Scientists search for a universal coronavirus vaccine
The Covid-19 pandemic had barely begun when VBI Vaccines, a biopharmaceutical company based in Cambridge, Massachusetts, initiated their search for a universal coronavirus vaccine.
It was March 2020, and while most pharmaceutical companies were scrambling to initiate vaccine programs which specifically targeted the SARS-CoV-2 virus, VBI’s executives were already keen to look at the broader picture.
Having observed the SARS and MERS coronavirus outbreaks over the last two decades, Jeff Baxter, CEO of VBI Vaccines, was aware that SARS-CoV-2 is unlikely to be the last coronavirus to move from an animal host into humans. “It's absolutely apparent that the future is to create a vaccine which gives more broad protection against not only pre-existing coronaviruses, but those that will potentially make the leap into humans in future,” says Baxter.
It was a prescient decision. Over the last two years, more biotechs and pharma companies have joined the search to find a vaccine which might be able to protect against all coronaviruses, along with dozens of academic research groups. Last September, the US National Institutes of Health dedicated $36 million specifically to pan-coronavirus vaccine research, while the global Coalition for Epidemic Preparedness Innovations (CEPI) has earmarked $200 million towards the effort.
Until October 2021, the very concept of whether it might be
theoretically possible to vaccinate against multiple coronaviruses remained an open question. But then a groundbreaking study renewed optimism.
The emergence of new variants of Covid-19 over the past year, particularly the highly mutated Omicron variant, has added greater impetus to find broader spectrum vaccines. But until October 2021, the very concept of whether it might be theoretically possible to vaccinate against multiple coronaviruses remained an open question. After all, scientists have spent decades trying to develop a similar vaccine for influenza with little success.
But then a groundbreaking study from renowned virologist Linfa Wang, who runs the emerging infectious diseases program at Duke-National University of Singapore Medical School, provided renewed optimism.
Wang found that eight SARS survivors who had been injected with the Pfizer/BioNTech Covid-19 vaccine had neutralising antibodies in their blood against SARS, the Alpha, Beta and Delta variants of SARS-CoV-2, and five other coronaviruses which reside in bats and pangolins. He concluded that the combination of past coronavirus infection, and immunization with a messenger RNA vaccine, had resulted in a wider spectrum of protection than might have been expected.
“This is a significant study because it showed that pre-existing immunity to one coronavirus could help with the elicitation of cross-reactive antibodies when immunizing with a second coronavirus,” says Kevin Saunders, Director of Research at the Duke Human Vaccine Institute in North Carolina, which is developing a universal coronavirus vaccine. “It provides a strategy to perhaps broaden the immune response against coronaviruses.”
In the next few months, some of the first data is set to emerge looking at whether this kind of antibody response could be elicited by a single universal coronavirus vaccine. In April 2021, scientists at the Walter Reed Army Institute of Research in Silver Spring, Maryland, launched a Phase I clinical trial of their vaccine, with a spokesman saying that it was successful, and the full results will be announced soon.
The Walter Reed researchers have already released preclinical data, testing the vaccine in non-human primates where it was found to have immunising capabilities against a range of Covid-19 variants as well as the original SARS virus. If the Phase I trial displays similar efficacy, a larger Phase II trial will begin later this year.
Two different approaches
Broadly speaking, scientists are taking two contrasting approaches to the task of finding a universal coronavirus vaccine. The Walter Reed Army Institute of Research, VBI Vaccines – who plan to launch their own clinical trial in the summer – and the Duke Human Vaccine Institute – who are launching a Phase I trial in early 2023 – are using a soccer-ball shaped ferritin nanoparticle studded with different coronavirus protein fragments.
VBI Vaccines is looking to elicit broader immune responses by combining SARS, SARS-CoV-2 and MERS spike proteins on the same nanoparticle. Dave Anderson, chief scientific officer at VBI Vaccines, explains that the idea is that by showing the immune system these three spike proteins at the same time, it can help train it to identify and respond to subtle differences between coronavirus strains.
The Duke Human Vaccine Institute is utilising the same method, but rather than including the entire spike proteins from different coronaviruses, they are only including the receptor binding domain (RBD) fragment from each spike protein. “We designed our vaccine to focus the immune system on a site of vulnerability for the virus, which is the receptor binding domain,” says Saunders. “Since the RBD is small, arraying multiple RBDs on a nanoparticle is a straight-forward approach. The goal is to generate immunity to many different subgenuses of viruses so that there will be cross-reactivity with new or unknown coronaviruses.”
But the other strategy is to create a vaccine which contains regions of the viral protein structure which are conserved between all coronavirus strains. This is something which scientists have tried to do for a universal influenza vaccine, but it is thought to be more feasible for coronaviruses because they mutate at a slower rate and are more constrained in the ways that they can evolve.
DIOSynVax, a biotech based in Cambridge, United Kingdom, announced in a press release earlier this month that they are partnering with CEPI to use their computational predictive modelling techniques to identify common structures between all of the SARS coronaviruses which do not mutate, and thus present good vaccine targets.
Stephen Zeichner, an infectious disease specialist at the University of Virginia Medical Center, has created an early stage vaccine using the fusion peptide region – another part of the coronavirus spike protein that aids the virus’s entry into host cells – which so far appears to be highly conserved between all coronaviruses.
So far Zeichner has trialled this version of the vaccine in pigs, where it provided protection against a different coronavirus called porcine epidemic diarrhea virus, which he described as very promising as this virus is from a different family called alphacoronaviruses, while SARS-CoV-2 is a betacoronavirus.
“If a betacoronavirus fusion peptide vaccine designed from SARS-CoV-2 can protect pigs against clinical disease from an alphacoronavirus, then that suggests that an analogous vaccine would enable broad protection against many, many different coronaviruses,” he says.
The road ahead
But while some of the early stage results are promising, researchers are fully aware of the scale of the challenge ahead of them. Although CEPI have declared an aim of having a licensed universal coronavirus vaccine available by 2024-2025, Zeichner says that such timelines are ambitious in the extreme.
“I was incredibly impressed at the speed at which the mRNA coronavirus vaccines were developed for SARS-CoV-2,” he says. “That was faster than just about anybody anticipated. On the other hand, I think a universal coronavirus vaccine is more equivalent to the challenge of developing an HIV vaccine and we're 35 years into that effort without success. We know a lot more now than before, and maybe it will be easier than we think. But I think the route to a universal vaccine is harder than an individual vaccine, so I wouldn’t want to put money on a timeline prediction.”
The major challenge for scientists is essentially designing a vaccine for a future threat which is not even here yet. As such, there are no guidelines on what safety data would be required to license such a vaccine, and how researchers can demonstrate that it truly provides efficacy against all coronaviruses, even those which have not yet jumped to humans.
The teams working on this problem have already devised some ingenious ways of approaching the challenge. VBI Vaccines have taken the genetic sequences of different coronaviruses found in bats and pangolins, from publicly available databases, and inserted them into what virologists call a pseudotype virus – one which has been engineered so it does not have enough genetic material to replicate.
This has allowed them to test the neutralising antibodies that their vaccine produces against these coronaviruses in test tubes, under safe lab conditions. “We have literally just been ordering the sequences, and making synthetic viruses that we can use to test the antibody responses,” says Anderson.
However, some scientists feel that going straight to a universal coronavirus vaccine is likely to be too complex. Instead they say that we should aim for vaccines which are a little more specific. Pamela Bjorkman, a structural biologist at the California Institute of Technology, suggests that pan-coronavirus vaccines which protect against SARS-like betacoronaviruses such as SARS or SARS-CoV-2, or MERS-like betacoronaviruses, may be more realistic.
“I think a vaccine to protect against all coronaviruses is likely impossible since there are so many varieties,” she says. “Perhaps trying to narrow down the scope is advisable.”
But if the mission to develop a universal coronavirus vaccine does succeed, it will be one of the most remarkable feats in the annals of medical science. In January, US chief medical advisor Anthony Fauci urged for greater efforts to be devoted towards this goal, one which scientists feel would be the biological equivalent of the race to develop the first atomic bomb
“The development of an effective universal coronavirus vaccine would be equally groundbreaking, as it would have global applicability and utility,” says Saunders. “Coronaviruses have caused multiple deadly outbreaks, and it is likely that another outbreak will occur. Having a vaccine that prevents death from a future outbreak would be a tremendous achievement in global health.”
He agrees that it will require creativity on a remarkable scale: “The universal coronavirus vaccine will also require ingenuity and perseverance comparable to that needed for the Manhattan project.”
Tapping into the Power of the Placebo Effect
When Wayne Jonas was in medical school 40 years ago, doctors would write out a prescription for placebos, spelling it out backwards in capital letters, O-B-E-C-A-L-P. The pharmacist would fill the prescription with a sugar pill, recalls Jonas, now director of integrative health programs at the Samueli Foundation. It fulfilled the patient's desire for the doctor to do something when perhaps no drug could help, and the sugar pills did no harm.
Today, that deception is seen as unethical. But time and time again, studies have shown that placebos can have real benefits. Now, researchers are trying to untangle the mysteries of placebo effect in an effort to better treat patients.
The use of placebos took off in the post-WWII period, when randomized controlled clinical trials became the gold standard for medical research. One group in a study would be treated with a placebo, a supposedly inert pill or procedure that would not affect normal healing and recovery, while another group in the study would receive an "active" component, most commonly a pill under investigation. Presumably, the group receiving the active treatment would have a better response and the difference from the placebo group would represent the efficacy of the drug being tested. That was the basis for drug approval by the U.S. Food and Drug Administration.
"Placebo responses were marginalized," says Ted Kaptchuk, director of the Program in Placebo Studies & Therapeutic Encounters at Harvard Medical School. "Doctors were taught they have to overcome it when they were thinking about using an effective drug."
But that began to change around the turn of the 21st century. The National Institutes of Health held a series of meetings to set a research agenda and fund studies to answer some basic questions, led by Jonas who was in charge of the office of alternative medicine at the time. "People spontaneously get better all the time," says Kaptchuk. The crucial question was, is the placebo effect real? Is it more than just spontaneous healing?
Brain mechanisms
A turning point came in 2001 in a paper in Science that showed physical evidence of the placebo effect. It used positron emission tomography (PET) scans to measure release patterns of dopamine — a chemical messenger involved in how we feel pleasure — in the brains of patients with Parkinson's disease. Surprisingly, the placebo activated the same patterns that were activated by Parkinson's drugs, such as levodopa. It proved the placebo effect was real; now the search was on to better understand and control it.
A key part of the effect can be the beliefs, expectations, context, and "rituals" of the encounter between doctor and patient. Belief by the doctor and patient that the treatment would work, and the formalized practices of administering the treatment can all contribute to a positive outcome.
Conditioning can be another important component in generating a response, as Pavlov demonstrated more than a century ago in his experiments with dogs. They were trained with a bell prior to feeding such that they would begin to salivate in anticipation at the sound of a bell even with no food present.
Translating that to humans, studies with pain medications and sleeping aids showed that patients who had a positive response with a certain dose of those medications could have the same response if the doses was reduced and a dummy pill substituted, even to the point where there was no longer any active ingredient.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders.
Those types of studies troubled Kaptchuk because they often relied on deception; patients weren't told they were receiving a placebo, or at best there was a possibility that they might be randomized to receive a placebo. He believed the placebo effect could work even if patients were told upfront that they were going to receive a placebo. More than a dozen so call "open-label placebo" studies across numerous medical conditions, by Kaptchuk and others, have shown that you don't have to lie to patients for a placebo to work.
Jonas likes to tell the story of a patient who used methotrexate, a potent immunosuppressant, to control her rheumatoid arthritis. She was planning a long trip and didn't want to be bothered with the injections and monitoring required in using the drug, So she began to drink a powerful herbal extract of anise, a licorice flavor that she hated, prior to each injection. She reduced the amount of methotrexate over a period of months and finally stopped, but continued to drink the anise. That process had conditioned her body "to alter her immune function and her autoimmunity" as if she were taking the drug, much like Pavlov's dogs had been trained. She has not taken methotrexate for more than a year.
An intriguing paper published in May 2021 found that mild, non-invasive electric stimulation to the brain could not only boost the placebo effect on pain but also reduce the "nocebo" effect — when patients report a negative effect to a sham treatment. While the work is very preliminary, it may open the door to directly manipulating these responses.
Researchers think placebo treatments can work particularly well in helping people deal with pain and psychological disorders, areas where drugs often are of little help. Still, placebos aren't a cure and only a portion of patients experience a placebo effect.
Nocebo
If medicine were a soap opera, the nocebo would be the evil twin of the placebo. It's what happens when patients have adverse side effects because of the expectation that they will. It's commonly seem when patients claims to experience pain or gastric distress that can occur with a drug even when they've received a placebo. The side effects were either imagined or caused by something else.
"Up to 97% of reported pharmaceutical side effects are not caused by the drug itself but rather by nocebo effects and symptom misattribution," according to one 2019 paper.
One way to reduce a nocebo response is to simply not tell patients that specific side effects might occur. An example is a liver biopsy, in which a large-gauge needle is used to extract a tissue sample for examination. Those told ahead of time that they might experience some pain were more likely to report pain and greater pain than those who weren't offered this information.
Interestingly, a nocebo response plays out in the hippocampus, a part of the brain that is never activated in a placebo response. "I think what we are dealing with with nocebo is anxiety," says Kaptchuk, but he acknowledges that others disagree.
Distraction may be another way to minimize the nocebo effect. Pediatricians are using virtual reality (VR) to engage children and distract them during routine procedures such as blood draws and changing wound dressings, and burn patients of all ages have found relief with specially created VRs.
Treatment response
Jonas argues that what we commonly call the placebo effect is misnamed and leading us astray. "The fact is people heal and that inherent healing capacity is both powerful and influenced by mental, social, and contextual factors that are embedded in every medical encounter since the idea of treatment began," he wrote in a 2019 article in the journal Frontiers in Psychiatry. "Our understanding of healing and ability to enhance it will be accelerated if we stop using the term 'placebo response' and call it what it is—the meaning response, and its special application in medicine called the healing response."
He cites evidence that "only 15% to 20% of the healing of an individual or a population comes from health care. The rest—nearly 80%—comes from other factors rarely addressed in the health care system: behavioral and lifestyle choices that people make in their daily life."
To better align treatments and maximize their effectiveness, Jonas has created HOPE (Healing Oriented Practices & Environments) Note, "a patient-guided process designed to identify the patient's values and goals in their life and for healing." Essentially, it seeks to make clear to both doctor and patient what the patient's goals are in seeking treatment. In an extreme example of terminal cancer, some patients may choose to extend life despite the often brutal treatments, while others might prefer to optimize quality of life in the remaining time that they have. It builds on practices already taught in medical schools. Jonas believes doctors and patients can use tools like these to maximize the treatment response and achieve better outcomes.
Much of the medical profession has been resistant to these approaches. Part of that is simply tradition and limited data on their effectiveness, but another very real factor is the billing process for how they are reimbursed. Jonas says a new medical billing code added this year gives doctors another way to be compensated for the extra time and effort that a more holistic approach to medicine may initially require. Other moves away from fee-for-service payments to bundling and payment for outcomes, and the integrated care provided by the Veterans Affairs, Kaiser Permanente and other groups offer longer term hope for the future of approaches that might enhance the healing response.
This article was first published by Leaps.org on July 7, 2021.
New tech helps people of all ages stay social
In March, Sonja Bauman, 39, used an online platform called Papa, which offers “family on demand,” to meet Mariela Florez, an 83-year-old retiree. Despite living with her adult children, Florez was bored and lonely when they left for work, and her recoveries from a stroke and broken hip were going slowly. That's when Bauman began visiting twice per week. They take walks, strengthening Florez’s hip, and play games like Connect Four for mental stimulation. “It’s very important for me so I don’t feel lonely all day long,” said Florez. Her memories, blurred by the stroke, are gradually returning.
Papa is one of a growing number of tech approaches that are bringing together people of all ages. In addition to platforms like Papa that connect people in real life, other startups use virtual reality and video, with some of them focusing especially on deepening social connections between the generations — relationships that support the health of older and younger people alike. “I enjoy seeing Mariela as much as she enjoys seeing me,” Bauman said.
Connecting in real life
Telehealth expert Andrew Parker founded Papa in 2017 to improve the health outcomes of older adults and families. Seniors can meet people — some their grandkids’ age — for healthy activities, while working parents find retirees to watch their children. These “Papa Pals” are provided as a benefit through Medicare, Medicaid and some employer health plans.
In 2020, Papa connected Bauman, the 39-year-old Floridian, with another woman in her mid-70s who lives alone and has very limited mobility. Bauman began driving her to doctor’s appointments and helping her with chores around the house. “When I’m not there, she doesn’t leave her apartment,” said Bauman. The two have gone to the gym together, and they walk slowly through the neighborhood, chatting so it feels less like exercise.
Parker was driven to start Papa by the problem of social isolation among seniors, exacerbated by the pandemic, but he believes users of all ages can benefit. “Many of our Pals feel more comfortable opening up with older members than their same-aged friends,” he said.
Other platforms aim for similar, in-person connections. Generation Tech unites teens with seniors for technology training. And Mon Ami, which provides case management software for aging and disability service providers, has an app that connects isolated older people with college-age volunteers.
Making new connections through video
Several new sites match you with strangers for real-time video chatting on various topics, such as finding common ground on political issues. Other video platforms focus on intergenerational connections.
S. Jay Olshansky, a gerontology professor at the University of Illinois-Chicago, recalls the first time he saw Hyunseung Lee, an 11-year-old from Seoul, through his computer screen. The kid was shy, but Olshansky, 67, encouraged him to ask questions. “Turns out, he was thirsting for this kind of interaction.”
They’d connected through Eldera, a platform that pairs mentors age 60 and up with mentees, using an algorithm, for video conversations. “The time and wisdom of older adults is the most important natural resource we can give future generations,” said Dana Griffin, Eldera's CEO. “Connecting through a screen is the opposite of social media.”
In weekly meetings, Olshansky noticed Lee’s unique interest in math. “There’s something special in you,” Olshansky told him. “How do we bring it to the surface?” He suggested Lee write a book on his favorite subject, and the preteen ran with it, cranking out 70 pages in two weeks. Lee has published his love letter to theorems on Amazon.
Hyunseung Lee, age 11, of Korea, and U.S. college professor Jay Olshanksy, 67, discuss math, strategy and Hyunsung's budding career as a book author during their video chats through a platform called Eldera. (Photo by Dana Palmer/Eldera)
Lee’s parents told Olshansky that their son has become more assertive — a recurring theme, Griffin said. “Confidence is the number one thing parents tell us about.” Since Eldera’s inception last year, the number of mentors has grown exponentially. Even so, Griffin said the waitlist for mentors typically numbers 200 kids.
Another site, Big and Mini, hosts video interactions between seniors and young adults; about 10,000 active users have joined since 2019, said co-founder Aditi Merchant.
Users often bring the benefits of their video interactions to their real-world relationships. Olshansky views Lee as an older version of his grandkids. “Eldera teaches me how to interact with them.” Lee, high on confidence, began instructing his classmates in math. Griffin noted that a group of Eldera mentors in Memphis, who met initially on Eldera, now take walks together in-person to trade ideas for helping each other’s Eldera kids solve problems in their schools and communities.
“We’ve evolved into a community for older adults who want to give back to the world,” said Griffin. Other new tools for connection take the form of virtual reality apps.
Connecting in virtual reality
During pandemic isolation, record numbers of people bought devices for virtual and augmented reality. Such gadgets can convince you that you’re hanging out with friends, even if they’re in another hemisphere. Lifelike simulations from miles away could be especially useful for meaningful interactions between people of different generations, since they’re often geographically segregated.
VR’s benefits require further study, but users report less social isolation and depression, according to MIT research. The immersive, 3-D experience is more compelling than FaceTime or Zoom. “It’s like the difference between a phone call and video call,” said Rick Robinson, Vice President of AARP’s Innovation Labs.
“When VR is designed right, the medium disappears,” said Jeremy Bailenson of Stanford.
Dana Pierce, a 56-year-old government employee in Indiana, got Meta's VR headset in May, 2021, thinking she’d enjoy it more than a new laptop. After many virtual group tours of exotic destinations, she has no regrets. Her adventures occur on Alcove, an app made by Robinson’s Innovation Labs. He co-created it with VR-company Rendever and sought input from people over age 50 to tailor it to their interests. “I’m an introvert,” said Pierce. “I’ve been more socially active since getting my headset than I am in real life.”
Tagging along with her to places like Paris are avatars representing real people around the world. She’s gotten to know VR users in their 70s, 80s and 90s, as well as younger people and some her own age. One is a new friend she plays chess with in relaxing nature settings. Another is her oldest son. He lives 90 minutes away but, earlier this year, Pierce welcomed him and his girlfriend to her virtual house on Alcove. They chatted in the living room decorated with family photos uploaded by Pierce. Then they took out a boat to go VR fishing — because why not — until 2 a.m.
“When VR is designed right, the medium disappears,” said Jeremy Bailenson, a communications professor who directs Stanford’s Virtual Human Interaction Lab. He’s teaching a class of 175 students entirely in VR. After months of covid isolation, the first time the class met, “there was a big catharsis. It really feels like you’re in a big crowd.” Like-minded people meet in VR for events such as comedy shows and creative writing meetups, while the Swedish pop group ABBA has performed this year as digital versions of themselves (“ABBA-tars”) during a virtual concert tour.
Karen Fingerman, a psychologist and director of the Texas Aging and Longevity Center at the University of Texas-Austin, supports the idea of VR for social connection, though she added that some people need it more than others. Hospitals and assisted-living facilities are using products such as Penumbra’s REAL I-Series and MyndVR to bring VR excursions to isolated patients and seniors. “If you’re in a bed or facility, this gives you something to talk about,” said Gita Barry, Penumbra’s executive vice president.
Pierce uses it on most days. She may see another adult son, who lives with her, less often as a result. But VR helps her manage real-world stressors, more than escaping them. After a long workday, she visits her back porch on Alcove, which overlooks a pond. “It’s my little retreat,” she said. “VR improves my mood. It’s added a lot to my life.”
Some seniors are using more than one technology. Olshansky and Lee discuss strategy while playing Internet chess. And Olshansky recently began using VR. He sees his sister, who lives far away, in a virtual beach house. “It’d be a great way to interact with Hyunseung,” he said. “I should get him a headset.”
A version of this article first appeared in The Washington Post on December 3, 2021.