Microscopic visualization of lung sections from mice in a model of house dust mite asthma, with hematoxylin and eosin staining showing bronchial obstruction and white blood cell infiltrate around the bronchi in the unvaccinated group ( left) but not in the vaccinated group (right). © Dr. Eva Condé.
To fight against allergic asthma, which affects millions of people around the world, scientists from Inserm, CNRS and Toulouse III-Paul Sabatier University in the laboratory Infinity[1], the Institut Pasteur and the French company NEOVACS, are developing and testing a new vaccine. In their latest study, the teams showed that this vaccine was effective in producing antibodies capable of neutralizing key human immune proteins in triggering allergic asthma, the cytokines IL-4 and IL-13. The results, published in the journal Allergypave the way for the organization of a clinical trial.
Asthma is a chronic disease that affects approximately 4 million people in France and 340 million worldwide. Allergic asthma, which accounts for approximately 50% of asthma cases, is characterized by inflammation of the bronchial tubes and respiratory discomfort caused by the inhalation of allergens, most often dust mites.
This exposure to dust mites and other allergens triggers an overproduction of antibodies called immunoglobulin E (IgE) and proteins called “type 2 cytokines” (specifically the interleukins IL-4 and IL-13) in the airways. This phenomenon leads to a cascade of reactions resulting in hyperreactivity of the airways, overproduction of mucus and eosinophilia (an excessively high level of white blood cells called eosinophils in the airways).
Currently, inhaled corticosteroids are the gold standard for controlling asthma. However, in the case of severe allergic asthma, this treatment is not always sufficient. It is then necessary to resort to treatments with therapeutic monoclonal antibodies precisely targeting IgE or the IL-4 and IL-13 pathways. However, these drugs are very expensive and force patients to perform injections for years, even throughout their lives.
For several years, Inserm research director Laurent Reber and his colleagues in the Toulouse laboratory Infinitywith the team of Pierre Bruhns at the Institut Pasteur, in collaboration with the French company NEOVACS, are working on the development of a vaccine in order to open up new therapeutic prospects for patients suffering from severe allergic asthma.
An effective vaccine against human cytokines
In a previous study, they had shown the effectiveness in mice of a conjugate vaccine[2]called Kinoid® (see box). The results suggested that this vaccine induced a long-lasting production of antibodies directed specifically against murine IL-4 and IL-13, as well as a reduction in the symptoms of allergic asthma in the animals.
Following these initial encouraging data and in order to envisage setting up clinical trials in humans, it was necessary to develop a vaccine capable of also neutralizing the human cytokines IL-4 and IL-13. In order to be able to test the effectiveness of this new vaccine, the scientists this time used a model of allergic asthma to house dust mites in “humanized” mice, whose genes encoding the murine cytokines IL-4 and IL-13 were replaced by the respective human genes.
Here again, the results are promising: vaccination induced a significant antibody response, capable of neutralizing the human IL-4 and IL-13 cytokines, without reducing the efficacy of the vaccine, up to more than three months after the injection (time corresponding to the total duration of this study).
A significant effect on asthma symptoms was also observed: in the animals studied, vaccination was associated with a decrease in IgE levels and eosinophilia as well as a reduction in mucus production and hyperresponsiveness of the airways.
« This study provides proof of concept of the efficacy of the vaccine in neutralizing human proteins that play a key role in allergic asthma. We are thus paving the way a little further for the organization of clinical trials. We are currently discussing with all the partners of the project to set up these studies in humans”, concludes Laurent Reber.
« Vaccination against allergic asthma represents hope for the long-term treatment of this chronic disease, and beyond that, a prospect of reducing allergy symptoms linked to other factors, since this vaccine targets molecules involved in different allergies », points out Pierre Bruhns, head of the Antibodies in Therapy and Pathology unit at the Institut Pasteur.
The Kinoid® vaccine is based on a technology that combines the recombinant cytokines IL-4 and IL-13 with a carrier protein called CRM197 (the non-pathogenic mutated form of diphtheria toxin, used in many conjugate vaccines).
This protein is very immunogenic, that is to say, it is able to provoke a significant immune response. Exposed to the CRM197 contained in the vaccine, the immune system begins to produce antibodies directed against this protein, but also against the cytokines IL-4 and IL-13. This makes it possible to control the overproduction of these proteins which are key in allergic asthma, and more generally in any allergic reaction.
Indeed, in addition to allergic asthma, IL-4 and IL-13 are implicated in many other allergic pathologies, including atopic dermatitis and food allergy. Preclinical studies in progress in the laboratories of the various partners aim to demonstrate that this vaccine can also induce a protective response against these major allergies.
[1] Toulouse Institute for Infectious and Inflammatory Diseases (Inserm/CNRS/Toulouse III University)
[2] And vaccine conjugate is a vaccine containing an antigen combined with a protein to increase its effectiveness