The Approach of Flu Season

It is mid-summer, the day after baseball’s all-star game here in Saint Louis, with the cooler days of fall in distant sight.  This is the time of year that public health officials begin to seriously prepare for the unwelcome guest that arrives each fall with the cool weather – influenza.  Fall is the flu season in the Northern Hemisphere, the time when many of us get flu shots and many others don’t, a time when many people will come down with the flu and thousands of us will die of it.  The CDC (Center for Disease Control and Prevention) estimates that on average 36,000 Americans died of the flu each year in the 1990s.  Flu season is not, and has never been, a joke.

This year the coming threat seems particularly ominous. A strain of flu virus appeared in Mexico last year and spread very quickly. Most flu viruses don’t pass easily from person to person.  That is why the deadly bird flu that has been much in the news in recent years has not killed many people – the bird flu virus passes from one person to another only with great difficulty. It turns out the bird flu virus particles  doesn’t survive well enough in the human respiratory tract to become established.

Not so this new flu.  Informally dubbed “swine flu” because it carries genes of three swine viruses (one of them related to the human virus that caused the deadly 1918 Spanish flu pandemic), this virus infects all of the respiratory tract, instead of staying in the nose and throat like seasonal flu.  Reports published this week in the journal Nature report that in monkeys swine flu thrives even in the lungs.

Over the course of the year swine flu spread to the United States, and quickly to Europe, South America, Asia and Africa.  By June it had been reported in 74 countries.  On June 11, WHO (the World Health Organization) declared a level six epidemic – a world-wide pandemic.

This declaration reflects how fast the novel flu virus spreads, not how deadly it is.  In fact, after its initial appearance in Mexico, the swine flu has proven quite mild, with cold-like symptoms and few fatalities. As of last week, swine flu has infected 37,246 Americans but caused only 211 deaths, according to the CDC.

The problem, of course, is that flu viruses do a very sloppy job in copying their genes while reproducing, so that many new mutations (random alterations of genes) occur each virus generation.  The 1918 Spanish flu was a mild virus when it first spread among Americans. So were the other two killer flu pandemics of the 20th century, in 1957 and 1968.  In each instance, mutations subsequently rendered the virus more lethal, and a few years later the virus cut a deadly swath in the fall flu season.

Now you can see what keeps the CDC up at night.  The deadly Spanish flu, which is estimated to have killed between 50 million and 100 million people worldwide, was both well-adapted to the human respiratory system (and so infected a lot of people) and deadly (and so killed a lot of the people it infected).  Bird flu kills few people because it is not well-adapted to the human respiratory system (and so does not spread from person to person), although it is deadly (it kills most of the people it infects). Swine flu kills few people because, although it is well-adapted to the human respiratory system (and so spreads quickly from person to person), it is not deadly.  The nightmare is that mutations could make bird flu better adapted to the human respiratory system or swine flu more deadly.  So we watch them.  Closely.

The CDC is constantly sequencing the genes of bird flu and swine flu isolates, monitoring the effects of any mutations.  If a deadly change were to be detected, a rapid-response could be mounted to contain the virus where it was found by flooding the local area with tamaflu. Meanwhile a full-bore effort could made to prepare and manufacture a vaccine directed against the threatening strain.  The whole point of the WHO June pandemic declaration was to signal the need for preparations to carry out these two responses.

This leaves public health officials in a bit of a quandary. The everyday seasonal flu hasn’t gone away, and it is likely that even with a vaccine available, over 30,000 Americans will die of it this year. So we know we have to produce a flu vaccine directed against this “everyday” threat.  But what about the swine flu threat?  Should we develop a vaccine directed against it?  If a deadly version were to appear, a vaccine against today’s version may offer little protection against it.  But even a little could protect a lot of people.   A hard call.  Public pressure will probably force the production of a swine flu vaccine this fall directed against the current mild version of the virus.  I know I will take it if offered.

Still, for both bird and swine flu, the major threat remains unaddressed: how do you quickly produce and distribute massive amounts of a vaccines directed against a newly-emerged killer virus?  The real effort to prepare needs to be focused here.  I hear much about the future potential of molecular procedures to speed vaccine development, but very little about massive government programs to accelerate development and application of these procedures.  If the money that will be spent on a swine flu vaccine this fall were instead spent on improving vaccine production methods, we would all be better served.  When the tomorrow comes that we need a vaccine targeted against a deadly bird or swine flu, we are likely going to need that vaccine very fast.  Learning today how to cut vaccine development and production times will be worth many lives saved on that tomorrow.

In this harsh light, any news suggesting a more promising approach to flu vaccines catches my immediate attention. An article published last February in the journal Nature Structural and Molecular Biology offers hope from an unlikely direction, certainly one I had never considered.  An entire tribe of scientists are names as authors of this article, researchers at Harvard Medical School, the CDC, and the Burnham Institute for medical Research.  They claim to have engineered vaccine antibodies that protect against many strains of the flu virus instead of just one, including even the 1918 Spanish flu and bird flu!

If these researchers are right, this would solve the key dilemma neatly.  A single vaccine that protects against both present and future versions of bird and swine flu is just what the doctor ordered.  Stockpiled worldwide, such a vaccine could effectively contain a future swine or bird flu high-mortality outbreak before it ignited into a deadly worldwide pandemic.

What the researchers did was identify a potential flu virus “Achilles’ heel,” a weak spot shared by all flu viruses.  Flu viruses use a lollipop-shaped molecule called hemagglutin (H) to invade nose and lung cells. There are 16 known types of hemagglutin, H1 through H16. The H gene mutates constantly, which is why flu shots have to be reformulated each year.

The research team found a way to expose the hemagglutin lollipop’s neck to antibodies.  Because the neck has an important function in penetrating a human cell, the virus does not tolerate mutations there, so that unlike the often-mutated tips, all necks are much alike.  The researchers guessed that an antibody directed at the lollipop’s neck would attach to almost all versions of the virus hemagglutin.

Why bother?  Once an antibody is clamped onto its neck, the hemagglutin can still penetrate a human cell, but it cannot open out (imagine trying to open out your fist after wrapping duct tape around it). Clamped shut like this, hemagglutin cannot do its job of injecting flu virus genes into the human cell to make more viruses.

To find neck-directed antibodies, the researchers screened a huge collection of 27 billion different antibodies directed against flu – basically all the random permutations of antibody sequence they could produce. They found ones directed against H1 and against  H5 necks.  This year’s seasonal flu is H1 (in other years it is often H3), as is swine flu. Bird flu is H5.  The researchers say they are hard on the heels of a H3 antibody as well.

We are still a long way from safe.  Clinical trials could begin within three years, but will take many years to complete. “This is a really good study,” said Dr. Anthony Fauci, former head of the CDC and now director of the National Institute of Allergy and Infectious Diseases. “It’s not yet at the point of practicality, but the concept is really quite interesting.”

Still, here is a place where we can, and I’m sure will, focus serious effort.  For once, the news on the flu front offers real hope.

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