around 10% of the $3 billion global COVID-19 mAb market this year, rising to 30% of the $1.67 billion market in 2022.

Other broadly cross-reactive mAbs could soon be jockeying for market share as well, as investment money flows in to rush some of the leading candidates through late-stage clinical development. In April, for example, Adagio Therapeutics raised $336 million (on top of the $130 million war chest it amassed last year) to bankroll large-scale trials of ADG20, an mAb now being evaluated for use as a therapy and for prevention. Startups such as Centivax, Corat Therapeutics, IDBiologics, Leyden Labs, Memo Therapeutics and SpikImm are working on next-generation mAbs for COVID-19 as well.

Sotrovimab traces its roots back to blood drawn in 2013 from an individual who had recovered from the 2003 outbreak of severe acute respiratory syndrome (SARS); ADG20 has a similar origin story, while most other clinical-stage mAbs were inspired by antibodies found in more recent COVID-19 survivors. Many companies then optimized their mAbs by extending half-lives, enhancing neutralizing activity, manipulating constant region (Fc)-mediated effector functions, or applying some combination of these engineering strategies.

To stay relevant, all mAb developers need to account for the wildcard that is viral evolution, says Jane Osbourn, CSO of Alchemab and former head of the UK BioIndustry Association’s antibody taskforce on COVID-19. “A number of the clinical candidates out there are falling over against the [emerging] variants,” she says. “So, as a community, we should really be taking the time to think through how you stay ahead of the game in terms of that mutational drift.”

In lab studies, sotrovimab seems to maintain its neutralization capacity against all circulating variants of concern, including some of the most worrying versions of the virus, first identified in South Africa, Brazil and India. Several of the leading phase 3 mAb candidates—including Adagio’s ADG20, AstraZeneca’s AZD7442 and Brii Biosciences’ BRII-196 and BRII-198—do as well. But Eli Lilly’s two-mAb cocktail is hobbled by escape mutations found in these variants, as is one of the agents, casirivimab, in Regeneron’s mAb combination. The other Regeneron agent, imdevimab, retains its activity, in large part because the mAb targets an epitope that does not overlap with that of its cocktail companion.

That non-redundancy offers some degree of protection against variant-mediated resistance, says Aeron Hurt, principal global medical science director for influenza and COVID-19 therapeutics at Roche, which partnered with Regeneron to handle manufacturing and distribution outside of the United States. “Single antibodies are vulnerable to single mutations,” Hurt says—whereas a cocktail of antibodies that bind at discrete sites provides “an extra insurance policy.”

But an even better variant evasion tactic, asserts Adagio CSO Laura Walker, is what her company and Vir have done: both organizations independently screened for ultra-rare broadly neutralizing mAbs that recognize highly conserved epitopes found across the entire family of SARS-like coronaviruses.

The scarcity of these antibodies limits the evolutionary selection pressure for escape mutations in nature, Walker points out. And because conserved residues typically serve essential protein functions, “the virus often can’t mutate those residues without suffering a fitness cost,” she says, “which means the barrier to escape is typically higher for these broadly neutralizing antibodies.”

“But antibodies are not merely things that bind to and neutralize a viral protein,” notes Vir CSO Skip Virgin. Through their Fc domain, mAbs also induce innate and adaptive immune responses that help destroy infected cells—and those Fc-mediated activities, Virgin says, “are fundamentally important for treatment of SARS and COVID-19.”

Mouse studies published in Cell, in the Journal of Experimental Medicine and as a preprint in recent months now support this idea. But last year, as the COVID-19 mAb race was just heating up, many companies—including AstraZeneca, Eli Lilly, Abpro and others—chose instead to dial down effector functions in their mAbs. They wanted to minimize the risk of antibody-dependent enhancement of viral infection, a phenomenon in which virus-specific antibodies can promote, rather than inhibit, disease.

This can be a real problem with certain pathogens, including the respiratory syncytial virus and the dengue virus, but Virgin and his colleagues realized early on that it did not seem to be an issue with SARS-CoV-2. So Vir doubled down on the need for strong Fc receptor binding. Not only did the company leave the effector functions intact for sotrovimab, but it also engineered its successor, the follow-on mAb VIR-7832, to have even greater Fc binding activity.

“The concept is to make the antibody vaccinal,” explains Virgin. “We’re trying to make the antibody so it not only protects the individual, but it also generates an immune response that outlasts it” through the generation of pathogen-specific CD4+ and CD8+ T cells responses. The Vir team joined forces last year with Jeffrey Ravetch’s lab at Rockefeller University in New York City to demonstrate the Fc engineering concept with an anti-influenza mAb tested in mice.

“These are predicted benefits. They haven’t been observed in people,” Virgin acknowledges, “but that’s why we’re taking the antibody forward.” VIR-7832 and sotrovimab—both of which possess an Fc mutation that confers extended half-life and enhances drug distribution to the lungs—are now part of a master protocol study taking place in the United Kingdom.

Adagio, for its part, has focused its engineering efforts largely on affinity optimization rather than Fc modifications. Although ADG20, like many other next-generation mAbs, does contain Fc changes that improve its circulation half-life, its most distinguishing selling point is the combination of potency and breadth that it offers.

“We took something from nature that was broad, but not very potent, and then improved the potency while maintaining the breath to essentially make a molecule that would never arise in nature,” explains Walker.

Walker and her colleagues started with a natural mAb made in response to a 2003 SARS infection. They then used yeast display technologies to introduce diversity into the parent clone, ultimately finding an offshoot with a handful of genetic changes that gave it 500-fold greater binding affinity to the SARS-CoV-2 spike protein and a 70-fold improvement in neutralization capacity—with no compromise in its breadth of activity across other SARS-related coronaviruses.

In phase 1 testing, clinicians found that a single dose of ADG20 yielded a similar level of virus-neutralizing activity in the blood as that seen among people vaccinated against COVID-19 with one of the marketed mRNA-based products. Pharmacokinetic profiling also indicated that the protection might last for up to a year. Two large global trials are ongoing.

ADG20, like some other late-stage candidates such as AZD7442, also offers the convenience of intramuscular injections—a formulation advantage that Janice Reichert, executive director of the non-profit Antibody Society, argues can be just as important as innovative mAb designs in the throes of a pandemic or other public health crisis. “Having both would be best, of course,” she adds. All the mAbs that already have EUAs must be given intravenously, although versions formulated for intramuscular or subcutaneous administration are now in clinical testing.

Some companies are beginning to explore inhaled delivery as well. Boehringer Ingelheim, for example, is evaluating both infused and inhaled versions of its phase 2 mAb before deciding which administration route to advance into pivotal testing. On 3 June, scientists from IGM Biosciences described promising mouse data on their nasally spritzed product, the immunoglobulin M mAb IGM-6286. And earlier this year, Leyden Labs launched with €40 million ($49 million) to support a portfolio of intranasal products that protect against respiratory viruses such as influenza and SARS-CoV-2.

According to Dinko Valerio, co-founder and executive chairman of Leyden Labs, the company’s nasal spray is designed to thwart viral replication at the site of infection. And because of its localized delivery, patients can get away with much lower doses than they would otherwise need for any systemically administered agent. “If you put it in the nose,” Valerio says, “you just need a tiny bit” of the product.

Whatever the mechanism of mAb delivery, the fact that so much development and therapeutic experimentation is happening today in response to COVID-19 should improve preparedness for the future. Not only are there now products like sotrovimab on the market that offer broad protection against a viral clade that could easily seed the next outbreak, but the engineering approaches being tried now to combat coronaviruses should help inform best practices for creating mAbs designed to thwart other viral families.

“It’s good for public health that all these strategies are being tested,” remarks James Crowe, director of the Vanderbilt Vaccine Center in Nashville, Tennessee. (A co-founder of IDBiologics, Crowe helped discover the mAbs that form the basis of two cocktail therapies now in clinical testing, AZD7442 from AstraZeneca and another one from Resilience with support from the US Department of Defense.) “It’s very exciting scientifically that COVID has allowed this many manufacturers to participate,” he says. “Every target is different, but you can typically learn some general principles.”

Change history

• 29 June 2021

  A Correction to this paper has been published: https://doi.org/10.1038/s41587-021-00997-2

• https://www.nature.com/articles/s41587-021-00980-x

Few Good COVID Antivirals, but That Could Be Changing

 COVID caseloads have plummeted in many areas with high vaccination rates. But as the number of people being infected daily worldwide still exceeds 400,000 and the highly contagious Delta variant of the virus spreads rapidly, treatment options are limited. Two of the current best available treatments, monoclonal antibodies and the drug remdesivir, are given by infusion. Patients only benefit during the first week or so of infection, when the virus is still present and replicating in the body. These medications are expensive and often unavailable outside of large teaching hospitals. In many instances, patients are treated too late, after the disease has already shifted to a more dangerous hyperinflammatory state.

Doctors want to give pills that infected people can take conveniently at home when symptoms first appear. Toward that end, the Biden administration announced in June that it would spend more than $3 billion on a program aimed at developing next-generation antiviral therapies—not just for COVID but also for other viruses that pose a future threat.

In an interview with Scientific American, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said he was cautiously optimistic that the new Antiviral Program for Pandemics (APP) would save lives and prevent surging hospitalizations. “It’s an ambitious program,” he said. “But if we can block the virus early on, then we can avoid the progression to advanced stages of the disease, which are so devastating to so many.”

Why is there still such a paucity of antivirals for COVID? Experts point to several factors. Antiviral research has been long neglected in general, and coronaviruses never garnered the sustained attention and funding that could have made more COVID treatments available sooner. “No one cared about coronaviruses,” says Timothy Sheahan, a virologist at the University of North Carolina at Chapel Hill. “Most of the coronaviruses that make people sick cause the common cold. And those that cause more severe disease were no longer considered a problem. The first SARS [severe acute respiratory syndrome] outbreak was over, and Middle East respiratory syndrome [MERS] wasn’t deemed a global threat.”

The COVID pandemic has now made new antiviral treatments a priority. But generating these therapies—especially direct-acting, orally administered drugs that inactivate viruses—is time-consuming. The reason monoclonal antibodies came along first is that scientists could simply follow the immune system’s lead and create synthetic versions of the natural antibodies that deflect the novel coronavirus, or SARS-CoV-2, from its host cell receptor in recovered patients. The goal of an antiviral pill is to stop the pathogen from replicating, but finding drugs that can do that without injuring the infected human cell is no easy task. Scientists start by screening thousands of compounds for their efficacy in targeting SARS-CoV-2 in cell culture. Promising candidates are then tested in animals—both to ensure that the drugs are not toxic and that they are not immediately destroyed in the body and reach tissues in the lungs and other organs in sufficient amounts. All this work takes place in high-level biosafety laboratories staffed by skilled workers, who are in short supply. “And then most of the compounds that work in cells ultimately fail in animal studies for lots of reasons,” says Sara Cherry, a microbiologist at the University of Pennsylvania’s Perelman School of Medicine. Cherry runs a biosafety lab at the university where researchers have so far screened 20,0000 compounds—including nearly every medication approved by the U.S. Food and Drug Administration—for anti-SARS-CoV-2 activity in isolated lung cells. Roughly 150 of these compounds have been selected for further evaluation in more complex lung models, “and then we’ll whittle down the top candidates for animal testing,” Cherry says.

Scientists at Emory University used this approach years ago to identify what is now the leading antiviral pill candidate for COVID: a drug called molnupiravir (also known as EIDD-2801) that was initially developed for influenza. Sheahan and other researchers, including virologists Mark Denison of Vanderbilt University Medical Center and Ralph Baric of the University of North Carolina at Chapel Hill, subsequently showed molnupiravir was effective against SARS-CoV-2 and other coronaviruses in human lung cells and infected mice. Molnupiravir has since been acquired by Merck and Ridgeback Biotherapeutics in Miami, and it is currently in clinical trials with patients experiencing mild to moderate COVID symptoms. A Merck spokesperson says that the company could file for an emergency use authorization for the drug in the U.S. later this year and in other countries in 2022.

Rachel Bender Ignacio, a physician-scientist at the Fred Hutchinson Cancer Research Center in Seattle, anticipates that the virus will develop less resistance against direct-acting small-molecule drugs such as molnupiravir than it has against monoclonal antibodies. Viruses are constantly mutating to avoid antibodies. Indeed, in June U.S. officials paused the distribution of two monoclonal antibodies developed by pharmaceutical company Eli Lilly after they stopped working against the newer COVID variants. By contrast, small molecules “target viral replication, which is a totally separate process from how their proteins interact with the immune system,” Bender Ignacio says. The viral replication machinery is “highly conserved,” meaning that it changes little over time or among different strains. According to Sheahan, a virus can only tolerate minimal damage to that machinery before replication goes awry.

Molnupiravir, which is in a class of drugs called nucleoside analogues, works by inserting itself into a newly forming viral RNA strand. The strand will then stop growing or become so heavily mutated that replication cannot continue. Scientists say molnupiravir and other direct-acting agents can also be combined in therapeutic cocktails, mirroring how drugs for viral diseases such as HIV and hepatitis C are given today. “You’re looking for drugs with different and complimentary mechanisms of action,” Sheahan says. “It’s extremely unlikely that a virus can figure out a way to get around two different drugs given at the same time.” Sheahan proposes that nucleoside analogues can, for instance, be combined with protease inhibitors, which target enzymes involved in viral replication. Along those lines, Pfizer currently has an oral protease inhibitor for COVID in early clinical trials. Known as PF-07321332, the drug “could be used at the at the first sign of infection,” a Pfizer spokesperson says.

Richard Whitley, a pediatric infectious disease specialist at the University of Alabama at Birmingham School of Medicine, says the success of the Biden administration’s new antiviral program hinges on its ability to carry promising drug candidates over a “valley of death” between basic discovery and human clinical trials. Many drugs perish in that in-between zone because pharmaceutical companies worry about potential losses. By “derisking” antiviral development with federal support, the APP will ideally help to alleviate those fears.

The Biden administration has already committed to purchasing 1.7 million courses of molnupiravir, should it be authorized for use. “Our investment in the APP follows the same strategy that allowed us to successfully develop drugs for HIV and hepatitis C,” Fauci said in his interview with Scientific American. In that case, “we had strong public-private partnerships with the pharmaceutical companies, as well as support for academic and industry partnerships aimed at finding new molecules.”

But even if successful antiviral pills materialize, Whitley says, getting them to patients during the critical first days of infection is by no means guaranteed. “Say you start feeling sick on a Saturday, and you don’t want to call your doctor,” he says. “By Monday, it might already be too late.”

Still, Whitley says he is encouraged by the sheer magnitude of the APP and its broader focus on other emerging infectious diseases. “It’s an unbelievably significant event that not only fuels the pump but generates action to come up with deliverable products,” he says. “The pharmaceutical industry can’t make enough profit to cover the costs of developing these drugs. The only way we’re going to get there is with the support of the federal government.”

https://www.scientificamerican.com/article/there-are-few-good-covid-antivirals-but-that-could-be-changing/

Covid vaccines for kids under 12 expected midwinter: FDA official

 Emergency authorization for Covid-19 vaccines in children under 12 could come in early to midwinter, a Food and Drug Administration official said Thursday, a move that could bring relief to many parents who have been unable to vaccinate their children. The agency hopes to then move quickly to full approval of the vaccine for this age group.

One sticking point for some families who remain hesitant, the official said, is that the vaccines currently in use are administered under emergency use authorization and have not been given full approval by the FDA. Full approval, if it comes quickly after the emergency round, could alleviate that concern.

Covid-19 vaccines have only been authorized for people ages 12 and up in the U.S., and none has received full approval yet.

Both Moderna and Pfizer-BioNTech launched trials of their Covid-19 vaccines for kids under 12 in March. Results are expected in the fall, and it will take FDA officials time to review the drug companies' applications.

The regulatory agency is asking for four to six months of safety follow-up data for kids under age 12, the FDA official said. Just two months of follow-up data was required for the clinical trials in adults.

That additional data could make the process of granting full approval easier. Six months of follow-up data is needed for what is known as a biologics license application, or BLA.

So far, only Pfizer-BioNTech has applied for full licensure of its vaccine for adults 18 and up. The FDA official said granting full approval for adults is the agency's highest priority.

Pfizer said in a statement to NBC News it anticipates results on its clinical trials in kids ages 5 to 11 sometime in September, and then could apply for emergency use authorization. "Data for kids 2 and under 5 could arrive soon after that," the company said, adding that results on kids ages 6 months up to 2 years may not be released until October or November.

Dr. Buddy Creech, one of the primary researchers for the Moderna KidCOVE clinical trials, which includes children as young as 6 months, predicted a rollout of pediatric data similar to Pfizer's.

"I can't imagine, except maybe for the 6- to 11-year-olds, that we're going to have too much data before the late fall," Creech, also a pediatric infectious disease expert and director of the Vanderbilt Vaccine Research Program at the Vanderbilt University Medical Center in Nashville, Tennessee, said.

Results on kids 5 years old and younger may take longer, he added. "There is still a lot of work left to be done."

A safe and effective vaccine for children is an important tool in stopping the spread of Covid-19, especially with the rapid rise of the more transmissible delta variant.

There is no indication that the variant is changing the virus to be more harmful to children. But its highly contagious nature means unvaccinated people, which includes all children under 12, are more vulnerable.

"Given that children are one of the groups that is unvaccinated, we will see more cases in children," said Dr. Richard Besser, a pediatrician and former acting director of the Centers for Disease Control and Prevention. "We will see more hospitalizations in children, and unfortunately we will see more deaths in children."

Besser, who is the current president of the Robert Wood Johnson Foundation, said he hopes the FDA will quickly move to full approval of the vaccines.

"Quite a number of people are saying that that will influence their decision to get vaccinated," he said.

Some pediatric infectious diseases doctors are not convinced full approval, rather than an EUA, would have much of an impact on vaccine hesitancy.

"In terms of how vaccines get approved, there isn't much of a functional difference" between emergency use authorization and full approval, said Dr. Sean O'Leary, vice chair of the Committee on Infectious Diseases for the American Academy of Pediatrics.

As of July 8, more than 4 million children had been diagnosed with Covid-19, representing 14.2 percent of all cases, according to the American Academy of Pediatrics. At least 335 children, ages 17 and younger, have died from Covid-19, according to the latest data from the CDC.

https://www.nbcnews.com/health/health-news/vaccines-kids-under-age-12-expected-mid-winter-fda-official-n1274057

No exit from Covid-19 pandemic without booster shots, vaccine developer says

 The world will not get the Covid-19 pandemic under control without using booster shots for messenger RNA vaccines, one of the key figures involved in the development of the Pfizer and BioNTech vaccine said Tuesday.

Ugur Sahin, co-founder and CEO of BioNTech, insisted booster shots are going to be necessary, despite caution from some experts.

“At the end of the day it really matters that we get this pandemic under control. And we will not get it under control without boosting. That’s my strong opinion,” Sahin said.

Sahin made the remarks during a panel session at the STAT Breakthrough Science Summit, where he was joined by Kathrin Jansen, head of vaccine research and development at Pfizer. Jansen said Pfizer’s decision to develop and test Covid-19 vaccine booster shots is being driven by data. “The booster situation is not about making money,” she said.

A large study of booster shots developed by the company will read out soon, Jansen added.

Pfizer triggered controversy last week — National Institutes of Health Director Francis Collins referred to it as “a dust-up’’ — when the company issued a statement suggesting booster shots will be needed to keep protection against the virus at high levels. The statement referred to data that have not yet been published.

The director-general of the World Health Organization, Tedros Adhanom Ghebreyesus, criticized the notion of giving residents of wealthy countries a third shot before health workers and older adults in many countries get their first Covid-19 jab. And Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said people are “jumping the gun” if they think booster shots are on the verge of being authorized.

Neither Jansen nor Sahin elaborated on the data that the companies say support their view that booster shots will be needed. Sahin said there is evidence of a slight decline in antibody levels in people four to six months after they were vaccinated. To date, there hasn’t been an indication that people who have been vaccinated are developing severe Covid infections, but Sahin said “we expect that we will also see some drop of protection against severe disease … a small drop.”

“Therefore our position is … that a booster shot could be helpful to restore immunity, full immunity, and thereby ensure we have a winter season which is not complicated by true infections in vaccinated people,” he said.

There is currently no sign that people in the United States who were vaccinated early in the country’s vaccine rollout are seeing their protection wane, Jay Butler, the deputy director for infectious diseases at the Centers for Disease Protection and Control, said earlier Tuesday.

“We’re not seeing evidence at this point in time that waning immunity is occurring among people who were vaccinated back last December or January and that they are at higher risk of breakthrough infections,” Butler said during a media briefing organized by the Infectious Diseases Society of America.

Jansen said part of the goal of the companies’ research on boosters — which includes studying the impact of giving people a third dose of vaccine that protects against one of the variants of concern — is to create a regulatory pathway for updating Covid vaccines if that becomes necessary.

Though she did not mention it, there is a regulatory pathway for updating influenza vaccines. Rather than requiring manufacturers to run large-scale clinical trials every time flu vaccines are tweaked to try to keep up with ever-changing viruses, the Food and Drug Administration allows manufacturers to update the viral targets through an expedited process referred to as a strain change. As long as the production process remains unaltered, manufacturers can swap out an old version of H1N1 flu, for instance, and include a strain that is currently causing disease.

In other remarks, Jansen voiced concern about Covid-19 vaccine uptake, saying the misinformation about vaccines that is prevalent on the internet is impeding progress toward getting enough people vaccinated to control the virus.

“I think it’s a huge issue for us, because we always will be behind the virus,” she said. “We cannot get ahead of it if large fractions of the population refuse to be vaccinated.”

Allowing the virus to continue to spread unchecked will give rise to additional variants, some which may be able to evade the protection of vaccines, Sahin and Jansen warned.

“As long as we allow the virus to have a breeding ground in unvaccinated people, we will force the virus to adapt, to mutate, to change, and it will be a disaster because we will not be able to get ahead of it,” Jansen said.

The two also talked about the challenges of developing a new vaccine in under a year. “In every vaccine development program you have enormous challenges. And the difference is that those challenges are over 10 years. Here we have the same challenges over nine months,” Jansen said with a laugh.

Asked what lies ahead for mRNA technology, after its enormously successful testing in the Covid pandemic, she said Pfizer wants to turn its focus to flu.

“We have aspirations to come up with a truly game-changing influenza vaccine that could actually far surpass the efficacy, potentially, of current vaccines,” she said. Existing flu vaccines aren’t adequately effective in elderly people, who are at high risk of developing severe illness if they contract the flu. But the Covid mRNA vaccines are highly effective in the elderly, she noted, which suggests the platform could be very useful for flu shots.

“It opens up a lot of possibilities in the infectious diseases space,” Jansen said.

https://www.statnews.com/2021/07/13/the-world-will-not-exit-covid-19-pandemic-without-booster-shots-vaccine-developer-says/

What Evidence Do We Need to Move Forward With COVID Boosters?

 On Monday, employees of Pfizer met with high level executives in the Biden administration to discuss the role of boosters -- a.k.a. a third vaccination with an mRNA vaccine for SARS-CoV-2. Some have speculated that, as with the first two doses, the emergency use authorization pathway will again be used to market boosters. With the rise of the Delta variant and others, enthusiasm in the media and the Twitter commentariat for boosters is growing. However, there are certain criteria that must be met before we jump on the booster bandwagon. Some of these criteria apply at home, and others apply abroad.

Abroad

As a general rule, if your goal is to avoid variants -- or mutated versions of a virus -- you want the virus to replicate less. When it comes to variants, it doesn't matter where the virus does the replicating. In a globally connected world, it is only a matter of time before an advantageous mutation finds its way to all parts of the world. As such, we in the U.S., are only as safe as the least safe place in the world.

What this means is that before we shift our manufacturing capacity to develop boosters for the current variants, we must make a real effort to ensure that the vaccines we do have get distributed to the greatest number of global citizens who will take them. I argued in April that, practically, this means that children in high income nations should be vaccinated after older citizens globally – this same logic extends to boosters.

Before we shift our manufacturing to booster production, we should make sure that we have manufactured adequate supplies of the original vaccine for all global citizens. Moreover, we need to put effort toward solving the last mile problem: how to deliver very cold mRNA vaccines to places in the world where it is difficult to deliver and keep things very cold. This is a technological problem well within our scope.

Efforts to manufacture and deliver vaccine boosters to already vaccinated individuals in high-income nations cannot take priority and must not interfere with efforts to vaccinate at-risk individuals around the world. In fact, it is in our best interest to vaccinate those at-risk first. If we pursue boosters in the U.S. without helping the rest of the world, then we might as well get ready for the fourth, fifth, and sixth boosters. We will watch rising death tolls around the world, while worrying that yet new variants may end up on our shores.

At Home

Here in the U.S., there are also metrics that need to be met before we contemplate widespread dosing of hundreds of millions of people with booster shots. Specifically: show me the data! I have no doubt that a third mRNA shot will lead to higher neutralizing antibody titers. For that matter, I would guess six shots would outperform three on that metric. But the burden of evidence to accept boosters is not simply a change in antibody titer -- or even demonstration of improved titers for rare variants.

We must show that boosters improve clinical endpoints before we ask Americans to roll up their sleeves again. A large randomized trial of vaccinated individuals powered for reduction in symptomatic SARS-CoV-2 or (better yet) severe COVID-19 is needed to justify the harms and inconvenience of boosters. If such a trial simply cannot be powered, or takes a very long time, due to the sparsity of serious infection in the U.S., then the argument for emergency use authorization is inherently flawed. When there's too little disease to run the definitive trial, you are, by definition, no longer in an emergency. One way to solve this problem might be to deliver boosters only in elderly individuals or those who are immunocompromised. Here, a trial measuring COVID-19 outcomes may be possible.

Alternatively, a case for boosters can be made if evidence shows that boosters alter the epidemic course for a nation or the globe. Here, too, antibody titers are insufficient. Moreover, ironically, clinical trials would have to be larger and more complex to demonstrate this. For these reasons, I think the burden is on vaccine manufacturers to show that severe COVID-19 outcomes are averted.

Finally, we need to consider the second order effects of boosters. Would we gain more if we took the effort that would go into boosters and instead used it to try to increase vaccination uptake by those who are reluctant to get their first and second dose? Is the mere fact that news outlets and companies report the possible need for boosters a disincentive to be vaccinated? A skeptical person may now no longer see SARS-CoV-2 vaccines as the path out of the pandemic, but a recurring, and possibly someday yearly obligation that they may prefer to avoid altogether. We can't ignore the potential impact of discussing boosters on vaccine acceptance.

Boosters Without Data

If we accept boosters in the U.S. while the rest of the world remains unvaccinated, and if we authorize them based on inevitable improved laboratory titers without clinical outcomes, we run the risk of creating a medical industrial perpetual motion machine.

We will continue to breed new variants outside of our nation, which will lead to calls for yet more boosters, and we will continue to get new boosters without any evidence they are necessary (i.e., lower severe COVID-19 outcomes). Our arms will ache, our hearts will hurt, our wallets will be empty, and so too will our brains, as we will have abandoned all principles of evidence-based medicine.

Vinay Prasad, MD, MPH, is a hematologist-oncologist and associate professor of medicine at the University of California San Francisco, and author of Malignant: How Bad Policy and Bad Evidence Harm People With Cancer.

https://www.medpagetoday.com/opinion/vinay-prasad/93565

'Acceptable' Lead in Drinking Water May Still Be Harmful With CKD

 Lead levels in drinking water that are permissible by the Environmental Protection Agency (EPA) may be harmful to patients with kidney disease, a new study suggested.

In about 600,000 people who started dialysis in the U.S. from 2005 to 2017, each 0.01 mg/L increase of lead in drinking water was associated with significantly lower hemoglobin concentrations (0.02 g/dL, 95% CI 0.01-0.02) and an increased use of erythropoietin-stimulating agents, commonly used to treat anemia (0.4%, 95% CI 0.2%-0.6%), reported John Danziger, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School in Boston, and colleagues.

As shown in the team's study online in the Journal of the American Society of Nephrology, the associations were observed at lead levels below the EPA's threshold (0.015 mg/L) that mandates regulatory action. In addition, racial inequities were observed, with significantly higher levels of lead in the drinking water of Black versus white patients.

"Our findings suggest that for those with kidney disease, there is no safe amount of lead in drinking water," the researchers wrote. "While water has generally been considered a minor cause of lead toxicity, increased absorption and decreased excretion in those with kidney disease confer an exaggerated susceptibility."

Children are at increased risk from lead exposure, and the complications of chronic kidney disease (CKD) confer similar susceptibility, the investigators explained. Metabolic conditions prevalent in CKD, such as hypocalcemia, iron deficiency, and malnutrition, increase the proportion of lead absorbed across the gastrointestinal tract. In addition, patients with CKD excrete lead less effectively, resulting in circulating levels that are much higher than in individuals with normal renal function.

In addition to its neurological, cardiovascular, and endocrine effects, lead can also cause significant hematological problems, the researchers noted. Studies have shown that lead interferes with heme biosynthesis, increases red cell destruction, and reduces gastrointestinal iron absorption, and lead toxicity has been linked with lower hemoglobin levels.

The EPA posted measures that individuals can take to reduce lead in their drinking water. These include using only cold water for drinking and cooking, running water for a period of time before drinking to help flush away any lead, and cleaning faucet aerators on a regular basis.

Danziger's group analyzed data on 597,968 CKD patients from the U.S Renal Data System, identifying the city of residence for each individual. The researchers assessed water quality for each patient using the EPA's Safe Drinking Water Information System, which includes information on lead testing reports for all public community water systems in the U.S. The team calculated the average lead levels in the water for the 5 years preceding dialysis for each patient.

The main outcome measures were hemoglobin concentrations, recorded up to 45 days before patients started dialysis, and use of erythropoietin-stimulating agents. The analysis adjusted for covariates including age, sex, race, body-mass index, estimated glomerular filtration rate, insurance and employment status, diabetes, heart failure, hypertension, cancer, and tobacco use.

The researchers said the findings were similar when the team focused on 208,912 patients with data from the first month of dialysis therapy. Each 0.01 mg/L higher lead concentration was associated with lower hemoglobin (0.05 g/dL, 95% CI 0.04-0.06) and increased use of erythropoietin-stimulating agents (0.3%, 95% CI -0.1% to 0.6%).

The study also found disparities in water quality when examined by race. Although the mean concentrations of lead in water decreased overall during 2005 to 2017, the rate of decrease was slower for Black compared with white patients (0.0001 vs 0.0002 mg/L per year, P<0.001).

"Our findings raise broader concerns about the aging water system infrastructure in the United States," Danziger and co-authors said. "The full extent of lead contamination is unknown, in part due to large numbers of lead lines that remain in service and older household plumbing. In addition, since federal regulations require water systems to non-randomly sample a small proportion of households and report only the 90th percentile of those values, there is no nationally representative measure of water quality at the household level. Accordingly, without accurate estimation of individual levels of exposure, further research is greatly hampered."

Study limitations, the team said, included that alternate sources of drinking water, such as bottled water or filtered water, were not assessed, that calculating the lead exposure of individuals who lived in areas serviced by multiple water systems was difficult, and that the analysis did not take into account other potential source of lead exposure.

Disclosures

No funding sources for the study were noted.

Danziger reported financial relationships with NxStage Boston South Dialysis Unit; several co-authors noted disclosures.

Primary Source

Journal of the American Society of Nephrology

Source Reference: Danzinger J, et al "Associations of lead concentrations in drinking water with hemoglobin concentrations and erythropoietin stimulating agent use among patients with advanced chronic kidney disease" J Am Soc Nephrol 2021; DOI: 10.1681/ASN.2020091281.

https://www.medpagetoday.com/nephrology/esrd/93588

FDA Clears Dexcom Real-Time APIs for Third-Party Apps and Devices

 DexCom, Inc. (NASDAQ:DXCM), the global leader in real-time continuous glucose monitoring for people with diabetes, announced today U.S. Food and Drug Administration (FDA) clearance of the Dexcom Partner Web APIs, enabling invited third-party developers to integrate real-time CGM data into their digital health apps and devices.

“FDA clearance of our real-time APIs further solidifies Dexcom as the leader in interoperable CGM, giving Dexcom users even more choice in how they view and interact with their glucose data,” said Jake Leach, chief technology officer at Dexcom. “The new APIs will help seamlessly integrate the power of real-time Dexcom CGM data into some of the leading diabetes and digital health solutions.”

Several prominent diabetes and digital health companies have been invited to access the real-time APIs and are already in the testing and development phase, including Garmin® and Teladoc Health’s Livongo® for Diabetes.

“Garmin welcomes the opportunity to bring Dexcom CGM data to runners, cyclists and everyday users who rely on the technology 24/7 to proactively manage their diabetes,” said Joe Schrick, vice president of fitness at Garmin. “We are proud to be part of this integration that will allow users a secondary way to quickly and discreetly view estimated glucose levels and trends right from their smartwatch at any time.”

https://www.businesswire.com/news/home/20210715006049/en/FDA-Clears-Dexcom-Real-Time-APIs-for-Third-Party-Apps-and-Devices