Using the same technology behind the Pfizer/BioNTech and Moderna coronavirus vaccines, US researchers have created a universal flu vaccine candidate. Candidate because they have only tested it in mice. And universal because it provides protection against 20 subtypes of the virus. Although those that affect humans are much fewer, the rest circulate among other mammals and birds. A jump of one of these animal flus that could be combined with the human ones could degenerate into a pandemic, as those that emerged in the last century show.
Every year there is a new flu vaccine, last year’s immunity is useless for this one. Much of the blame lies with a protein called hemagglutinin. Influenza disease in humans is caused by type A and type B influenza viruses. Both can be classified into subtypes. For example, influenza A H1N1 and H3N2 circulate among humans. The H refers to hemagglutinin (there are 18 different versions) and the N refers to another molecule, neuraminidase (there are 11 versions) also present on the viral surface. Meanwhile, only two different hemagglutinin versions of the type B influenza virus are known. As with the coronavirus vaccines, which focused on the S spike, which it used to sneak into the cell, the hemagglutinin is the key target. Current vaccines and most vaccine candidates target H. The problem is that, on the one hand, it is not known which subtype will circulate next winter and, on the other, that its end, the head, has a high mutation rate, evading attempts to achieve a universal vaccine. For this reason, recent efforts have been directed against the hemagglutinin stem, which mutates less often and tends to be very similar between the different subtypes.
What a group of researchers from the University of Pennsylvania (United States) has done is bet on going against all subtypes of influenza viruses at the same time. To do this, they have relied on messenger RNA technology already used by two of the most successful vaccines against coronavirus. In essence, this technique introduces the genetic instructions into nanospheres so that the host cell itself makes the hemagglutinin, which itself does not have a viral load. This is how they got 20 vaccines in one. Before putting them all together in a formulation, they tested each nanocapsule separately, to ensure its effectiveness. The next thing was to test it on several groups of mice, hoping that all of them would maintain their capacity and without cross-reactions. It is the first time that mRNA has been used to search for a universal vaccine candidate.
It would be difficult to make a vaccine like ours using conventional platforms because you would have to produce the twenty different recombinant proteins, purify them, and add an adjuvant to them.”
Claudia Arevalo, a virologist and first author of the study while at the University of Pennsylvania and now at Pfizer
Bolivian virologist Claudia Arévalo, first author of the study, explains that this approach would have been impossible using more traditional platforms, such as those that use viral proteins to design current vaccines: “It would be necessary to produce the twenty different recombinant proteins, purify them, and add an adjuvant. This would be a very expensive and laborious endeavor.” Regarding the other more classic option, that of using inactivated viruses, she says that “it would pose other challenges, such as having to isolate the strains and propagate them successfully; The strains we included are all known influenza subtypes, meaning some have pandemic potential and others have yet to cross from animal reservoirs, so she can imagine the challenges of isolating and spreading viruses like those.” At the University of Pennsylvania, where Arévalo completed her studies, where Katalin Karikó and Drew Weissman devised taking advantage of messenger RNA to introduce genetic instructions into cells.
The trials with mice, the results of which have just been published in the prestigious magazine Science, showed that the rodents had generated antibodies against all 20 influenzas and immunization lasted at least four months. In the second part of the work, 28 days after being vaccinated, the scientists infected several groups of these animals with two different subtypes of influenza A, one of them similar to the predominant influenza virus among humans, H1N1. All the mice in the control group, which had been injected with a placebo instead of the vaccine formulation, died. However, those actually vaccinated and exposed to the homologous virus did not die or even lose weight. No viral load was detected in the lungs either. Meanwhile, those immunized and exposed to the strangest virus, all became ill, lost weight, but after seven or eight days the majority recovered, only 20% dying. For the authors, these results mean two things: their vaccine is not sterilizing, that is, it does not protect against infection, but, as with coronavirus vaccines, they protect against the harshest version of the disease, even against viral varieties whose antigen did not include the vaccine.
“Current flu vaccines do not protect against flu viruses with pandemic potential; This vaccine, if it works well in people, would do this.”
Adolfo García-Sastre, director of the Institute for Global Health and Emerging Pathogens at Mount Sinai Hospital in New York
“Current flu vaccines do not protect against flu viruses with pandemic potential; This vaccine, if it works well in people, would achieve this,” says Adolfo García-Sastre, director of the Institute for Global Health and Emerging Pathogens at Mount Sinai Hospital in New York, not related to the research, in statements to the SMC Spain platform. “Current flu vaccines do not protect against flu viruses with pandemic potential; This vaccine, if it works well in people, would achieve this”, adds Sastre, who immediately recalls that the work has been done with mice. “The studies are preclinical, in experimental models. They are very promising and, although they suggest the ability to protect against all subtypes of influenza viruses, we cannot be sure of this until clinical trials are carried out in volunteers”, he recalls.
For Raúl Ortiz de Lejarazu y Leonardo, professor of microbiology and emeritus director of the Valladolid National Influenza Center, the most relevant aspect of this research lies in the fact that “it uses many antigens from different hemagglutinin subtypes (all that exist, including those from bats). ) instead of going to conserved regions of one or few antigens”. With traditional platforms it did not seem feasible, but “current messenger RNA vaccine platforms allow the inclusion of many mRNAs that will induce many different proteins, giving a multivalency and breadth of response that was not easy to achieve before with protein platforms,” he concludes.
For his part, the professor of microbiology and parasitology at the Faculty of Pharmacy of the Complutense University, Víctor Jiménez Cid, highlights why this idea of 20 vaccines in one is important: “Seasonal influenza A viruses that circulate in the human population they are only H1N1 and H3N2. Why include other H antigenic types in the vaccine? Firstly, A viruses are zoonotic and, although the other types do not circulate in the human population, they do circulate in other animals, such as types H5, H7 and H9 in the case of birds. This implies that new pandemic viruses could emerge if one of these types becomes implicated in a antigenic jump generating a new A virus that combines the genes of animal viruses with those of viruses that circulate in humans”, he declared to SMC. The idea is not unlikely, in fact it is what happened in the four great pandemics of the last 100 years: that of 2009, that of 1968, then called the Hong Kong flu, the Asian flu of 1957 or that of 1918, when the combination between a human flu and another avian flu a few years earlier would cause the death of between 50 and 100 million people.
On the keys to the efficacy of the vaccine, the virologist Arévalo concludes: “This candidate is so successful because it involves multiple weapons of the immune system. In particular, our vaccine elicits different types of antibodies with various functions. It also generates different types of T cell responses. [que eliminan las células infectadas y activan macrófagos]. As in all scientific endeavors, we need to do more research to determine the exact mechanism of our vaccine’s success.” Arevalo wanted to record that his views do not necessarily represent the views of the University of Pennsylvania or Pfizer.
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