A Live Olfactory Mouse Cytomegalovirus Vaccine, Attenuated for Systemic Spread, Protects against Superinfection
- 13 October 2021
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 95 (21)
- https://doi.org/10.1128/jvi.01264-21
Abstract
Vaccination against the β-herpesvirus, human cytomegalovirus (HCMV) is a public health goal. However, HCMV has proved difficult to vaccinate against. Vaccination against single HCMV determinants has not worked, suggesting that immunity to a wider antigenic profile may be required. Live attenuated vaccines provide the best prospects for protection, but the question remains as to how to balance vaccine virulence with safety. Animal models of HCMV infection provide insights into identifying targets for virus attenuation and understanding how host immunity blocks natural, mucosal infection. Here we evaluated the vaccine potential of a mouse cytomegalovirus (MCMV) vaccine deleted of a viral G protein-coupled receptor (GPCR), designated M33, that renders it attenuated for systemic spread. A single non-invasive olfactory ΔM33 MCMV vaccine replicated locally, but as a result of the loss of the M33 GPCR, it failed to spread systemically and was attenuated for latent infection. Vaccination did not prevent host entry of a superinfecting MCMV but spread from the mucosa was blocked. This approach to vaccine design may provide a viable alternative for a safe and effective β-herpesvirus vaccine. IMPORTANCE Human cytomegalovirus (HCMV) is the most common cause of congenital infection for which a vaccine is not yet available. Subunit vaccine candidates have failed to achieve licensure. A live HCMV vaccine may prove more efficacious, but it faces safety hurdles which include its propensity to persist and to establish latency. Understanding how pathogens infect guide rational vaccine design. However, HCMV infections are asymptomatic and thus difficult to capture. Animal models of experimental infection provide insight. Here we investigated the vaccine potential of a MCMV attenuated for systemic spread and latency. We used olfactory vaccination and virus challenge to mimic its natural acquisition. We provide proof-of-concept that a single olfactory MCMV that is deficient in systemic spread, can protect against wild type MCMV superinfection and dissemination. This approach of deleting functional counterpart genes in HCMV may provide safe and effective vaccination against congenital HCMV disease.Funding Information
- Department of Health, Queensland
- ARC Discovery Project (DP190101851)
- Department of Health, Australian Government | National Health and Medical Research Council (APP1140169)
This publication has 45 references indexed in Scilit:
- Natural Killer Cell Dependent Within-Host Competition Arises during Multiple MCMV Infection: Consequences for Viral Transmission and EvolutionPLoS Pathogens, 2013
- Vaccines: From Empirical Development to Rational DesignPLoS Pathogens, 2012
- A Heparan-Dependent Herpesvirus Targets the Olfactory Neuroepithelium for Host EntryPLoS Pathogens, 2012
- Efficacy Results of a Trial of a Herpes Simplex VaccineThe New England Journal of Medicine, 2012
- Partial Functional Complementation between Human and Mouse Cytomegalovirus Chemokine Receptor HomologuesJournal of Virology, 2011
- Antibody limits in vivo murid herpesvirus-4 replication by IgG Fc receptor-dependent functionsJournal of General Virology, 2009
- The M33 Chemokine Receptor Homolog of Murine Cytomegalovirus Exhibits a Differential Tissue-Specific Role during In Vivo Replication and LatencyJournal of Virology, 2009
- Vaccine Prevention of Maternal Cytomegalovirus InfectionThe New England Journal of Medicine, 2009
- Cytomegalovirus vaccines fail to induce epithelial entry neutralizing antibodies comparable to natural infectionVaccine, 2008
- Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjectsThe Journal of Experimental Medicine, 2005