"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.
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.
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.
"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."
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.]
Making Sense of Science features interviews with leading medical and scientific experts about the latest developments and the big ethical and societal questions they raise. This monthly podcast is hosted by journalist Kira Peikoff, founding editor of the award-winning science outlet Leaps.org.
Episode 1: "COVID-19 Vaccines and Our Progress Toward Normalcy"
Bioethicist Arthur Caplan of NYU shares his thoughts on when we will build herd immunity, how enthusiastic to be about the J&J vaccine, predictions for vaccine mandates in the coming months, what should happen with kids and schools, whether you can hug your grandparents after they get vaccinated, and more.
KIRA: Hi, and welcome to our new podcast 'Making Sense of Science', the show that features interviews with leading experts in health and science about the latest developments and the big ethical questions. I'm your host Kira Peikoff, the editor of leaps.org. And today, we're going to talk about the Covid-19 vaccines. I'm honored that my first guest is Dr. Art Caplan of NYU, one of the world's leading bio-ethicists. Art, thanks so much for joining us today.
DR. CAPLAN: Thank you so much for having me.
KIRA: So the big topic right now is the new J&J vaccine, which is likely to be given to millions of Americans in the coming weeks. It only requires one-shot, it can be stored in refrigerators for several months. It has fewer side-effects and most importantly, it is extremely effective at the big things, preventing hospitalizations and deaths. Though not as effective as Pfizer and Moderna in preventing moderate cases, especially potentially in older adults with underlying conditions. So Art, what's your take overall, on how enthusiastic Americans should be about this vaccine?
DR. CAPLAN: I'm usually enthusiastic. The more weapons, the better. This vaccine, while maybe, slightly less efficacious than the Moderna and the Pfizer ones, is easier to make, is easier to ship. It's one-shot. You know, here there's already been problems of getting people to come back in for their second shots. I would say 5... 7% of people don't show up even though you remind them and you nag them, they don't come back. So a one-shot option is great. A one-shot option that's easy to, if you will, brew up in your rural pharmacy without having to have special instructions is great. And I think it's gonna really facilitate herd-immunity, meaning, we'll see millions and millions and millions of doses of the Janssen vaccine out there as an option, I'm gonna say, summer.
KIRA: Great. And to be fair, it's worth mentioning that the J&J vaccine was tested in clinical trials after variants began to circulate, and it's only one-shot instead of two, like the other vaccines, and it gets more effective over time. So is it really fair to directly compare its efficacy to the mRNA vaccines?
DR. CAPLAN: Well, you know, people are gonna do that. And one issue that'll come up ethically is people are gonna say, "Can I choose my vaccine? I want the most efficacious one. I want the name brand that I trust. I don't want the new platform. I like Janssen's 'cause it's an older, more established way to make vaccines or whatever." Who knows what cuckoo-cockamamie reasons they might have. To me, you take what you can get, it'll be great. It's way above what we normally would expect, those 95% success rates are off the charts. Getting something that's 70% effective, it's perfectly wonderful. I wish we had flu shots that were 70% effective.
And the other thing to keep in mind is we're gonna see more mutations, we're gonna see more strains. That's just a reality of viruses. So they'll mutate, more strains will appear, we can't just say, "Oh my goodness. There's a South-African one or the California one or the UK one. We better... I don't know, do something different." We're just gonna have to basically resign ourselves, I think, to boosters. So right now, take the vaccine. I'm almost tempted to say, "Shut up and take the vaccine. Don't worry about choosing."
Just get what you can get. If you live in a rural community and all they have is Janssen, take it. If you're in another country and all they ship to you is Janssen, take it. And then we'll worry about the next round of virus mutations, if you will, when we get to the boosters. I'm more concerned that these things aren't gonna last more than a year or two than I am that they're not gonna pick up every mutation.
KIRA: So on that note, shipping to rural places or low-income countries that lack the ultra-cold freezers that you need for the super effective mRNA vaccines, the Janssen vaccine seems like a really great option, but are we going to encounter a potential conflict of people saying, "Well, there's "poor or rich vaccines," and one is slightly less effective than the other." And so are we gonna disenfranchise people and undermine their actual willingness to take the vaccine?
DR. CAPLAN: Well, it's interesting. I think the first problem is gonna be, "I have vaccine and I don't have any vaccine," between rich and poor countries. Look, the poor countries are screaming to get vaccine supply sent to them. I think, for example, Ghana received recently 600 million doses of AstraZeneca vaccine. It was freed up by South Africa, which decided they didn't wanna use it 'cause they thought there was "a better vaccine" coming. So even among the poorer nations or the developing nations, some vaccines are getting typed as the not-as-good or the less-desirable... We've already started to see it.
But for the most part, the rich countries are gonna try and vaccinate to herd immunity, you can argue about the ethics of whether that's right, before they start sharing. And I think we'll have haves and have-nots, herd immunity produced in the rich countries, Japan, North America, Europe, by the end of the year anyway. And still some countries floundering around saying, "I didn't get anything," and what are you gonna do?
KIRA: And I know you said to people, which is a very memorable quote, "just shut up and take the vaccine, whatever you can get, whatever is available to you now, do it." But inevitably, as you mentioned, some people are going to say, "Well, I just wanna wait to get the best one possible." When will people have a choice in vaccines, do you think?
DR. CAPLAN: I don't think you'll see that till next year. I think we're gonna see distribution according to where the supply chains are that the vaccine manufacturers use. So if I use McKesson and they ship to the Northeast, and that's where my vaccine goes, that's what's available there. If I'm contracted to Walmart and they buy Janssen, that's what you're gonna see at the big box store. I don't think you're really gonna get too much in the way of choice until next year, when then they're gonna say they ship three different kinds of vaccine, and I can offer you one dose or two dose... One of them lasts a year, one of them lasts 18 months. I don't think we're gonna have the informed choice until next year.
KIRA: Okay. And right now the steep demand is outstripping the supply, and there's been a lot of pressure put on the vaccine makers to ramp up as quickly as possible. Of course, they say that they're doing that and the government is pressuring them to do that, but when do you think we'll cross over to the point where vaccine hesitancy is a bigger issue than vaccine demand?
DR. CAPLAN: Yeah. So this is a really interesting issue. I'm glad you asked me this because I think it's got good foresight. The big ethics fight now is scarcity and who goes first, and the ethicists, including me, are having a fine old time arguing about healthcare workers versus policemen versus people who work for UPS versus somebody who's working at the drug store. Who's more important? Why are they more important? Who's essential?
Actually, I think most of that is nonsense, because what we've learned is that you can't do much in the way of micro-allocation, the system strains, and it doesn't work. You've gotta use some pretty broad categories like over 65, still breathing and working, and a kid. The kid will go last, 'cause we don't have the data, everybody else should get in line and the over 65s should probably be first 'cause they're at high risk. We can't do this. We stink at the micro-management of vaccine supply, plus it encourages cheating. So everybody's out there with vaccine hunters, vaccine tourism, bribing, lying, dressing up like a grandmother to get a vaccine. My favorite one was some rich people in Vancouver flew up to the Yukon and pretended to be Inuit aboriginal people to get a vaccine. That will all pass.
We'll have enough vaccine by the summer, more or less, that the issue will then be, "How are we gonna get to herd immunity or at least maximal immunity, knowing that we don't have data on kids?" People under 18, I think are something like 20% of our population. That means the best you could do is 80%. The other population still could be passing the virus, kids here or Europe or wherever. Well, the military refusal rate that I just saw was 30% saying no. I've heard nursing home staff rates, nursing attendants, nursing aids up at 40% to 50% saying no. So these are huge refusal rates, people are nervous about how it works, the vaccine. Some of them are like, "Well Art you take it. If you're still alive in six months, then maybe I'll take it, but I wanna see that it really works and it's safe." And other people say, "We don't wanna be exploited. We don't trust the government, whatever, to offer us these vaccines."
I'm gonna answer that was a long-winded way of saying we're gonna see some mandates, we're gonna see some coercions start to show up in the vaccine supply, because I think, for example, the military. The day one of these license gets... Excuse me, one of these vaccines get licensed, right now they're on an emergency approval, collect data for three or four more months, get the FDA to formally license the thing. I'd say between five minutes and 10 minutes, the military will be mandating. They have no interest in your objection, they have no interest in your choice, they know what the mission is. It's traditionally, we're gonna get you as healthy as we can to fight a war.
The fact that you say, "Gee, I might die." They kind of say, "Yeah, we noticed that, but that's in the military culture. We fight wars and do stuff like that." So they'll be mandating, I think, very rapidly. And I think healthcare workers will. I think most hospitals are gonna say 50% refusal rate among this nursing group? Forget it. We can't risk that. Nursing homes have been devastated by COVID. They're not gonna have aids out there unvaccinated. The only thing holding up the mandates right now is that we don't have full licensure. We have emergency use approvals, and that's good.
But it's a little tough to mandate without full license. The day we get it, three months, four months, we're gonna start to see mandates. And I'll make one more prediction, as long as I'm in a crystal ball mode. It won't be the government at that point that says, you have to be vaccinated. It'll be private business, 'cause they're gonna say, "You know what? Come on my cruise ship, 'cause everybody who works here is vaccinated." "Come on into my bar, everybody who works here is vaccinated." They're gonna start to use it as an advertising marketing lure. "It's safe here. Come on in." So I think they'll say, "If you wanna work on an airline as a flight attendant, you get vaccinated. We have vaccine proof. You can show it on your iPhone, on your whatever, you have a card that you did it." And so I think we'll see many businesses moving to vaccinate so that they can bring their customers back in.
KIRA: So private businesses, that's one thing, because people do not have to patronize those places if they don't wanna get vaccinated. But of course, this is gonna open up a can of worms with schools. Public schools, if they mandate teacher vaccines and you have to send your kid to school and you have to go to work at a school. What happens then?
DR. CAPLAN: Well, schools are gonna be at the end of the line. That's where we have the least data. So I don't think we're gonna see school mandates on kids, maybe not till next year. But we already have school mandates on kids. They were the first group to feel the force of mandates, because it turns out that measles and mumps and whooping cough are easy to get at school, sneezing and coughing on one another. Some states have added flu shots. Many states, California, Maine, New York have actually eliminated exemptions. The only way out for those kids is if they have a health reason. They're not even allowing religious or so-called philosophical or personal choice exemptions. COVID vaccines will just line up right next to those things.
Teachers will demand it, the pressure will be there. We'll have a lot of information by next year on safety. I'm even gonna say people are gonna be less tolerant of non-vaccinators. Now it's sort of like, "Wow. Yeah, I guess." But this time next year, if you haven't vaccinated, people are gonna come to your house and board it up and make you stay inside.
KIRA: Well, given how much we're so dependent on these vaccines to get us back to a regular life, I can understand the sentiment. What is your take on the big controversy right now, just going back towards the present day a little bit more on having kids in schools. Is that something you support before all the teachers have been vaccinated?
DR. CAPLAN: I do, but I have a problem with the definition of a teacher and a school. So by the way, some people that I know, friends of mine have said, "Well, I'm a teacher, I'm a yoga instructor. I'm a teacher, I'm an aerobics instructor. So I should get priority access to vaccination." I don't think that's what we meant by teacher. And here's the difference in schools. I live in Ridgefield, Connecticut. Up the street for me is a very fancy private elementary school. It has endless grounds, open classrooms. If there are eight kids in a class, I'll pass out. It is great. I wish I went to college there. It's a wonderful set up. Do they need to vaccinate everybody? Probably not, they're all sitting six feet apart, everybody in there is gonna mask, they have huge auditoriums. They never have to come in contact.
I've been in some other schools in the Bronx. No ventilation, no plumbing, 35 kids in a class, the teacher's 65. And you sort of think, "Boy, I'd wanna have vaccinate everybody in sight in this place because unless we re-haul the buildings and downsize the class size, people are gonna get sick in here."
They probably were getting sick anyway before COVID, but now COVID makes it worse. They're probably getting the flu or colds at nine times the rate that they were in Ridgefield, Connecticut. So my point is this, high school kids doing certain things, they can come in on a mixed schedule three days a week, two days a week, do their thing, they know how to mask. Am I worried about vaccinating there? Not too much. Elementary school kids need psychosocial development, need to learn social skills, sometimes going to schools that aren't that wonderful. Yeah, let's vaccinate them. So even though I was complaining a bit about micro-management and trying to parse out, here I think you need to do it. I think you're probably gonna say college, I don't know that you have to vaccinate there. High schools, 50/50. Elementary school, let's do them first.
KIRA: Got it. And one more question on kids before I wanna move on, there's been talk about whether it's necessary before kids are allowed to get this vaccine to have the FDA go to full approval with the full bulk of data necessary for that versus just an emergency authorization for the general population, given that kids are at so much lower risk than adults. But then of course, it'll take a lot more time, I imagine, to get the kids the vaccines. What's your take on that?
DR. CAPLAN: We historically have demanded higher levels of evidence to do anything with a kid, and I think that's gonna hold true here too. I don't think you're gonna see emergency-use authorization for people under 18. Maybe they'd cut it and say, "We'll do it 12-18," but just looking at the history of drug development, vaccine development, people are really leery of taking risks with kids and appropriately so. Kids can't even make their own decision. I can decide if I wanna take an emergency-use vaccine, if I think it's too iffy I don't take it right now. So up to me to weigh the risk-benefit. I don't think so. I think you'll see licensing required before we really get it, at least 12 and under. Let's put it there. And I'm not worried about the safety or efficacy of these things in kids. I think there's no reason, given the biological mechanisms, to think they're gonna be any different. But it's gonna be pretty tough pre-licensure to impose anything.
KIRA: And when do you think that licensure for kids under 12 could come?
DR. CAPLAN: Well, two groups of people are now being studied, pregnant women, the studies just launched. They'll probably be done sufficiently by the end of the year. Kids for full licensure, spring next year.
KIRA: Okay. And because this is a big question for a lot of women that I know and women in general who are pregnant, what would you say to them now, where we don't have the data yet on the safety, but they have to decide and they can't wait six or nine more months?
DR. CAPLAN: Vaccinate yesterday. Literally, I think the COVID virus is too dangerous, I think it's dangerous to the mom, I think it's dangerous to the fetus. It is an unknown, but boy, I would bet on the vaccine more than I would taking my chances with the virus.
KIRA: Got it. So let's pivot a little bit and talk about some of the big open questions around the vaccines that we're starting to get some early evidence about. For one thing, do they prevent transmission and not just symptomatic disease. And I think it's worth pointing out for our audience here that there is a big difference between preventing symptoms and preventing infections, as lots of asymptomatic people know. And we have a lot of new real-world evidence from Israel, from Scotland, reporting that even asymptomatic infections are greatly reduced by the Pfizer vaccine, for example. What is your take on how this new data is going to change guidance around post-vaccination behaviors?
DR. CAPLAN: Yeah. What do we got in the podcast? Seven or eight hours to go? That's a tough one. It's complicated. But trying to over-simplify a little bit. So there is a difference, and this has gotten confusing, I fear. Some vaccines prevent you from getting infected at all. It looks like the Pfizer and the Moderna fall into that category. That's great, 'cause no matter what else, it probably means you're gonna reduce transmission, 'cause if you can't be infected, I don't know how you're gonna give it to somebody else. So I'll bet that that's a transmission reduction. Looks like Johnson & Johnson, unclear. Seems to prevent bad symptoms and death but not moderate disease, and it isn't clear that it stops you from getting infected. So that may become an issue in terms of how we strategically approach when we have enough vaccine of the different types. We may wanna say, "Look, in some environments, we've gotta control spread... Nursing home. We wanna see the Moderna there. We wanna see the Pfizer there."
In other situations, we just wanna make sure you're not dead, let's get the Janssen thing out there. And that'll be great. I'll tell you... I'll give you an example from my own current existence. So I've been pretty cautious... As I said, I live in Ridgefield, Connecticut. I have a house, pretty roomy, but I haven't left it very often. I'm willing to take the chance to go shopping. I'll confess I'm even willing to take the chance wearing a mask to go to the drug store and I've had a hair-cut or two. So I've been not hyper-cautious, but cautious. I don't invite people over that I don't know where they've been, so to speak. But now I'm vaccinated, and my wife is fully vaccinated. And the other night for the first time, we went out to an indoor restaurant. Probably haven't done that in 10 months... No, I don't know, six months. But a long time...
KIRA: I hope you really enjoyed that first meal out, 'cause that's something that I dream about. Boy, where am I gonna go and what am I gonna order?
DR. CAPLAN: Yeah. We went to the fanciest restaurant in town, as a matter of fact, and they were social distancing and everybody was masked and the wait staff. But I figure, good enough for me. If the thing isn't gonna kill me, if I was just told I was gonna have a risk of being sick for three days or something, that's good enough for me. I don't wanna infect somebody else. So I'll still mask and do that, I'm not sure. But I'm absolutely ready to say, and in fact, I've scheduled two trips. We're gonna take a trip to Florida, we're gonna take a trip to North Carolina in March and April. I'm figuring even then, things will be better. But everybody's gonna have choices like that to make. It'll be really interesting. If I'm Tony Fauci or one of our big public health guys, I don't want anybody going anywhere, I'm risk-averse, until maybe 2027. I think it'll be controlled and eliminated... We'll have lots of data and everything will be great. I'm a little bit more, shall we say, individual choice-oriented, making individual risk things, like I said. As long as I'm responsible to others.
I don't wanna make anybody else sick, but if I am ready to take the chance of just being sick for a few days, and I believe the vaccines available will keep me out of the hospital and keep me out of the Morticians building. Okay, I'm ready to do it. So each one of us is gonna have to make a value decision, this is what I find interesting, about what's normal. It isn't science. It isn't medicine. It's ethics. You're gonna have to decide how much risk do you wanna take. Do you wanna be a jerk to your neighbor, if you could still have a teeny chance of infecting them? Am I willing to live in a world where COVID is around but it's kinda rare? I know kids are still transmitting, but it's not really a huge risk. That's the kind of value choice that each of us will be faced with.
KIRA: I really appreciate your emphasis on individual choice and values here and letting... Basically allowing people to make those judgments based on their circumstances for themselves. If you're not deathly afraid of getting a mild cold-type illness, then I can understand why you wanna fly or go to a restaurant, and other people might not be comfortable with any risk at all, and they're perfectly welcome to stay home.
DR. CAPLAN: Or they may say, "I'm 80, I have nine chronic diseases. A mild illness still freaks me out." Okay, I get that. I'm perfectly respectful of that. It's interesting. I think we've been used to public health messaging, and people have this attitude that at some point, Fauci or the head of the CDC, somebody's gonna show up on TV and say, "All clear, everything's over, back to normal, we've declared victory over the enemy. It's armistice day." Whatever. It isn't gonna work like that is my prediction. It's gonna be a slow creep, different people deciding, "I'm safe enough, I'm wandering out." Other people say, "No, no, not ready." Or somebody saying, "I'm pregnant. I'm staying in. I don't care what's going on. I'm not gonna take that risk." I think people will be surprised that there isn't going to be a national day of resolution or something. [chuckle]
KIRA: Right. It's more about these individual behaviors and over time, letting people decide what to do. So for example, if you had grandkids and they were not vaccinated, but you are, would you hug them, would you get close to them, how would you behave and how do you think they should behave around you?
DR. CAPLAN: So I'd be still nervous about them transmitting, but I'm also a very strong believer in my vaccine. So yes, I would hug them, and yes, I would have them come to visit. And that's probably gonna happen actually fairly soon. But their parents aren't vaccinated yet. And so I'm still nervous that maybe better not to do a lot of social mingling right now. But yeah, people have said to me, "My grandmom is 94. I don't know how long she's gonna be here. You think if I'm vaccinated it's okay to pay a visit." I'm gonna start to say, "Yeah, I get that."
KIRA: And I think one thing that's lost in these discussions of safety is also the aspect of benefits to human life and why we even live in the first place. We don't live lives of complete safety. We drive, we fly, we do things that are risky, but we take those risks, because it's worth it. So I think that should be part of the discussion overall, not just safety, period.
DR. CAPLAN: And not just saving lives. So ski slopes, there are a lot of orthopedic clinics at the bottom of big ski slopes, and sending a message like, "You can break bones here." But people say, "I wanna do it, I enjoy it." Okay, I'm not sure all the time that we should factor all of that into our pooled insurance plan, but that's a fight for another day. Nonetheless, I would... You know something, I would pay for it 'cause I like to encourage people to enjoy themselves. So I have my bad habits, they have their bad habits. I think it's sort of a wash in a certain way. But more to your point, I think if you look out there and say, there are some areas where we don't let you choose. You must put your kid in a car seat. A kid can't make a decision, the thing is very effective, really saves their lives, they should have a life ahead of them, and we're gonna force it. And I'm all for that.
In other instances, I might go into the restaurant. I think it's part of the general, "Am I gonna drive a car, am I gonna cross a busy street... " As you said, there are many things I have to do where I have to think about the risk-benefit. I may make a lousy calculation and underestimate what it means to get in my car and drive in terms of risk relative to getting hit by lightening or some other risks, but that's a little bit more for me.
KIRA: So that's a really thought-provoking conversation, but I wanna switch for a minute to another question mark around the vaccines besides transmission, is the long-term studies of their effects on the immune system. And one thing that I've noticed some experts are concerned about is the fact that a lot of the people in the placebo groups have dropped out of the trials and gotten the vaccine because ethically you can't withhold the vaccinations from these volunteers, but at the same time, that could be hurting our ability to compare the vaccine's long-term effects against people who haven't had the vaccine for a long time. So how significant is this issue in your mind?
DR. CAPLAN: Big. Some people actually proposed that we not let them drop out, we not tell the subjects in these big trials of vaccines if they were in the placebo group. Can't do that. It's clearly unethical... Achieved consensus on that decades ago, with various studies where the researcher said, "We don't have to tell the subjects that there's a treatment." Tuskegee did that, for example, the horrible study in the early, late '60s, early '70s, where they didn't tell people there was a cure and kept the study going of venereal disease, but there have been many others since. We already know you gotta give them the option. Some people may stay in anyway, but not enough to allow the study to really have integrity. So I think current studies are likely to fall apart and we won't get answers in the way we're used to with randomized trials to the long-term effects or even to the how long does it last question.
We need to build a system that can follow people. We can't rely on them being in an observed clinical trial. We have to start to say, "You register, we're gonna check on you every year to see how you're doing." That's gotta be done. And one other provocative idea, I pushed it long ago, challenge studies. Deliberately infect a small group of people, hopefully healthy people that choose to do it with mild COVID and then see what the vaccine does in them and then get an answer faster if you study them over time, they volunteered knowingly to get exposed this way. I think you're gonna see some challenge studies done particularly to compare vaccines. There are still more vaccines coming, maybe some of them will last longer, cheaper, safer, I don't know. The only way you're gonna study the next round of vaccines is in a challenge study. You're never getting anybody to sign up to be in a placebo control randomized trial.
KIRA: So that was actually my next question, that the UK just approved the first ever challenge study to infect the volunteers on purpose with the virus. Now, the UK has often been much more progressive in doing medical research than the US. Do you think the US will ever get to that point or are we just gonna rely on other countries to do that for us?
DR. CAPLAN: I think we won't get there. We're so conservative, so litigation conscious. People are freaked out that if somebody got sick and died in a challenge study, it would bankrupt the sponsor. I think the UK is on the right path, but I don't really think we're gonna follow.
KIRA: Okay, well, I hope that they can do the work that we really need. And I'm grateful that there are other countries that are more permissive of risk-taking and doing the controversial studies that are required.
DR. CAPLAN: Ironically, if you don't do the challenge studies, the only other way you're gonna get to do big-scale randomized placebo trials is in the poorest countries that can't get anything. And that makes it an awful lot like exploitation, taking advantage, as opposed to choice. But that's where you'd go, you'd say, "Oh, I got this new vaccine, I'll test it out in Sierra Leone and they don't have anything anyway. So better that half of them get the vaccine than not." And I still think the challenge study makes more ethic sense.
KIRA: Yeah, absolutely. That would really be a shame to be put in that position instead of just allowing people to decide. We let people sign up for the army where they might die. What's the ethical difference with signing up for a potentially dangerous study, but if you're young and healthy, the risk is low?
DR. CAPLAN: By the way, the risk from COVID to say, 18 to 35-year-olds, who's who you'd be looking at, is about the same as donating a kidney, which we also allow all the time.
KIRA: Right, right. Great point. Before we finish up here, I just wanna quickly touch on, of course, the big elephant in the room, which we all have to deal with, unfortunately, which is the variants. So I wanna talk about where we stand. I've heard some vaccine experts recently say, like Paul Offit, for example, has said he doesn't expect a fourth surge due to this, but others are more cautious and take the flip side saying, "This is the calm before the storm. We're about to see another huge explosion." California has recently reported a new strain as accounts for maybe potentially 50% of cases now, and it could be 90% by the end of March. But we're seeing such big declines in the numbers in hospitalizations, in cases. So what should people make of these conflicting messages?
DR. CAPLAN: There's an attitude in medicine that many doctors take toward things like incipient or new prostate cancer, sometimes toward breast cancer, or at least lumps. It's called watchful waiting. You pay attention. You watch what's going on. But you don't do anything right away. I would still get vaccinated, I would still take what I could get. I still believe that it's likely that these vaccines are gonna provide some protection, if not against infection, then at least against the worst symptoms and the worst chances of dying because they're really gonna boost up the basic immune system, which should be able to start to fight against viruses.
That said, could we wind up with some virulent new strain that evades the current vaccine platforms? Yes. Is it likely? I don't think so. But what it does mean is get ready to get boosters because the response to new strains that have been a result of viral mutations is you gotta adjust your vaccine. That's what we'll do. I hope it doesn't send us back into quarantine and isolation and distancing and all the rest of it as our only control. I'm hoping that the manufacturers can roll out boosters more quickly than the first round of vaccines.
KIRA: And the FDA has just said that the vaccine developers will not need to start over with new clinical trials to these boosters. So that will greatly expedite the process. And do you think that's the right call?
DR. CAPLAN: Yes, absolutely. You're not changing the fundamental nature of the vaccine platform, you're just tweaking, if you will, which chemistry responds to the virus. So yeah, I do.
KIRA: And one question then that necessarily everyone is gonna wonder is, "Well, if I got the J&J vaccine, can I get an mRNA booster?" Can you mix and match? Is that gonna work for your immune system?
DR. CAPLAN: Yeah. We don't have any idea. And I wouldn't do that right away. I know some countries are thinking about that to get more, if you will, use out of a limited supply. I'd say wait three months and do it the right way, where the data is in evidence. I'm not worried about people getting a second shot of something different and dropping dead. I'm just worried that it won't work. [chuckle] So I'm not a fan of mix and match. You can do it in some studies, by the way. You could do it in some challenge studies and get a faster answer than you would having to try and do this in 30,000 people over a year. But no, I don't think that's a good way to go. And I'm not a big fan of one-shot strategies either. I think, what we know is that the second shot really kicks your immune system into high gear and that's what you want for real protection. So I know why people say it but I wouldn't advocate for it.
KIRA: Right. And for my last question. One of our big themes this year that we'll be following all throughout the year at leaps.org is our progress towards an eventual return to life and return to normalcy. So I have to ask that question to you. Given everything that you know and that we've discussed today, when do you think our lives and society will start to look normal again, with schools, and restaurants, and businesses open, people are flying and gathering without fear, traveling, etcetera?
DR. CAPLAN: I think you're gonna see a lot of that this summer. There's gonna be enough vaccine out there, even if the epidemiologists aren't 100% happy. As I said, I think a lot of people are gonna say, "I'm happy enough, good enough for me. I'm going to sports and I'm flying, and I'm taking a vacation." And we'll be outside again. Remember we had the ability to eat outdoors and congregate less when the weather's better around the whole country, and I think that will open up Europe and the US in addition. What I'm worried about is if we had to go back in the fall to a more controlled environment, either 'cause a new strain appeared, or just because things weren't as efficacious as we hoped they'd be. But I think summer is gonna be good this year.
KIRA: Well, I hope you're right. I hope your crystal ball is working today. [chuckle]
DR. CAPLAN: [chuckle] And if it's not working right, email Kira. Don't talk to me.
KIRA: Yeah, I cannot be held liable for this. Thank you Art for a fascinating discussion. And thanks to everyone for listening. If you like this show, follow Making Sense of Science to hear new episodes coming once a month. And if you wanna give us feedback, we'd love to hear from you. Get in touch on our website, leaps.org. And until next time, thanks everyone.
Thursday, March 11th, 2021 at 12:30pm - 1:45pm EST
On the one-year anniversary of the global declaration of the pandemic, this virtual event will convene leading scientific and medical experts to discuss the most pressing questions around the COVID-19 vaccines. Planned topics include the effect of the new circulating variants on the vaccines, what we know so far about transmission dynamics post-vaccination, how individuals can behave post-vaccination, the myths of "good" and "bad" vaccines as more alternatives come on board, and more. A public Q&A will follow the expert discussion.
SPEAKERS:<img lazy-loadable="true" data-runner-src="https://leaps.org/media-library/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNTY3Mzc4NS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY0NjYwNjU4NX0.Tdrh5pze5P4XxgiJK3J4JFrsrijfabIzNJz-AATghDE/image.jpg?width=534&coordinates=365%2C3%2C299%2C559&height=462" id="87554" class="rm-shortcode" data-rm-shortcode-id="b6c7311be7aec25807f9af19b683bf1d" data-rm-shortcode-name="rebelmouse-image" data-width="534" data-height="462" />
Dr. Paul Offit speaking at Communicating Vaccine Science.commons.wikimedia.org<p><strong><a href="https://www.research.chop.edu/people/paul-a-offit" target="_blank" rel="noopener noreferrer">Dr. Paul Offit, M.D.</a>, is the director of the Vaccine Education Center and an attending physician in infectious diseases at the Children's Hospital of Philadelphia. He is a co-inventor of the rotavirus vaccine for infants, and he has lent his expertise to the advisory committees that review data on new vaccines for the CDC and FDA.</strong></p>
Dr. Monica Gandhi
UCSF Health<p><a href="https://profiles.ucsf.edu/monica.gandhi"></a><strong><a href="https://profiles.ucsf.edu/monica.gandhi" target="_blank">Dr. Monica Gandhi, M.D., MPH,</a> is Professor of Medicine and Associate Division Chief (Clinical Operations/ Education) of the Division of HIV, Infectious Diseases, and Global Medicine at UCSF/ San Francisco General Hospital.</strong></p>
Dr. Onyema Ogbuagu, MBBCh, FACP, FIDSA
Yale Medicine<p><strong><a href="https://medicine.yale.edu/profile/onyema_ogbuagu/" target="_blank" rel="noopener noreferrer">Dr. Onyema Ogbuagu, MBBCh</a>, is an infectious disease physician at Yale Medicine who treats COVID-19 patients and leads Yale's clinical studies around COVID-19. He ran Yale's trial of the Pfizer/BioNTech vaccine.</strong></p>
Dr. Eric Topol
Dr. Topol's Twitter<p><strong><a href="https://www.scripps.edu/faculty/topol/" target="_blank" rel="noopener noreferrer">Dr. Eric Topol, M.D.</a>, is a cardiologist, scientist, professor of molecular medicine, and the director and founder of Scripps Research Translational Institute. He has led clinical trials in over 40 countries with over 200,000 patients and pioneered the development of many routinely used medications.</strong></p>