As America begins to reopen its parks, beaches, and restaurants, while COVID-19 cases continue to grow in some places, The Lens was presented with this cautionary tale, recounted by the chair of genetics and director of precision medicine at LSU Health Sciences Center New Orleans.
“Everyone has been curious about where their cases first began, and Germany has gone to extraordinary lengths to track back its initial cases, “ said geneticist and professor Lucio Miele, MD, Ph.D. “Let’s remember, Germany began to see cases back in January, and in the ensuing months they have tried diligently to find Patient Zero — the very first case. They were able to contact trace back to Patient Four, and proceeded to determine how Patient Four infected Patient Five. They elaborately tracked down all of the people each one knew, whom they’d been with, in what rooms, with all of the specifics. The only link between number four and number five was a salt shaker. These two men were working at the same company in Bavaria, were in the same cafeteria, but not at the same table, when one of them said ‘Pass the salt, please.’ ”
The rest is a story of exponential infections, eventually taking Germany to its current count of more than 169,000 cases, with the largest outbreak in Bavaria.
It’s just one of many examples of just how contagious the novel coronavirus can be. That’s the reason there’s a race across the world for a vaccine.
Recently, children in New York have been admitted to emergency rooms with puzzling symptoms that look to some like toxic shock syndrome or Kawasaki disease, an illness that causes blood vessels to become inflamed.
The symptoms being seen in children — which are rare — may be linked to COVID-19. According to a New York state health advisory, the majority of patients showing the symptoms either tested positive for the disease or for antibodies indicating that they had been previously infected with it.
“At the moment, no one knows if it’s actually Kawasaki’s disease, or if the symptoms are merely very similar,” explained Dr. John Schieffelin, associate professor and pediatric infectious disease specialist at Tulane University School of Medicine. “These kids are presenting in emergency rooms with rashes, fevers, abdominal symptoms and diarrhea, but it can escalate quickly. We’ve already seen one child go into heart failure. It seems to be an inflammatory response in the aftermath of some kids being infected with COVID-19. At the moment we’re seeing most of the cases in New York, where you have the largest population. Naturally, it would show up there in the greatest numbers.”
Gov. Andrew Cuomo’s May 6 advisory identified 64 potential cases of pediatric multi-system inflammatory syndrome associated with COVID-19 in the state.
But New York is not alone. Right here in New Orleans, Juliet Daly was airlifted to Ochsner Medical Center at the end of April, where she was diagnosed with a rare heart condition caused by inflammation.
Dr. Jake Kleinmahon told The Lens, through an Ochsner spokesperson, that Juliet did indeed have the same condition as those in New York, which he referred to as pediatric inflammatory Covid-related syndrome. Diagnosed quickly and treated, Juliet has now fully recovered.
“There are not quite 200 cases of this worldwide, but it’s still very troubling,” said Dr. John Torres, a medical correspondent for NBC News. “We’re seeing this in Boston now, as well as New York, and with six children in the ICU in New York City as of May 7, it’s certainly a concern. Strangely, many children who never had symptoms we’re used to seeing with this coronavirus, then presented with this delayed inflammatory response. When they are tested for COVID-19, most, but not all are positive.”
Doctors are only now realizing that there may be serious repercussions down the road from this particular coronavirus well after patients are thought to have recovered. When Dr. Lorna Breen, medical director of the emergency department at New York-Presbyterian Allen Hospital in Manhattan, died of self-inflicted injuries on April 26th, after recovering from COVID-19 herself, her colleagues and family began to wonder what sort of depression had befallen her, and why. Her sister has now ordered an autopsy to determine if the virus caused neurological changes altering Breen’s brain.
Vaccine development complicated by many unknowns
The list of unknowns about this new virus is still long, making the rapid development of a vaccine all the more daunting.
“We have never been able to make a vaccine for a coronavirus,” explained geneticist Dr. Miele. “Our attempts in the past have come up short, and have ultimately triggered immune system malfunctions. Remember, we are not adapting existing technology here, like in a flu vaccine. This is completely different as we work on genetic vaccines which require reprogramming genetic code, rather than trying to manipulate the live virus itself. You see, with a highly pathogenic virus that just wouldn’t be safe.”
Potentially complicating the task is the fact that viruses — including this one — mutate. Some researchers now believe it may have mutated to become more contagious, according to a 33-page report released by the Los Alamos National Laboratory on April 30. The report has not been peer reviewed, and many researchers have expressed skepticism. But the researchers said they felt there was an “urgent need for an early warning” because a mutation could have implications for current vaccine development.
The authors of the report focused on a mutation they called D614G, which they said is responsible for the change in the virus’ “spikes.” (The coronavirus is so-named for its crown-shaped spikes used to enter human cells.)
“This virus has won the evolutionary lottery,” Miele said. “It has continually adapted to its host [the human population] to ensure its spread. RNA viruses [coronaviruses] don’t replicate as easily as DNA viruses [like chickenpox*], so their trick is to mutate in order to survive. They also notoriously jump species from animals to humans. Animals [like bats with the coronavirus] are resistant because they’ve shared their lives with this virus for such a long time. But when a coronavirus jumps species, anything can happen. We know that SARS came from a variety of animals, MERS came from camels, and AIDS from monkeys, and while these animals may experience no adverse repercussions from this virus, they are known carriers.”
With mutations occurring, we may need a vaccine with multi-strain coverage.
That may be easier said than done. As major pharmaceutical companies conduct clinical trials, trial vaccines have now been injected into many healthy Americans who are ready and willing to become human guinea pigs in the interest of science. But solving the ongoing riddle of this spreading coronavirus is complex and means that a vaccine must carry messenger RNA which instructs the cells to make proteins associated with the virus, but without making the subjects they’re injected into sick.
“With genetic engineering, we take the COVID-19 virus, made out of RNA, and we only encode those proteins which we want responses to, but without the entire viral gene, making it safer” said Miele.
“But there are many ways of making vaccines. You can graft genes from COVID-19 to another virus that humans are strongly immune to like adenoviruses (common causes of fever, sore throats, and diarrhea), and you create a Frankenstein virus which our immune systems are already familiar with,” Miele said. “Currently, Mass General and Harvard University are using an adeno-associated virus (AAV), by delivering small pieces of the coronavirus to trigger an immune response. This sort of technology is already being used in FDA-approved gene therapy products used to fix other defects in humans.”
According to Miele, we use this technology now with people lacking certain vital genes, by delivering an outside helper without changing the genome (the genetic material of an organism consisting of DNA). For example, the FDA has approved gene therapy for a particular type of eye disorder called retinal dystrophy which comes from a gene called RPE65. When it’s put into an AAV which is accepted by the body, it delays the progression of the disease. It’s the same sort of delivery system.
“It is this sort of vector which Mass General is using to deliver a coronavirus vaccine,” Miele said. “It’s probably the best backbone for gene therapy so far, and there is much hope amongst scientists that this new vaccine will illicit the proper immune response in test-patients by not overwhelming their immune systems.”
We don’t currently have RNA vaccines. In the past, they have worked well in lab animals but that hasn’t translated to humans.
‘The long haul’
“Look, we’re in this for the long haul,” Schieffelin said. “When you have a crisis, everyone wants to step up and try something. I personally don’t think it will happen as early as September, as Pfizer has predicted. We could perhaps see phase 2 by then, but not an FDA-approved vaccine. If the researchers can get phase 1 done pretty quickly this summer, and watch the results for a month, then moving on is possible.”
Miele noted that his colleagues sincerely believe that if we don’t come up with an effective vaccine, this virus will continue to spread until we have herd immunity. But he said that presently scientists believe that only a small percentage of the US population has been infected. But until reliable antibody testing is widely available, they won’t know for sure.
“New vaccines are dependent on the rate of mutation.,” Miele said. “We know that influenza mutates faster than the coronavirus, and that’s why every year we have to manufacture a new flu vaccine. But once you have an established technology, it’s not that difficult to adjust or tweak the vaccine.”
“With mutations, it depends where they are,” Schieffelin said. “Are they in the critical epitopes [the specific pieces of a toxin to which an antibody binds] that the immune system really focuses on? We need to cover all of the different circulating strains in order to be effective, because with certain mutations, some vaccines just won’t fly.”
For Miele, whose hero growing up was Dr. Albert Sabin, the man who developed the oral live virus polio vaccine, the parallels are obvious.
“Let’s remember that when Jonas Salk came up with an injectable vaccine for polio years before Sabin’s work, very little was known about the human genome and no one was doing genetic engineering,” Miele said. “This was good old-fashioned trial and error until they found attenuated strains that wouldn’t cause polio but did elicit an immune response. We’re learning more about this virus with each passing day.”
“There was a massive effort to conquer polio in the 50s because it was literally crippling people,” Miele said. “We are working our hardest at the moment to come up with a mass vaccination that covers a lot of genotypes. However, at this point, even if we get partial immunity, it gives us some protection, and may make this virus manageable, until we can conquer it entirely. In the meantime, I cannot tell you that I feel safe sitting inside a restaurant without a vaccine. Italy at the moment has done far more testing per capita than the United States, has had the virus longer, and is still not trying to return to a pre-COVID life. I’m hoping against hope that we don’t see Americans going back to work, going about their business as usual, and getting sick.”
*Correction: As originally published, this story incorrectly identified measles as a DNA virus. (May 9, 2020)