Fears over the H1N1 virus circulating the globe have abated somewhat this week, as a growing number of mild cases suggest that the swine flu virus is not as deadly as initially feared. However, public-health officials caution against becoming too complacent, and the Centers for Disease Control (CDC), in Atlanta, and others are still taking steps to produce a vaccine: the flu season is just beginning in the Southern Hemisphere, where the virus could mutate to become more pathogenic. It’s also possible that the virus could prove much deadlier in a second wave around the world, as was the case for the 1918 flu, which ultimately killed millions.
The CDC is currently growing a seed stock of the H1N1 virus–the first step in making a vaccine. This stock will be distributed to vaccine manufacturers around the world, who will begin production of a vaccine once they’re given the go-ahead from the CDC. However, existing methods for making flu vaccines carry some disadvantages: they are relatively slow and require large amounts of the virus to be grown in chicken eggs. Due to limited production capacity and a limited egg supply, manufacturers would need to halt or decrease production of the seasonal flu vaccine. “This is a very inefficient system that requires a nine-month lead time,” says Ted Ross, a microbiologist at the University of Pittsburgh. “We need something more rapid with something like swine flu.”
Thanks to previous pandemic fears–largely from the avian flu, a much deadlier but less transmissible virus–alternative methods for making vaccines have received a significant boost in recent years. In 2006, for example, the U.S. Department of Health and Human Services awarded $1 billion in funding to a number of vaccine makers, including GlaxoSmithKline, Novartis, and MedImmune, to develop alternative production methods. Now, for the first time during an active pandemic, researchers and pharmaceutical companies are using these approaches to make vaccines against the current strain even before efforts have begun using traditional methods.
Novartis has already developed a vaccine for seasonal flu that is grown in cell culture, using methods similar to those employed to make biological drugs and other products; it has been approved for use in Europe. “The advantage is that cell culture can be expanded enormously,” says Andrea Gambotto, also at the University of Pittsburgh. “You can culture thousands of liters of cells, whereas there is a limited capacity to produce eggs.”The company is now using both cell-culture-based and egg-based technology to create an H1N1 vaccine. While the former is faster, cell-based manufacturing capacity is limited for this new approach, says a spokesperson for Novartis.
Despite the quick start, “it’s not clear that anything but the conventional technology will be in place in time to generate clinical vaccines that are going to be needed next year,” says Gary Nabel, director of the Vaccine Research Center at the National Institute for Allergy and Infectious Diseases (NIAID), in Baltimore. That’s because these new vaccines will need to undergo extensive animal and human testing before they can be marketed. (That process may move faster in the European Union, where cell-culture-based methods have already been approved for commercial use, than in the United States.) Still, the effort will not be wasted. Researchers see the latest flu scare as sort of a trial run for the next potential pandemic strain, which may be much more serious. “It’s more of a research exercise to see how quickly we can respond to a new strain of influenza,” says Gambotto.
Others are developing vaccines that use only portions of the virus, and are thus easier to grow in cells. (Intact viruses can sometimes be toxic to both eggs and cell culture.) Nabel and his collaborators at NIAID’s Vaccine Research Center are developing DNA-based vaccines, in which circular pieces of DNA containing the virus’s HA gene are grown in bacteria. Researchers have already developed an H5N1 vaccine using this technology; it is currently in human trials. “We could have a vaccine ready to go into clinical trials in two to three months,” says Nabel. “But whether that will elicit the same magnitude of response as a conventional vaccine, or whether we have to do something to enhance that response, we don’t know.”
Ross and others are taking another approach: developing viruslike particles. “We take a set of genes from the virus and use it to generate a particle that looks like a virus but isn’t able to replicate,” says Ross. “The immune system reacts to it, even more robustly than it reacts to a traditional vaccine.” The advantage of this approach is that a candidate vaccine can be generated as soon as the viral sequence is available. “The H1N1 sequences are already on the Internet, so you can generate a vaccine even without access to the virus itself,” says Ross. “We will have a vaccine to test in preclinical trials in a few weeks.”
Many unknowns will affect how vaccine production proceeds in the coming months. The CDC still hasn’t decided whether to begin production of an H1N1 vaccine soon, or whether to hold off and include the H1N1 strain in next year’s seasonal flu vaccine. “We’re already working to ramp up the production of the seasonal flu vaccine so that, should we decide to manufacture a vaccine for the H1N1, we’d be able to do that,” said Richard Besser, acting director of the CDC, at a press conference earlier this week.
“We’ll be working very closely with the international community to understand what happens to this virus over the next few months as flu season begins in the Southern Hemisphere,” said Besser. “That will tell us a lot about whether the virus is changing, whether it’s becoming more severe, and what measures we might want to take in the fall.” For example, if the virus does mutate to become more deadly, it’s not clear that a vaccine made against the circulating strain would protect against the new strain.