Genetic Profile of an Oka Varicella Vaccine Virus Variant Isolated from an Infant with Zoster

Abstract

Varicella (chickenpox) is a widespread, highly contagious disease caused by varicella-zoster virus (VZV). Serious complications of varicella include secondary bacterial infection, pneumonia, encephalitis, congenital infection, and, rarely, death (4, 21). Following the acute infection, VZV establishes a lifelong latent infection in neurosensory ganglia that commonly reactivates to cause zoster, typically in elderly or immunocompromised patients (24). A safe and effective live-attenuated varicella vaccine was developed in 1968 and has been licensed and recommended in the United States since 1995 (25). Commercial varicella vaccines (all of which are derived from the Japanese Oka strain) have never been cloned, and complete genomic sequencing of the V-Oka-Biken vaccine revealed that it contained several strains that could be separated in tissue culture (9, 10). Three manufacturers (Merck & Co Inc., Pasteur Merieux Connaught, and Biken Inc.) accepted the original V-Oka vaccine preparations, and each has the vaccine in production, with some variation in manufacturing processes. GlaxoSmithKline (Uxbridge, United Kingdom) reported the use of a selected, plaque-purified variant of V-Oka vaccine (2, 7). V-Oka has been used successfully for vaccination in the United States, Canada, Australia, Japan, and South Korea. In some European countries, varicella vaccination is recommended for persons at risk of severe chickenpox and/or for seronegative health care workers. Germany also recommends varicella vaccination for adolescents with no history of chickenpox (23). The vaccine provides 90% protection from any disease and over 95% protection from moderate to severe disease (8).V-Oka is known to establish latent infection in the dorsal root ganglia, and zoster has been demonstrated as a rare adverse consequence among vaccinees (8,13,14,22,26). However, in all of these cases, the status of vaccine-specific mutations was not documented. In addition, the primary DNA sequence was not compared to that of the material used for vaccination. Until recently, laboratories evaluated only three single nucleotide polymorphism (SNP) mutations in open reading frames (ORFs) 38, 54, and 62 to differentiate V-Oka from wild-type strains, but only the ORF 62 SNP reliably differentiates Japanese genotype wild-type strains from vaccine (15,20). Conceivably, genomic mutations or reversions to wild type, particularly those that confer amino acid substitutions, could affect virulence and restore wild-type pathogenicity. Furthermore, VZV strains with unique pathogenic qualities could emerge. The comparison of DNA sequences between V-Oka and P-Oka revealed 42 base substitutions associated with 20 amino acid changes (11). Specific amino acid substitutions in ORF 62 have been associated with enhanced virus growth and spread in cell culture, and substrains purified from the vaccine mixture display variable properties in cell culture (11).This study sought to compare vaccine mutations associated with amino acid changes in V-Oka-GSK to published V-OkaBiken and ...

Complete DNA Sequences of Two Oka Strain Varicella-Zoster Virus Genomes

“…Comparison of the four Oka strain sequences of VZV indicated that Oka-V GSK is genetically closer to Oka-V than Oka-V Merck is but that Oka-V Merck is closer to Oka-P than Oka-V GSK is (reference 50 and the present study). In agreement with these findings, Sauerbrei et al demonstrated that Oka-V Merck is genetically closer to Oka-P than Oka-V GSK is (59). Nevertheless, it is well established that both vaccine strains are attenuated but remain strongly immunogenic (43,73).…”

“…Comparison with partial sequencing information published on these strains and the other Oka strains, Oka-P and Oka-V, is shown in Table 7 (3,22,32,59,60,63,69 (3,60). Two sequence differences were found for Oka-V Merck in ORF 59 (position 101089; A versus A/G) and ORF 62 (position 105310; G versus A/G) (3).…”

Molecular Analysis of Varicella Vaccines and Varicella-Zoster Virus from Vaccine-Related Skin Lesions

“…In contrast, Varivax lots revealed VZV strains with pure vaccine types at these positions (13,14). These data and those presented here show that the mixtures of variant strains in the vaccines as well as the relative strain proportions change with time in different vaccine batches.…”

“…Second, vaccine-type VZV strains causing rash-associated clinical syndromes in vaccinees have been reported to contain a number of wild-type (wt) SNPs. It has been hypothesized that these vaccine-type, wt SNP-containing VZV strains are minor components of the vaccines (1,9,10,13). To substantiate this hypothesis and to search for genetic correlates of the observed differences among the vaccines, we compared the SNP profiles of (i) VZV from the three vaccine brands, (ii) rash-associated vaccine-type VZV from German vaccinees, and (iii) wt VZV from nonvaccinated and vaccinated individuals suffering from varicella by PCR, quantitative pyrosequencing (PSQ), and chain termination sequencing (CTSQ).…”

Characteristics of Varicella Zoster (Vzv) Virus

“…All of the currently available varicella vaccines consist of an avirulent virus derived from a Japanese wild-type strain isolated from a boy with typical chickenpox named Oka (p-Oka). All commercially distributed vaccines have been reported to differ only in the number of passage of virus in tissue culture used and in stabilizers, as well as other components of the formulation (12)(13)(14)(15)(16). Targeted vaccination of susceptible high-risk patients and/or their household contacts, recommended in many European countries, is an alternative strategy which necessitates a well-organized healthcare system.…”