News Feature: Avoiding pitfalls in the pursuit of a COVID-19 vaccine

Lynne Peeples - PNAS April 14, 2020 117 (15) 8218-8221

Figure: SARS-CoV-2—the virus that causes COVID-19 and the focus of numerous vaccine development efforts—has three surface proteins attached to a lipid bilayer, as seen in this illustration based on X-ray diffraction data. Image credit: Science Source/Juan Gaertner.

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.

A vaccine is designed to boost our natural immune response to an invading virus by priming it to recognize antigens, unique molecules found on the surface of pathogens. Ideally, the immune system responds to the presence of these antigens by producing special immune cells that directly attack the pathogen, or by producing proteins called antibodies. Antibodies attach to an antigen and attract immune cells that engulf and destroy the pathogen. A dysregulated immune response may involve antibodies or immune cells—or both.

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.”

Picking the Right Problem

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.

Yet some experts doubt that ADE is relevant for COVID-19. “We have no evidence that ADE is actually occurring in human patients,” says Angela Rasmussen, a virologist at Columbia University Mailman School of Public Health in New York, citing such findings.

In principle, anecdotal reports of COVID-19 reinfections in China (6) could lend credence to relevance of ADE—that is, the production of antibodies to the virus (resulting from immunization or an initial natural infection) ends up enhancing entry of the virus into cells. But Rasmussen and other experts underscore the lack of real evidence for COVID-19 reinfections. Any repeat cases so far reported, they say, could be explained by false negative tests between the positive tests. “It’s not clear that patients were ever not infected,” says Rasmussen.

And there is some preliminary experimental evidence casting doubt on ADE. Two papers published in March in Cell show that antibodies against the original SARS infection, which emerged in China in 2002, could also block entry of SARS-CoV-2 into human cells. Another preprint study showed that rhesus macaques infected with SARS-CoV-2 and allowed to recover were not infected after a second exposure to the virus. Unless future data correlate severe COVID-19 cases with original SARS infections—or other diagnostic, pathology, or clinical findings indicate ADE—then there is “not much to go on that suggests ADE is a factor,” Rasmussen says.

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. Dengue is a flavivirus, a family of viruses that are known to infect macrophages. FIPV also infects macrophages. ADE is unlikely to occur in the current coronavirus, Graham argues, because it does not target or grow in macrophages. Rather, SARS-CoV-2 primarily infects the respiratory epithelial cells, which present different receptors.

See https://www.pnas.org/content/117/15/8218