Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein–Barr virus vaccine in healthy adults

Moutschen, Michel; Léonard, Philippe; Sokal, Étienne; Smets, Françoise; Haumont, Michèle; Mazzu, Pasqualina; Bollen, Alex; Denamur, Françoise; Peeters, Pascal; Dubin, Gary; Denis, Martine

doi:10.1016/j.vaccine.2007.04.008

Cited by 154 publications

(113 citation statements)

References 25 publications

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“…Although this vaccine seemed to diminish the incidence of IM, its efficacy in preventing virus infection and/or EBV-associated diseases remains unknown. 49,50 It seems unlikely that sterilizing immunity against EBV can be achieved via vaccination because 1 to 10 virus particles are enough for the establishment of lifelong ␥-herpesvirus infections, 51,52 and reinfection of healthy EBV carriers with new EBV strains has been documented. 53,54 Thus, more recent immunotherapeutic approaches against primary EBV infection have concentrated on inducing T-cell responses to aid in asymptomatic seroconversion, rather than preventing infection, and to target EBVassociated malignancies.…”

Section: Discussionmentioning

confidence: 99%

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Gurer

Strowig

Brilot

et al. 2008

Blood

121

129

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IntroductionEpstein-Barr virus (EBV) is a ubiquitous human ␥-herpesvirus that latently infects B cells and establishes chronic infection in more than 90% of the adult population. Although infection with EBV during adolescence can lead to infectious mononucleosis (IM), the vast majority of infected people acquires and harbors EBV as a benign lifelong infection, which is controlled by strong T-cell immunity. However, in a small subset of infected individuals, EBV latency programs with different viral antigen expression patterns are associated with malignancies such as Hodgkin and Burkitt lymphomas as well as nasopharyngeal carcinoma (NPC). 1 The nuclear antigen 1 (EBNA1) is the one EBV antigen that is expressed in all of these EBV-associated tumors as well as in EBV-positive proliferating cells in healthy carriers. 2 EBNA1 is crucial for viral persistence, because it initiates viral DNA replication and anchors the circular viral episome to the mitotic chromosomes during cell division, thereby ensuring the survival of the viral genome in proliferating cells. Thus, even in the absence of all other EBV proteins, such as in Burkitt lymphoma, EBNA1 expression must be maintained, and from an immune surveillance point of view, EBNA1 should be a critical target of protective immunity. Indeed, EBNA1 is consistently recognized by Th1-type CD4 ϩ T cells, [3][4][5][6] and can elicit CD8 ϩ T-cell responses 7-9 in healthy EBV carriers. These T cells that recognize mostly epitopes in the C-terminal domain of EBNA1 can target EBV-transformed B cells and prevent their outgrowth in vitro. 10 While EBNA1-specific T-cell responses can also be detected in peripheral blood of NPC patients, 11 they are greatly diminished in patients with EBVassociated non-Hodgkin lymphoma in the context of HIV infection, 12 EBV-associated Hodgkin disease (K. N. Heller, F.A., P. Steinherz, C. Postlook, A. Chadburn, K. Kelly, C.M., manuscript submitted) and endemic Burkitt lymphomas (Ann Moormann, Case Western Reserve University, Cleveland, OH, personal communication April 2008), thus making EBNA1, and specifically its C-terminal domain, a logical target for vaccine development against all EBV-associated malignancies.A promising cell type, to which EBNA1 could be targeted for vaccine design, is dendritic cells (DCs). These sentinels of the immune system have an exceptional T-cell stimulatory capacity, which includes their ability to efficiently process antigens, and present them on both major histocompatibility class (MHC) I and class II molecules in combination with T-cell costimulatory molecules. 13 DCs are also crucial for initiating protective innate and adaptive immune responses against bacterial and viral pathogens in vivo, 14,15 which further supports targeting DCs for therapeutic vaccination. However, many current DC-targeted immunization approaches use individualized culture, antigen loading, and activation of DCs in vitro for adoptive transfer. 16 A more recent strategy that circumvents the analysis of ex vivo DCs is to target antigens to DCs in...

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Section: Discussionmentioning

confidence: 99%

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Gurer

Strowig

Brilot

et al. 2008

Blood

121

129

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“…The obvious immunogen is the EBV gp350 protein, which is a major target for antibodies that neutralize EBV infection, and almost all studies have focused on this protein. The data reported to date suggest that a gp350 vaccine administered to a population of EBV-negative volunteers (ages 18-37) who were then monitored for IM and serologi-cally assessed for EBV infection for 3 years had little effect on the frequency of silent seroconversion but greatly reduced the frequency of IM (20). This is an important result because it suggests that a vaccine to prevent IM might actually work and also because it points the way to the most sensible vaccine strategy, namely to try to prevent IM but not the normal silent infection with EBV.…”

Section: An Ebv Vaccine To Prevent Immentioning

confidence: 99%

Role for HLA in susceptibility to infectious mononucleosis

Farrell

2007

J. Clin. Invest.

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Factors involved in determining whether infectious mononucleosis occurs after primary EBV infection may include age, dose of virus received, and various genetic markers. A study by McAulay and colleagues reported in this issue of the JCI shows that the presence of certain HLA class I alleles correlates with the incidence and severity of infectious mononucleosis (see the related article beginning on page 3042). These same HLA alleles are also risk factors for EBV-associated Hodgkin lymphoma (HL), supporting recent epidemiology that indicates that a history of infectious mononucleosis predisposes to HL. Recent studies suggest that an EBV vaccine might help to prevent infectious mononucleosis, and further development of this should now be considered.Nonstandard abbreviations used: EBNA, EpsteinBarr nuclear antigen; HL, Hodgkin lymphoma; IM, infectious mononucleosis; LMP, latent viral protein. Conflict of interest:The author has declared that no conflict of interest exists.

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“…The first involves a vaccine based on the major surface glycoprotein of EBV, gp350. This vaccine was originally conceived to induce neutralizing antibodies; however, antibody responses do not appear to correlate with protection, with some evidence suggesting that gp350-specific CD4 T-cell responses might mediate protection (40). The second approach seeks to generate EBV-specific CD8 ϩ T cells that control the expansion of EBV-infected B cells after infection, thereby promoting asymptomatic seroconversion rather than preventing infection (38,39).…”

mentioning

confidence: 99%

Phase I Trial of a CD8⁺T-Cell Peptide Epitope-Based Vaccine for Infectious Mononucleosis

Elliott

Suhrbier

Miles

et al. 2008

J Virol

140

101

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Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein–Barr virus vaccine in healthy adults

Cited by 154 publications

References 25 publications

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Role for HLA in susceptibility to infectious mononucleosis

Phase I Trial of a CD8⁺T-Cell Peptide Epitope-Based Vaccine for Infectious Mononucleosis

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Phase I/II studies to evaluate safety and immunogenicity of a recombinant gp350 Epstein–Barr virus vaccine in healthy adults

Cited by 154 publications

References 25 publications

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Targeting the nuclear antigen 1 of Epstein-Barr virus to the human endocytic receptor DEC-205 stimulates protective T-cell responses

Role for HLA in susceptibility to infectious mononucleosis

Phase I Trial of a CD8+T-Cell Peptide Epitope-Based Vaccine for Infectious Mononucleosis

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Phase I Trial of a CD8⁺T-Cell Peptide Epitope-Based Vaccine for Infectious Mononucleosis