777s and HIV, or your body is not an airplane

What the challenges of building a safe plane show us about vaccines
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Heart of patient 777: a Rolls-Royce Trent 800 engine

What the challenges of building a safe plane show us about vaccines

Investigators pinpoint a glitch in the 777 from just two incidents, and a fix is on the way. Yet HIV researchers with data from thousands of subjects can'ꀙt explain how a vaccine trial went awry. Why?

Following mysterious power failures in Boeing 777s last year, the National Transportation Safety Board recently urged a redesign of engines to handle ice formation in fuel lines. Based on just two incidents, investigators determined that this ice broke free and then blocked the flow of fuel to the engine. Suggestively, heart attacks occur in a like manner in humans, plaque breaking away from artery walls and obstructing blood flow to the heart. Yet the human body is not an airplane. And vaccine design is a long way from aeronautical engineering.

While isolated 777s were suffering these "thrust rollbacks," the most recent HIV/AIDS vaccine trial crashed to earth in September 2007. As was widely reported, the vaccine not only didn'ꀙt work, it appeared to make HIV infection more likely. But poring over data from thousands of trial enrollees, scientists at the Fred Hutchinson Human Vaccine Trials Network and elsewhere have been unable to pinpoint why.

The vaccine used a cold virus to deliver its genetic payload, the fragments of HIV meant to stimulate a protective immune response. Subjects who'ꀙd had this cold already (and thus existing antibodies to it) seemed more susceptible to contracting HIV. Some research has subsequently absolved this cold virus while at least one more complicated explanation still implicates it. Regardless, what is certain is that in biology, unlike aerospace, how your satellite works depends on the rocket you launched it with. And there are numerous vaccine launch vehicles, or "vectors," tamed versions of canarypox, vaccinia and even salmonella, for example.

But it'ꀙs not only immune interactions with the vector that puzzle researchers. HIV directly targets the immune system, in particular a very specific kind of T cell. So how do you craft a vaccine that elicits a protective response without just providing more T cell fodder for the virus? As the perverse outcome of the last vaccine trial attests, we don'ꀙt know.

T cells were discovered in the late 1960s — and they are still being discovered. With the 2007 failure, vaccine research went "back to basics" — way back. One group of scientists looked at T cell responses to the original vaccine, smallpox, and the also venerable yellow fever vaccine. Confusingly, T cells act differently depending on the disease. Based on the smallpox and yellow fever investigations, researchers claimed to have developed a method for disentangling "the true antiviral response" for a given disease.

T cells are as fundamental to immunology as wings are to flight. In aerodynamics, much of the "basic research" was performed by Claude-Louis Navier and George Gabriel Stokes...in 1882. Open a current aeronautics textbook and you'ꀙll find a chapter that teaches the Navier-Stokes equations. Unlike germ theory, elaborated around the same time by Louis Pasteur and others, Navier-Stokes remains on the tool belt of practicing engineers. And unlike understanding of T cells, Navier-Stokes hasn'ꀙt and won'ꀙt change. In addition, there'ꀙs plenty of immune system beyond T cells. Ellen Vitetta, an immunologist at the University of Texas Southwestern Medical Center at Dallas, in an acknowledged guess, believes we understand perhaps 10 percent of the immune system.

On the plus side, we are witness to a vast rate of new discovery. But the dawn of much-anticipated "rational" vaccine design lies over the horizon. It'ꀙs walk before you run — or fly. And the miracle of flight offers an encouraging example. Computers have enabled consummately rational design of aircraft engines. By the 1990s, increased computing power enabled three-dimensional aerodynamic modeling. This led to technology, debuting commercially on the 777, of composite turbine blades, very differently shaped but stronger and 10 percent lighter than their hollow titanium predecessors.

Similarly, vaccine researchers are working to engineer antibodies capable of neutralizing HIV. Scientists plan to map the three-dimensional shape of the virus at the atomic level and then design an antibody that snicks into it. The hitch is that protein shapes and how they interact is vastly more complicated than even aerodynamic modeling. Brute force calculation of some predictions about proteins has been shown to essentially take forever — after which the virus might simply mutate. But engineers have produced useful aircraft based on approximations of our new friends, the aforementioned Navier-Stokes equations, which are plenty hard to calculate out to the last decimal. Art and craft might — just might — succeed where brute force cannot.

Many antibody and other experiments can take place in a petri dish. But when it comes to models, HIV researchers have no wind tunnel for tests and experiments. They have the rhesus macacque. Like an apt simile, macaques can disclose a facet of universal (or at least cross-species) truth. They show tremendous fidelity to humans in succumbing to AIDS when infected with the simian version of HIV. Still, it'ꀙs akin to asking engineers to test 737 winglets on a 1950s-era Tupolev 104.

Assisting investigators of the 777 troubles, genetic diversity within the species is very low. For the 777, airlines could choose engines from GE, Pratt & Whitney or Rolls Royce. Both incidents involved engine trouble and both aircraft featured Trent 800 engines from Rolls Royce.

By contrast, humans have far, far more than three genetically distinct immune systems. Now add the question of whether an individual has had a cold, which could turn out to play a role, and the immunological narrative gets very hard to follow. Also remember that when we say "HIV," we really mean nine different subtypes of the virus. A universal vaccine would need to work on four of them. These are but a sampling of the difficulties a vaccine faces. We perhaps won'ꀙt know what went wrong with the last trial until after a future one goes right — for which there is no guarantee. Even the (still ongoing) 777 investigation hasn'ꀙt achieved complete resolution.

An HIV vaccine would defy biological gravity. (If god had meant humans to be invulnerable to HIV, we'd have T cells more like African Green monkeys or sooty mangabeys.) Both human and viral evolution appear to have moved in directions that exacerbate the conflict. And unlike other diseases, we have no examples of natural immunity to mimic.

But then airplanes fly without flapping their wings.


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