Development of novel vaccines against human cytomegalovirus

Cui, Xinle; Snapper, Clifford M.

doi:10.1080/21645515.2019.1593729

Cited by 17 publications

(21 citation statements)

References 130 publications

(207 reference statements)

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“…Though the pentameric complex elicits a high titer of HCMV neutralization activity, the antibodies elicited are protective against HCMV infection of epithelial cells, endothelial cells and monocytes, but not fibroblasts or primary trophoblast progenitor cells [ 46 , 47 , 48 , 49 , 68 , 69 , 70 , 71 ]. It has been suggested that the combination of trimeric gB and pentameric complex proteins may be an optimal prophylactic HCMV vaccine [ 37 , 72 , 73 ]. The effect of gB in combination with pentameric complex has been evaluated using MVA vectored or RNA vaccine that simultaneously express gB and the pentameric complex [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…A variety of experimental vaccine approaches have been evaluated over the past 50 years. Although live attenuated, subunit, DNA/RNA and viral vectored HCMV vaccines have each demonstrated promising results, none of them meet the requirements of licensing [ 34 , 35 , 36 , 37 ]. An HCMV recombinant gB vaccine adjuvanted with MF59 has advanced the furthest in clinical trials [ 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

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Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

et al. 2020

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Human cytomegalovirus (HCMV) core fusion machinery proteins gB and gH/gL, and accessory proteins UL128/UL130/UL131A, are the key envelope proteins that mediate HCMV entry into and infection of host cells. To determine whether these HCMV envelope proteins could elicit neutralizing activities synergistically, we immunized rabbits with individual or various combinations of these proteins adsorbed to aluminum hydroxide mixed with CpG-ODN. We then analyzed serum neutralizing activities with multiple HCMV laboratory strains and clinical isolates. HCMV trimeric gB and gH/gL elicited high and moderate titers of HCMV neutralizing activity, respectively. HCMV gB in combination with gH/gL elicited up to 17-fold higher HCMV neutralizing activities compared to the sum of neutralizing activity elicited by the individual proteins analyzed with both fibroblasts and epithelial cells. HCMV gB+gH/gL+UL128/UL130/UL131A in combination increased the neutralizing activity up to 32-fold compared to the sum of neutralizing activities elicited by the individual proteins analyzed with epithelial cells. Adding UL128/UL130/UL131A to gB and gH/gL combination did not increase further the HCMV neutralizing activity analyzed with fibroblasts. These data suggest that the combination of HCMV core fusion machinery envelope proteins gB+gH/gL or the combination of gB and pentameric complex could be ideal vaccine candidates that would induce optimal immune responses against HCMV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

et al. 2020

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“…Antibodies elicited by the pentameric complex are likely to prevent HCMV infecting epithelial cells, endothelial cells, and monocytes, but not fibroblasts or primary trophoblast progenitor cells [58,59,60,61,62,63,64,65]. Since HCMV gB elicits higher HCMV neutralization activity for fibroblasts than epithelial cells, whereas the pentameric complex mainly elicits high HCMV neutralization activity for epithelial cells, endothelial cells, and monocytes, it has been suggested that an optimal prophylactic HCMV vaccine will consist of both trimeric gB and pentameric complex proteins [31,66]. Immunization with the combination of gB and the pentameric complex has been tried using RNA vaccine or the MVA vectored vaccine expressing simultaneously gB and the five subunits of the pentameric complex, although enhanced HCMV-neutralizing activity was induced, no synergistic or additive effects in the elicitation of HCMV-neutralizing activity was reported [55,56].…”

Section: Discussionmentioning

confidence: 99%

“…There is currently no HCMV vaccine approved for clinical use, although the development of an HCMV vaccine is a public heath priority. Over the past 50 years, a variety of experimental vaccine approaches have been evaluated, and many are currently in various stages of evaluation [28,29,30,31]. An HCMV vaccine consisting of an adjuvanted recombinant monomeric gB protein has advanced the furthest in clinical trials [32,33].…”

Section: Introductionmentioning

confidence: 99%

Immunization of Rabbits with Recombinant Human Cytomegalovirus Trimeric versus Monomeric gH/gL Protein Elicits Markedly Higher Titers of Antibody and Neutralization Activity

Cui

Cao

Wang

et al. 2019

IJMS

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Congenital human cytomegalovirus (HCMV) infection and HCMV infection of immunosuppressed patients cause significant morbidity and mortality, and vaccine development against HCMV is a major public health priority. HCMV envelope glycoproteins gB, gH, and gL, which constitute the core fusion machinery, play critical roles in HCMV fusion and entry into host cells. HCMV gB and gH/gL have been reported to elicit potent neutralizing antibodies. Recently, the gB/gH/gL complex was identified in the envelope of HCMV virions, and 16–50% of the total gH/gL bound to gB, forming the gB/gH/gL complex. These findings make the gB/gH/gL a unique HCMV vaccine candidate. We previously reported the production of HCMV trimeric gB and gH/gL heterodimers, and immunization with a combination of trimeric gB and gH/gL heterodimers elicited strong synergistic HCMV-neutralizing activity. To further improve the immunogenicity of gH/gL, we produced trimeric gH/gL. Rabbits immunized with HCMV trimeric gH/gL induced up to 38-fold higher serum titers of gH/gL-specific IgG relative to HCMV monomeric gH/gL, and elicited ~10-fold higher titers of complement-dependent and complement-independent HCMV-neutralizing activity for both epithelial cells and fibroblasts. HCMV trimeric gH/gL in combination with HCMV trimeric gB would be a novel promising HCMV vaccine candidate that could induce highly potent neutralizing activities.

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“…Both vaccines were used to immunize mice and induce a neutralizing antibody response 10-fold higher compared to their soluble recombinant protein counterpart [90]. The vaccine was entered in phase I clinical studies enrolling HCMV-seronegative individuals for evaluation of safety and immunogenicity in early 2016 [91]. An additional eVLP vaccine candidate, targeting both the gB and pp65 antigens, has also been manufactured by VBI.…”

Section: Virus-like Particles and Nanoparticles For Antigen Displaymentioning

confidence: 99%

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

Perotti

Perez

2019

Viruses

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Human cytomegalovirus (HCMV) infects more than 70% of the human population worldwide. HCMV is responsible for high morbidity and mortality in immunocompromised patients and remains the leading viral cause of congenital birth defects. Despite considerable efforts in vaccine and therapeutic development, HCMV infection still represents an unmet clinical need and a life-threatening disease in immunocompromised individuals and newborns. Immune repertoire interrogation of HCMV seropositive patients allowed the identification of several potential antigens for vaccine design. However, recent HCMV vaccine clinical trials did not lead to a satisfactory outcome in term of efficacy. Therefore, combining antigens with orthogonal technologies to further increase the induction of neutralizing antibodies could improve the likelihood of a vaccine to reach protective efficacy in humans. Indeed, presentation of multiple copies of an antigen in a repetitive array is known to drive a more robust humoral immune response than its soluble counterpart. Virus-like particles (VLPs) and nanoparticles (NPs) are powerful platforms for multivalent antigen presentation. Several self-assembling proteins have been successfully used as scaffolds to present complex glycoprotein antigens on their surface. In this review, we describe some key aspects of the immune response to HCMV and discuss the scaffolds that were successfully used to increase vaccine efficacy against viruses with unmet medical need.

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Development of novel vaccines against human cytomegalovirus

Cited by 17 publications

References 130 publications

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

Immunization with Human Cytomegalovirus Core Fusion Machinery and Accessory Envelope Proteins Elicit Strong Synergistic Neutralizing Activities

Immunization of Rabbits with Recombinant Human Cytomegalovirus Trimeric versus Monomeric gH/gL Protein Elicits Markedly Higher Titers of Antibody and Neutralization Activity

Virus-Like Particles and Nanoparticles for Vaccine Development against HCMV

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