This article is taken from the monthly journal Sciences et Avenir – La Recherche #913 of March 2023.
Virulent, heavy and early. This winter, the bronchiolitis epidemic was “highly atypical in terms of its scope and onset. This is the most important one in the last twelve years,” emphasizes Prof. Albert Faye, Head of the Pediatric Service at the Robert Hospital. Paris). The first admissions to the emergency department began at the end of September last year, a month earlier than in previous years.
Another feature is the age of the patients. If bronchiolitis mainly affects children, many more infants under 3 months of age have been admitted to hospitals this winter, “and unfortunately they are the ones with the most serious bronchiolitis,” says Brigitte Virey, president of the National Union of French Pediatricians (SNPF).
This respiratory disease, which mainly affects infants but also the elderly, is the second leading cause of infant mortality in the world. Respiratory syncytial virus (RSV) causes most cases. And, as with most viral infections, doctors have few resources to treat the sick.
“One possible explanation for the resurgence of viral diseases this winter is the concept of ‘immune debt,'” suggests Brigitte Viray. Perhaps the population today has less immune defenses because they have experienced fewer viruses in the past two years, especially with barrier gestures. However, this is certainly not the only factor, and the notion remains highly controversial: “In the last week of November, the French Public Health Service recorded an exceptional epidemic peak with more than 8,000 emergency room visits for bronchiolitis in children under 2 years of age.
But recent announcements could change things as early as next winter. In November 2022, AstraZeneca and Sanofi Laboratories announced the validation by the European Commission of a new nirsevimab molecule that will prevent severe bronchiolitis. “This is not a vaccine or a cure. This molecule has a prophylactic purpose, ”explains Albert Fay. It consists of an injection of monoclonal antibodies, which are immune molecules “cloned” in large numbers from the antibodies produced by people infected with RSV.
Antibodies modified to increase their duration of action
How do these antibodies protect against a serious infection? To understand, you need to go into the details of molecular reactions. To infect a cell, a virus must fuse its membrane with that of a human cell. Among the mechanisms that enable this fusion, a protein plays a key role: the F protein. “It exists in two conformations, and it is the transition from one state to another that allows the assembly of membranes,” explains Timothy Bruel, a researcher in the Department of Viruses and Immunity of the Pasteur Institute in Paris . The monoclonal antibody binds accurately to the F protein when it is in the first conformation. Thus, this prevents the fusion process from occurring and RSV can no longer infect human cells (see infographic below). Early results from a phase 3 trial called Melody show over 70% efficacy of nirsevimab in bronchiolitis. “This is a significant proportion, and it gives great hope to hospitals whose services have been saturated this year,” insists Albert Faye.
The monoclonal antibody binds to the F protein, preventing the virus from fusing with human cells to infect them. Credit: BRUNO BOURGEOS
Better: protection promises to be not only reliable, but also durable. “Another feature of nirsevimab is that the antibodies have been modified to significantly increase their half-life,” adds Timothy Bruel. Half-life is the time it takes for the body to eliminate 50% of a compound. Specifically, this means that these new antibodies will stay in the blood longer than natural antibodies.
“This modification extends the half-life to six months. In addition, one injection can provide protection for the whole winter, ”says the researcher. Significant advantage over another monoclonal antibody, palivizumab, already in use in France. This also targets RSV, but without this modification, it must be administered monthly. This restriction and its price – almost 670 euros per bottle – have led to its use for premature and at-risk babies.
New mRNA vaccine with 84% efficiency
As promising as it is, this new treatment does not mean the end of bronchiolitis. “There will still be cases, of course: on the one hand, because there may be failures, and on the other hand, because there are other viruses that can give bronchiolitis, such as metapneumovirus, parainfluenza virus, adenovirus … But this would be disproportionate to what we know so far,” says Albert Fay. Especially since nirsevimab may not be the only way to change the rules of the game in this disease.
At the end of January, the biotech company Moderna reported promising results from its new messenger RNA vaccine against bronchiolitis, which will be about 84% effective. The first injections may be given in late 2023 or early 2024. Phase 3 trials involved 37,000 people over the age of 60, but other studies are underway to determine the effectiveness of the vaccine in infants and pregnant women.
As with the Covid-19 vaccine, the lab uses messenger RNA (mRNA) to prevent bronchiolitis. mRNA contains part of the viral circuitry. It is injected into the body protected by a fatty membrane called a “lipid nanoparticle”. Inside human cells, it triggers the production of a virus-specific protein that migrates to the cell surface. This protein is then recognized by immune cells, B-lymphocytes, which activate the production of antibodies specific to this protein. Thus, the vaccine elicits a response from the body’s immune system by presenting it with part of the virus.
Two hopes associated with two different approaches. “In the case of a vaccine, the body is taught to defend itself by producing the antibodies it needs on its own. This is called active prevention. On the other hand, the introduction of monoclonal antibodies simply provides the body with enough to protect itself.” in and of itself: it is passive prevention,” sums up Timothy Bruel. Other classic vaccines could be on the market by next year, such as those from the American Pfizer laboratory tested on pregnant women and those from the British GSK for the elderly. With this new arsenal, bronchiolitis treatment could quickly become a turning point.
Make babies breathe easier
Until now, doctors have had few tools to treat bronchiolitis, and the challenge has been to reduce the symptoms, which can be very impressive for new parents and cause complications. At first, bronchiolitis leads to a slight fever and possibly a slight cough. On the other hand, this infection progresses very quickly, especially in toddlers. “We are experiencing severe respiratory discomfort. The cough gets worse and the baby may stop eating,” warns Bridget Virey. Thus, the goal is to make babies breathe easier, enable them to eat properly and avoid dehydration.
Its oxygen saturation – the level of oxygen carried by red blood cells after they pass through the lungs – is monitored to provide respiratory support when needed. As of 2019, the Higher Health Authority no longer recommends respiratory physiotherapy, a method widely used in the treatment of bronchiolitis, to clear the bronchi in children under 1 year of age. Uncertainty about its effectiveness with a lack of scientific data in this area is questionable.