This workshop is an offshoot of the DIMACS Working Group on Methodologies for Comparing Vaccination Strategies.
There is a clear need for the development of a predictive framework, based on
mathematical modelling and computer simulations, that can be used to help design
optimal vaccination strategies. This was the primary objective of the working group
organized by John Glasser and Herbert Hethcote that met at DIMACS in May, 2004.
One aspect of vaccine use that does not often receive much attention, however, is
the evolutionary consequences of these vaccines. For example, what effects might
vaccine use have on the evolutionary dynamics of pathogen populations, and how
might these evolutionary changes affect the ability of the vaccine to control a certain
disease? Additionally, do different vaccination strategies result in different evolutionary
outcomes? Given the extensive genetic variability in many pathogens (such as HIV,
influenza A H2N2, malaria and some vaccine-preventable diseases like polio, MMR,
Chickenpox, yellow fever, tetanus, pneumococcal disease etc.), evolutionary change in
response to vaccination is potentially significant. Our main objective is to to examine
general evolution-related questions for any disease for which there is a vaccine (or hope
for one).
The proposed workshop will focus on the following five main themes:
(i) Modes of Vaccine Action. Vaccines work in different ways. Some block trans- mission, some reduce pathogen replication, others might slow the progression of disease, etc. Questions of interest include: how does the mode of action of a vaccine affect the evolutionary response in the pathogen population within a vac- cinated individual? Are some types of vaccine more apt to result in evolutionary change than others? For example, are escape mutants more likely to occur, and be evolutionary successful, in individuals that are vaccinated with transmission- blocking vaccines or replication-inhibiting vaccines? Are some types of vaccine more likely to result in beneficial evolutionary responses than others in terms of disease control? In the context of live vaccines, under what conditions might we expect reversion to the virulent form to be likely?
(ii) Multiple Levels of Natural Selection. Evolutionary change in pathogen populations takes place on at least 2 distinct scales. Evolutionary change in pathogen sub-populations within a host can occur (as has been well-documented in HIV), but evolutionary change in the pathogen population can also take place at the community level if some strains are more effective at being transmitted from person-to-person than others. Evolutionary biologists have long been inter- ested in such "levels of selection" and it is clearly important that these issues be incorporated into any theory that deals with the evolutionary consequences of vaccination. Under this theme, the following questions would be addressed: how do different types of vaccines and/or vaccination strategies affect evolutionary change at these two levels? Is evolutionary change at one level often expected to oppose evolutionary change at the other? For example, does vaccination tend to result in the evolution of escape mutants within vaccinated individuals, but these escape mutants are nevertheless selected against at the population level (because they do not transmit well)? If so, when might we expect there to be suffcient time for compensatory evolution to occur within an individual that allows for effi- cient transmission between hosts? Are there vaccination protocols that minimize the probability of these sorts of problems occurring?
(iii) Conflicts Between Epidemiology and Evolution. Vaccination strategies that are optimal from an evolutionary standpoint need not be optimal from an epidemiological standpoint. For example, perhaps the strategy that is most likely to be successful in the absence of evolutionary change is also the one that is most likely to lead to adverse evolutionary outcomes. Can we predict when these sorts of conflicts between evolutionary and epidemiological processes are likely? If these sorts of conflicts do exist for vaccination strategies, how can we weight the relative importance of evolutionary and epidemiological issues in order to make informed decisions?
(iv) Vaccination & Virulence. A key question here is what is the expected rela- tionship between vaccine use and the evolution of pathogen virulence? Examples of evolution of virulence include the prevalence of non-toxigenic diphtheria in highly vaccinated populations and the classical example of myoxma virus/rabbit studies of Australia. To date, most work on the evolutionary effects of vaccination has focused on escape mutants, but recently there has also been some influential work done of virulence evolution as well. Important questions we will address are: (1) how do different vaccination strategies affect the expected virulence of a pathogen? and (2) how are these evolutionary changes related to the appearance and spread of escape mutants? Escape mutants are also a consequence of the high mutation rates found among most viruses which make of them a moving target from the immunological point of view. This phenomenon can be seen as one of the facets of virulence with important implications to vaccine development and use. For example, one of the recognized difficulties in developing an HIV vaccine is attributed to the virus diversity within and among individuals and countries. Besides, new influenza vaccines need to be developed each new season to cope with the virus ever changing composition. Another facet of virulence manifests as adverse events caused by live attenuated virus vaccines. Morbidity associated to vaccinal viruses is well described for polio and yellow fever.
(v) Mechanisms of Vaccine Delivery. Modern vaccines comprise purified, inac- tivated microorganisms typically administered by a sterile if painful injection. Today's vaccines generally introduce a weakened version of an antigen that stim- ulates the production of specific antibodies. In a new and promising approach, DNA vaccination, genes encoding an antigen are delivered to cells that then pro- duce the antigen and display it on their surface. New drive systems are at the heart of the new delivery mechanisms. They can include, among others, genetic vaccination using plasmid DNA, microparticle-based DNA delivery (in which the genes are encapsulated within or immobilized on a spherical polymer particle), and live attenuated transgene vectors. The new delivery mechanisms can im- prove vaccine potency by targeting the genes to appropriate cells of the immune system, and allow for the expression of antigens in synchrony with the life cycle of white blood cells and pathogen life-cycle stages. This approach stimulates a cell-killing immune response (cellular immune response) as well as a humoral immune response. Control of a vaccine delivery mechanism can become crucial in the management of a pathogen virulence trajectory.
The proposed workshop will bring together scientists from diverse backgrounds (mathematicians, epidemiologists, virologists, immunologists, vaccine developers etc.) in order to address the questions raised within the aforementioned themes.
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