The flu virus is a known problem, presenting itself every year in a different guise. Not knowing in advance which strain will be predominant next winter forces scientists to set up surveillance systems and create a new vaccine each season based on data available in February for the northern hemisphere and December for the southern hemisphere. In parallel, the research community is pursuing the philosopher’s stone of the vaccine: a universal recipe that immunizes the population against this infection and all its variants with a single formula.
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Magazine Science has published this Thursday the preliminary results of a new prototype that brings humanity closer to that hitherto unknown formula. A group of researchers from the University of Pennsylvania, led by Claudia Arévalo, have carried out a preclinical study with mice and ferrets that have been inoculated with a vaccine against the 18 known subtypes of the influenza A virus and the two B that cause the flu. The result, although experimental, is encouraging: the animals generated antibodies that protected them, at least partially, from matched and mismatched viral strains.
“For the classification into subtypes, the HA and NA proteins are taken into account. Ha is the protein that the virus has to enter cells and the one that induces a greater amount of antibodies that protect against the disease. There are many subtypes, but the problem is that these proteins change a lot and the virus has the ability to mutate in them,” explains Marta López Diego, a researcher at the National Center for Biotechnology.
This winter, following the recommendations of the World Health Organization (WHO) for the northern hemisphere, in Spain a quadrivalent influenza vaccine is being inoculated against types H1/N1 and H3/N2 and one of B. [que se investiga] includes the 18 known types of hemagglutinin spikes of influenza A viruses (H1 – H18), plus two corresponding to virus B”, explains the professor of the Department of Microbiology and Parasitology of the Faculty of Pharmacy of the Complutense University of Madrid , Víctor Jiménez, to the platform Science Media Center Spain.
A universal RNA vaccine
“Several universal influenza vaccines are being developed to provide protection against various virus subtypes, but most contain a limited number of antigens that have epitopes that are conserved across different virus subtypes. An alternative approach to induce universal immunity is to design multivalent vaccines that encode antigens of all known subtypes,” the researchers note. “This approach may be impractical with conventional influenza vaccine technologies, but is now feasible with nucleic acid-based vaccine platforms,” they continue.
To do so, the researchers have used one of the technologies that have emerged as a result of the health crisis caused by the pandemic and the race to find a vaccine against SARS-CoV-2. Specifically, they imitated the formulation used by Moderna in its vaccine against Covid-19. “The formulation includes modified RNAs formulated in lipid nanoparticles”, indicates Jiménez, who points out that “it seems that the presentation of the antigen to our immune system is much more efficient in the formulations based on mRNA, which forces our cells to produce the antigen in situ, than in the classic ones based on directly inoculating the antigen”. That is, if the traditional vaccines directly introduce the antigen that protects against the virus into the body, the new RNA ones force the body to manufacture it.
The research, like most of those seeking a universal flu vaccine, seeks to directly affect the protein stem. “These have two regions. One is the globular region, against which the greatest amount of antibodies is induced. The other is the stem, which varies much less. The idea of universal vaccines is that they are aimed at enhancing the response to the region that does not change so much”, López Diego develops.
The stem has a three-dimensional structure in the form of helices, which allows fusion between the virus membrane and those of the cells. “What these vaccines seek is to generate a series of antibodies that will bind to that region of the stem and will prevent the virus from entering the cell. If it can’t get in, it won’t replicate”, clarifies the researcher in conversation with elDiario.es.
“Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses through the simultaneous induction of antibodies against multiple antigens”
“Seasonal influenza vaccines offer little protection against pandemic influenza virus strains. It is difficult to create effective pre-pandemic vaccines, because it is not clear which subtype of the virus will cause the next one,” the scientists say. Including all types of the virus makes it possible to prevent infection by an antigenic jump due to the combination of genes from animal viruses, such as H5, H7 and H9, and those currently circulating among humans. “This is what happened in 2009, in 1968 with the Hong Kong flu, in 1957 with the Asian flu and in the terrible 1918 pandemic that killed at least 50 million people,” says the professor.
In the study published Science, one of the highest impact journals, scientists develop “a nucleoside-modified mRNA-LNP vaccine that encodes hemagglutinin antigens of all 20 known influenza A and B virus subtypes. This multivalent vaccine caused high levels of specific antibodies and cross-reactivity in mice and ferrets, which reacted to the 20 encoded antigens”, the authors point out. “Our studies indicate that mRNA vaccines can provide protection against antigenically variable viruses through the simultaneous induction of antibodies against multiple antigens,” they defend.
“The researchers present a strategy similar to that used to generate the messenger RNA vaccine against SARS-CoV-2, but in which they introduce messenger RNA from the 20 versions of the hemagglutinins of type A and B influenza viruses that could give rise to a virus with the possibility of infecting us. The results show that this vaccine is capable of inducing a robust antibody-mediated response in mice and ferrets (animal models widely used to study influenza) against different subtypes of influenza viruses, including viruses that are far from appreciably similar to those of the influenza virus. sequences included in the vaccine”, assesses the virologist and professor of Microbiology at the CEU San Pablo University, Estanislao Nistai, at SMC.
In December 2020, the magazine Nature published the results of another Phase I human trial demonstrating the safety and ability of hemagglutinin-based chimeric vaccines to generate antibodies reactive against the hemagglutinin stem domain in healthy US adults ages 18 to 39. years. Again, this research also points to the stem of the virus.
The emeritus director of the National Influenza Center of Valladolid, Raúl Ortiz de Lejarazu y Leonardo, agrees on the value of the new research, its good conception and exhaustive work, but points to “a long journey ahead, sometimes insurmountable, from the animal model to humans” because “the type of response, its amplitude, persistence, etc. They are not similar.” While waiting for studies to advance to a phase in humans, this professor of microbiology is sarcastic: “Mice and ferrets around the world must be in luck because they now have a universal flu vaccine.”