COVID-19 Vaccine Developers Look for “First-Harm” Antibodies

The coronavirus pandemic has brought the world rapid research into the complexity of immunology. “Hard immunity” and “serologic testing” are household terms. The front and center of these concepts are antibodies. These immune proteins usually appear two or three weeks after infection, gather at invaders, and prevent them from invading human cells. When antibodies that target a particular virus are detected in blood samples, their appearance confirms an immune response that prevents reinfection.

It is the goal of dozens of vaccine developers to elicit the appropriate antibodies to disarm SARS-CoV-2, the current causative agent of pandemics. Human trial started Record speed. But public health officials and scientists warn against moving too fast. Rarely, these immune defenders can make the disease worse, not prevent it.

That concern has not yet been realized in the early stages of manufacturing the COVID-19 vaccine. However, based on past studies related to coronavirus outbreaks, vaccine manufacturers do not consider the hurdles to be purely theoretical.

Normally, SARS-CoV-2 and the previously related coronavirus SARS-CoV enter the cell via the docking site, a cell surface receptor called ACE2. Vaccines that provide the sought-after vaccination make “neutralizing” antibodies to viral proteins and block the entrance of pathogens through the ACE2 portal.

Yale University immunologist Akiko Iwasaki says that just because an antibody can prevent a virus from invading cells in an dish doesn’t mean that it will behave that way in the body. She explains in a recent scenario Nature Reviews Immunology ExplanationAntibodies can help block the immune cells that the virus invades and usually swallows and clears pathogens.

If some of the antibodies produced do not bind well to the virus or are not present at the proper concentration, they may latch on to the antibody and exacerbate the disease through a process called antibody-dependent enhancement (ADE). There is. In ADE, antibody-coated viruses acquire “backdoor” entries via antibody receptors on macrophages and other members of the cell cleanup crew. That is, it destroys the cells that have been shredded and chemically disposed of. In some cases, this process can cause an adverse inflammatory response.

Indeed, some pathogens, including coronaviruses, seem to have “find a way to infect disease-fighting cells by using antibodies as Trojan horses,” Iwasaki said. In her lab, we are working to understand the immune responses that help recover from COVID-19 and the types of immune responses that contribute to the disease.

Through ADE, Iwasaki suggests that the virus can cause overproduction of inflammatory signaling proteins called cytokines, which can lead to a “cytokine storm” that promotes acute respiratory distress syndrome and damages lung tissue. I will. Similar problems Released to some COVID-19 patients by other immune cells called neutrophils.

Scientists still do not know whether ADE actually promotes cytokine storm or immune-related tissue damage at COVID-19. They hypothesized that some immunized animals developed more severe disease based on previous studies of vaccines against previous outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). Connecting the dots. In addition, previous work by Iwasaki et al. Shows that pathogens that invade cells through backdoors are shunted into various receptor-rich cell compartments that sense microbial threat and release molecules associated with cytokine storms. Suggests that. “That is a well-known fact,” says Iwasaki. “Why isn’t SARS-CoV-2 recognized this way?”

Some research from the early coronavirus outbreaks, in fact, Supports the idea that antibodies may induce inflammatory pathologies when combined with macrophages. In the monkey analysis released last year, JCI Insight, Chinese researchers show that SARS-CoV antibodies from vaccinated animal sera Enough to cause a series of unvaccinated lung disorders. The transferred antibodies exacerbated the disease and apparently switched pulmonary macrophages from a protective state to a pathogenic state, as judged by examination of the genetic activity of immune cells.

ADE has emerged as a suspicious problem with other vaccines. Certain dengue and respiratory syncytial virus vaccines cause a severe immune response. Antibodies may be one of the initiators, but vaccine scientists say damage to immune-related tissues is a greater potential concern. Liver and lung damage caused by inflammatory reactions Occurred In animals infected with the SARS virus after vaccination. But ADE as a mechanism was documented in lab dishes, so this phenomenon is “a bit more theoretical,” says Peter Hotez, co-head of the Texas Pediatric Vaccine Development Center. COVID-19 vaccine created based on SAV vaccine research.

Although suboptimal antibodies can cause inflammation and tissue damage, these problems also Abnormal activity of T cells, Which acts as another viral fighter in the stockpiling of the immune system. Research published May 14 cell Suggest SARS-CoV-2 specific T cells may help fight COVID-19 if functioning normally.

Scientists are well aware of the potential dangers of ADE. This is “what could happen,” said Paul Henri Lambert, a vaccine scientist at the University of Geneva and a consultant at the Alliance for Innovative Disease Control (CEPI). “But at this stage, there is no evidence that this is a vaccine problem against SARS-CoV-2.”

Moderna, a biotechnology company in Massachusetts, Preliminary findings from early clinical trials of RNA-based COVID-19 vaccine published Last week, no serious health problems were found in study participants. Another COVID-19 vaccine tested in Initial test According to a May 22 study in China, some of the 108 participants in the study appeared to produce safe and neutralizing antibodies. Lancet.

Several additional COVID-19 vaccines have been tested in non-human primates. One was made from a virus inactivated by Chinese researchers. Highest dose gave protection. The team found no evidence of increased disease in four monkeys analyzed seven days after being infected with SARS-CoV-2. Ah Non-Refereed Paper on the Second VaccineWas developed using the SARS-CoV-2 protein involved in virus entry into host cells and was posted on the preprint server bioRxiv on May 13. Also, there were no signs of disease enhancement. Also, in a May 20 study of monkeys immunized with another type of candidate (a DNA vaccine), scientists observed, “even the suboptimal vaccine constructs that failed to protect observed an increase in clinical symptoms. I didn’t. “

Stanley Perlman, a physician and viral immunologist at the University of Iowa, is a member of the COVID-19 Vaccine Commission established by both the National Institutes of Health and the World Health Organization. He said these committees have thoroughly discussed the risks that ADE could pose. But given the urgency of the pandemic, Pearlman adds. “People say yesterday that they have to get a vaccine, while some say,” Oh, we really need to be careful. ” How do you balance this? Until we get the vaccine and secure the immunity, we cannot open the country. That raises a difficult question: what is the most correct course of action? “

The real question is whether the COVID-19 vaccine causes ADE when administered to hundreds of thousands of people. This concern is shared by researchers testing whether plasma from recovered patients can safely treat people hospitalized for illness. ADE has never been reported A study of 5,000 patients nationwide fed this convalescent plasma, Was posted on the preprint server medRxiv on May 14th.

An analysis of the immune response in early clinical trial volunteers and non-human primates studied before moving on to the next phase of routine research should be able to identify vaccines at potential risk of immune enhancement, Lambert said. I am. Hotez believes it is important to note that when immunizing study participants in areas where the virus is widespread, it impairs ADE and the inflammatory response. “If there’s a problem, it’s displayed,” he says. “In individuals who have been exposed to the virus since they were vaccinated, liver and lung function should be monitored to make sure there is no deterioration.”

In addition to vaccines, ADE may affect other aspects of the immune response to SARS-CoV-2. Jorge Caballero, an anesthesiologist at Stanford University, COVID-19 monitoring test data and engineering support, Wondering if the process underlies the symptoms of other diseases.COVID toes, Dyspnea and associated with lung pathology Mysterious inflammatory condition Illness attacks some children. Emerging data suggest that “a common link (Occam razor, if so) could be a poorly understood phenomenon called antibody-dependent enhancement” ..

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