Research ArticleInfectious Disease

A gene deletion that up-regulates viral gene expression yields an attenuated RSV vaccine with improved antibody responses in children

Science Translational Medicine  04 Nov 2015:
Vol. 7, Issue 312, pp. 312ra175
DOI: 10.1126/scitranslmed.aac8463

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Outflanking RSV

Respiratory syncytial virus (RSV) infection may lead to severe respiratory illness in young children. Researchers are working to develop a live attenuated vaccine, which would mimic the natural course of infection; however, inhibiting viral replication also limits the immune response. Now, Karron et al. report that a version of RSV lacking the M2-2 protein can induce immunity despite decreased vaccine virus shedding in young children. The lack of M2-2 resulted in decreased viral RNA replication needed for virus production while allowing gene transcription and antigen synthesis required for stimulating the immune response. Children who received the vaccine produced anti-RSV antibodies without medically attended illness in the subsequent RSV season, suggesting that this approach may provide protective immunity to RSV.

Abstract

Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and a safe and effective vaccine for use in infancy and early childhood is needed. We previously showed that deletion of the coding sequence for the viral M2-2 protein (ΔM2-2) down-regulated viral RNA replication and up-regulated gene transcription and antigen synthesis, raising the possibility of development of an attenuated vaccine with enhanced immunogenicity. RSV MEDI ΔM2-2 was therefore evaluated as a live intranasal vaccine in adults, RSV-seropositive children, and RSV-seronegative children. When results in RSV-seronegative children were compared to those achieved with the previous leading live attenuated RSV candidate vaccine, vaccine virus shedding was significantly more restricted, yet the postvaccination RSV-neutralizing serum antibody achieved [geometric mean titer (GMT) = 1:97] was significantly greater. Surveillance during the subsequent RSV season showed that several seronegative RSV MEDI ΔM2-2 recipients had substantial antibody rises without reported illness, suggesting that the vaccine was protective yet primed for anamnestic responses to RSV. Rational design appears to have yielded a candidate RSV vaccine that is intrinsically superior at eliciting protective antibody in RSV-naïve children and highlights an approach for the development of live attenuated RSV vaccines.

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