Imperfect Vaccination Can Enhance the Transmission of Highly Virulent Pathogens

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.

Fig 1. Impact of vaccination on mortality and viral shedding of five strains of MDV.

Experiment 1. Groups of 20 Rhode Island Red chickens were unvaccinated (dotted lines, light shading) or HVT-vaccinated (solid lines, dark shading) at 1 d of age and challenged with viral strains HPRS-B14 (black), 571 (purple), 595 (green), Md5 (blue), or 675A (red) 8 d later. Viral strains vary in virulence in unvaccinated hosts, and vaccination protects against death (top panels, with strains arranged in order of increasing virulence from left to right.). Vaccination suppresses the concentration of virus in dust, but by keeping hosts alive, prolongs the infectious periods of hyperpathogenic MDV (middle panels). This means that cumulative number of virus genome copies (VCN) shed per bird is suppressed by vaccination for the least virulent strain and enhanced by several orders of magnitude for the most virulent (bottom panels). Error bars and shaded regions indicate 95% confidence interval (c.i.) Raw data can be found at http://dx.doi.org/10.5061/dryad.4tn48.

Fig 2. Vaccination enhances transmission of hyperpathogenic MDV.

Experiment 2. Groups of ten birds were HVT-vaccinated (solid lines) or not (dotted lines) and experimentally infected with one of our three most virulent MDV strains, 595 (green), Md5 (blue) and 675A (red), and co-housed with ten unvaccinated sentinel birds. Vaccination prolonged the survival of experimentally infected birds (A), ensuring that sentinel birds became infected (B) and, hence, died (C). In B and C, solid lines denote sentinels cohoused with vaccinated experimentally infected birds and dotted lines denote sentinels cohoused with unvaccinated experimentally infected birds. Raw data can be found at http://dx.doi.org/10.5061/dryad.4tn48.

Fig 3. Maternal vaccination enhances viral shedding and onward transmission of hyperpathogenic MDV.

Experiment 3. Groups of ten unvaccinated chicks produced by hens that were Rispens-vaccinated (solid lines) or not (dotted lines) were infected with viral strains HPRS-B14 (black) or 675A (red) and cohoused with sentinels of the same maternal antibody status. Maternally derived antibodies prolonged the survival of experimentally infected birds (A) and enhanced the amount of virus shed into the environment by the hyperpathogenic strain (B), making possible the infection of sentinels with the most virulent strain (C), which led to their death (D). Shaded regions represent 95% c.i. for unvaccinated (light) and vaccinated (dark). Raw data can be found at http://dx.doi.org/10.5061/dryad.4tn48.

Fig 4. Transmission of hypervirulent MDV to modern commercial birds.

Experiment 4. Groups of ten modern commercial broiler chicks derived from Rispens-vaccinated hens were HVT-vaccinated at 1 d of age and experimentally infected with the hypervirulent MDV strain 675A. Those experimentally infected birds were co-housed with groups of ten sentinel birds from the same commercial stock (and thus also derived from Rispens-vaccinated hens) which were HVT-vaccinated (solid lines) or not (dotted lines). The experiment was performed twice (experiment 4a, red; experiment 4b, blue). Independent of their vaccine status, all sentinel birds became infected (A), with high levels of virus replication in feather follicles (B). Vaccination prolonged the survival of sentinel birds (C), and consequently their infectious period (D). In panel D, “x” denotes death because of MDV. Error bars, 95% c.i. Raw data can be found at http://dx.doi.org/10.5061/dryad.4tn48.