Vaccines, enzymes and malaria.

Several books or chapters on vaccines begin with a statement that goes something like this: the virtual elimination of childhood diseases from the face of this earth must surely rank as one of the great accomplishments of medicine. Even a generation ago, children born in many countries of the world were potential victims of devastating diseases such as polio, smallpox, mumps or measles. A child born today in most parts of the world can expect to go through childhood without experiencing a major debilitating or lethal infectious disease. Those of us who work, directly or indirectly, on generating vaccines for infectious diseases consistently remind those who will listen that only one human disease has been successfully eliminated – smallpox – and this was a result of the availability of a safe and effective vaccine. The WHO holds a realistic hope that polio will be eliminated within the next few decades.The salutary developments in pediatric infectious disease have fostered the belief that similar developments will, one day, permit us to live in a world in which adults could also be free from infectious diseases. Immunological intervention is seen as the mechanism for reducing human suffering not only through prophylactic vaccines but also through therapeutic vaccines, which can boost the immune system and provide relief even during chronic ongoing processes (such as AIDS, tumors including malignant neoplasms and chronic diseases including those caused by eukaryotic parasites). While we proceed with our efforts to manipulate the immune system for prophylaxis and therapy, it is noteworthy that successful vaccines proven to be useful in practice share certain common features. Vaccines need to possess properties permitting deployment on the global scale, including the capacity for cheap mass production, relative resistance to degradation by climactic conditions and freedom from unacceptably high incidence of untoward side-effects. Features of the etiological agent must also be considered, such as the fact that humans are the only susceptible hosts for smallpox. Hence, there was no need to deploy the vaccine among any other species, which would have been impossible to achieve on a global scale. Finally, the natural history of the disease must be acknowledged, which might be responsible for the success of pediatric vaccines. If we examine the natural history of smallpox, for example, there is a high probability of fatality from infection. Depending on the particular epidemic and the susceptibility of the host population, the smallpox epidemics were associated with mortalities ranging up to 40%. Whereas survivors were often left with lifelong sequelae (the after-effects of infection) ranging from cosmetic issues (e.g. cutaneous scarring) to disabling ones (e.g. blindness), they were resistant to smallpox for the rest of their lives. This resistance to re-infection is true of the natural history for other pediatric infectious diseases for which there are effective vaccines, including measles, mumps, rubella and other childhood diseases.When I ponder over the difficulties we seem to be encountering in generating vaccines for the parasitic diseases that we are interested in, I wonder if the experience with pediatric vaccines has led us to expect more from vaccines than they can deliver. Is it possible that pediatric vaccines have worked so well because they recapitulate the natural history of the diseases?I believe a useful way to consider a vaccine is to draw an analogy with enzymes. Enzymes convert one or more reactants into one or more products, facilitating the initiation of a reaction by reducing the activation energy and speeding the reaction by acting as organic catalysts. However, enzymes do not change the equilibrium of the reaction and the end state recapitulates what would have been the case in the absence of such enzymes. Similarly, although the analogy might be stretched in some aspects, vaccines appear to convert an individual from the pre-infectious state to the post-infectious state without undergoing the pathological sequelae attendant on natural infection. However, the vaccination process might not change the equilibrium between the individual and the infectious agent. Thus, if the equilibrium were that the individual becomes immune and resistant to re-infection, then the vaccine might accomplish the same. By contrast, if the natural history of the disease was that the post-infectious individual is only partly immune or immune for a short period of time, such equilibrium might also be recapitulated in the vaccine formulation. Certainly, the experience with malaria vaccines appears to be consistent with this formulation. However, it is conceivable that part of the reason for this is the vaccine effort in malaria appears to have been directed against accomplishing sterile long-lasting immunity, which might not be possible in the framework of the natural history of the disease. The natural progression of this disease appears to be that a child becomes infected, and should the child survive the acute infection, the child will maintains a lifelong low-level of parasitemia. Is it possible that vaccine effort in malaria would not be seen as ‘unsuccessful’ if the goals were set at accomplishing a chronic 1% parasitemia?My purpose is to provoke argument and raise the possibility that the effective, inexpensive, sterilizing, long-lasting pediatric examples might not be the only ‘effective’ vaccines. Instead, at least in some chronic diseases, would it be more productive to view our goals as to accomplish the long-term, often stable and not highly pathogenic relationships between the infectious agent and the infected or post-infected individual?