Centessa claims a place in the antitrypsin deficiency pipeline

 Vertex lost $6bn in market cap in June after failing in its second attempt in alpha-1 antitrypsin deficiency. Meanwhile, Arrowhead has more than doubled in value, to $6.7bn, since its RNAi approach to the rare disease first showed promise.

There is always more than one driver behind a company’s valuation, of course, but these two examples help illustrate the substantial potential that investors see in a successful AATD treatment. There are only a handful of projects in clinical development, and Arrowhead remains in pole position, though approaching readouts from the likes of Mereo and Inhibrx could firm up the pipeline.

Centessa claimed to join that queue yesterday with the first look at clinical data on its phase 1 project ZF874. A liver toxicity signal means that investors remain to be convinced, however, and for now the biggest bets are being placed on more advanced assets. 

Current market

AATD is an inherited condition causing no or very low levels of a protective enzyme inhibitor, alpha 1 antitrypsin. In its natural form AAT, which is made in the liver, protects the lungs from damage. This means that AATD patients, particularly those who inherit two copies of the malfunctioning gene, are at heightened risk of developing lung diseases like emphysema.

In the liver, mutated or misfolded versions of AAT, sometimes called Z-AAT, build up, causing progressive damage and in rare cases requiring liver transplant. There are no specific treatments available for liver manifestations, although AAT augmentation therapy has been developed for those with severe lung disease.

That treatment involves harvesting normal AAT from blood plasma for infusion, though its benefits have been long debated, and it is not available in all countries. This has not hindered a billion-dollar market, however; it is worth noting that AAT augmentation products are very costly.

Grifols is the dominant player here thanks to a product it acquired with the US biotech Talecris a decade ago; Takeda has a presence thanks to its Shire purchase, which it in turn gained it via Baxter. This explains the Japanese pharma company’s ongoing interest, which last year included cornering certain rights to Arrowhead’s project for $300m up front.

It seems that, should new approaches to AATD make it to market, Grifols has the most to lose.

 Prolastin-C (Grifols): $857m

In terms of the pipeline, RNAi approaches are the most advanced, although these are primarily directed at the liver problems caused by AATD. Arrowhead’s ARO-AAT is considered most promising for now, based on small cuts of data that have been released this year from an ongoing, open-label phase 2 study.

The latest update will emerge at the AASLD meeting this coming weekend. The project, also called TAK-999, works by knocking down production of the mutated Z-AAT protein in the liver. Like most work in this space the focus here is on patients with a homozygous PiZZ mutation, who are most likely to develop severe complications of AATD.

The newly released AASLD abstract describes mean reductions of Z-AAT in the liver of 80-89%, over two cohorts of 16 patients in total, measured at 24 and 48 weeks. Signals of improving liver function and fibrosis have also been seen.

Some analysts reckon ARO-AAT could reach the US in 2022. A more rigorous phase 2 trial called Sequoia is fully enrolled, and should also start generating data next year; how quickly the FDA is prepared to move here is a big question for Arrowhead investors.

Coming behind is Dicerna’s similar RNAi therapy belcesiran, though so far only early results in 18 patients have been reported. These were promising, however, and a larger phase 2 trial, Estrella, has already begun. Alnylam has an option over ex-US rights but, unless a clear safety or efficacy advantage is seen, Dicerna needs to bring on a larger partner if belcesiran is to be considered real competition to Takeda and Arrowhead.

The AATD pipeline
Project	Company	Mechanism	Details
Phase II
TAK-999	Arrowhead/Takeda	RNAi therapeutic	Ph2 Sequoia fully recruited; awaiting plans for pivotal development/filing
Belcesiran	Dicerna (Alnylam option)	RNAi therapeutic	Ph2 Estrella study recruiting
Alvelestat	Mereo (from Astrazeneca)	Neutrophil elastase inhibitor	Ph2 data due by YE 2021 (targeting lung manifestations only)
Phase I
INBRX-101	Inhibrx	Recombinant AAT fusion protein	Ph1 data reported Oct 2021; next update expected H1 2022
ZF874	Centessa	Small-molecule AAT inhibitor	Initial ph1 data reported Nov 2021
Preclinical
AAT gene therapy	Intellia Therapeutics	Crispr/Cas-9 gene therapy	Preclinical work ongoing
AAT research programme	Vertex Pharmaceuticals	AAT correctors	Next-gen programmes to enter clinic in 2022
APB-101	Apic Bio	AAT gene therapy	IND enabling studies ongoing
KB408	Krystal Biotech	Gene therapy	Preclinical data presented Oct 2021
Source: Evaluate Pharma & company statements.

The other mid-stage contender is Mereo, which is aiming at patients with AATD lung disease. Its project, alvelestat, is proposed to work by inhibiting the lung-damaging neutrophil elastase enzyme, a role normally played by AAT.

A phase 2 trial that should yield data before the end of the year primarily measures reductions in desmosine, a biomarker of neutrophil elastase activity. A larger phase 3 trial looking at harder endpoints is a likely next step.

Back further in the pipeline are Inhibrx and Centessa, both of which claim to have the solution for both liver and lung manifestations of AATD.

Centessa

Lying behind Centessa’s efforts is a belief that the disease can be treated by prompting the faulty AAT protein to fold correctly. ZF874 is a pharmaceutical chaperone that, as the company describes it, acts as a molecular patch. Clinical proof of mechanism was claimed yesterday from data in three patients – levels of functional AAT returned to normal in the two who received ZF874.

A toxicity signal in one patient removed the shine, however, and the company’s insistence that a way forward could be found by changing the dosing schedule failed to impress. Centessa’s shares dropped 19% on the update. 

Finally, Inhibrx is pursuing arguably the most straightforward approach with its recombinant AAT-Fc fusion protein, INBRX-101. This could offer a more convenient and cost effective option over AAT augmentation therapy and, according to Inhibrx, complement RNAi approaches.

Shares in the company have advanced 68% since the first look at phase 1 data were released in October. The next update, which will concern a larger patient cohort, is due in the first half of 2022; the attention of bigger players already present in AATD has presumably already been piqued.

That will likely include CSL and Grifols. True, several gene therapies are in preclinical development, but it is easy to understand how INBRX-101 might feel like a surer bet for those with market share to lose.

https://www.evaluate.com/vantage/articles/news/trial-results/centessa-claims-place-antitrypsin-deficiency-pipeline

Nearly half of recent COVID-19 cases in Seoul breakthrough infections: city gov't

 Nearly half of all recent COVID-19 cases in Seoul were breakthrough infections, a Seoul city official said Tuesday.

"Of the 646 new cases confirmed in Seoul on Sunday, 49.4 percent, or 319 cases, were breakthrough cases," Park Yoo-mi, a disease control official at the Seoul metropolitan government, said in a briefing.

"The rate of breakthrough infections in Seoul is higher than the nationwide average," she noted.

According to the city government, Seoul has recorded 12,663 breakthrough infections so far.

Of them, 5,164 cases involved those who were inoculated with the AstraZeneca vaccine, 4,818 with the Pfizer vaccine and 2,030 with the Janssen vaccine. The rest received Moderna or other kinds of COVID-19 vaccines.

The official advised senior citizens and those with underlying diseases, for whom a vaccine booster shot is currently available, to receive the additional dose.

As of Tuesday, 76.7 percent, or about 7.28 million, of all residents in Seoul have been fully vaccinated against COVID-19, the city government said.

https://www.koreatimes.co.kr/www/nation/2021/11/119_318072.html

Delta variant, AY.4.2, has been spotted in 8 states

 A potentially faster-spreading "sub-lineage" of the coronavirus Delta variant named AY.4.2 has been spotted by labs in at least 8 states, and health authorities in the United Kingdom say they are investigating a growing share of cases from this strain of the virus.

Labs in California, Florida, Maryland, Massachusetts, Nevada, North Carolina, Rhode Island and Washington state, plus the District of Columbia, have so far spotted at least one case of AY.4.2.

While it may spread somewhat faster, health authorities have not found evidence of more severe illness caused by the variant, and they say current vaccines remain effective against it.

The sub-lineage has remained a small fraction of circulating cases in the U.S. for several weeks, but American health officials say they are already ramping up efforts to study the new Delta variant descendant. 

"We have teams that are constantly reviewing the genetic sequence data and looking for blips, an increase in a certain proportion or just something that's completely new," says Dr. Summer Galloway, executive secretary of the U.S. government's SARS-CoV-2 Interagency Group. 

Galloway, who also serves as policy lead on the CDC's laboratory and testing task force, said U.S. labs began preparing last month to prioritize tests to assess whether AY.4.2 can evade antibodies from vaccinated Americans, or from currently authorized monoclonal antibody treatments for the virus.

That process can take up to four weeks, Galloway said, across several laboratories that will run tests with harmless "pseudoviruses" designed to impersonate the variant's characteristic mutations.

Scientists have already turned up worrying combinations of mutations in other sub-lineages of Delta called AY.1 and AY.2, which like AY.4.2 have also sometimes been interchangeably called "Delta plus" variants. 

Last month, the Biden administration temporarily halted distribution of a monoclonal antibody treatment in Hawaii after estimated cases of AY.1 climbed up to 7.7% in the state. The Food and Drug Administration said lab experiments with AY.1 suggested it was "unlikely" the drug would be effective against the variant.

The state has since resumed use of the antibody treatment, after AY.1 dropped below 5% in Hawaii. Nationwide, AY.1 has hovered around 0.1% of cases.

"Right now, I think there's not a lot that we know. But in terms of the risk that it poses to public health, the prevalence is very low in the U.S. and we don't really anticipate that the substitutions [of AY.4.2] are going to have a significant impact on either the effectiveness of our vaccines or its susceptibility to monoclonal antibody treatments," said Galloway.

In the U.K., AY.4.2 has climbed to more than 11% of cases of the Delta variant. Health officials there say the variant does not appear to have led to a "significant reduction" in vaccine effectiveness or an uptick in hospitalizations, but it could be spreading faster because of "slightly increased biological transmissibility." 

"Estimated growth rates remain slightly higher for AY.4.2 than for Delta, and the household secondary attack rate is higher for AY.4.2 cases than for other Delta cases," said a report published Friday by the U.K. Health Security Agency.

The Centers for Disease Control and Prevention estimates that AY.4.2 has made up less than 0.05% of circulating cases in the U.S. for several weeks, according to an agency spokesperson. Grouped together, CDC estimates that the Delta variant and its sub-lineages has been virtually 100% of cases in the U.S. for months.

"Even based on the data in the U.K., if you look at the transmission advantage, it looks smaller. It's not like Delta, which as soon as they came in, it was almost a 50[%] to 60% advantage over all previous lineages," says Dr. Karthik Gangavarapu, a postdoctoral researcher at UCLA's Suchard group.

Gangavarapu was part of the team to lead Scripps Research's variant tracking effort at Outbreak.info, which has tracked variants like AY.4.2 as they have emerged in an international database of "sequenced" viruses maintained by a group called the GISAID Initiative.

"It could have a slight transmission advantage, but it could also have other factors that are important. For example, how is the population immunity in a given location? What is the vaccination rate? Those may have some sort of impact on how the variant is spreading," said Gangavarapu. 

The largest share of circulating virus in the U.S. remains closely related to the original Delta variant, among samples reported to GISAID. Scientists have speculated that the next major variant of concern could emerge as a mutation from the Delta variant, though Gangavarapu cautioned that highly-contagious strains have arisen largely independently from one another. 

Delta variant sub-lineages like AY.25, AY.3, and AY.44 also currently make up large U.S. proportions of cases, though not necessarily because they have an advantage over their siblings. 

Outbreak.info had previously counted AY.4.2 sightings in at least 35 states. However, Gangavarapu said a bug in the "Pangolin" system used to generate reports of variants had resulted in some false positives for the sub-lineage showing up in some tallies.

New sub-lineages are frequently re-categorized by scientists to "help researchers track the virus" clustered in certain regions, even when they sport mutations that end up having no meaningful impact on the public health risk of the variant.

"Probably over the next month or so we will get more data to actually see if there is the same sort of increase in prevalence that we see in the U.K. in the U.S. as of now," says Gangavarapu.

https://www.cbsnews.com/news/covid-delta-plus-variant-ay-4-2-states/

Who Are the Scientists Behind the COVID-19 Vaccines?

 There's the slick, turtleneck-loving CEO who's really good at raising cash for his company that has yet to release any data. There's the workaholic power couple focused on curing cancer. There's the researcher who co-invented a recombinant DNA technology but stays at a small biotech that's limping along.

All of these characters are the unlikely heroes who helped bring COVID-19 vaccines into the world, and their personalities are brought to life by Wall Street Journal reporter Greg Zuckerman in his new book, A Shot to Save the World: The Inside Story of the Life-or-Death Race for a COVID-19 Vaccine.

A lot went wrong in the race to develop a COVID-19 vaccine, but Zuckerman calls his book the story of what went right. He details the long and winding road of scientific advances that laid the groundwork for the vaccines, as well as the researchers, executives, and government officials who made it all happen.

Zuckerman spoke with MedPage Today about his new book by phone. The following is an edited transcript of that conversation.

What's missing from other accounts of the scientists and executives who made COVID vaccines a reality?

Zuckerman: We're all aware of the vaccines, but it struck me that the full story of how they were developed wasn't understood. What's important to understand is that there were a series of small breakthroughs over the years. I think some people are aware of Katalin Karikó and her work. Maybe some people are aware of Derrick Rossi and his work. But it was almost like a relay race. They ran strong races and they contributed a lot, but in some ways, they just sort of passed the baton.

It was my suspicion that there were breakthroughs that no one was aware of behind the scenes, so I wanted to shed some light on those. People like Kerry Benenato at Moderna. No one's ever really heard of her and she never gets much publicity. She's not a senior scientist. Yet she played a really important role [in modifying the lipid nanoparticle delivery system in order to diminish unwanted side effects of mRNA delivery].

How was it getting access to those people, in addition to the big names?

Zuckerman: Some were easier to speak with than others. Government and academic scientists are much easier. That's part of why they've gotten so much attention. There's a reason why most writers talk about Barney Graham or Kizzmekia Corbett. Academics and government scientists are usually easier to access, and as a result they get a lot of the limelight.

They clearly deserve the credit, but it takes some digging to figure out who are the young scientists or mid-level scientists within Moderna who contributed a lot.

For instance, I was struck by Jason Schrum, the early Moderna scientist who didn't even stay there that long. He was their first employee. He's the one who came up with ... the actual modification [to the mRNA molecule itself that is currently used in Moderna's vaccine].

That modification is the one that BioNTech uses also. It's not the one from Karikó and [Drew] Weissman. They're really important and they're pioneers, and I'm not sure we would have these vaccines without them. But I also don't know if we would have them without Jason's work.

This book gets at the personalities behind the science. Who are some of the most interesting ones?

Zuckerman: I don't think enough attention has been paid to the Chinese scientist who was struggling with whether to share the genetic sequence [of SARS-CoV-2] in early January 2020, Zhang Yongzhen. The guy's a hero. He risked so much. The Chinese did share the genetic sequence subsequently, like a day later, but I'm not sure they would have done it without him. I think he doesn't get enough credit.

Juan Andres, the head of manufacturing at Moderna, is one of my favorites. Very early on, he's freaking out [about COVID-19] and his family thinks he's nuts.

He also encapsulates this theme of how a lot of Moderna people are just emotionally shot from the past year. I don't think people appreciate that. We all think they're focused on the stock price and how wealthy they are, and that they're not giving enough vaccines for the rest of the world. There are reasons to criticize that. But they've never had a partner and I don't think that's been emphasized enough. They tried to get Merck on board, and they couldn't, so they've had to go all out over the past year. There are people who are just killing themselves working so hard.

Yet Juan Andres doesn't feel like he's done enough. I'm not saying they're perfect human beings and I'm sure they want to get wealthy as much as the next guy. But there are a lot of really caring people who really do seem to want to do good for the world.

Novavax's first big product was an estrogen cream that was done in by side effects seen with hormone replacement therapy in the early 2000s. The company has almost made a comeback but they're not quite there yet. What happened?

Zuckerman: I found the Novavax story just fascinating. We dismiss companies, dozens and dozens of them, whose stock prices are $5 a share. They say they're making progress even though there's no proof, so we tend to dismiss them.

What I've learned is that there are credible, serious scientists within these companies, including Novavax. They're just plugging away. They're resilient, they're stubborn. Maybe they're deluding themselves, or maybe they are making slow progress.

A lot of them could have left, like Gale Smith [who developed the insect baculovirus system used to make proteins for recombinant DNA products]. He could have worked elsewhere and done well. Yet these people just liked the work. They believed in their approach. Sure, maybe nine times out of 10 it won't work out, but there's a lesson in having respect for the bench scientists at the company that's selling at under $5 a share.

Novavax hasn't quite succeeded yet. There's that Politico story from last week. ... They had to sell their manufacturing assets right before 2020. ... They got kicked out of the Emergent BioSolutions plant. The manufacturing is what hobbled them. I find them easy to root for.

Why was Katalin Karikó, now of BioNTech, treated so terribly for most of her academic career?

Zuckerman: Karikó was treated as a second-class citizen at the University of Pennsylvania for too many years. ... She was up against all kinds of skepticism and career setbacks, and she just persisted and believed.

She illustrates a larger theme that for decades the conventional wisdom was that mRNA sure would be a great molecule to work with, but there's no way anyone should waste their time on it. It's hard to handle, it's unstable. You can't get it where it needs to go in the cell. The skepticism about Karikó reflects just the broader skepticism about mRNA, how the conventional wisdom can be so wrong, and how it takes some really determined, innovative scientists to overcome it.

It's interesting that Pfizer almost didn't go with the full spike protein for their vaccine. Would things have been different for that vaccine if they had chosen something else?

Zuckerman: I asked them, and they weren't sure themselves. It would have been great if I could have said, you know, that change had saved the day. It's not clear what would have happened. Truth be told, COVID-19 isn't as much of a challenge relative to other diseases. So maybe it would have been fine.

But it is fascinating that so late in the game, they were still debating that. Maybe you do have to give Pfizer a lot of credit for putting its foot down and saying, alright we have to make a decision here. We're taking too long and we need to speed things up. So maybe that was the important role they played.

Why wasn't Moderna the most likely candidate to respond to the global challenge of COVID-19?

Zuckerman: Among my colleagues in journalism, but also in the world of science too, we have a rearview mirror, and everyone was scarred by the Elizabeth Holmes/Theranos experience. People didn't want to be burned again, so we all looked for the next Theranos.

No one really was sure it was Moderna, but they raised suspicions, and for good reason. They weren't very transparent. They didn't share their work. They raised money, and often it was from these kinds of "tourist" investors who weren't really biotech investors and didn't have the greatest track record in this space -- sovereign wealth funds, people with maybe too much money.

[CEO Stéphane Bancel] raised so much money that it reminded people of Theranos and of Holmes. He never had people outright accusing him of fraud. There was no evidence of that. But he did raise suspicions. There were reminders of Holmes. He had the black turtleneck, he wasn't a scientist. He's an MBA, he's an engineer. He's super smart and very, very smooth.

There was jealousy, too. There was envy in the industry. Here's Bancel raising all this money, so others are wondering, why can't I raise this money? There's got to be something wrong, he's got to be doing something fishy.

It's striking that these are the people who partly saved the world. They're not the most likely candidates. It wasn't Merck, GlaxoSmithKline, Sanofi, the vaccine giants. Johnson & Johnson is a household name but it's not a vaccine giant. Pfizer had closed down its infectious disease business, they weren't a vaccine giant.

The J&J/Janssen vaccine has a long history using its Ad26 adenoviral vector technology in vaccines. Why is that history important?

Zuckerman: The average vaccine skeptic is a little concerned that we produced these vaccines so quickly. They think there's got to be something rushed here, so it's unsafe. I understand that impulse. Part of the reason I wrote this book is to reassure them that these techniques, these approaches ... took years and years of hard work and honing and improving.

Dan Barouch dedicated his life to the Ad26 approach and also to an HIV vaccine. It hasn't worked for HIV.

There's been failure after failure with HIV. I kept hearing, we learned this back with HIV, and we learned that with HIV. We don't have a vaccine yet, but we learned so much, and it's paid off with COVID.

Ad26 was honed [in HIV research], as was the chimpanzee adenovirus approach that led to the Oxford/AstraZeneca vaccine. It's important to underscore that these vaccine approaches took years and years to develop, not a matter of months.

The book ends with BioNTech's Ugur Sahin saying that the work has just begun. What do you see as some of the most promising applications coming out of the COVID-19 work?

Zuckerman: I'm a journalist, I'm inherently a skeptic. I have seen biotech and other companies be over-optimistic too frequently. I know that, historically, there's a reason why there's such frustration with mRNA. My book is all about the success of mRNA, among other vaccine approaches, but I'm also keenly aware that at one point Moderna was called Moderna Therapeutics, and they had to shift from therapeutics. Broadly, I think one needs to be somewhat cautious about having optimism about some of the diseases and illnesses they're looking at.

That all said, BioNTech and Moderna have made so much money from these vaccines. They're going to take all that cash and plow it into cancer and immune-mediated conditions like multiple sclerosis and lupus.

You can't count these people out, Ugur Sahin and Stéphane Bancel and their teams. I know how hard they're all working and how [they] don't see COVID-19 as the end, but the beginning. It gives one encouragement that they will figure things out. They have the resources now, and they have the will.

For Moderna it was always about dominating the mRNA space broadly and developing lots of applications. Ugur Sahin's a cancer guy so this is one step in a long journey. His whole goal in life has been to tackle cancer.

So you could potentially see that this past year or two, as awful as it's been, may be a net positive for society, if it allows us to make real headway on things like cancer and multiple sclerosis and lupus and malaria. It is fascinating to envision that this has been just the first chapter of other breakthroughs.

https://www.medpagetoday.com/special-reports/exclusives/95403

COVID Vaccine Mandates and the Question of Medical Necessity

 COVID-19 vaccination policy in the U.S. is highly variable, whether in regard to boosters, vaccinations for children, or workplace requirements. While many states require vaccination for state employees and workers at state-funded institutions, other states are banning vaccination requirements. Despite the political nature of vaccination policy, best practices should be based on scientific evidence. So, what does the evidence say regarding people who have previously been infected with SARS-CoV-2?

While COVID-19 vaccination is safe and highly effective, several studies show that people who have recovered from COVID-19 are at least equally protected compared to fully vaccinated COVID-naive people. Therefore, vaccination in those who have recovered may not be medically necessary. Rather than blanket mandates requiring vaccination, it may be more politically tenable and scientifically sound to focus on the documentation of immunity -- whether through infection or vaccination -- to control the pandemic and stratify persons at risk. Identifying immunity is not challenging, and several other countries already have models on which the U.S. could base its approach.

Immune System Protection From COVID-19

After SARS-CoV-2 infection or vaccination, the body's immune system reacts to the presence of foreign SARS-CoV-2 molecules by producing antibodies and expanding immune system cells to clear the foreign material. Within a period of weeks to months, the newly produced antibodies decline and the recently created immune system cells go into various tissues, lymph nodes, or bone marrow, waiting for the next exposure to the virus or viral proteins. Observed reinfection in people with healthy immune systems who have recovered from COVID-19 is uncommon, on the order of 0 to 1 per 100 persons per year, showing high levels of protection in this population.

One argument some have put forth in favor of vaccination after recovery from infection is that antibody levels increase with vaccination after recovery. Indeed, recent studies have found that people who had SARS-CoV-2 and later received one dose of the Pfizer mRNA vaccine were more highly protected against reinfection than those who once had the virus and were still unvaccinated. However, the benefit is generally modest. Also, it is well known that repeat exposure to the virus or viral proteins created by vaccination will quickly boost antibodies and at least temporarily further reduce risk for reinfection. What remains unknown is whether that antibody increase truly adds additional long-term protection against getting infection or illness.

Researchers at the Cleveland Clinic Health System conducted a study of 52,238 employees with and without a history of COVID-19, with or without vaccination. They found that those who recovered from COVID-19 and were vaccinated had equally low rates of repeat infection when compared with those who recovered and were unvaccinated. The investigators concluded that those previously infected were unlikely to benefit from COVID-19 vaccination. In another study looking at the duration of immunity among the COVID-19-recovered, researchers found that the immune response against SARS-CoV-2 was persistent and relatively stable for at least a year. While a recent CDC study concluded that mRNA vaccination provides stronger protection against COVID-19 hospitalization than prior infection, there were several study limitations, including that it was not a randomized controlled trial and that the follow-up period was short. The findings also don't negate the robust protection from prior infection. In fact, in a CDC science report published last week that reviews the totality of evidence, agency staff found that both infection-induced and vaccine-induced immunity are durable for at least 6 months.

However, for select groups of people, such as the immunocompromised or those with a history of low antibody response to vaccination, getting at least one dose of vaccination after recovery from COVID-19 may be beneficial. That brings us to the question of medical necessity.

What Is Medical Necessity?

The definition of medical necessity describes a broad standard for medical insurance coverage. While the term is not formally defined by the federal government and varies by state, medical necessity generally refers to services that improve health or lessen the impact of a condition, prevent a condition, or restore health.

For those who have not been infected with COVID-19, vaccination is an absolute medical necessity. But for those who already have protection against SARS-CoV-2 from prior infection, vaccination or vaccine boosters after initial vaccination may not be medically necessary.

There is currently a lot of tension regarding vaccination requirements for essential workers. One way to reduce that tension, and possibly increase public confidence in government, would be for policymakers to explore alternatives to blanket mandates -- they could allow those who can prove prior COVID-19 infection to qualify for a medical exemption or perhaps only be required to get one mRNA dose.

Diagnosis of Previous COVID-19 Infection

To establish a COVID-19 diagnosis, accurate and reproducible tests are needed to detect the causative virus, SARS-CoV-2. Most high-quality COVID-19 testing relies on the polymerase chain reaction (PCR). Other methods use the presence of proteins of SARS-CoV-2 (antigen) in clinical specimens or antibodies that are specific for viral proteins. However, antigen and antibody tests may be less accurate than PCR tests, although when positive, they are highly likely to correctly indicate current or past infection.

Demonstrating prior infection is not medically difficult. Prior infection can be documented with: a previous positive PCR test, clinic or a laboratory-based antigen test, a positive antibody test, or a T-cell test. A physician can easily interpret those test results and confirm that an individual was previously infected. While some have expressed concern that we haven't yet established a definitive antibody titer that guarantees protection, quantitative testing isn't necessary. Studies clearly show that those with prior infection are highly protected.

Because many symptoms of COVID-19 are non-specific, an individual's "word" that they were previously infected would not be sufficient.

Requirements Abroad

Several countries have introduced COVID-19 workplace, travel, or access mandates based on vaccination or infection history or the absence of current infection. In the European Union, Greece requires employees to carry a vaccination certificate to gain access to their place of work. Additionally, Greece allows for documentation by a healthcare professional or authorized laboratory of prior COVID-19 within 30 days after the day of the first positive COVID-19 test as sufficient for travel within 180 days. France requires documentation of vaccination to enter cafes, bars, and restaurants. If one has recovered from infection, only one vaccination dose is required.

Some countries have used history of prior COVID-19 as equivalent to vaccination to obtain COVID-19 certificates/passports. Italy requires all workers to be either vaccinated, recovered from COVID-19, or have a recent negative test result to avoid suspension from employment. Switzerland will grant COVID-19 certificates -- needed to enter bars, restaurants, and fitness centers -- to people who have been either vaccinated or recovered from COVID-19 within the past 365 days as documented by a prior positive PCR test or current positive antibody test.

We unequivocally support vaccination as a critical individual and public health intervention to control the COVID-19 pandemic. But the case for mandating vaccination in those who have recovered is much less strong. It is likely unethical to mandate a medical intervention in people who may not benefit, and may only be exposed to the risks, however small. Public health policy must be updated to recognize that recovery from prior infection is equivalent to vaccination. Healthcare professionals can play a key role in advocating for equivalence by understanding the evidence, educating the public, and knowing how to confirm prior infection.

Jeffrey D. Klausner, MD, MPH, is a former CDC medical officer and current professor of medicine and population public health science at the University of Southern California Keck School of Medicine. Noah Kojima, MD, is an internal medicine resident at University of California Los Angeles.

Disclosures

Klausner is medical director of Curative, a testing company, and disclosed fees from Danaher, Roche, Cepheid, Abbott, and Phase Scientific. He has previously received funding from the NIH, CDC, and private test manufacturers and pharmaceutical companies to study new ways to detect and treat infectious diseases. Kojima has received payments from Curative for clinical research services.

https://www.medpagetoday.com/opinion/second-opinions/95399