World War I (1914-18) counted 15.9 million combat deaths. Of that number, 53,513 were U.S. casualties. These horrendous mortality figures were trumped in 1918 by the 20 million or more civilian lives lost to influenza following that war.

It took until 1946 before the first influenza vaccine was launched. Nowadays, young children and the vulnerable elderly are urged to take their annual flu shots. Globally, the virus causes 3 million to 5 million cases of severe illness a year, and 250,000 to 500,000 deaths annually. In the U.S., 10 percent to 20 percent of the American population contracts influenza. Of 114,000 hospitalized with the flu each year, 36,000 die.

The Catch-22 is that the influenza pathogen fights back. Year after year it puts forth a new mutant strain, which outdates last year's vaccine. Therefore, immunologists and virologists attempt to second-guess the ever-changing viral target. They foregather in February at the World Health Organization headquarters in Geneva to plan and produce the forthcoming flu season's vaccine of the year. Again, the viral enemy counterpunches, this time by fielding every few years a far more virulent strain than the relatively manageable varieties of normal years. That sends the world's vaccinologists back to their drawing boards with a vengeance.

A new prototype vaccine constructed by researchers at the Wistar Institute in Philadelphia, however, aims to protect recipients from infection, not only against this year's strains but also against those to come. This futuristic prospect might in fact eliminate the need for an annual shot in the arm. In fact, this anti-influenza vaccine would be given through the nose - by nasal spray.

A full report on this innovative development appears in the June 2, 2003, issue of the journal Vaccine. Its 26-word title reads: "Induction of influenza Type A virus-specific resistance by immunization of mice with a synthetic multiple antigenic peptide vaccine that contains ectodomains of matrix protein 2."

The paper's two co-senior authors, at the Wistar Institute, are immunologist Walter Gerhard and medicinal chemist Laszlo Otvos.

Main Goal: Curtailing Influenza's Moving Target

"Current vaccines are quite effective," Gerhard observed, "but they are based on regions of the virus that mutate rapidly, so health officials are constantly faced with the problem of updating them. A vaccine directed against a more stable region of the virus would offer important public health advantages," he added, "which is what we are hoping to develop."

"The novelty in our finding," Otvos told BioWorld Today, "is twofold. One is our use of the viral antigen, matrix protein 2 [M2] as a potential immunogen. That would mean you need not get a fresh vaccine every year. So we made a synthetic peptide construct corresponding to this so-far-unexplored M2 antigen of the influenza virus.

"No one ever used synthetic peptide constructs corresponding to M2 as a vaccine," Otvos noted. "And this is important because when you have a synthetic peptide that is well defined, it can be made at high purity. It is desirable to have synthetic peptide immunogens in a vaccine, rather than full protein or entire inactivated viruses. Some other laboratories are using full proteins, but the best would be synthetic subunit vaccines, because you can make them in high-quality, large quantities - which is what we did."

M2 is the molecular centerpiece of this new vaccine. "It is a small protein," Otvos explained, "and has a very short extracellular region, which we call ectodomain. M2 is really the outside face of the viral membrane. In every protein, the extracellular region is the immunogenic one. So it's an ideal candidate for a subunit synthetic peptide vaccine.

"We made a construct," Otvos recounted, "that has four copies of this M2 protein fragment. Four copies because in the protein, the virus forms this cationic channel, that has four copies of M2 together. There is a hole in between. We just wanted to mimic the natural conditions as much as possible. So we needed a peptide construct with four copies of this M2 extracellular domain, plus two copies of other T-cell determinants. And this six-peptide copy construct we used as our target immunogen.

"Type A," he added, "is the most common infectious influenza virus."

Why is this vaccine administered intranasally rather than by injection?

"Because influenza virus spreads through the airways," Otvos said. "So the best protection against infection can be at airway organs. You could not find the conventional inactive virus intranasally. But with a subunit vaccine it is possible. I know others in Australia," Otvos recalled, "who are trying to use intranasally administered subunit vaccines, but theirs' are directed against other proteins in the virus."

New Nasal Vaccine Would End Fear of Shots

"Basically," he pointed out, "the influenza virus infects your lung, your trachea, your respiratory tract. So of course the best thing would be to administer this peptide construct into the site of infection. And the other thing is that many people are phobic about getting shots, afraid of the needle, which the intranasal route avoids. But if you have something that can be administered through the airways, like a spray, people would prefer that of course."

At this point, the vaccine is being tested in mice.

"We gave the mice this peptide construct through the nose," Otvos recounted, "and infected them afterward with the active infectious virus. Following vaccination, a steep rise in M2-specific antibodies appeared in their blood, and they exhibited significant resistance to viral replication in their respiratory tracts. Those mice are not dying of our vaccine."

The Wistar team is nowhere near human field tests of its intranasal vaccine. "For human trials," Otvos explained, "you need to show long-term efficacy, the lack of mutation and antigenic drift, as well as that we can protect mice from lethal challenge. I hope," he concluded, "that we can reach the point of going into humans."

Wistar has a patent pending that covers the future vaccine, with Gerhard and Otvos its principal inventors.