Elsevier

The Lancet

Volume 363, Issue 9426, 19 June 2004, Pages 2073-2075
The Lancet

Rapid Review
Live flavivirus vaccines: reasons for caution

https://doi.org/10.1016/S0140-6736(04)16459-3Get rights and content

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Flaviviruses

The flaviviruses are enveloped positive-sense single-stranded RNA viruses of about 11 kb. Both ends of the genome contain non-translated nucleotides (NTR). The open-reading frame is translated into three structural proteins (core, premembrane, envelope) and seven non-structural proteins (NS1, NS2a, NS2b, NS3, NS4a, NS4b, NS5). Some flaviviruses are mosquitoborne, some are tick borne, and others have no known vector.8 The mosquito borne species comprise those transmitted by Culex spp, often with

Recombination

RNA viruses can recombine within and between species, as a result of transfer of RNA polymerase between viral genomes during RNA synthesis. One example is the appearance of western equine encephalitis virus from recombination between two alphaviruses with different pathogenetic characteristics (figure, A).10 Homologous recombination (between strains of the same species) in flaviviruses was firmly established in 1999, and has now been seen in all four dengue serotypes and in Japanese and St

How likely is inter-species flavivirus recombination?

The main requirement for recombination is simultaneous infection with two flaviviruses. Unfortunately the risk of recombination resulting in more virulent virus cannot be quantified. However, the expanding geographic dispersal of flaviviruses greatly increases the chances of natural co-infection. Although low concentrations of blood-borne virus are common in West Nile infection, as in other flavivirus infections in which human beings are normally a dead-end host, a high prevalence of infection

Lessons from other live virus vaccines

Five main problems have been recognised: reversion of vaccine strains to increased virulence; development of disease in immunocompromised individuals; fetal malformation particularly when the vaccine is given in the first trimester; spread of vaccine strains to unvaccinated persons; and the discovery of previously unknown complications. With live poliovirus vaccines, reversion to virulence as a result of recombination,14 disease in immunocompromised recipients (especially in IgA deficiency),15

Assessment

Live virus vaccines offer considerable promise in terms of efficacy and cost. Unfortunately, the risks of recombination between vaccine virus and other wild-type flaviviruses resulting in recombinants with novel properties cannot be estimated. The surprising emergence of western equine encephalitis virus, a non-homologous recombinant estimated to have arisen some 1300 years ago, has had prolonged consequences.32 Reports of the decreased ability of candidate vaccine strains to grow in mosquito3,

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      A principle determinant of risk is the type of vaccine. YFV vaccine, which is a live-attenuated virus, has rarely caused cases of severe neurotropic and viscerotropic reactions during decades of use,191 and possible teratogenic effects have been investigated. Potential for reversion to wild type or fully virulent virus, pathogenicity in immunocompromised hosts, or recombination events between vaccine and circulating strains that lead to new, deleterious phenotypes have all been put forward as reasons for trepidation with these vaccines,191 although the latter phenomenon has never been observed in nature.13

    • Natural recombination in alphaherpesviruses: Insights into viral evolution through full genome sequencing and sequence analysis

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      The relatively low rate of recombination in VZV compared to HSV-1 may be due to the distinct biology and epidemiology of VZV (Kaufman et al., 2005; Schmidt-Chanasit et al., 2009; Wang et al., 2010) as well as geographical separations of strains (Norberg et al., 2004; Schmidt-Chanasit et al., 2009). However, ongoing monitoring of recombination in field isolates of VZV is needed, as recombination between attenuated viruses such as vaccine strains has been detected, to create recombinant virulent progeny in other alphaherpesviruses (Lee et al., 2012), as well as in several other virus families (Becher et al., 2001; Camus-Bouclainville et al., 2011; Chong et al., 2010; Cuervo et al., 2001; Dahourou et al., 2002; Holmes et al., 1999; Liu et al., 2003; Norberg et al., 2013; Seligman and Gould, 2004; Wenhui et al., 2012). Over the past ten years natural recombination has been assessed in alphaherpesviruses from five non-human mammalian hosts; EHV-1, EHV-4, EHV-9, FeHV-1 and PRV (Greenwood et al., 2012; Pagamjav et al., 2005; Vaz et al., 2016a; Vaz et al., 2016b; Ye et al., 2016) (Table 2).

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