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How Did the Vaccine Cross the Road?

New Methods, Free of Chicken Eggs, Could Speed Production of Flu Vaccine

close up of medical care professional providing injection SOURCE: AP/TOBY TALBOT Vaccines grown in cell cultures, virus-like particles that stimulate the immune system without threat of infection, and antibodies that could attack any flu strain are all promising routes to slowing pandemics.

A recent report on national preparations for this year’s H1N1 influenza pandemic from the President’s Council of Advisors on Science and Technology could leave the readers in a state of suspended animation—not safe enough to feel relief, but also not completely panicked. Consider that while the projected increase in deaths during the upcoming flu season, estimated at 30,000-90,000 in the United States, raises serious concerns, conditions could have been much worse if the virus strain was deadlier. This uneasy limbo offers a perfect occasion to ponder one approach to curbing infections in the United States: the flu vaccine. But as the report describes, there need to be improvements in current vaccine production methods, as well as in the process of vaccine development.

But how do we make the process faster? And how do we make it better? The first step on the path to a solution first requires understanding the virus, the current vaccine, and how it’s made. Without faster processes for producing influenza vaccines that protect against new strains, this pharmaceutical backstop won’t help us slow a pandemic.

schematic of flu virus with H and N proteins on surface

Figure 1: Schematic of Influenza Virus, with H and N proteins in the surface (adapted from Wikipedia)

The influenza virus, in general, has evolved into a fuzzy, tennis-ball like shape with tiny legs coming out of it (Figure 1). On the surface, it carries a set of proteins that vary between strains, one of which acts as the legs that attach to healthy cells and infect them. Once they attach to the healthy cell, a cascade of events follows that essentially turn your healthy cells into generators of virus particles that will be released to your system (click here to see a nice animation of the process). Two of these surface proteins are what give the different strains their characteristic names; instead of the swine flu, we now call it the H1N1 influenza virus.

The “N” stands for neuraminidase, the component that enables newly generated virus particles in the cell to escape into the system. Several well-known flu medications like Tamiflu and Relenza target this protein, as it is important to dissemination of the virus. If N holds the passage to the exit, then “H,” which stands for hemagglutinin, is the proverbial key to entry. These proteins act as the legs or anchors that enable the virus to latch onto the cell and grant it access inside. More on H later.

There are more than 10 forms of H and 9 versions of N to watch. Those alterations on the surface of the viral ball are what the scientists and World Health Organization researchers continuously assess each season, so that they can effectively target the different strains of the flu.

Once they characterize the blueprint for the season, WHO sends it to the Centers for Disease Control and Prevention, where scientists grow a strain as an initial seed virus. That strain is then sent out to manufacturers who grow the influenza virus in a hen’s egg, purify it, and completely kill it with ethyl ethers or detergents. The purified, inactivated vaccine is then packaged into vials. This is a lengthy process that is tedious and dependent on the health of large flocks of hens. All in all, at highest efficiency, you are looking at 6-8 months from strain isolation to market distribution.

For decades, most experts have agreed that the process of manufacturing influenza vaccine through hens’ eggs is archaic and needs to be improved. However, because biotech funding seems to follow the trail of new super drugs generated by pharmaceutical companies, the standard has remained. But what if a deadlier strain hits? Will this process suffice?

Producing a vaccine to protect the entire U.S. population against a pandemic would require an enormous supply of eggs: 900 million are necessary to produce 300 million doses, according to the Department of Health and Human Services. In addition, avian strains have been difficult to grow in eggs. If strains hit that are too virulent and deadly, this process will fall short. We need alternatives. Fortunately, there are a few promising paths to faster production and better quality of flu vaccines.

Looks like a virus, smells like a virus…

The current approach described above involves taking the actual influenza virus, growing it, and inactivating or killing it. Aside from the time-consuming nature of the process, it also eliminates many of the surface proteins (recall the furry surface of the tennis ball) that may be important in the immune response. But what if you could make the process faster and keep the protein surface layer intact?

Combining cell-based and recombinant approaches may just do the trick. A cell-based vaccine uses viruses grown in cultured cells (typically kidney cells) rather than hens’ eggs. In this case, cells (as opposed to eggs) become the bio-generators of the virus. Because cells don’t have the limitations flocks of chickens do (hen health varies, as does biological timing; and some fail to produce embryonated eggs; eggs are prone to contamination, etc.), they can conceivably achieve higher production levels. The cells are just waiting in an incubator near you. Thus, this method could potentially meet the demands of “surge capacity” in the face of a pandemic, as cells can be frozen, while reducing the risk of contamination and reliability posed by egg-based methods.

Recombinant vaccines use cells, typically bacteria or yeast, to create large quantities of viruses (or parts of a virus) without disease-generating qualities—these are called virus-like particles or, VLPs. That is, they create what looks like a virus from the perspective of your immune system (it elicites an immune response), but it actually lacks the contents that would make it a dangerous entity. It looks like virus, smells like a virus, walks like a virus… but it’s not a virus. When VPLs are injected into a patient, the immune system reacts as if it were attacking a real virus, creating anti-bodies against it, and giving the patient immunity when the real strain attacks. Unlike traditional vaccines, these VLPs do not run the risk of becoming virulent again, making them safer to use.

With these two approaches, scientists could produce more powerful vaccines in a fraction of the time. In fact, instead of waiting 6-8 months, the process could take just 4 weeks. A small company called Novavax claims to have produced an effective vaccine this way. While this is only a start, it is certainly a promising one in our quest to make better vaccines and make them faster.

However, this does not change the fact that we will always be in a reactionary position with regard to the flu. As such, WHO and the CDC will always have to be observing, predicting, and blueprinting what comes next in the flu repertoire. That is, unless we have a way to create vaccines that don’t have to change with the varying flu strains.

A “conserved” approach

Recall that the proteins on the tennis-ball surface of the flu virus are always changing. But what if the flu vaccine instead targeted a region of the proteins that is not changing? Even better, what if it targeted a region that is consistent throughout most (if not all) influenza strains? This is referred to as a “conserved regions” approach, and the strategy is to find antibodies that latch into these conserved regions within the legs (or H proteins) of the viral ball (again, see Figure 1). Those regions are where the virus fuses to the cell it infects, and by binding to these stable areas, the antibodies prevent the virus from fusing with the host cells, incapacitating it.

But there’s more. Because these regions are conserved, this strategy has the potential makings of a super vaccine—one that can treat many, if not all, flu strains. Current research on this method is underway at the Dana Faber Cancer Institute and Scripps Research Institute, among others. From a practical perspective, a successful “conserved regions” vaccine would minimize the need to be on standby alert all of the time, and would allow for the continuous generation of antibody stock, in the event of a rapidly spreading flu outbreak. This means we won’t have to be running against the clock every time a potential influenza pandemic rears its ugly head.

Borrowing a phrase from popular seismology, the big one has yet to strike. Yet, it is important to understand that pandemics are not a question of “if,” but rather “when.” Although it is true, as the PCAST report states, that our methods now are more sophisticated than in 1918—when the Spanish flu pandemic, which was responsible for more deaths than World War I, struck—our tiny enemy, the flu virus, may also get more complex with time. Improving vaccine production will require significant investments, but the risk far outweighs the cost.

Ricardo Antonio Rossello, Ph.D., is a Doctor in Biomedical Engineering at the Duke University and an entrepreneur in bioengineering and technology.

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