US-UK Collab: The consequences of transmissible vaccines on disease ecology and pathogen evolution: Marek's disease virus as a case study

疫苗接种可以是控制传染病的最有效和最有效的工具之一，但在许多情况下，包括野生动物和农场动物疾病，后勤和经济障碍使得接种足够大比例的宿主以实现群体免疫是不切实际的。传染性疫苗是指能够从接种疫苗的宿主传播到未接种疫苗的宿主的疫苗，通过扩大疫苗接种活动的影响，为这些挑战提供了一种潜在的解决方案。然而，传染性疫苗并非没有风险。毒力回复或与野生型病原体重组可能导致传染性疫苗使情况变得更糟或使消除工作复杂化。这项拟议的工作将首次量化传染性疫苗对疾病生态和进化的影响，使用目前在家禽养殖场广泛使用的具有经济重要性的自然传染疫苗。马立克氏病是一种家禽特有疾病，对可持续家禽生产构成威胁，目前由“Rispens”疫苗控制，这是一种减毒活疫苗，已广泛使用20年。最近的实验发现，这种疫苗能够有效地从接种疫苗的鸟类传播到未接种疫苗的鸟类。这些结果与最近的田间监测研究一致，这些研究在未直接接种疫苗的队列中发现了疫苗分离株。此外，全基因组测序的进展已经揭示了疫苗病毒和野生型病毒之间的重组，考虑到疫苗病毒携带致癌meq基因的高毒性形式，这是令人担忧的。总之，这些观察结果表明，Rispens疫苗是一种能够进化并可能促进野生型马立克氏病病毒不利进化的传染性疫苗。我们的主要目标是量化使用传染性疫苗的后果。具体而言，我们将：1）开发传染性疫苗接种的通用模型，以确定关键的知识差距，2）表征疫苗传播及其对野生型病毒传播的影响，3）表征野生型病毒和疫苗病毒的遗传进化，4）模拟Rispens疫苗接种对马立克氏病病毒及其疫苗的总体影响

Vaccination can be one of the most efficient and effective tools for controlling infectious diseases, but in many settings, including wildlife and farm animal diseases, logistical and economic hurdles make it impractical to vaccinate large enough fractions of hosts to achieve herd immunity. Transmissible vaccines, defined as vaccines capable of disseminating from vaccinated to non-vaccinated hosts, offer one potential solution to these challenges by amplifying the impact of vaccination campaigns. However, transmissible vaccines are not without risk. Reversion to virulence or recombination with wildtype pathogens could cause transmissible vaccines to make matters worse or complicate elimination efforts. This proposed work will for the first time quantify the effects of transmissible vaccines on disease ecology and evolution using an economically important, naturally transmissible vaccine currently in widespread use on poultry farms. Marek's disease, a poultry-specific disease that is a threat to sustainable poultry production, is currently controlled by the "Rispens" vaccine, a live, attenuated vaccine that has been widely used for two decades. Recent experiments have found that this vaccine is capable of efficiently transmitting from vaccinated to non-vaccinated birds. These results are consistent with recent field surveillance studies that have found vaccine isolates in cohorts that have not been directly vaccinated. In addition, advances in whole genome sequencing have revealed recombination between the vaccine virus and the wildtype virus, which is concerning given that the vaccine virus harbors highly virulent forms of the oncogenic meq gene. Together, these observations demonstrate that the Rispens vaccine is a transmissible vaccine capable of evolving and potentially facilitating adverse evolution of wildtype Marek's disease virus. Our primary objective is to quantify the consequences of transmissible vaccine use. Specifically, we will: 1) Develop a general model of transmissible vaccination to identify key knowledge gaps, 2) Characterize vaccine transmission and its impact on wildtype virus transmission, 3) Characterize the genetic evolution of wildtype virus and vaccine virus, 4) Model the overall impact of Rispens vaccination on Marek's disease virus and its vaccine