Page 867 - Hematology_ Basic Principles and Practice ( PDFDrive )

750 Part VI Non-Malignant Leukocytes

TABLE Frequently Determined Epstein-Barr Virus–Specific Antibodies
54.1
Antibody Specificity Positive in IM (%) Time of Appearance in IM Persistence Comments
Viral Capsid Antigen
VCA-IgM 100 At clinical presentation 4–8 weeks Highly sensitive and specific; of major diagnostic
utility
VCA-IgG 100 At clinical presentation Lifelong Useful for documentation of past EBV infection
Early Antigen (EA)
Anti-D 70 Peaks 3–4 weeks after 3–6 months Correlates with disease severity; seen in patients
onset with NPC
Anti-R Low 2 weeks to several 2 months to >3 years Occasionally seen with unusually severe cases;
months after onset seen in patients with African Burkitt lymphoma
EBNA 100 3–4 weeks after onset Lifelong Presence excludes primary EBV infection
EBV, Epstein-Barr virus; IM, infectious mononucleosis; NPC, nasopharyngeal carcinoma.
Modified from Schooley RT: Epstein-Barr virus (infectious mononucleosis). In Mandell GL, Bennett JE, Dolin R, editors: Principles and practice of infectious diseases,
Philadelphia, 2000, Churchill Livingstone, p 1599.

consistent with recent infection, because titers disappear after recov- of gp350-ferritin complexes that induce significantly higher titers of
ery. IgG antibodies to EBNA appear late in the course of almost all neutralizing antibodies in preclinical models have been developed,
cases of EBV infection and persist throughout life; their presence but require testing in humans.
early in a suspected case of primary EBV infection excludes the Vaccine strategies in the therapeutic setting for the immuno-
diagnosis. Aberrations in this pattern of serum reactivity are observed therapy of EBV-associated malignancies should seek to elicit or boost
in many EBV-associated diseases and will be discussed under the the EBV-specific cellular immune response against EBV latency.
specific disease sections. For example, the absence of EBNA antibod- Individuals likely to benefit from this approach are EBV-seronegative
ies despite previous EBV infection is one of the serologic markers patients scheduled to undergo SOT or patients who have an EBV-
suggestive for chronic active EBV infection. associated malignancy with a low tumor burden or are in remission
(see box on EBV-Associated Malignancies). Three vaccine studies
have been conducted in patients with EBV-positive NPC. In two
Cellular Immune Responses studies patients with advanced disease were vaccinated with either
dendritic cells (DCs) loaded with peptides derived from LMP2 or
In normal individuals, primary EBV infection often results in a DCs transduced with an adenoviral vector encoding full-length
massive expansion of activated, antigen-specific T cells. Using tetra- LMP2 and an inactive form of LMP1. Administration of DC vac-
mer technology to enumerate antigen-specific T cells, it has been cines was safe, and a transient increase in the frequency of LMP2-
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documented that the CD8 T-cell response may be dominated by T specific T cells was observed on the DC/peptide vaccine trial.
cells specific for a limited number of epitopes, as seen with T-cell However, the clinical benefit in both studies was limited. Thus future
responses against other herpesviruses. T cells specific for epitopes studies should focus on DC vaccines with greater potency adminis-
derived from immediate early and several early EBV proteins of the tered to subjects with less tumor burden. In another phase I clinical
lytic cycle are dominant during the acute phase of IM, and long-term study, after frontline therapy, patients with NPC were vaccinated
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persistence of EBV-specific, CD8 T cells has been documented after with a modified vaccinia virus Ankara encoding the c-terminal
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primary EBV infection. As many as 5.5% of the circulating CD8 T portion of EBNA1 and LMP2 (MVA-EL). Induction of CD4 and
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cells in a healthy virus carrier may be positive for a single EBV CD8 antigen-specific T-cell responses was observed in the majority
epitope, illustrating how persistent EBV infection can influence the of patients after vaccination, and a phase II clinical study is in pro-
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composition of the host’s T-cell pool. Besides EBV-specific CD8 T gress. In addition, a clinical study combining MVA-EL with a PD-
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cells, EBV-specific CD4 T cells play an important role in the control L1-specific checkpoint monoclonal antibody (pembrolizumab) is in
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of EBV infections, and EBNA1-specific CD4 T cells have been the planning phase. Lastly, a recombinant adenovirus vaccine encod-
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implicated in the control of newly infected B cells. As for CD8 T-cell ing LMP2 was evaluated in patients with NPC. While vaccine
responses, there is a marked hierarchy of immunodominance, with
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the majority of CD4 T cells being specific for EBNA1 and to a lesser
extent EBNA3C.
Epstein-Barr Virus (EBV)–Associated Malignancies
EPSTEIN-BARR VIRUS VACCINE DEVELOPMENT Malignancy EBV Frequency
At present there is only limited experience with human EBV vac- Hodgkin disease ~40%
Non-Hodgkin lymphomas
8
cines. Four vaccine studies have been conducted in healthy donors Burkitt lymphoma 20–95%
in the prophylactic setting using recombinant vaccinia virus encoding Diffuse large B-cell lymphoma and CD30 Ki-1 + 10–35%
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the major viral glycoprotein gp350 (1), recombinant gp350 protein anaplastic large cell lymphoma
(2), or an EBNA3A peptide. While vaccination with gp350 induced Lymphomatoid granulomatosis 80–95%
neutralizing antibodies, and in one study prevented the clinical T-cell–rich B-cell lymphoma 20%
picture of IM, these vaccines did not significantly reduce the inci- Angioimmunoblastic lymphoma >80%
dence of EBV infection. Also no reduction in the incidence of EBV T-cell, natural killer (NK)-cell, and T/NK-cell 30–90%
infection was observed with the EBNA3A peptide vaccine. Addition- lymphomas
ally, a recombinant gp350 protein was evaluated in patients with Nasopharyngeal carcinoma >95%
5–10%
Gastric adenocarcinoma
chronic kidney disease prior to kidney transplantation. Although the Pyothorax-associated lymphoma >95%
vaccine induced transient neutralizing antibodies, it did not reduce Leiomyosarcoma in immunocompromised patients >95%
the incidence of EBV-LPD posttransplant. Newer vaccines consisting