MVA-Vectored Pentameric Complex (PC) and gB Vaccines Improve Pregnancy Outcome after Guinea Pig CMV Challenge, but Only gB Vaccine Reduces Vertical Transmission.

Heidi Contreras,Don J Diamond,Claudia Fernández-Alarcón,Mark R Schleiss,Felix Wussow,Jenny Nguyen,Craig Bierle

doi:10.3390/vaccines7040182

Heidi Contreras, Don J Diamond + Show 5 more

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https://doi.org/10.3390/vaccines7040182

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Journal: Vaccines	Publication Date: Nov 14, 2019
Citations: 11	License type: CC BY 4.0

Affiliation: City of Hope, University of Minnesota Medical Center

Abstract

(1) Background: A congenital cytomegalovirus (cCMV) vaccine is a major research priority, but the essential glycoprotein target(s) remain unclear. We compared CMV gB (gpgB), gH/gL (gp75/gL), and pentameric complex (gpPC, composed of gH/gL/GP129/GP131/GP133) vaccines in a guinea pig CMV (GPCMV) congenital infection model. (2) Methods: Modified vaccinia virus Ankara (MVA) vaccines expressing GPCMV glycoproteins were used to immunize GPCMV-seronegative, female Hartley guinea pigs (three-dose series, 3 × 107 pfu/dose). After pregnancy was established, the dams underwent an early third-trimester challenge with salivary gland (SG)-adapted GPCMV. (3) Results: All vaccines elicited GPCMV-specific binding and neutralizing antibodies. Preconception immunization resulted in 19.5-, 4.9-, and 698-fold reductions in maternal DNAemia in MVA-gp75/gL, MVA-gpPC and MVA-gpgB groups, respectively, at day 14, post-SG challenge. Vaccination improved pups’ birth weight and reduced mortality and congenital CMV transmission. In controls, cCMV infection was observed in 100% of pups (mean viral load in all visceral organs, 2.4 × 104 genomes/mg), versus 50% in the gB group (visceral viral load, 9.4 × 102 genomes/mg; p < 0.05). No significant reductions in congenital transmission were noted in the MVA-gp75/gL and MVA-gpPC groups. (4) Conclusions: MVA-vectored gB, gH/gL, and PC vaccines were immunogenic, and protected against maternal DNAemia and pup mortality. These results support the inclusion of multiple glycoprotein complexes in a cCMV vaccine.

Highlights

Human cytomegalovirus (HCMV) is the most common congenital viral infection globally, and is a major cause of neurodevelopmental delays and long-term disability [1,2]
Subunits were inserted into two modified vaccinia virus Ankara (MVA) insertion sites: (1) gH and gL in G1L; and (2) GP131, GP129, and GP133V5-His in IGR3 (Figure 1a)
Against the backdrop of the urgent need to generate a vaccine capable of preventing the disabilities caused by congenital HCMV infection, there is considerable interest in developing a vaccine platform that targets the HCMV pentameric complex (PC)

Summary

Introduction

Human cytomegalovirus (HCMV) is the most common congenital viral infection globally, and is a major cause of neurodevelopmental delays and long-term disability [1,2]. A major challenge in vaccine development is the fact that the protective correlate(s) of immunity, essential for preventing infection of the developing fetus, remain unknown [5,6]. It is not clear if a vaccine platform should be based on a live, attenuated strain of HCMV; Vaccines 2019, 7, 182; doi:10.3390/vaccines7040182 www.mdpi.com/journal/vaccines. Several HCMV vaccines based on these, and other, strategies are currently in various phases of preclinical and/or clinical trial evaluation [7]

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