Comparison of homologous and heterologous prime-boost vaccine approaches using Modified Vaccinia Ankara and soluble protein to induce neutralizing antibodies by the human cytomegalovirus pentamer complex in mice.

Flavia Chiuppesi,Felix Wussow,Pamela J Bjorkman,Louise Scharf,Han Gao,Zhuo Meng,Jenny Nguyen,Peter A Barry,Heidi Contreras,Don J Diamond

doi:10.1371/journal.pone.0183377

Flavia Chiuppesi, Felix Wussow + Show 8 more

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https://doi.org/10.1371/journal.pone.0183377

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Abstract

Since neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) pentamer complex (PC) potently block HCMV host cell entry, anti-PC NAb induction is thought to be important for a vaccine formulation to prevent HCMV infection. By developing a vaccine strategy based on soluble PC protein and using a previously generated Modified Vaccinia Ankara vector co-expressing all five PC subunits (MVA-PC), we compared HCMV NAb induction by homologous immunization using prime-boost vaccine regimen employing only PC protein or MVA-PC and heterologous immunization using prime-boost combinations of PC protein and MVA-PC. Utilizing a recently isolated anti-PC NAb, we produced highly pure soluble PC protein that displayed conformational and linear neutralizing epitopes, interfered with HCMV entry, and was recognized by antibodies induced by HCMV during natural infection. Mice vaccinated by different immunization routes with the purified PC protein in combination with a clinically approved adjuvant formulation elicited high-titer and durable HCMV NAb. While MVA-PC and soluble PC protein either alone or in combination elicited robust HCMV NAb, significantly different potencies of these vaccine approaches were observed in dependence on immunization schedule. Using only two immunizations, vaccination with MVA-PC alone or prime-boost combinations of MVA-PC and PC protein was significantly more effective in stimulating HCMV NAb than immunization with PC protein alone. In contrast, with three immunizations, NAb induced by soluble PC protein either alone or combined with two boosts of MVA-PC increased to levels that exceeded NAb titer stimulated by MVA-PC alone. These results provide insights into the potency of soluble protein and MVA to elicit NAb by the HCMV PC via homologous and heterologous prime-boost immunization, which may contribute to develop clinically deployable vaccine strategies to prevent HCMV infection.

Highlights

Since human cytomegalovirus (HCMV) is a leading cause of birth defects in newborns and complications in immunologically vulnerable individuals such as transplant recipients and AIDS patients, developing a vaccine to prevent HCMV infection is considered a major public health priority [1, 2]
It has been recognized by studies using more “clinical-like” HCMV strains including TB40/E, TR, and VR1814 with intact cell tropism that neutralizing antibodies (NAb) responses blocking HCMV entry into many non-FB cell types target in majority a pentamer complex (PC) composed of gH, gL, UL128, UL130, and UL131A [14,15,16]
SDS-PAGE analysis of the purified protein under denaturing and reducing conditions showed five protein bands that were consistent with previously described molecular weight values of the HCMV PC subunits (~85 KDa for gH; ~35 KDa for gL; ~15 KDa for UL128; ~35 KDa for UL130; and ~18 KDa for UL131A) [33, 34]

Summary

Introduction

Since human cytomegalovirus (HCMV) is a leading cause of birth defects in newborns and complications in immunologically vulnerable individuals such as transplant recipients and AIDS patients, developing a vaccine to prevent HCMV infection is considered a major public health priority [1, 2]. The absence of HCMV animal models, poorly understood immune correlates of protection, incomplete protection by naturally acquired immunity, and difficulties of conducting sufficiently powered vaccine trials are a number of obstacles that complicate HCMV vaccine development [3, 4] Despite these impediments, promising findings for the feasibility of an effective HCMV vaccine candidate have been obtained with an approach based on envelope glycoprotein gB combined with MF59 adjuvant, showing partial efficacy to prevent primary infection of young women or adolescent girls and ability to reduce viremia in solid organ transplant recipients [5,6,7]. These findings suggest that induction of PC-specific NAb could be important for a vaccine candidate to prevent congenital HCMV infection

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