While T cell-based vaccines have the potential to provide protection against chronic virus infections, they also have the potential to generate immunopathology following subsequent virus infection. We develop a mathematical model to investigate the conditions under which T cells lead to protection versus adverse pathology. The model illustrates how the balance between virus clearance and immune exhaustion may be disrupted when vaccination generates intermediate numbers of specific CD8 T cells. Surprisingly, our model suggests that this adverse effect of vaccination is largely unaffected by the generation of mutant viruses that evade T cell recognition and cannot be avoided by simply increasing the quality (affinity) or diversity of the T cell response. These findings should be taken into account when developing vaccines against persistent infections.Vaccination expands the numbers of lymphocytes specific for a given pathogen. However, in some circumstances, increasing the number of antigen-specific lymphocytes may fail to provide protection and instead lead to an adverse outcome following exposure to the pathogen. Vaccine-induced pathology can occur for many reasons. For instance, the recent adenovirus 5-based vaccination against human immunodeficiency virus (HIV) led to an increased probability of infection following exposure (18). Alternatively, the severity of infection might increase, as seen with respiratory syncytial virus (RSV) following early attempts at immunization (10, 13, 14) and as potentially occurs with dengue virus, with which previous infection with one serotype may result in more severe pathology following challenge with heterologous serotypes (11,19). The problem of adverse effects is of current relevance in the context of the development of vaccines against persistent infections. Conventional techniques have not yielded effective vaccines, but a promising approach involves the generation of vaccines that induce T cell responses against such infections. In this paper, we use mathematical models to explore pathology following T cell-based immunization against persistent infections.Laboratory experiments with mice have demonstrated that increasing the number of specific lymphocytes can lead to increased pathology in chronic diseases, such as those caused by lymphocytic choriomeningitis virus (LCMV) and hepatitis B virus (HBV). HBV-transgenic mice, which are used as a model for chronic human HBV infection, develop acute liver failure due to loss of liver cells after adoptive transfer of HBV-specific CD8 T cells (8). In mice infected with chronic LCMV, the extent of immunopathology depends on the initial dose of virus and initial numbers of naive-phenotype-specific CD8 T cells (6,9,22). Since these experiments tested only narrow immune responses, a natural hypothesis was that the increased pathology might be avoided by broadening the immune response (22). However, predicting pathology requires understanding the complex interplay between virus replication, immune exhaustion, and immune escape.In th...

The general consensus from epidemiological game-theory studies is that vaccination coverage driven by self-interest (Nash vaccination) is generally lower than group-optimal coverage (utilitarian vaccination). However, diseases that become more severe with age, such as chickenpox, pose an exception to this general consensus. An individual choice to be vaccinated against chickenpox has the potential to harm those not vaccinated by increasing the average age at infection and thus the severity of infection as well as those already vaccinated by increasing the probability of breakthrough infection. To investigate the effects of these externalities on the relationship between Nash and utilitarian vaccination coverages for chickenpox, we developed a game-theory epidemic model that we apply to the USA and Israel, which has different vaccination programmes, vaccination and treatment costs, as well as vaccination coverage levels. We find that the increase in chickenpox severity with age can reverse the typical relationship between utilitarian and Nash vaccination coverages in both the USA and Israel. Our model suggests that to obtain herd immunity of chickenpox vaccination, subsidies or external regulation should be used if vaccination costs are high. By contrast, for low vaccination costs, improving awareness of the vaccine and the potential cost of chickenpox infection is crucial.

Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in seasonal influenza A(H1N1) between 2006 and 2009. This sudden rise in resistance seemed puzzling given the low overall level of the oseltamivir usage and the lack of a correlation between local rates of resistance and oseltamivir usage. We used a stochastic simulation model and deterministic approximations to examine how such events can occur, and in particular to determine how the rate of fixation of the resistant strain depends both on its fitness in untreated hosts as well as the frequency of antiviral treatment. We found that, for the levels of antiviral usage in the population, the resistant strain will eventually spread to fixation, if it is not attenuated in transmissibility relative to the drugsensitive strain, but not at the speed observed in seasonal H1N1. The extreme speed with which the resistance spread in seasonal H1N1 suggests that the resistant strain had a transmission advantage in untreated hosts, and this could have arisen from genetic hitchhiking, or from the mutations responsible for resistance and compensation. Importantly, our model also shows that resistant virus will fail to spread if it is even slightly less transmissible than its sensitive counterpart-a finding of relevance given that resistant pandemic influenza (H1N1) 2009 may currently suffer from a small, but nonetheless experimentally perceptible reduction in transmissibility.

No abstract

Does specific immunity, innate immunity or resource (red blood cell) limitation control the first peak of the blood-stage parasite in acute rodent malaria infections? Since mice deficient in specific immunity exhibit similar initial dynamics as wild-type mice it is generally viewed that the initial control of parasite is due to either limitation of resources (RBC) or innate immune responses. There are conflicting views on the roles of these two mechanisms as there is experimental evidence supporting both these hypotheses. While mathematical models based on RBC limitation are capable of describing the dynamics of primary infections, it was not clear whether a model incorporating the key features of innate immunity would be able to do the same. We examine the conditions under which a model incorporating parasite and innate immunity can describe data from acute Plasmodium chabaudi infections in mice. We find that innate immune response must decay slowly if the parasite density is to fall rather than equilibrate. Further, we show that within this framework the differences in the dynamics of two parasite strains are best ascribed to differences in susceptibility to innate immunity, rather than differences in the strains' growth rates or their propensity to elicit innate immunity. We suggest that further work is required to determine if innate immunity or resource limitation control acute malaria infections in mice.