Arguments for live flavivirus vaccines

Abstract

In their Rapid Review,1Seligman SJ Gould EA Live flavivirus vaccines: reasons for caution.Lancet. 2004; 363: 2073-2075Summary Full Text Full Text PDF PubMed Scopus (96) Google Scholar Stephen Seligman and Ernest Gould discuss safety concerns with respect to the use of live attenuated flavivirus (LAV) vaccines in people. Here, we address the theoretical risk posed by recombination of a dengue-LAV vaccine with naturally occurring flaviviruses. The greater level and duration of protection and the lower cost of manufacture of LAV vaccines in the context of the massive burden of disease due to dengue viruses in countries with limited health-care resources warrants an examination of the scientific basis for the concerns raised by Seligman and Gould. What is the likelihood that an adverse ecological event would result from the use of a dengue-LAV vaccine? Furthermore, is the risk posed by the use of the LAV vaccine different from that posed by the circulation of wild-type dengue virus? Recombination within the envelope gene of two strains of the same dengue serotype has been reported to occur rarely,2Twiddy SS Holmes EC The extent of homologous recombination in members of the genus Flavivirus.J Gen Virol. 2003; 84: 429-440Crossref PubMed Scopus (111) Google Scholar and evidence that the recombinants differed in pathogenic properties from wild-type dengue virus was not found. Despite extensive sequence analysis of many dengue viruses and the opportunity for these viruses to exchange genes in mosquito or human hosts, a recombinant dengue virus with a unique pathogenic capability has not been identified. Furthermore, recombination between two different dengue virus serotypes has not been observed in nature, despite the annual worldwide occurrence of up to 50 million dengue virus infections. Dengue viruses replicate up to 108 infectious units per mL of blood in human beings,3Vaughn DW Green S Kalayanarooj S et al.Dengue viremia titer, antibody response pattern, and virus serotype correlate with disease severity.J Infect Dis. 2000; 181: 2-9Crossref PubMed Scopus (1229) Google Scholar and such levels of viraemia amidst the co-circulation of the four serotypes should support the double infection of cells needed to generate intertypic dengue recombinant viruses, yet none has been seen. Since vaccine viruses replicate 104–107 less efficiently than wild-type viruses,4Durbin AP Karron RA Sun W et al.Attenuation and immunogenicity in humans of a live dengue virus type-4 vaccine candidate with a 30 nucleotide deletion in its 3'-untranslated region.Am J Trop Med Hyg. 2001; 65: 405-413Crossref PubMed Scopus (241) Google Scholar the likelihood of recombination between a wild-type virus and a vaccine virus is much less than that between two wild-type viruses. We are very encouraged by the lack of data to support the emergence in nature of problematic recombinant flaviviruses, which suggests that the use of a dengue-LAV vaccine would pose no greater risk for generation of pathogenic dengue recombinant viruses than the risk presented daily by wild-type dengue viruses. Additionally, highly pathogenic, recombinant flaviviruses bearing yellow fever vaccine virus sequences have not been observed despite use of more than 400 million doses of this vaccine during the past 6 decades. The lack of scientific evidence for the generation of problematic recombinant flaviviruses indicates that we should not prematurely abandon the use of the LAV vaccine. Why have pathogenic recombinant flaviviruses not emerged? Evidence from the generation of antigenic chimeric flaviviruses in the laboratory provides some possible answers. First, chimeric viruses made between two dengue serotypes are attenuated in mammals and mosquitoes, indicating that recombination actually leads to attenuation for both hosts.5Whitehead SS Hanley KA Blaney JE Gilmore LE Elkins WR Murphy BR Substitution of the structural genes of dengue virus type 4 with those of type 2 results in chimeric vaccine candidates which are attenuated for mosquitoes, mice, and rhesus monkeys.Vaccine. 2003; 21: 4307-4316Crossref PubMed Scopus (87) Google Scholar Second, chimeric viruses made between a dengue virus and another mosquito-borne flavivirus (West Nile virus) or a tick-borne flavivirus are even more attenuated than the intertypic dengue viruses and are being considered as vaccine candidates. Thus, lack of evidence for the generation of highly pathogenic flaviviruses by recombination in nature and in the laboratory should serve to encourage, rather than discourage, the use of LAV vaccines. Our analysis is not meant to dismiss the theoretical concerns raised by Seligman and Gould. Rather, our analysis provides a framework for the continued assessment of LAV vaccines, being mindful that unexpected events can arise and that one should always proceed with both caution and vigilance.