Imagine my shock to learn that there is a significant risk of worsened illness or higher mortality for vaccines for several past strains of coronavirus, including RSV, SARS, and feline coronavirus. The vaccines end up enhancing the infection by increasing the body’s uptake of the pathogen. It’s almost as if they picked a coronavirus on purpose. The following article is three months old, so bear that in mind, but all of the facts remain relevant. Full annotation at the source link.
As they race to devise a vaccine, researchers are trying to ensure that their candidates don’t spur a counterproductive, even dangerous, immune system reaction known as immune enhancement.
The teams of researchers scrambling to develop a coronavirus disease 2019 (COVID-19) vaccine clearly face some big challenges, both scientific and logistical. One of the most pressing: understanding how the immune system interacts not only with the pathogen but with the vaccine itself—crucial insights when attempting to develop a safe and effective vaccine.
Researchers need to understand in particular whether the vaccine causes the same types of immune system malfunctions that have been observed in past vaccine development. Since the 1960s, tests of vaccine candidates for diseases such as dengue, respiratory syncytial virus (RSV), and severe acute respiratory syndrome (SARS) have shown a paradoxical phenomenon: Some animals or people who received the vaccine and were later exposed to the virus developed more severe disease than those who had not been vaccinated (1). The vaccine-primed immune system, in certain cases, seemed to launch a shoddy response to the natural infection. “That is something we want to avoid,” says Kanta Subbarao, director of the World Health Organization Collaborating Centre for Reference and Research on Influenza in Melbourne, Australia.
This immune backfiring, or so-called immune enhancement, may manifest in different ways such as antibody-dependent enhancement (ADE), a process in which a virus leverages antibodies to aid infection; or cell-based enhancement, a category that includes allergic inflammation caused by Th2 immunopathology. In some cases, the enhancement processes might overlap. Scientific debate is underway as to which, if any, of these phenomena—for which exact mechanisms remain unclear—could be at play with the novel coronavirus and just how they might affect the success of vaccine candidates.
Some researchers argue that although ADE has received the most attention to date, it is less likely than the other immune enhancement pathways to cause a dysregulated response to COVID-19, given what is known about the epidemiology of the virus and its behavior in the human body. “There is the potential for ADE, but the bigger problem is probably Th2 immunopathology,” says Ralph Baric, an epidemiologist and expert in coronaviruses—named for the crown-shaped spike they use to enter human cells—at the University of North Carolina at Chapel Hill. In previous studies of SARS, aged mice were found to have particularly high risks of life-threatening Th2 immunopathology (2). Baric expresses his concern about what that might mean for use of a COVID-19 vaccine in elderly people. “Of course, the elderly are our most vulnerable population,” he adds.
Experts generally agree that animal experiments and human clinical trials of candidate vaccines for COVID-19, which is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), should include a careful assessment of possible immune complications before releasing the vaccine to the public. If any of the mechanisms under investigation are indeed involved, they say, the resulting risks are real. “You really have to test a vaccine carefully,” says Marc Lipsitch, an epidemiologist at the Harvard Chan School of Public Health in Boston, MA, “and not just roll it out because people are clamoring for it with an epidemic underway.”
Upwards of 80% of patients who contract COVID-19 develop only mild flu-like symptoms. “The immune system fights off the virus and people might hardly notice,” says Darrell Ricke, a researcher with the MIT Lincoln Laboratory’s Bioengineering Systems and Technologies Group in Lexington, MA, who posted a preprint in March on the possible COVID-19 vaccine risks (3). “But there seems to be a tipping point: Some individuals appear equally healthy yet can progress to a more severe disease.”
Ricke points to ADE as a potential explanation for this variability. The phenomenon has been reported in some tissue culture and animal studies of HIV, influenza, and SARS. But it is best known for its influence on the immune response to the dengue virus. If a person is infected with one of dengue’s four serotypes, their immune system should confer lifelong protection against that serotype. But as researchers have discovered, if that person is later infected by a different dengue serotype, then they can develop a severe and potentially deadly illness. In fact, according to one study in the 1980s, more severe responses were found to be 15 to 80 times more likely in secondary dengue infections than in primary infections (4). Instead of the antibodies neutralizing encountered dengue viral proteins, they enhance uptake of the virus. The back end of the antibody binds to macrophages, a type of white blood cell, and helps the virus enter those cells and accelerate viral replication.
ADE has posed a similar challenge in the creation of vaccines for infections including dengue and a cat coronavirus, feline infectious peritonitis virus (FIPV). In one study, cats vaccinated against FIPV got sicker than cats left unvaccinated (5). Again, the virus-specific antibody increased the virus uptake by macrophages.
Barney Graham, deputy director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases, in Bethesda, MD, which is collaborating with the Cambridge, MA-based biotech Moderna on a COVID-19 vaccine candidate, also questioned the role of ADE… Graham emphasizes alternative ways in which a vaccine could potentially induce more serious COVID-19 infections: Th2 immunopathology, in which a faulty T cell response triggers allergic inflammation, and poorly functional antibodies that form immune complexes, activating the complement system and potentially damaging the airways.
Both processes were at play as an unfortunate situation unfolded in the 1960s, according to Graham. Researchers at the time were pursuing a vaccine against RSV, the leading cause of severe respiratory illness in infants. In trials of one vaccine candidate, several children who received the vaccine developed a serious illness when infected with the natural virus (7). Two toddlers died. In this case, researchers noticed severe damage and the unexpected presence of lots of neutrophils and eosinophils, both immune cells, in the children’s lung tissue. A similar inflammatory response was seen in animal models of RSV, in which cytokines, a type of immune cell, had invaded and damaged tissue.
“That really killed RSV vaccines for a generation,” says Peter Hotez, a vaccine researcher and dean of the National School of Tropical Medicine at Baylor College of Medicine in Houston, TX. After more than 50 years of further study, a candidate RSV vaccine is finally back in clinical trials.
When SARS, also a coronavirus, appeared in China and spread globally nearly two decades ago, Hotez was among researchers who began investigating a potential vaccine. In early tests of his candidate, he witnessed how immune cells of vaccinated animals attacked lung tissue, in much the same way that the RSV vaccine had resulted in immune cells attacking kids’ lungs.
Moderna’s mRNA vaccine candidate has progressed at unprecedented speed, thanks in large part to China’s January release of the genetic sequence of the virus. A phase 1 clinical trial began on March 16 in Seattle, WA. “We need to get some answers by next winter so we can at least be more prepared for the winter of 2021–2022,” adds Graham.
But immune enhancement concerns linger. Stanley Perlman, a professor of microbiology and immunology at the University of Iowa in Iowa City, agrees that a good T cell response should sidestep enhancement concerns. He is also part of a special committee convened by the World Health Organization (WHO) to address immune enhancement, which they refer to as vaccine enhancement. The committee now aims to define what exactly this enhancement means, what the relevant issues are for a COVID-19 vaccine, and what to do with that information, notes Perlman. A subgroup of the committee is expected to produce a summary report within a few months.
Vaccine experts have underscored the need to avoid mistakes from the past, such as the halting of SARS vaccine development. More coronaviruses are likely waiting in wild bats, primates, and rodents, ready to make the jump to humans. “Ecological disruption really increases the odds that we might encounter a pathogen that we’ve never seen before but grows in us just fine,” says Rasmussen.