EXCLUSIVE: The World's First Known Person Who Naturally Beat HIV Goes Public
"You better get your things in order, you probably have about six months to live," the nurse told Loreen Willenberg upon returning test results that showed she was HIV-positive in July 1992.
The test measures antibodies to the virus that the immune system develops several weeks after initial infection. The nurse's words were standard advice at the time, when the epidemic was at its worst in the U.S. and effective treatment was still years away. They created "this emotional fear that I was going to die," which would take years to dissipate in Loreen's mind.
Loreen has not benefited from those drugs; remarkably, she has not had to.
The plague had arrived quietly; only a portion of those infected with the virus show flu-like symptoms when first exposed, and soon even those go away. Initially there was no test to detect the virus; it didn't even have a name. But from the moment HIV enters CD4 T cells -- the key helper cells of the immune system -- it slowly, methodically begins to wipe them out until after several years or even a decade, the body lays vulnerable to a panoply of diseases that a fully functioning immune system might fight off with ease.
The quiet phase of the epidemic had passed by the time Loreen received her test results in 1992. Healthy young men would wither to cadaverous forms wracked with disease over the course of just a few months after an AIDS diagnosis but years after they had become infected. They filled half the beds in San Francisco General Hospital. AIDS had become the leading cause of death of young men in the United States, more than 50,000 that year alone. And so a diagnosis was seen as a death sentence.
Stigma accompanied the disease because it was so prevalent among gay men. Many of the sick were disowned and abandoned by their families. Countless AIDS deaths were attributed to other causes to shield the deceased or their families from shame.
Loreen had taken that same test earlier, in 1988, and it had come back negative. Now, after ending an engagement and considering dating again, she had taken the HIV test a second time. The positive results filled her with terror.
The ensuing 27 years have seen a complete change in the epidemic and in Loreen. The introduction of anti-HIV drugs have allowed patients to rise like Lazarus from their death beds, and better yet, keep them from becoming sick, not just in rich nations but throughout the world.
Loreen has not benefited from those drugs; remarkably, she has not had to. Over the years, she has learned from leading HIV researchers across the nation that her unique immune biology has been able to control the virus naturally.
"Loreen, I can't find any HIV in your body. I've looked high and low and think you might have cleared it," said the voice on the other end of the line. It was April 2011 and the caller was a prominent HIV researcher at the National Institutes of Health (NIH).
"I was astonished. I thought it was just extraordinary," says Loreen in recalling that moment. "And then my curiosity kicked in. It's like, how the hell did that happen. What is the mechanism? For twenty years I've understood that the virus actually blends itself into your DNA, the literal blueprint of life. So to have a researcher tell you that your immune system might have cleared it, just like it was the flu, it's like, that is astonishing."
It was a landmark moment for Loreen in a personal and scientific journey from a fearful, stigmatized, and isolated patient, through learning of her unique immune biology that is able to control the virus, to becoming an educated and empowered research participant whom some leading HIV researchers have come to see as a colleague and peer. Her cells have led to a better understanding of HIV, and perhaps will lead to a cure.
The Secret Patient
Loreen didn't fit neatly into the demographics of the AIDS epidemic of 1992 when she was diagnosed. She wasn't a gay man and she didn't live in San Francisco but several hours away in Placerville, a small town of less than 10,000 people in the foothills of the Sierra Nevadas. The town had been the epicenter of the California gold rush in the mid-1800s but now was little more than a dot on the map halfway between Sacramento and Lake Tahoe.
Loreen on vacation in Las Vegas in 1992, the year of her diagnosis with HIV.
(Photo courtesy of Willenberg)
She was 38, tall at 5'7", with auburn hair down to the middle of her back that the sun would streak red. She had grown up in a tough part of Los Angeles, a self-described surfer girl who dropped out of UCLA after a few months of college at the age of 17. She was a voracious reader, curious about a thousand things.
More than a decade of wandering had landed Loreen in Placerville where she befriended a local horticulturalist who taught her much of the trade and encouraged her to start her own business. By now she had a small crew designing, building, and maintaining landscapes in surrounding communities. She was strong from digging and planting alongside her crew, never asking them to do what she would not do herself.
The HIV test results shook her (she suspects she acquired the virus from her then fiancée) and she responded in her typical fashion, by quietly hunkering down and learning all she could about the still-new disease. She told no one except family and a few close friends, afraid that others might shun her and her business, or even worse. Children with hemophilia and HIV had been barred from school in some parts of the country; one family even had their home firebombed. Secrecy was a must in a small community where tongues could wag.
The first step was to find a physician she could trust. A call to the Project Inform Hotline, an AIDS education group in San Francisco, identified two doctors in private practice who treated HIV in Sacramento, a good hour drive away. The Hotline volunteers would become a lifeline, her first teachers in what would become a lifetime of learning about the disease.
Bruce Cohn was a young internist then in private practice. Working with HIV patients "became kind of the best thing I ever did," he recalled in a recent interview. "Most of these [patients] were my peers who were getting sick, about the same age, and so it was easy to relate. I identified, oh, that could be me, and so there was a lot of personal connection to the patients."
He also was driven by the intellectual challenge. "I got to learn something new every day if I wanted to; it was learning on steroids." First came new ways to treat opportunistic infections that plagued those with a compromised immune system, and later antiviral drugs to treat HIV itself.
He shielded himself emotionally by thinking of it as "aging and dying compressed; everything just got more intense, shorter. Their illness was a sort of crisis. People would get sick and if we treated them effectively they would get better. Not as good as they were before, but better."
When Loreen started seeing Cohn, her CD4 T cells, the part of the immune system that HIV infects and replicates within, were even higher than what one would expect to see in a normal healthy person and many times higher than the low level that then existing guidelines recommended for beginning treatment. In addition, the few available anti-HIV drugs were not very good -- the virus often mutated resistance to them within a year and so they were reserved for a last-ditch effort. She and Cohn decided to draw blood and monitor the level of her CD4s along with her regular primary care. First every three months, then twice a year, she drove down from Placerville to Sacramento.
Loreen would track the results of every laboratory test from her medical care, and later every research visit and procedure. First they filled a 3x5 index card which she hid; later they would be saved on a computer spreadsheet.
"We didn't believe what we were seeing"
The CD4 count in a typical untreated HIV-infected person declines by 30 to 50 cells a year. But Loreen's didn't budge.
"Maybe there was something goofy going on because your T cells aren't heading south like they should," Cohn told her after a few years. He retested Loreen several times to confirm the original diagnosis and each time the lab results came back antibody positive. There was no doubt that she had been exposed to HIV and her immune system had developed a response to the virus.
Dr. Bruce Cohn in 1994.
(Courtesy of Cohn)
He also ran the newer, more sensitive viral load tests when they became available, which measure the level of the virus itself in blood, and he couldn't find any. But Cohn didn't pay that much mind, chalking it up to the insensitivity of those early assays that were available for use in medical care. He followed the guidelines for treatment at the time, which were based on CD4 count, not viral load. The years ticked by and Loreen remained robustly healthy, working with her crew and the plants she adored.
Meanwhile, researchers were poking around at the left end of the bell curve of response to HIV, identifying a group they inelegantly dubbed long-term non-progressors (LTNPs) most of whom would later be referred to as controllers. People respond differently to all diseases. Most fall in the middle of the curve and that average response is used to define the course of the disease, but there are some to either side who progress more and others less rapidly than average. Studying those outliers often yields insights that help to better understand the disease and develop treatments.
An early paper on HIV LTNPs was published in 1995 and caught Cohn's eye. He told Loreen about it on her next visit and suggested that researchers would probably want to study her someday. "We looked for a study for the next seven or eight years," she says.
New anti-HIV drugs began to come to market in developed nations starting in 1996. They would lift the pall of death that surrounded the disease and turn it into a chronic, manageable one. Curbing the stigma and discrimination associated with HIV would be slower to yield.
But the fear kept nagging at Loreen. Her physical health was excellent; mentally she was a wreck, still fearful and anxious that people might find out her secret, and that she might sicken and die. It was compounded by menopause.
Women had a harder time than men dealing with HIV, says Cohn. "It was more shameful, more stigmatizing for them, and they had less support." Most of the early social services and support groups had been built by and for gay men. "Women just didn't have the people to connect with or share their experiences or stories with."
Loreen had found and was accepted into a support group mainly for gay men in Placerville. "They really teased me and said 'you're our token straight white woman.' God bless them. Really." But Loreen remained healthy as other members of the group sickened and dealt with the problems of their medications. Eventually, they felt her experience was so different that she did not belong and asked her to leave the group.
Not fitting the normal patterns of HIV disease carried its own burdens. Loreen calls it "a double stigmatization" of HIV and "alienation from within the community itself." Other controllers would have a similar experience, and simply keep their unusual condition a secret for decades, as the stress built within.
The internal pressures became so great that she left the anchoring rock of her business and literally ran away, moving in quick succession to Idaho, then Dallas, then Los Angeles. Only years later would she realize and acknowledge that she had been looking for a savior, someone to protect her from the stigma and take care of her if she became sick. "I was like a bum magnet, looking for love in all the wrong places... and pretty screwed up in my head." She returned to Placerville and Cohn helped her realize the problems were about relationships, not health. His understanding and an antidepressant helped Loreen break the cycle and get back on track.
Then in the fall of 2004, Loreen spotted a small, boxed ad in the back of POZ, a magazine launched in New York City in 1994 to educate and build a community for people living with HIV. The ad was from the Partners AIDS Research Center at Massachusetts General Hospital in Boston and was looking for LTNPs.
"I broke down in tears because I knew that they were looking for me. I called Dr. Cohn the very next day" to make the arrangements, Loreen recounts. They wanted samples of her blood to run a series of experiments. She was so eager to help that she even paid close to $650 out of her own pocket to have the blood samples drawn by her physician "because I didn't have insurance," and FedExed eleven vials out in November. And then she waited.
The phone call came in mid-February 2005 from Florencia Pereyra, then a research fellow in the Partners lab of Bruce Walker at Harvard University. "Part of the reason that it has taken us so long to get back to you and Dr. Cohn is that we didn't believe what we were seeing," she told Loreen.
"Your cells were resisting close to 60 percent of all those bad guys instead of the typical 20-30 percent."
She asked if Loreen might fly to Boston to donate more blood cells, because cells "flatten out" when they are shipped and the lab needed fresh cells. Oh, and by the way, they had not been able to secure funding to fly her there.
Loreen asked why it was so important? What did they find in her original blood donation? "'We exposed your fighter cells, your immune cells, to different viral proteins,'" she recalls Pereyra saying. "'And your cells were resisting close to 60 percent of all those bad guys instead of the typical 20-30 percent.' That's when it dawned on me that there was something really unique about me." Her immune cells were unusually good at fighting HIV.
She was hooked. And in her innocence and eagerness to help, she began cold calling local AIDS researchers asking if they might spare some cash to fly her to Boston. It came as a splash of cold water to be told that scientists were not just one big happy collaborative family, but rather a highly competitive lot scrambling for a limited amount of research dollars. Loreen now laughs at her early naiveté.
Gut Feeling
But she did learn of a research study in her own backyard at the University of California at Davis and eagerly jumped in as a donor. Most HIV research is done using blood because it is a relatively accessible, inexpensive, and painless window to the dynamics of the disease.
The big drawback is that only a small percentage of the CD4 T cells that become infected and spew out HIV are found in blood; a far larger portion are found in lymphoid tissue in the gut. This makes sense; most germs we are exposed to come through what we eat and drink every day, so the immune system focuses much of its attention to take on those challenges in the gut.
Barbara Shacklett, at UC Davis, was conducting the first major study of the immune response to HIV that looked at what was going on in both blood and gut at the same time. She wanted volunteers to give not just a sample of blood but also have a colonoscopy. A tube would be inserted up the rectum and small pieces of gut tissue would be pinched off from along the colon for scientists to analyze.
Shacklett has a wide-eyed charm and easy laugh that belie three and a half years of HIV research in Paris and later stints in labs in New York and San Francisco. Then, nearly twenty years ago, she set up her own lab at Davis. The study was important and broke new ground in understanding that there are significant differences in how HIV replicates in the gut and the blood; simply looking at blood gave an incomplete picture of the disease.
"Loreen was one of the very first two HIV controllers that we had the opportunity to study. She was a very willing study participant, kind of the perfect study volunteer," Shacklett recalled in a recent conversation in her office. "But behind that, she was very, very interested in the research itself, wanted to read the papers and attend some of the conferences."
Loreen would return a handful of times for procedures that removed well over a hundred tissue samples. She received a $100 honorarium for each visit, something that not all studies provide.
One thing puzzled Shacklett; Loreen didn't have the strong T cell immune response that was seen in other HIV controllers -- it was modest at best. T cells comprise a major part of the adaptive immune response, the body's second line of immune defense against an invading pathogen. When T cells encounter parts of a bacteria or virus they have been trained to identify, they surround it, expand in numbers and secrete chemicals that kill the invaders or the cells that are infected. Once the job is completed and the foe vanquished, there is no sense in wasting energy and T cells, and so the immune system pulls back, reducing the number of T cells and dozing off to await the next time there is a threat.
Perhaps the immune system had done its job so well that HIV was no longer there, and the T cells could afford to relax. Perhaps somehow Loreen's body had found a way to not simply reduce the number of virus but to do the unimaginable and actually purge it. That seemed like a wild hypothesis, barely considered at the time, but as the years passed and additional studies documented just how unusual her immune system was, the hypothesis became less far-fetched.
Looking Inside the "Black Box" for Clues
Bruce Walker, a Harvard doctor and researcher, initially thought that people like Loreen -- whose immune systems could control the virus better than most others -- were extremely rare. Then one day, speaking in New York at a postgraduate course on HIV, he asked if others had seen such patients and was shocked when more than half the doctors raised their hands. "And I went, Oh my God, this is not that rare," he recounted.
Walker is tall and handsome in the manner of Superman's alter ego Clark Kent, complete with square jaw and glasses. The smooth talker's superpower is building collaborations and what many consider to be the premier HIV research center in the world, now called The Ragon Institute, in honor of its principal benefactors. He was the first HIV researcher among the nearly 300 investigators supported by the Howard Hughes Medical Institute, the fifth largest foundation in the world with an endowment of $22.6 billion.
He had been an intern and resident at Massachusetts General Hospital (MGH) in the 1980s when the first AIDS cases began to appear. It shaped his decision to focus on HIV and particularly the search for a vaccine. Early vaccine failures led him back to basic science and particularly to HIV LTNPs, that small portion of the bell curve of infected persons whose immune systems could control the virus better than most other people.
Walker convinced Wall Street financier Mark Schwartz and his wife Lisa to donate $5 million to underwrite a genome-wide association study (GWAS) to try and unlock the genetics of how some people were controlling their HIV infection. Experts at the Massachusetts Institute of Technology (MIT) would collaborate on the effort.
"When I first encountered Loreen, there was a sense that the answer was right there for us to figure out."
That funding paid to fly Loreen to Boston in December 2005, about a year after she had sent in those original vials of blood. It was the first of many times she would meet with Walker. "He invited me into his office to talk, and was so excited to be building this cohort [of LTNPs]. He told me of the difficulties in finding us because we were so healthy. I was told I was participant number 10," she says.
"When I first encountered Loreen, there was a sense that the answer was right there for us to figure out," Walker reminisced. "She harbored the answer, but it was really a black box. And since that first encounter with her, we've gotten now to the point where I believe we understand how she is doing it, and how other people are doing it. And I believe that is something we can act upon."
The GWAS study was a major attempt to figure it out. The surface of immune cells is a messy assemblage of proteins that make up the human leukocyte antigen (HLA) system, which governs immune function. The HLA is genetically determined, so Walker hoped the GWAS study could identify specific genetic variants that were associated with control of HIV infection.
It worked. The analysis identified several genetic variations in the immune system that are strongly associated with control of the virus. But no single HLA is common to all controllers and the presence of specific HLAs does not guarantee that a person can control the virus. As an example, Loreen carries some protective HLA variants but not others. So the match is imperfect. It "only explains 20 to 25 percent" of control, says Walker. "But it pointed us in the direction of these killer cells, cytotoxic T cells [CD8 T cells], being important."
A Powerful Sense of Purpose
That trip to Boston was the first time Loreen had been given a tour of a lab, looked through a microscope, and seen how her cells were being put to use. "A light went off in my brain; I understood what I was seeing. I experienced an epiphany," she recalls. "I really think that was about the time I started to let go of the fear" that had plagued her for 13 years since the HIV diagnosis.
"I was fascinated by the hypothesis of the study and I remember telling Dr. Walker that day, 'you need to find more of us. It is very important that you do and I am going to help you. I don't know exactly how I'm going to do it because I'm still living and hiding as an HIV-positive woman. I'm terrified that I'm going to lose my business if I come out about my status in my highly conservative, small, foothills mountain town.'"
"I promised him then that I am going to do it, I'm going to dedicate the rest of my natural life to the work," she remembers telling Walker. "I'm going to need your help because I don't come from a biomedical background. I'm a landscape designer, I'm a horticulturalist, that's my life. I didn't even finish college." He grinned, and the rest is history.
A few months after that first trip to Boston, driven by a desire to help, Loreen formalized her compulsion into a nonprofit organization she called the Zephyr LTNP Foundation. "Zephyr means the wind from the west," she says. It was the screen name she had hidden behind when she first joined HIV forums on the Internet. She dove into reading the scientific and medical literature.
Zephyr was essentially a one-woman organization where she shared the latest journal articles she found interesting, built a network of fellow HIV controllers, and encouraged them to participate in research. Loreen would spend endless hours on the phone, counseling controllers who felt isolated and alone, helping them to build a positive sense of who they were and what they might contribute.
Learning she had a unique biology that people wanted to study "gave her life some meaning, and that was so awesome," says Cohn, Loreen's personal physician for more than a dozen years as she transitioned into active participation in research studies.
Medical ethics, and particularly the U.S. law known as HIPAA (Health Insurance Portability and Accountability Act of 1996), strictly protects the privacy of patients and study participants. This limits why and how researchers can communicate with those participants. Unfortunately, this also acts as a barrier for people like controllers who feel alone and isolated. Networking and recruiting people for these types of studies is difficult.
Through the public attention she brought to controllers via media coverage and on HIV-oriented websites such as thebody.com, she was able to attract and build a network of controllers and educate them, where researchers might be restricted and generally did not have the money or staff to invest in patient education. That's why they have been so appreciative of Loreen.
"She just completely engaged with us and helped make that early GWAS study possible by basically connecting to people across the country, really in a way serving as a recruiter for us, explaining the study, explaining the importance of it, and getting people to become engaged and contribute blood samples," says Walker.
Travel to research sites and AIDS activism increased to such a tempo for Loreen, every month for one year, that she decided to close her business and reduce her travel burden by moving to Sacramento at the end of 2007. She stitched together a series of part time jobs to pay the bills.
Perhaps the high point of Zephyr was a small conference she organized in the fall of 2009 that brought together a handful of researchers studying controllers and a dozen of these patients from various cities. Never before had so many been in the same room.
Then, in the fall of 2011, Loreen started taking college courses to strengthen her critical thinking on medical research and bioethics, completing two AA degrees with honors in 2017.
Visiting the National Institutes of Health
Loreen is not one for half measures. Soon after her initial trip to Boston, she also joined the HIV cohort at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH). It follows how the disease progresses in people, how it might affect health more broadly, and possible long-term side effects of the drugs they are on. Visits to the Bethesda, Maryland campus are at least once a year and ongoing. The group also includes 142 LTNPs.
"I think she is a very rare person who is at the tail, the extreme end of the spectrum."
Stephen Migueles is a senior research physician with the cohort and the first of his south Florida family to go to college. As an openly gay man doing his medical residency at Georgetown University Hospital in the early 1990s at the depths of the AIDS epidemic, he was both riveted and terrified by the experience, "struggling to come out and accept myself, my family not accepting me, and then seeing everybody dying. It was a really hard time."
He had wanted to be a doctor ever since he could remember and wasn't particularly interested in research because he didn't think he was smart enough. But during a rotation at NIH he caught the eye of senior staff who convinced him to give it a try; that was 22 years ago. He has advanced in the U.S. Public Health Service to wear the eagle of a naval Captain on his collar. "The NIH feels like a family to me and a place where I can do something meaningful ... advancing the science to help find a cure," he says humbly. In an earlier age he might have become a priest loyally serving his parish.
The raw materials that Migueles and others work with are immune cells residing in the body. Researchers gather them through a procedure called leukapheresis. Blood is drawn off through a needle, fed through tubes into a special machine that spins off about 100 million immune cells, and returns the rest of the depleted blood complex to the body, over the course of several hours. The immune cells are then taken to a lab where they are further divided into specific subsets that are closely studied.
Loreen undergoing a leukopheresis at NIH in November 2009. The machine to the right is separating immune cells from the rest of her blood for further analysis.
(Photo Credit: Bob Roehr)
The procedure always leaves Loreen feeling exhausted for the rest of that day and the next. She came down with the flu early this spring, soon after the last time she went through a leukapheresis. Was it because so many of her immune cells had been siphoned off by the procedure that she was less able to fight off the infection? Researchers claim not, that the cells should replace themselves in a day or two, but the question is not well studied. And just to be safe, most research protocols allow that type of donation only once every three or six months.
Scores of different procedures over the years at various research centers have left Loreen's thin veins so scarred that NIH has stopped asking her to undergo any more leukapheresis for science. They realize she may need ready access to those veins for her own medical care at some point in the future.
Migueles' work focuses on CD8 T cells, "the assassins of the immune system." He says the cells of people who control the virus don't necessarily recognize the virus any better than do others; instead, the cells function better. Typically CD8 T cells surround a CD4 T cell that is infected with HIV, proliferate in numbers, then use a protein called perforin to puncture the outside membrane of the cell, and pour in granzyme B, an enzyme that kills the cell.
Typical progressors don't even do a very good job at the stage of proliferation, he says, while controllers are very efficient at every step of the process. Interestingly, with the HIV vaccine candidates that have been developed, the CD8 cells "proliferate really exuberantly, they load their killing granules very efficiently, but then they can't get them out" and into an infected CD4 cell to kill it. A successful vaccine will have to solve this puzzle.
"I knew from our exchanges before she got here that Loreen was going to be a big personality," says Migueles. "A lot of her questions are very much like, 'what do you think is going on with me?' but there are bigger-picture issues, which always makes it very admirable to me.... She would come back at follow up visits and pull out of her bag a bunch of papers with highlighting, and dog-eared, and notes written, which is a lot like me."
Loreen had found another kindred soul and mentor in Migueles, united in scientific curiosity and a sense of service. It was apparent during her latest visit to NIH in June 2019, when the pair would interrupt and complete each other's sentences just as an old married couple might.
After her initial visit in 2006, Loreen had been back home only about a week when Migueles called again, asking how soon she could come back, a recurring motif in her story. A few months later, she was back at NIH watching in awe as a movie played before her eyes of her own CD8 cells destroying cells infected with HIV. "I was saying things like, wow, this is like science fiction."
Loreen's CD8 cells did that job very well indeed. "I think she is a very rare person who is at the tail, the extreme end of the spectrum," Migueles says. "I don't think she's controlling by a different mechanism, but maybe her CD8s have a little more of a kick earlier on and it helped to really knock things down so much that she just doesn't have a lot of replication competent virus around." Perhaps it's like compounding interest in saving for retirement, where a little bit of difference early on in controlling the virus might have a huge effect down the road.
A Cure?
Then in early 2011, Migueles made the astonishing phone call saying that some of her results suggested she might have actually cleared the virus from her body. He needed Loreen to come back and donate tissue from her gut to see if they could find any HIV lingering there. Loreen didn't have to think twice; she traveled to Bethesda over her birthday for the procedure.
The paper came out in April 2012 in the journal Blood. It was a series of four case studies of unnamed HIV elite controllers, a label affixed to those who are best able to control their virus. Elite controllers comprise less than half of one percent of those infected with HIV. One of Migueles' colleagues had made a heroic effort to find HIV in CD4 T cells taken from Loreen's blood and gut tissue, but couldn't detect any complete virus integrated into the 184 million CD4 T cell genomes sampled.
Migueles didn't explicitly say in the paper that, unlike the other three people in the study, he thought Loreen had completely purged the virus -- he's much too cautious a scientist. He knows the only way to absolutely prove that is through an autopsy looking for traces of the virus in every tissue compartment including her brain. But reading between the lines, it was clear that he believes it is a plausible hypothesis.
Researchers called it a "functional cure" of the disease. Loreen recognized all of the data points as hers.
The paper didn't make much of a splash at the time. Scientists were still reluctant to accept that Timothy Ray Brown, the "Berlin Patient," might have been cured of the infection. Brown had been doing well on anti-HIV drugs until he also developed leukemia, a cancer of the blood system. The treatment for leukemia is a brutal regimen of radiation and chemotherapy, which carries a high rate of mortality, to kill off the immune system and replace it with a bone marrow transplant containing stem cells to grow a replacement immune system.
Previously, researchers had isolated CCR5 as a coreceptor that HIV uses to enter and infect CD4 T cells. They later identified a small group of people who carry a genetic mutation, the delta32 deletion, who do not express the CCR5 receptor on the surface of their cells. As a result, people who carry a double version of this mutation, inherited from both parents, are virtually impervious to HIV infection.
The doctor treating Brown decided to do an experiment. Since he had to replace Brown's immune system in treating the cancer, why not try and do it with a version that might also protect him from HIV? Germany has the world's largest registry of bone marrow donors, but still, among those millions of potential donors, only two were a close enough overall HLA genetic match to use with Brown and also contained the double delta32 mutation he sought.
Brown's leukemia recurred and the series of procedures had to be repeated, but eventually he was declared both cancer free and cured of HIV. Controversy remains over the necessity and importance of various aspects of the treatment. However, over time, the medical community has come to accept that he was the first person to be cured of HIV. Other attempts at similar treatments have not been successful, though some believe the "London Patient," announced in early 2019, might also represent a cure.
But back in 2012, when Migueles' paper came out, the first session of the International AIDS Conference that used the word "cure" was still some months away. So to think that someone might have achieved a cure on her own -- without drugs or any of the other miracles of modern medicine -- was unimaginable to most researchers. Still, the paper has stuck in the back of the minds of several scientists and they mention it in conversation whenever Migueles presents his research at a conference.
Talk of a cure came roaring back this spring in a paper from the Ragon Institute team in Boston. It laid out a topographic map of how the various HIV proteins are linked together. Some nodes contain only a few connections while others contain many more. The simpler nodes can more easily change shape when under attack from the immune system and still carry out their functions, while the more complex nodes are less flexible; they can't mutate and still function. The immune systems of HIV controllers focus their energies on those key connections where the virus can't mutate and don't waste their efforts on less important nodes.
"This is the first time we've been able to differentiate controllers from progressors on the basis of an immunologic parameter," says Walker. "And what's very exciting about that is it's not just that we've made an observation, it's an observation that is actionable, we can now try and replicate that in other people." He acknowledges they still don't understand how some people can do this naturally, and is grappling with how they might stimulate others to do it too.
Then this July, at a big international AIDS conference in Mexico City, Ragon researchers compared the cells of a "San Francisco patient" with another elite controller and found scant evidence of HIV. There were a few fragments of HIV RNA as evidence of past infection, but no complete virus capable of replication. They called it a "functional cure" of the disease. Loreen recognized all of the data points as hers; she was the mislabeled San Francisco patient. But she didn't mind, it meant a few more weeks out of the spotlight leading a normal life.
A "Difficult and Ambiguous Moral Space"
Medical research is based upon the foundation of informed consent, where a volunteer is told of the potential risks and benefits of participating in a study and does so willingly, under no pressure. Loreen became very familiar with this process in reading the informed consent documents for each of the dozen or so studies she has participated in. It sparked a growing interest in bioethics.
Another spark came from the outside. "The Immortal Life of Henrietta Lacks" is a landmark and best selling book by Rebecca Skloot that was published in early 2010. It told the story of a poor black woman who in 1951 unknowingly was the source of cervical cancer cells that were turned into a perpetual cell line (HeLa), which is an important tool used in much of biomedical research to this day. Lacks was never told of or benefited from that contribution before she died. The book dug deep into issues of race, class, and medical ethics that underlay what was once accepted practice, and still resonates today.
An HIV controller Loreen had befriended through the Zephyr Foundation sent her a digital version of the book almost as soon as it came out. But reading on a screen didn't suit her and Loreen purchased a hardcover version, pouring through the chapters and filling them with multiple Post-it notes.
"While my donations (and those from my community) have all been made from an altruistic perspective, I can't help but think that my community has signed away our rights to future compensation (for minimal stipends of $200 or less, depending upon the donation procedure and the institution) for extremely valuable data that may contribute to cures for HIV/AIDS, and other diseases," Loreen wrote Skloot in an email the following year.
"The donors are expected to be 100-percent altruistic, when in fact no one else is 100-percent altruistic."
The book also led Loreen to Mark Yarborough, a bioethicist at UC Davis, who would become a mentor in this area. "Not to demonize, but to a certain extent people are in biomedical research for the money," says Yarborough. The pharmaceutical industry wants to bring lucrative new products to market, researchers want to advance their careers and increasingly to form companies to commercialize their work, and even universities stake a claim to patents from the research.
"The expectation is that the donors will do things entirely out of the goodness of their hearts, when everyone else is in it for very good intentions, but also have a lot of self-interest at stake," he says. "The donors are expected to be 100-percent altruistic, when in fact no one else is 100-percent altruistic."
Yarborough has been impressed with the dedication and work Loreen has done on her own and through the Zephyr Foundation. She has struggled with the question, "If I do have this unique biological characteristic that might make an important contribution to finding a vaccine, a cure, an effective treatment, how do I dare not say yes to anyone and everything?"
"You feel compelled to help. You feel like it would be selfish not to help. But at the same time, it's hey, I'm a human person," Yarborough says. "She was always very measured in the way she described things, but she was struggling with, am I being treated appropriately?...She had a strong sense that she was supposed to be treated in a certain way, but she was unclear what that way was. I think that to this day she remains unclear. I remain unclear as well."
"It's almost like a duty to me," Loreen once said while she was laying in a hospital bed at the NIH during a leukapheresis in 2009. "I'm lying here today and I'm thinking about the 40 million people in the world who are living with HIV and who suffer. Who need the medications, who have the side effects from them. And here I am, basically untouched by it physically. That's why I call it a duty...I'm convinced we're going to beat it."
For the last several years, Yarborough has invited Loreen to speak at a required medical school course in ethics he teaches in a graduate degree program that prepares people for a career in biomedical research: the students include medical and PhD research students and junior faculty. "The room is very quiet when Loreen is speaking because people quickly get caught up in her stories. They value the opportunity to ask her questions and there is good discussion afterwards."
"She comes across very much as a peer, and light years ahead of the students in many ways. [She] has been involved in twelve clinical trials and can give you every publication that her samples have contributed to," he continues. "Whereas these people, even if they are junior faculty, may not have been in their first clinical trial yet. So they view Loreen very much as a peer, as opposed to someone who is not on that equal playing field."
Mark Yarborough, a bioethicist at UC Davis, invites Loreen to speak at a medical school course on research ethics.
(Courtesy Yarborough)
"What stands out for me is just how Loreen is living with the difficult and ambiguous moral space that she is living in," says Yarborough. "And the journey that has been for her, the evolution in her own mind and her own thinking."
Going Public
Loreen had seen the media circus that surrounded Tim Brown when his name was made public in 2010 as the first person to be cured of HIV and she wanted no part of it. "I watched every single thing about Tim Brown and I'm not going there. I don't want to live like Timothy Brown does now. I don't want the attention. I live a very quiet private life, and I like it."
What changed her mind was another call from NIH. Documentary filmmakers were shooting a series that would eventually run in the summer of 2017 on The Discovery Channel as "First In Human: The Trials of Building 10," narrated by the ultimate TV science nerd, "The Big Bang Theory" star Jim Parsons. After much soul-searching, she agreed to be filmed.
But the segment didn't make the final cut, perhaps because Loreen represents a mystery that has not yet been translated into a cure for others. She was disappointed. But a psychological barrier had been crossed and she came to see that telling her story was a way to draw attention to controllers and the contribution they might make to finding a cure and perhaps a preventive vaccine for HIV.
Loreen also came to realize, and more importantly internalize, that she was no longer the same person she was in 1992. She knows through meticulously kept records that over the years she has donated to science more than the equivalent of every drop of blood that courses through her body: 91 billion immune cells through leukapharesis; 371 gut tissue samples gathered through more than a dozen colonoscopies and endoscopies; and countless swabbings, poking, and proddings associated with medical examinations.
Those experiences, plus years of reading scientific journals and going to conferences, engaging with researchers, and educating other controllers, have changed her from a scared patient to an empowered participant in the research process.
Loreen donating blood at her most recent visit to NIH, in June 2019. (Photo Credit: Bob Roehr)
Loreen donating blood at her most recent visit to NIH, in June 2019.
(Photo Credit: Bob Roehr)
She realizes that her life is likely to change after her full story becomes public, as the first known person to actually conquer HIV without any medical intervention. And she is resigned to paying that price to help advance the search for a cure.
Researchers believe they have figured out major pieces, but likely not all, of how Loreen's immune system controls HIV. They have hypotheses of how they might generate this same capacity within others using a therapeutic vaccine. But HIV has proven a wily adversary over the last four decades and their success is not assured.
The one thing they can say for certain is that Loreen will be there by their sides, even after death. She has willed her body to research and wears a pendant around her neck indicating the protocol on how it should be handled, so that Migueles can look in every organ for complete copies of the virus. Then science may finally lay to rest any doubts that her immune system has completely overcome HIV.
[Ed.Note: This article was originally published on October 16, 2019.]
On the one-year anniversary of the World Health Organization declaring SARS-CoV-2 a global pandemic, it's hard to believe that so much and yet so little time has passed. The past twelve months seem to have dragged by, with each day feeling like an eternity, yet also it feels as though it has flashed by in a blur.
Nearly everyone I've spoken with, from recent acquaintances to my closest friends and family, have reported feeling the same odd sense of disconnectedness, which I've taken to calling "pandemic relativity." Just this week, Ellen Cushing published a piece in The Atlantic about the effects of "late-stage pandemic" on memory and cognitive function. Perhaps, thanks to twelve months of living this way, we have all found it that much more difficult to distill the key lessons that will allow us to emerge from the relentless, disconnected grind of our current reality, return to some semblance of normalcy, and take the decisive steps needed to ensure the mistakes of this pandemic are not repeated in the next one.
As a virologist who studies SARS-CoV-2 and other emerging viruses, and who sometimes writes and publicly comments on my thoughts, I've been asked frequently about what we've learned as we approach a year of living in suspension. While I always come up with an answer, the truth is similar to my perception of time: we've learned a lot, but at the same time, that's only served to highlight how much we still don't know. We have uncovered and clarified many scientific truths, but also revealed the limits of our scientific knowledge.
The Most Important Lessons Learned
The dangers of false dichotomies.
From the early days, we have been guilty of binary thinking, and this has touched nearly every aspect of the pandemic. The following statements are not true, but the narratives are all too common: The only outcomes of COVID-19 are full recovery or death. Masks either work perfectly or they don't work at all. Transmission only occurs entirely by droplets or is entirely airborne. Children are either complete immune or they are equally as susceptible as adults. Vaccines either completely protect against infection and illness or they are completely useless. Any true student of biology can tell you that there are very rarely binary certainties that apply to every situation, but sensible public health advice can be rapidly derailed by discussing biological realities that exist on a continuum as if they are all categorically true or false.
It's a natural impulse to reduce complex systems to a choice of two options, and also to seek absolute certainty. A challenge for all scientists is how to communicate uncertainty when many people are understandably frustrated at this point and sick of hearing "we don't know." If we don't know now, when will we know? How much do we need to know to make good decisions? When will we get back to "normal"? In trying to simplify complex scientific concepts, we've made them hopelessly complicated. An important lesson going forward is that we should move away from black and white conversations about the emerging science and embrace the shades of gray, with all the nuance and uncertainty that entails.
Novel pandemic viruses can be controlled without a vaccine or effective antiviral therapeutics, and there is no one right way to do so.
Coronaviruses are very different from influenza.
Since the beginning of the pandemic, the superficial similarities between SARS-CoV-2 and influenza viruses have inevitably led to comparisons: both are primarily respiratory viruses with some symptoms in common, both have a relatively low overall mortality rate, both are zoonotic viruses that spilled over into the human population from animals, both are enveloped viruses that use RNA, rather than DNA, as their genetic material.
But these similarities disguise the fact that these are two fundamentally different pathogens. They have very different biology at virtually every step of the viral replication cycle, or the process that a virus goes through when it infects a cell and transforms it into a virus factory. SARS-CoV-2 enters cells by interacting with a protein on cell surfaces called ACE-2, while influenza viruses interact with a sugar molecule called sialic acid that "decorates" cell surface proteins. This means the viruses infect different types of cells in the respiratory tract and throughout the body. They also encode vastly different types of viral proteins meant to subvert and hijack the cells they infect: the genome of influenza virus is less than half the size of the genome of SARS-CoV-2, and encodes fewer than half as many viral proteins that can interact with the host cell.
As a result, these viruses each interact with host cells in unique ways and induce different responses to infection. The host response to infection is critically important for determining disease severity in both influenza and COVID-19, with the most severe disease associated with an uncontrolled inflammatory response that results in damaging the lungs and other affected tissues. Indeed, comparative studies have now shown that COVID-19 and influenza infection induce very different host response profiles in infected cells, leading to fundamentally different diseases. Our early reliance on pandemic response plans and public health strategies designed for influenza virus was a mistake, and this will be critical to preparedness and improved response plans going forward.
Transmission is situational.
Another way in which SARS-CoV-2 is very different from influenza is how it spreads through a population, which is relevant to how it is transmitted. Early on, many people focused on the fact that the basic reproduction number (R0) of SARS-CoV-2 was between 2 and 4, similar to the 1918 influenza pandemic. R0 describes the number of people that an infected person will transmit the virus to, but this is an average.
Another key measurement epidemiologists use to look at spread is dispersion, or patterns of transmission. If R0 is 2, and you have a population of 10 people, does that mean that all 10 people transmitted the virus to exactly 2 people? Or did 4 of the people each transmit to 5 people, with the other 6 of the 10 transmitting to nobody? In both situations, the average number of new infections is still 2, but the latter situation is described as overdispersion. While influenza is typically not very overdispersed, SARS-CoV-2 is heavily overdispersed. This is reflected in the high frequency of "superspreading events", where many people are infected at the same time.
Superspreading events are highly dependent on circumstances that need to align to create a conducive environment for transmission. SARS-CoV-2 is primarily transmitted by either inhalation of infectious aerosols (smaller respiratory particles suspended in the air) or direct contact with infectious droplets (larger respiratory particles that can be transferred from the body to the nose or mouth). This means that transmission is more likely to occur in situations with increased exposure risk. The risk is additive, with the likelihood of transmission being higher with more potential sources of virus (people from different households), higher respiratory particle emissions (lack of masks and/or shouting or singing), a physical environment that concentrates potentially infectious particles (an enclosed, poorly ventilated indoor space), close physical proximity (crowding), and increased exposure time.
We have seen repeatedly that when these conditions are met, such as in crowded bars or restaurants, gyms, cruise ships, buses, or weddings, superspreading can occur. The good news, however, is that identifying all these different risk factors has also allowed us to identify methods to mitigate transmission, and these are also additive: masks, physical distancing, avoiding enclosed spaces, limiting interactions with people outside your household, improving ventilation, and practicing good hand hygiene all reduce exposure risk.
Presymptomatic and asymptomatic transmission are critical to controlling a pandemic.
Another critical early mistake was assuming that SARS-CoV-2 would be transmitted only by symptomatic people. This was an understandable assumption to make, as people infected with "classic" SARS-CoV reliably developed fevers and could be identified based on body temperature and symptom screening. However, by March 2020, it was apparent that symptom-based screening was inadequate. The symptoms of COVID-19 fall along a very broad spectrum, ranging from completely asymptomatic infection to lethal pneumonia, with everything from loss of taste and smell to "COVID toes" to diarrhea to kidney failure to strokes in between.
Furthermore, last spring several studies showed that viral loads in the nose and throat were highest at the time of symptom onset, suggesting that people were likely to be contagious before they would be aware that they were sick. This created a tremendous challenge that repeatedly thwarted efforts to control community transmission in many countries, including the U.S. Without sufficient testing and surveillance, and with prevalence too high to enable robust contact tracing, efforts to identify and quarantine exposed people were unsuccessful. While the percentage of cases resulting from silent asymptomatic or presymptomatic transmission is still not precisely determined, it may account for nearly half of new infections and has been observed repeatedly. However, our policies have not caught up, and overeager reopening and blanket lifting of mask mandates often fail to account for contagious people who don't realize they are infected. Unfortunately, it's now also well-established that prematurely letting up on precautions can drive new surges in case numbers.
There's more than one way to stop a pandemic. While we've certainly seen examples of failed pandemic responses by looking at the U.S. and most of Western Europe, there have been a number of other countries that have very effectively controlled the pandemic within their borders. This hasn't been a one-size-fits-all approach, either. China infamously instituted a draconian lockdown in late January after the pandemic quickly spread from Wuhan to the rest of the country. A number of other countries, including Taiwan, Hong Kong, South Korea, Vietnam, Australia, New Zealand, and Japan, have implemented various combinations of policy measures (travel restrictions, lockdowns), epidemiological approaches (contact tracing, isolation and quarantine), data collection (testing capacity and surveillance), and mitigation measures (mask availability and mandates, exposure risk reduction education campaigns), that have effectively kept prevalence low and in some cases eliminated COVID-19 altogether. It shows that novel pandemic viruses can be controlled without a vaccine or effective antiviral therapeutics, and also that there is no one right way to do so.
We can develop safe, effective vaccines in record time.
Last March, Dr. Anthony S. Fauci estimated that a vaccine might be available in 12 to 18 months. At the time this was thought to be an extremely optimistic estimate, given that vaccines typically take years to design, develop, and test to ensure they are safe and effective. So how did we go from the drawing board to authorized vaccines, which so far appear to be very safe and effective, in less than a year? In part this is due to streamlining the clinical trial process, allowing previously sequential steps in the pipeline to occur simultaneously, such as phase 3 clinical trials and manufacturing.
The expedited trial process also built upon previous studies with the vaccine technologies, including extensive preclinical studies and clinical trials that tested mRNA (Pfizer/BioNTech and Moderna) and adenovirus-vectored (Johnson and Johnson and AstraZeneca) vaccines against other viruses, including MERS-CoV, a cousin of SARS-CoV-2. Prior to the phase 3 clinical trials "reading out" (amassing enough data to enable a statistically robust appraisal of their safety and efficacy), our expectations were modest, hoping for 50 to 60% protection against COVID-19. Thus far, all the vaccines that have completed phase 3 trials have exceeded that expectation. While future vaccines will likely still take years to fully evaluate, we can apply the achievements of the SARS-CoV-2 vaccines to make the regulatory process more efficient for other vaccines, as well as develop ways to further expedite the process in emergencies without compromising safety or effectiveness. A more efficient regulatory environment could improve access to other technologies, such as promising new tests and therapeutics, as well.
The Biggest Unknowns
While we have made extraordinary strides forward in better understanding SARS-CoV-2 and both the triumphs and the failures of the response to the greatest public health challenge of our lifetime, the lessons we've learned have highlighted the many questions that remain. We will be studying many aspects of the pandemic for decades. Long after SARS-CoV-2 is finished with humanity on a global scale, we will not be finished with it. Some of these remaining questions won't have easy answers, and in fact may not even be answerable. But it is critical to engage with these questions as we move into a post-pandemic future.
The origin of SARS-CoV-2.
This topic is as confusing and murky as it is contentious, proving to be as confounding to science as it is disruptive to geopolitics. Multiple hypotheses abound: SARS-CoV-2 emerged into the human population naturally, passing from an infected animal to an unlucky human in the wrong place at the wrong time in a process called zoonotic spillover. This natural origin hypothesis is considered the most likely, as this is overwhelmingly the most common path for novel viruses to emerge in the human population.
Tracing SARS-CoV-2 back to its source is critical for both understanding how this pandemic began and preventing the emergence of SARS-CoV-3, which almost certainly is circulating in wildlife along with a frighteningly large number of other potential pandemic pathogens.
However, the evidence supporting this hypothesis is scant, and limited to genetic analyses that don't indicate anything artificial or engineered about the SARS-CoV-2 genome, as well as some very small studies suggesting that people who live close to bat caves in southern China have antibodies to closely related viruses. Such uncertainty has led to several other hypotheses, including that the virus emerged from a laboratory at the Wuhan Institute of Virology, either through accident or design. While there is far more speculation than evidence affirming any laboratory origin hypothesis, neither can be definitively excluded and both should be fairly investigated. In addition, the Chinese government has suggested that SARS-CoV-2 was imported via frozen seafood from Europe or North America. This hypothesis strains credulity, given that the most closely related viruses have been identified in China and transmission by indirect contact (with contaminated objects, or fomites, is thought to be uncommon), but it still should be ruled out objectively.
About the only thing most experts agree on is that SARS-CoV-2 evolved from an ancestral betacoronavirus that likely was circulating in bats. However, because we have not yet found that ancestral virus in nature, we are left still looking. Sometimes origin investigations into zoonotic origins can take decades, since we live in a big world, with many wild animals carrying many different viruses at different times in their lives. Trying to find the immediate forbear of SARS-CoV-2 in wildlife is like seeking a very specific tiny needle in a planet-sized haystack that is also littered with other tiny needles.
To further complicate matters, there is the possibility that SARS-CoV-2 did not spill over from bats to humans directly, but stopped off in another species along the way. Intermediary species have been involved in the transmission of both SARS-CoV and MERS-CoV, and we already know that SARS-CoV-2 can infect other animal species, including minks, dogs, and cats.
And if the science weren't complex enough, conducting any type of origin investigation, but particularly a rigorous independent investigation of lab origin theories, depends on other countries maintaining a productive diplomatic relationship with the Chinese government. That relationship erodes every time another piece is published outside China that treats laboratory origin as a foregone conclusion. Tracing SARS-CoV-2 back to its source is critical for both understanding how this pandemic began and preventing the emergence of SARS-CoV-3, which almost certainly is circulating in wildlife along with a frighteningly large number of other potential pandemic pathogens. But it won't be easy and we need to prepare ourselves for the possibility of a very long and arduous search for answers.
The long-term consequences of COVID-19.
While it is not clear how common "long COVID" is, one thing is certain: it has impacted a substantial number of COVID-19 survivors' lives. It remains unknown what predisposes a person to this outcome, now dubbed post-acute sequelae of COVID-19 (PASC). Nor does anyone truly know how long it lasts, or even what the most common presentation of it looks like. Many patients have reported a diverse array of symptoms, some very severe, that have persisted for months.
PASC can range from recurring neurological problems to hair and tooth loss to permanent lung injury. Some people have reported relapsing pain and severe fatigue similar to myalgic encephalomyelitis or chronic fatigue syndrome. Even more troubling, PASC can be severe in patients who reported having extremely mild acute COVID-19. Last month, the National Institutes of Health announced plans to study PASC in detail, but it may be some time before we know the cause (or causes) of PASC, much less how to treat it and ameliorate its impact on those suffering from it. But the potential for long-term debilitating illness persisting long after the resolution of acute SARS-CoV-2 infection suggests that even when the pandemic is behind us, public health will continue to struggle with the legacy of COVID-19.
Immune correlates of protection and durability.
While vaccine trials were designed to sacrifice little in the way of assessing short-term efficacy, they did not assess the length of time that protective immunity will last. This was because of the urgency of the situation, and allowed us to begin vaccinating as soon as we learned that the vaccines were safe and effective in the short term. Durability studies are one reason why normally vaccine trials can take over a decade, as unfortunately the only way to assess how long a vaccine lasts is to wait and see when protection begins to wane.
Furthermore, because the virus is novel and the technologies underlying the vaccine platforms are being used for the first time at population scale, we haven't yet defined correlates of protection for the vaccines. Correlates of protection are easily measurable features, such as antibody levels or cell counts, that can be used as surrogates for vaccine function. In other words, what we are missing is the knowledge of how many antibodies, or T-cells, does your immune system actually need to protect you from infection? We know that a high number is protective, but the question is how high.
Until we have enough data to define these correlates, we have to continue to follow trial participants and analyze observational studies of vaccinated individuals, which can be tedious as well as time-consuming. So it may be some time before we can advise people confidently about how long vaccine protection will last beyond a year or so, based on the duration of immune function in people who have recovered from natural SARS-CoV-2 infection. The good news is that protective immune responses can be easily restored with a booster shot, but that will present major logistical challenges if needed while global immunization efforts are still underway.
What price will we pay for nationalizing vaccine responses?
Finally, one of the biggest questions as we move into the post-pandemic future in the developed world is what the decision to respond nationally, rather than as a cooperative global community, will cost us in terms of truly ending the pandemic. Without question, in countries like the U.S., which will have enough vaccine doses in the next few months to vaccinate every American who wants one, the pandemic will end for most people's daily lives. But globally, the reality is very different. Many countries have yet to administer a single dose of any vaccine. While this may not seem relevant to people who do not intend to travel to those countries, it is relevant to every human being on earth. None of us are safe until all of us are safe.
Viruses infect their hosts regardless of what passport they carry. Pandemics, by definition, are global epidemics, and thus impact the global population. If people are vaccinated only in certain countries, SARS-CoV-2 can continue to circulate in populations with less immunization and fewer barriers to infection. As the U.S. today reaches this grim anniversary along with the rest of the world, we would do well to remember the lessons we've learned as we forge ahead with filling the remaining gaps in our knowledge.
No, the New COVID Vaccine Is Not "Morally Compromised"
The approval of the Johnson & Johnson COVID-19 vaccine has been heralded as a major advance. A single-dose vaccine that is highly efficacious at removing the ability of the virus to cause severe disease, hospitalization, and death (even in the face of variants) is nothing less than pathbreaking. Anyone who is offered this vaccine should take it. However, one group advises its adherents to preferentially request the Moderna or Pfizer vaccines instead in the quest for morally "irreproachable" vaccines.
Is this group concerned about lower numerical efficacy in clinical trials? No, it seems that they have deemed the J&J vaccine "morally compromised". The group is the U.S. Conference of Catholic Bishops and if something is "morally compromised" it is surely not the vaccine. (Notably Pope Francis has not taken such a stance).
At issue is a cell line used to manufacture the vaccine. Specifically, a cell line used to grow the adenovirus vector used in the vaccine. The purpose of the vector is to carry a genetic snippet of the coronavirus spike protein into the body, like a Trojan Horse ferrying in an enemy combatant, in order to safely trigger an immune response without any chance of causing COVID-19 itself.
It is my hope that the country's 50 million Catholics do not heed the U.S. Conference of Bishops' potentially deadly advice and instead obtain whichever vaccine is available to them as soon as possible.
The cell line of the vector, known as PER.C6, was derived from a fetus that was aborted in 1985. This cell line is prolific in biotechnology, as are other fetal-derived cell lines such as HEK-293 (human embryonic kidney), used in the manufacture of the Astra Zeneca COVID-19 vaccine. Indeed, fetal cell lines are used in the manufacture of critical vaccines directed against pathogens such as hepatitis A, rubella, rabies, chickenpox, and shingles and were used to test the Moderna and Pfizer COVID-19 vaccines (which, accordingly, the U.S. Conference of Bishops deem to only raise moral "concerns").
As such, fetal cell lines from abortions are a common and critical component of biotechnology that we all rely on to improve our health. Such cell lines have been used to help find treatments for cancer, Ebola, and many other diseases.
Dr. Andrea Gambotto, a vaccine scientist at the University of Pittsburgh School of Medicine, explained to Science magazine last year why fetal cells are so important to vaccine development: "Cultured [nonhuman] animal cells can produce the same proteins, but they would be decorated with different sugar molecules, which—in the case of vaccines—runs the risk of failing to evoke a robust and specific immune response." Thus, the fetal cells' human origins are key to their effectiveness.
So why the opposition to this life-saving technology, especially in the midst of the deadliest pandemic in over a century? How could such a technology be "morally compromised" when morality, as I understand it, is a code of values to guide human life on Earth with the purpose of enhancing well-being?
By any measure, the J&J vaccine accomplishes that, since human life, not embryonic or fetal life, is the standard of value. An embryo or fetus in the earlier stages of development, while harboring the potential to grow into a human being, is not the moral equivalent of a person. Thus, creating life-saving medical technology using cells that would have otherwise been destroyed is not in conflict with a proper moral code. To me, it is nihilistic to oppose these vaccines on the grounds cited by the U.S. Conference of Bishops.
Reason, the rational faculty, is the human means of knowledge. It is what one should wield when approaching a scientific or health issue. Appeals from clerics, devoid of any need to tether their principles to this world, should not have any bearing on one's medical decision-making.
In the Dark Ages, the Catholic Church opposed all forms of scientific inquiry, even castigating science and curiosity as the "lust of the eyes": One early Middle Ages church father reveled in his rejection of reality and evidence, proudly declaring, "I believe because it is absurd." This organization, which tyrannized scientists such as Galileo and murdered the Italian cosmologist Bruno, today has shown itself to still harbor anti-science sentiments in its ranks.
It is my hope that the country's 50 million Catholics do not heed the U.S. Conference of Bishops' potentially deadly advice and instead obtain whichever vaccine is available to them as soon as possible. When judged using the correct standard of value, vaccines using fetal cell lines in their development are an unequivocal good -- while those who attempt to undermine them deserve a different category altogether.
Dr. Adalja is focused on emerging infectious disease, pandemic preparedness, and biosecurity. He has served on US government panels tasked with developing guidelines for the treatment of plague, botulism, and anthrax in mass casualty settings and the system of care for infectious disease emergencies, and as an external advisor to the New York City Health and Hospital Emergency Management Highly Infectious Disease training program, as well as on a FEMA working group on nuclear disaster recovery. Dr. Adalja is an Associate Editor of the journal Health Security. He was a coeditor of the volume Global Catastrophic Biological Risks, a contributing author for the Handbook of Bioterrorism and Disaster Medicine, the Emergency Medicine CorePendium, Clinical Microbiology Made Ridiculously Simple, UpToDate's section on biological terrorism, and a NATO volume on bioterrorism. He has also published in such journals as the New England Journal of Medicine, the Journal of Infectious Diseases, Clinical Infectious Diseases, Emerging Infectious Diseases, and the Annals of Emergency Medicine. He is a board-certified physician in internal medicine, emergency medicine, infectious diseases, and critical care medicine. Follow him on Twitter: @AmeshAA