Population- and Variant-Based Genome Analyses of Viruses from Vaccine-Derived Rabies Cases Demonstrate Product Specific Clusters and Unique Patterns.

Sten Calvelage,Susan Nadin-Davis,Anna Orłowska,Thomas Müller,Paweł Trębas,Christine Fehlner-Gardiner,Dirk Höper,Conrad Martin Freuling,Marcin Smreczak

doi:10.3390/v12010115

Sten Calvelage, Susan Nadin-Davis + Show 7 more

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https://doi.org/10.3390/v12010115

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Abstract

Rabies in wildlife has been successfully controlled in parts of Europe and North America using oral rabies vaccination, i.e., the distribution of baits containing live-attenuated virus strains. Occasionally, these vaccines caused vaccine virus-induced rabies cases. To elucidate the mechanisms of genetic selection and the effect of viral populations on these rabies cases, a next generation sequencing approach as well as comprehensive data analyses of the genetic diversity of Street Alabama Dufferin (SAD) and ERA vaccine virus strains and vaccine-induced rabies cases from Canada and several European countries were conducted. As a result, twelve newly generated sets of sequencing data from Canada and Poland were added to a pool of previously investigated samples. While the population-based analysis showed a segregation of viruses of ERA vaccine-induced rabies cases from those of SAD Bern original (SAD Bernorig)-derived rabies cases, the in-depth variant analysis revealed three distinct combinations of selected variants for the ERA vaccine-induced cases, suggesting the presence of multiple replication-competent haplotypes in the investigated ERA-BHK21 vaccine. Our findings demonstrate the potential of a deep sequencing approach in combination with comprehensive analyses on the consensus, population, and variant level.

Highlights

Vaccination programs are one of the most effective means of controlling infectious diseases [1] and with the development of oral vaccines and bait delivery systems, the elimination of diseases circulating in wildlife populations has become a realistic possibility
The distance plot generated from the population data segregates the different oral rabies vaccine viruses into two major clusters, i.e., ERA-BHK21- and Street Alabama Dufferin (SAD) Bernorig -derived vaccines (Figure 1), confirming previous observations [14,15]
Batch B/SAD/B19/958 clustered with SAD Bern (Lysvulpen) vaccine batches, whereas vaccine batch B/SAD/Bern/0213 was shifted to the vaccine-induced rabies cases (Figure 1) as previously described [15]

Summary

Introduction

Vaccination programs are one of the most effective means of controlling infectious diseases [1] and with the development of oral vaccines and bait delivery systems, the elimination of diseases circulating in wildlife populations has become a realistic possibility. In Europe, with the exception of a recombinant vaccinia virus expressing the rabies virus glycoprotein, all constructs have been based on live attenuated rabies virus strains [4], derived from the SAD Bern original (SAD Bernorig ) vaccine virus strain, a successor of the ERA strain [2,8]. While all these vaccines have been highly efficient in fox rabies control, the first generation of SAD-derived vaccines demonstrated residual pathogenicity in non-target species in rodents [9,10,11,12]. Several cases of vaccine virus-induced rabies were observed even in species other than rodents over the course of vaccination campaigns in a number of countries, including Germany [1], Austria [1], Slovenia, Romania [13], Poland, and Canada [7], such cases were without epidemiological relevance [1,7,8]

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