Strain variation in adenovirus serotypes 4 and 7a causing acute respiratory disease

Abstract

In order to determine the suitability of vaccine strains established in the 1960s for a new vaccine, a comprehensive study of strain variation of adenovirus serotype 4 (AV 4) and AV 7 was undertaken. A 1,500-bp region of the hexon gene containing the AV neutralization epitopes from prototype, vaccine, and community-acquired strains and from wild-type strains from military personnel that cause acute respiratory disease (ARD) was sequenced and analyzed. The whole hexon gene from prototype strains, vaccine strains, and selected isolates was sequenced. AV 7 and AV 7a were found to have distinct genotypes, and all vaccine and wild-type strains recovered from 1963 to 1997 had the AV 7a genotype. There was no significant strain variation in the neutralization epitopes of the AV 7a genotype over a 42-year period. The evolution of AV 4 was more complex, with continuous genetic drift punctuated by replacement with a new strain. The current strain of AV 4, which has been in circulation since 1995, is significantly different from the AV 4 prototype and the vaccine strains. Genetic differences were confirmed to be antigenic differences by neutralization tests, which define the new strain as an AV 4 variant. A type-specific PCR for AV 4, AV 7/7a, and AV 21 was developed, and this PCR facilitated the rapid identification of isolates from outbreaks of ARD.

FIG. 1

Gene map of the AV hexon protein showing HVRs (shaded), the regions sequenced, and generic and type-specific primers. Adapted from reference with permission of the publisher. aa, amino acids.

FIG. 2

Type-specific PCR of military isolates and prototype strains. The wells are loaded with 5 μl (10%) of each PCR product. Lane M, molecular mass ladder. Numbers on the left are in base pairs.

FIG. 3

Major coding differences in the HVRs between AV 7 (Gomen), AV 7a (S-1958), and the AV 7 vaccine strain (55142) indicated by shading. The deletion characteristic of AV 7a strains is indicated by the unfilled box.

FIG. 4

Major coding changes in the HVRs among AV 4 strains indicated by shading: prototype (RI-67), vaccine strain (CL 68578), and the AV 4 variant (Z-G 95-0620). The unique deletion from the strains recovered in 1988, represented by strain 88-16306, is indicated by unfilled box.