Stable and Consistent Genetic Profile of Oka Varicella Vaccine Virus Is Not Linked with Appearance of Infrequent Breakthrough Cases Postvaccination

Recently, Dr. Sauerbrei and his colleagues reported (8) on the genetic profile of an Oka varicella vaccine virus variant (V-Oka-zoster) isolated from an infant with herpes zoster. Those authors hypothesized that the isolated variant had an increased ability to cause zoster and was present as a subspecies within the vaccine that was used to immunize the infant. The rationale for linking this variant with the hypothetical altered capacity to cause zoster was based on a limited comparison of its nucleotide sequence with the respective sequence of Oka parental (P-Oka, or “wild-type,” parental Oka strain), Oka vaccinal (V-Oka), and Varilrix (GlaxoSmithKline Biologicals) strains. Sauerbrei et al. claimed that several positions, including one within open reading frame 62 (ORF 62) of the V-Oka-zoster variant, had “reverted” to those found in P-Oka. They also claimed that the V-Oka-zoster variant contained six P-Oka bases in single-nucleotide polymorphisms (SNPs) at targeted regions (Table 1), located in ORFs 9A, 10, 21, 52, 55, and 62 (position 108838), that could be associated with an increased rate of zoster reactivation. Sequencing of the viral regions analyzed by Sauerbrei et al. has been published in a comprehensive analysis of Varivax (Merck) and Varilrix vaccine strains and related viruses (6) and is in agreement with our sequencing data for the same viral regions. A comparison among P-Oka, V-Oka, Varilrix, and Varivax viral sequences reveals that the Varivax strain matches more closely P-Oka in its SNP pattern for the positions, which those authors suggested to be linked with the ability of the vaccine to reactivate and cause zoster. However, this by no means implies that the Varivax strain has an increased ability to reactivate. Postmarketing reports on the safety profile of the Varivax vaccine indicated a rate of reactivation of only 1.3 cases per 100,000 vaccine doses (10), which is in line with postmarketing surveillance of the incidence of zoster after vaccination with Varilrix (data not published). Based on postmarketing data, the U.S. Centers for Disease Control and Prevention have reported a rate of herpes zoster after vaccination of 2.6/100,000 vaccine doses distributed (2). Previously published reports and our sequencing of the fulllength genomes of Varilrix and Varivax strains (GenBank accession numbers DQ008354 and DQ008355) revealed multiple discrepancies with the work done by Sauerbrei et al. (Table 1). There are a number of possible explanations for these discrepancies. As mentioned by those authors in Discussion, “amplification of some regions (e.g., ORF 62 105331, 107252, and 107797) presented technical difficulties that conceivably reduced the quality of correspondent sequence data.” Furthermore, and this is a critical issue given the mixed genomic composition of all Oka vaccines, the authors do not comment whether their sequence information was partially obtained by sequencing of plasmid clones or by direct consensus sequencing of PCR amplicons. In addition, the experimental design employed by Sauerbrei et al. included two intermediate cell culture passages of all strains on primary human thyroid cells, followed by two passages on human embryonic lung fibroblasts.