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      Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens

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          Abstract

          Could some vaccines drive the evolution of more virulent pathogens? Conventional wisdom is that natural selection will remove highly lethal pathogens if host death greatly reduces transmission. Vaccines that keep hosts alive but still allow transmission could thus allow very virulent strains to circulate in a population. Here we show experimentally that immunization of chickens against Marek's disease virus enhances the fitness of more virulent strains, making it possible for hyperpathogenic strains to transmit. Immunity elicited by direct vaccination or by maternal vaccination prolongs host survival but does not prevent infection, viral replication or transmission, thus extending the infectious periods of strains otherwise too lethal to persist. Our data show that anti-disease vaccines that do not prevent transmission can create conditions that promote the emergence of pathogen strains that cause more severe disease in unvaccinated hosts.

          Abstract

          A study using Marek's disease virus in poultry shows that by reducing natural selection against highly virulent strains, imperfect vaccination enables the spread of viral strains that would otherwise be too lethal to persist.

          Author Summary

          There is a theoretical expectation that some types of vaccines could prompt the evolution of more virulent (“hotter”) pathogens. This idea follows from the notion that natural selection removes pathogen strains that are so “hot” that they kill their hosts and, therefore, themselves. Vaccines that let the hosts survive but do not prevent the spread of the pathogen relax this selection, allowing the evolution of hotter pathogens to occur. This type of vaccine is often called a leaky vaccine. When vaccines prevent transmission, as is the case for nearly all vaccines used in humans, this type of evolution towards increased virulence is blocked. But when vaccines leak, allowing at least some pathogen transmission, they could create the ecological conditions that would allow hot strains to emerge and persist. This theory proved highly controversial when it was first proposed over a decade ago, but here we report experiments with Marek’s disease virus in poultry that show that modern commercial leaky vaccines can have precisely this effect: they allow the onward transmission of strains otherwise too lethal to persist. Thus, the use of leaky vaccines can facilitate the evolution of pathogen strains that put unvaccinated hosts at greater risk of severe disease. The future challenge is to identify whether there are other types of vaccines used in animals and humans that might also generate these evolutionary risks.

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          Most cited references37

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          Targeting virulence: can we make evolution-proof drugs?

          Antivirulence drugs are a new type of therapeutic drug that target virulence factors, potentially revitalising the drug-development pipeline with new targets. As antivirulence drugs disarm the pathogen, rather than kill or halt pathogen growth, it has been hypothesized that they will generate much weaker selection for resistance than traditional antibiotics. However, recent studies have shown that mechanisms of resistance to antivirulence drugs exist, seemingly damaging the 'evolution-proof' claim. In this Opinion article, we highlight a crucial distinction between whether resistance can emerge and whether it will spread to a high frequency under drug selection. We argue that selection for resistance can be reduced, or even reversed, using appropriate combinations of target and treatment environment, opening a path towards the development of evolutionarily robust novel therapeutics.
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            Imperfect vaccines and the evolution of pathogen virulence.

            Vaccines rarely provide full protection from disease. Nevertheless, partially effective (imperfect) vaccines may be used to protect both individuals and whole populations. We studied the potential impact of different types of imperfect vaccines on the evolution of pathogen virulence (induced host mortality) and the consequences for public health. Here we show that vaccines designed to reduce pathogen growth rate and/or toxicity diminish selection against virulent pathogens. The subsequent evolution leads to higher levels of intrinsic virulence and hence to more severe disease in unvaccinated individuals. This evolution can erode any population-wide benefits such that overall mortality rates are unaffected, or even increase, with the level of vaccination coverage. In contrast, infection-blocking vaccines induce no such effects, and can even select for lower virulence. These findings have policy implications for the development and use of vaccines that are not expected to provide full immunity, such as candidate vaccines for malaria.
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              Virulence and competitive ability in genetically diverse malaria infections.

              Explaining parasite virulence is a great challenge for evolutionary biology. Intuitively, parasites that depend on their hosts for their survival should be benign to their hosts, yet many parasites cause harm. One explanation for this is that within-host competition favors virulence, with more virulent strains having a competitive advantage in genetically diverse infections. This idea, which is well supported in theory, remains untested empirically. Here we provide evidence that within-host competition does indeed select for high parasite virulence. We examine the rodent malaria Plasmodium chabaudi in laboratory mice, a parasite-host system in which virulence can be easily monitored and competing strains quantified by using strain-specific real-time PCR. As predicted, we found a strong relationship between parasite virulence and competitive ability, so that more virulent strains have a competitive advantage in mixed-strain infections. In transmission experiments, we found that the strain composition of the parasite populations in mosquitoes was directly correlated with the composition of the blood-stage parasite population. Thus, the outcome of within-host competition determined relative transmission success. Our results imply that within-host competition is a major factor driving the evolution of virulence and can explain why many parasites harm their hosts.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                PLoS Biol
                plos
                plosbiol
                PLoS Biology
                Public Library of Science (San Francisco, CA USA )
                1544-9173
                1545-7885
                27 July 2015
                July 2015
                : 13
                : 7
                : e1002198
                Affiliations
                [1 ]Center for Infectious Disease Dynamics, Departments of Biology and Entomology, The Pennsylvania State University, University Park, Pennsylvania, United States of America
                [2 ]Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America
                [3 ]Avian Oncogenic Virus Group, The Pirbright Institute, Compton, Newbury, Berkshire, United Kingdom
                [4 ]School of Environmental and Rural Science, The University of New England, Armidale, Australia
                Imperial College London, UNITED KINGDOM
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: AFR SJB CP LPS SWWB VKN. Performed the experiments: SJB CP LBK LB LPS. Analyzed the data: AFR SJB CP DAK. Wrote the paper: AFR SJB CP DAK. Conceived the study and raised the funding: AFR VKN.

                Article
                PBIOLOGY-D-15-00154
                10.1371/journal.pbio.1002198
                4516275
                26214839
                a849aae3-4fac-4980-b90b-d8b3b1259fdc
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 15 January 2015
                : 11 June 2015
                Page count
                Figures: 4, Tables: 0, Pages: 18
                Funding
                This work was funded by the Institute of General Medical Sciences, National Institutes of Health (R01GM105244) and by UK Biotechnology and Biological Sciences Research Council as part of the joint NSF-NIH-USDA Ecology and Evolution of Infectious Diseases program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                All data files are deposited in Dryad, doi: 10.5061/dryad.4tn48.

                Life sciences
                Life sciences

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