THE NEW GERM THEORY OF DISEASE: TOOLS OF DOMESTICATION
Although the conquest metaphor has limited applicability in the control of infectious diseases, the diversity of warfare situations offers a diversity of metaphors. The matches should not be surprising, because in a very real sense we are in a state of war with many of our microbes. They are invading us. We are killing them. The mistake in the standard war metaphor was in thinking that there was only one successful solution: unconditional surrender. In real warfare as in antimicrobial warfare we have learned, sometimes very painfully, that there are other solutions.Consider the Soviet war in Afghanistan. Although the Soviet Union had overwhelming superiority in fire power, the United States saw that it could tip the balance in favor of the Afghan rebels by providing Stinger missiles, which could knock out the main Soviet threat: attack helicopters. The United States provided this weapon after considering which of the two sides was more dangerous to U.S. interests. There was no opportunity to groom a successor. If there had been, the U.S. government might have called on the CIA to deploy a different strategy. Whether one supports or condemns any such covert action depends on how one weighs the expected geopolitical benefits against the compromises of individual rights and national sovereignty. The quality of the assessment depends on the range of strategies considered.Health policy strategists have a wider range of opportunities because bacteria and viruses do not have rights. They are free to use any strategy regardless of the destruction that is imposed on innocent microbes. Yet in spite of this freedom of action, health strategists have not drawn on the range of tactics the CIA employs. Imagine how much less effective it would have been if the United States had intervened in Afghanistan by battering down both sides. Yet that is just what vaccination programs attempt to do. Instead of making vaccines that favor the mild strains by selectively knocking out the truly dangerous opponents, or by grooming the microbial successor, we have been trying to make vaccines for over two centuries that knock out all the variants of a target microbe, whether the variants are mild or extremely dangerous. When a vaccine does that, we no longer have the mild variants predominating in the wake of the campaign to protect against the harmful variants.If vaccine efforts lapse, as they often do, then the mix of pathogens that was there before the vaccine effort will quickly expand to fill the void. If only mild variants are left, the situation is more stable against reinvasion by harmful variants. The overall kill rate is lower, but it is selective; the outcome is thus more favorable.The second most cost-effective vaccination program in history, the one that controlled diphtheria, inadvertently showed how well this selective strategy can work. The people who made the diphtheria vaccine may have thought of their efforts as an all-out war to eradicate an enemy, but the bacterium that causes diphtheria, Corynebacterium diphtheriae, was not eradicated by the vaccine program. Rather, the vaccine selectively suppressed the dangerous competitor, altering the balance in favor of the benign competitor. This selective intervention virtually banished diphtheria for more than a half century without the need for an all-out eradication campaign. If we understand why this campaign worked so well, we might use it as a model for other vaccine campaigns.The diphtheria bacterium causes most of its damage as a result of a toxin it produces when it is short on resources, particularly iron. The toxin costs the bacterium about 5 percent of its protein budget, but the investment pays back dividends because the toxin kills the cells of the respiratory tract near the bacterium, thereby liberating the nutrients the bacterium needs. The diphtheria vaccine was made by modifying this toxin a little so that it no longer damaged respiratory tract cells but still caused the immune system to generate antibodies that would recognize and sequester the unmodified toxin. If a toxin-producing C. diphtheriae invades a person who has been vaccinated, the toxin is sequestered by antibodies before it can destroy a person’s cells and provide nutrients for the bacterium. The 5 percent cost of toxin is simply a drain on the bacterium’s ability to compete with toxinless bacteria. The overall effect is that the strains that do not produce the toxin win out over the harmful strains. Wherever the strains left in the wake of a diphtheria vaccination program were assessed, the same trend occurred: the toxin-producing strains vanished, replaced by the milder, toxinless strains. That is a good outcome for us because strains that do not produce toxin not only fail to cause diphtheria but also protect us against the harmful strains that do. They therefore act like free live vaccines.These arguments lead to a simple rule for vaccine development. Whenever possible, use virulence antigens: those components of a pathogen that make viable, benign organisms harmful. Doing so will generate an immune response that selectively protects against the harmful organisms. Including antigens against components of the pathogen that do not make it virulent must be avoided. Otherwise the vaccine will remove mild strains that could further suppress the harmful strains.This virulence antigen strategy has been used inadvertently in one other vaccine program, the one against Hemophilus influenzae, which has been an important cause of encephalitis in children. That program was so successful that it left researchers scratching their heads. But extraordinary success is what one should expect from virulence antigen vaccines. The strategy should be applicable to all vaccines, yet it has not been considered as part of the strategy for making any vaccine, largely because vaccine developers tend not to look at their task from an evolutionary point of view.The virulence antigen strategy requires that vaccine experts shift away from eradication as a goal. This shift is dictated for some diseases by the ability of vaccines to prohibit disease but not infections. When children are vaccinated against pertussis (whooping cough), for example, the disease is generally prevented but the organism is still present and transmissible. Prospects for eradication by such vaccines are obviously very dim, no matter how pervasive the vaccination program. We can expect to be living with the agents. If we have to live with the organism anyhow, we should make it a benign organism that supplements vaccination efforts rather than a mix of largely harmful organisms. Pertussis vaccination is a perfect candidate for a virulence antigen strategy, not just for this reason but also because virulence antigens are already identified and can generate a protective effect that is comparable to the best vaccines available. The pertussis vaccines that are currently being used have other antigens, particularly one called filamentous hemagglutinin, which trigger immune responses that suppress benign strains as strongly as harmful strains.*62\225\2*
