February 24, 2018
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Making a flu vaccine without the virus

By Kai Kupferschmidt, ScienceNOW

A new vaccine strategy could make flu shots cheaper, safer, and easier to produce. Using synthetic messenger RNA, or mRNA, instead of proteins purified from viruses, German scientists have shown they can protect mice, ferrets and pigs against influenza.

“This is a very interesting new approach,” said Hans-Dieter Klenk, a virologist at the University of Marburg in Germany who was not involved in the work.

Now most flu vaccines consist of hemagglutinin and neuraminidase, the two proteins covering the surface of the virus. To produce these molecules, the three predominant influenza strains are cultured in fertilized chicken eggs or, increasingly, in cell culture. Virus is then harvested and broken up so that the two proteins can be purified.

How well a given strain grows in either eggs or cells is hard to predict, however, and producing enough virus for millions of vaccine doses takes many months every year. This is a particular problem when a new pandemic influenza strain emerges, as happened in 2009 with swine flu. Most of the vaccine against that virus became available well after the pandemic was past its peak.

Now scientists at the Friedrich-Loeffler-Institute (Germany’s Federal Research Institute for Animal Health), and biotech company CureVac in Tubingen have developed a new approach. They designed a piece of mRNA encoding the hemagglutinin of the influenza strain H1N1. Cells use mRNA to shuttle the information contained in the genome from the nucleus into the periphery of the cell, where it is translated into a protein. By injecting synthetic mRNA into the skin of mice, the researchers coaxed the animals’ cells into producing the virus protein themselves. This elicited an immune response that later protected the animals from infection with otherwise lethal doses of influenza virus, the researchers reported online on 25 November in Nature Biotechnology.

An mRNA vaccine could have other advantages. There’s no need to grow the virus; all that is needed is the sequence of the influenza strain. That means shots ready for distribution could be produced within six to eight weeks, the authors write, and production costs would fall. The vaccine does not need to be kept refrigerated for storage or distribution either, they claim, and it does away with the danger of an anaphylactic shock in people who are allergic to ovalbumin, a protein in chicken eggs that is often present in the shots in very low amounts.

Other researchers have tried using DNA rather than RNA to vaccinate against influenza. But while mouse experiments were promising, the results in human trials were disappointing, Klenk cautions. That the mRNA vaccine also showed an effect in ferrets and pigs “makes it more likely that these results could hold true in humans as well,” he said.

One reason for the failure of the DNA approach could be that DNA has to cross two membranes to get into a cell’s nucleus, says Karl-Josef Kallen, an immunologist at CureVac and one of the authors: It has to enter not just the cell but also the nucleus, the only place its information can be read.

Using RNA, which does its job outside the nucleus, is much simpler, but scientists long thought that RNA was too unstable to be used as a vaccine. CureVac has overcome this problem by changing the sequence of the mRNA in a way that increases its stability up to 10,000-fold without changing the protein it encodes, Kallen says.

The new vaccine would still have some of the drawbacks of current vaccines: It only protects against a single influenza strain, in this case H1N1. And because the flu virus changes its coats so rapidly, it would still have to be reformulated every year, like the current shots.

The ideal for flu experts is a “universal vaccine” that could confer immunity against a broad variety of flu strains; to find it, scientists should look for other parts of the virus that the immune system could attack, says microbiologist Katie Ballering from the University of Minnesota.

“Truly game-changing vaccines probably would not use [hemagglutinin] at all,” Ballering says.

Kallen says the mRNA technique can be used to design vaccines against a variety of other diseases: CureVac is already working on mRNA vaccines against other pathogens in a collaboration with pharma company Sanofi and DARPA, the U.S. Department of Defense’s research agency. The next step, a safety study in humans is being prepared, he says, but he does not want to say for which disease.

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