Abstract
Modified-live herpesvirus vaccines are widely used in humans and animals, but field strains can emerge that have a higher virulence and break vaccinal protection. Since the introduction of the first vaccine in the 1970s, Marek's disease virus overcame the vaccine barrier by the acquisition of numerous genomic mutations. However, the evolutionary adaptations in the herpesvirus genome responsible for the vaccine breaks have remained elusive. Here, we demonstrate that point mutations in the multifunctional meq gene acquired during evolution can significantly alter virulence. Defined mutations found in highly virulent strains also allowed the virus to overcome innate cellular responses and vaccinal protection. Concomitantly, the adaptations in meq enhanced virus shedding into the environment, likely providing a selective advantage for the virus. Our study provides the first experimental evidence that few point mutations in a single herpesviral gene result in drastically increased virulence, enhanced shedding, and escape from vaccinal protection.
Highlights
Vaccines have revolutionized modern medicine and industrial animal farming by dramatically lowering disease incidence and mortality [1,2]
An example of a virus that has shown repeated shifts to higher virulence in response to more efficacious vaccines is the oncogenic Marek’s disease virus (MDV) that infects chickens. It remained unknown which mutations in the large virus genome are responsible for this increase in virulence
We could demonstrate that very few amino acid changes in the meq oncogene of MDV can significantly alter the virulence of the virus
Summary
Vaccines have revolutionized modern medicine and industrial animal farming by dramatically lowering disease incidence and mortality [1,2]. It is crucial to understand the evolutionary changes that facilitate vaccine resistance in order to develop more effective vaccines. A well-documented example of virus evolution towards a greater virulence is the highly oncogenic Marek’s disease virus (MDV) [5,6]. MDV is an alphaherpesvirus that infects chickens and is controlled by the wide application of modified live virus vaccines. In the absence of vaccination, infected chickens typically develop an acute rash, and edematous neuronal and brain damage, severe lymphomas, paralysis, and death at a very young age [7,8]. The tumors induced by MDV are considered to be one of the most frequent cancers in the animal kingdom [9]
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