Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis.

BACKGROUND: Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated. METHODS: Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens. RESULTS: EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005). In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP. DISCUSSION: Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.

Genetics of immune response to Epstein-Barr virus: prospects for multiple sclerosis pathogenesis.

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 [EBNA-1, truncated = amino acids (aa) (325-641), peptide = aa(385-420)] and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched control subjects. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 [odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.60-1.88] and EBNA-1, particularly the peptide (OR = 3.13, 95% CI = 2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to 12× the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g. DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defence against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defence against EBV. Last, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.

Evaluation of novel Epstein-Barr virus-derived antigen formulations for monitoring virus-specific T cells in pediatric patients with infectious mononucleosis.

BACKGROUND: Infection with the Epstein-Barr virus (EBV) elicits a complex T-cell response against a broad range of viral proteins. Hence, identifying potential differences in the cellular immune response of patients with different EBV-associated diseases or different courses of the same disorder requires interrogation of a maximum number of EBV antigens. Here, we tested three novel EBV-derived antigen formulations for their ability to reactivate virus-specific T cells ex vivo in patients with EBV-associated infectious mononucleosis (IM). METHODS: We comparatively analyzed EBV-specific CD4+ and CD8+ T-cell responses to three EBV-derived antigen formulations in 20 pediatric patients during the early phase of IM: T-activated EBV proteins (BZLF1, EBNA3A) and EBV-like particles (EB-VLP), both able to induce CD4+ and CD8+ T-cell responses ex vivo, as well as an EBV-derived peptide pool (PP) covering 94 well-characterized CD8+ T-cell epitopes. We assessed the specificity, magnitude, kinetics, and functional characteristics of EBV-specific immune responses at two sequential time points (v1 and v2) within the first six weeks after IM symptom onset (Tonset). RESULTS: All three tested EBV-derived antigen formulations enabled the detection of EBV-reactive T cells during the early phase of IM without prior T-cell expansion in vitro. EBV-reactive CD4+ and CD8+ T cells were mainly mono-functional (CD4+: mean 64.92%, range 56.15-71.71%; CD8+: mean 58.55%, range 11.79-85.22%) within the first two weeks after symptom onset (v1) with IFN-γ and TNF-secreting cells representing the majority of mono-functional EBV-reactive T cells. By contrast, PP-reactive CD8+ T cells were primarily bi-functional (>60% at v1 and v2), produced IFN-γ and TNF and had more tri-functional than mono-functional components. We observed a moderate correlation between viral load and EBNA3A, EB-VLP, and PP-reactive CD8+ T cells (rs = 0.345, 0.418, and 0.356, respectively) within the first two weeks after Tonset, but no correlation with the number of detectable EBV-reactive CD4+ T cells. CONCLUSIONS: All three EBV-derived antigen formulations represent innovative and generic recall antigens suitable for monitoring EBV-specific T-cell responses ex vivo. Their combined use facilitates a thorough analysis of EBV-specific T-cell immunity and allows the identification of functional T-cell signatures linked to disease development and severity.

Characteristics of Virology and Immune Inflammation of Epstein-Barr Virus Infection Related Non-Neoplastic Diseases in Children.

BACKGROUND: The goal was to study the difference of virological, immunologic, and inflammatory indicators between Epstein-Barr associated infectious mononucleosis (EBV-IM) and EBV associated hemophagocytic lymphohistiocytosis (EBV-HLH) and to explore the evaluation indicators for monitoring the therapeutic efficacy of EBV-HLH. METHODS: Twenty children with EBV-IM (IM group) and 10 children with EBV-HLH (HLH group) were selected. Virology indicators were detected; the absolute count of lymphocyte, and lymphocyte subsets were detected; the levels of immunoglobulin and ferritin were assayed. RESULTS: Compared to the IM group, the HLH group showed a decrease in EBV-specific VCA-IgM antibody levels (U = 29.0, p = 0.006) and an increase in EBV-specific NA-IgG antibody levels (U = 17.0, p = 0.001), while there was no significant difference in EB-DNA loads (t = 0.417, p = 0.680). The counts of lymphocytes, and various lymphocyte subsets in the HLH group were lower than those in the IM group. Inflammatory markers in the HLH group were significantly higher than those in IM group. Dynamic monitoring of virological, immunological, and inflammatory indicators in HLH patients during treatment showed that EBV DNA gradually decreased in patients with good prognosis. Inflammatory indicators significantly decreased and returned to normal, lymphocyte count significantly increased and returned to normal during treatment. However, patients with poor prognosis showed rebound increase in EBV DNA and inflammatory indicators in the later stage of treatment, while lymphocyte count further decreased with the recurrence of the disease. CONCLUSIONS: Exhausted and damaged immune function in host by persistent stimulation of EB viral antigen is one of the main pathogeneses of EB-HLH. Lymphocyte count and serum ferritin level are effective indicators to monitor the therapeutic efficacy during the treatment to HLH.

Infectious mononucleosis due to Epstein-Barr virus reactivation in an immunocompromised 60-year-old patient with COVID-19.

Epstein-Barr virus (EBV) reactivation in COVID-19 patients has been reported, but studies on its clinical significance are lacking. We herein report the occurrence of infectious mononucleosis (IM) due to EBV reactivation in a 60-year-old man with rheumatoid arthritis being treated with methotrexate and tocilizumab. The patient presented with a fever and tested positive for COVID-19. Laboratory findings revealed an increased atypical lymphocyte count, decreased platelet count, and elevated liver enzyme levels. Flow cytometry showed predominant expansion of reactive T cells. EBV reactivation was confirmed using real-time polymerase chain reaction. The patient was treated with remdesivir, and clinical improvement was observed after 10 days of treatment. Follow-up showed a gradual decrease in the EBV-DNA load with no recurrence of atypical lymphocytes. These findings suggest that COVID-19 in immunocompromised patients may lead to unexpected EBV reactivation and IM, even for patients outside the age at which IM is likely to occur.

Effects of chloroquine or hydroxychloroquine treatment on non-SARS-CoV2 viral infections: A systematic review of clinical studies.

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non-SARS-CoV2 infection supported the use of these agents in the present SARS-CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non-SARS-CoV2 viral infections do not support these agents' use for the SARS-CoV2 outbreak.

Diagnostic value of serological and molecular biological tests for infectious mononucleosis by EBV in different age stages and course of the disease.

Epstein-Barr virus (EBV)-based serologic antibody and viral nucleic acid assays have been found to be feasible means to diagnose infectious mononucleosis (IM) caused by EBV in children. In this study, we will further explore their diagnostic value for IM by EBV in different age stages and over the course of the disease. A collection of 616 children from clinically suspected IM cases was studied. Indirect immunofluorescence (IIF) for EBV-specific antibody (Euroimmun) combined with plasma EB viral nucleic acid assay (real-time fluorescence quantitative polymerase chain reaction reverse-transcription polymerase chain reaction) were used as reference methods. The diagnostic efficiency of the peripheral blood routine test, serologic antibody test, and plasma EB viral nucleic acid assay for the diagnosis of IM was evaluated, respectively. The sensitivity, specificity, Youden' index and the area under curve (AUC) were 93.08%, 87.77%, 0.81 and 0.904 (95% confidence interval [CI]: 0.878-0.931) for the peripheral lymphocyte test (lymphocytosis > 5 × 109 /L), 98.27%, 91.13%, 0.89 and 0.947 (95% CI: 0.927-0.967) for the plasma EBV-DNA test, and 84.08%, 96.33%, 0.80 and 0.902 (95% CI: 0.874-0.930) for the EBV viral capsid antigen (VCA)-IgG avidity test. The plasma EBV-DNA test has a higher diagnostic value than the VCA-IgG avidity test in children aged <6 years, especially aged <3 years; the peripheral lymphocyte test and plasma EBV-DNA test are suitable for the early stage of the disease, while the VCA-IgG avidity test for after 7 days of the disease. EBV antibody detection (IIF) should be combined with EBV nucleic acid detection in children age <6 years and the early stage of the disease.

Comparison of seven heterophile antibody assays for laboratory diagnosis of infectious mononucleosis in pediatric patients.

Heterophile antibody assays have been used to aid the diagnosis of infectious mononucleosis caused by the Epstein-Barr virus. Seven commercially available assays currently widely utilized in clinical laboratories were compared in this study. Variable performance characteristics and assay times are observed, and these pieces of data may assist clinical laboratories in assay selection and result interpretation.

Primary EBV Infection Induces an Acute Wave of Activated Antigen-Specific Cytotoxic CD4+ T Cells.

CD4+ T cells are essential for immune protection against viruses, yet their multiple roles remain ill-defined at the single-cell level in humans. Using HLA class II tetramers, we studied the functional properties and clonotypic architecture of EBV-specific CD4+ T cells in patients with infectious mononucleosis, a symptomatic manifestation of primary EBV infection, and in long-term healthy carriers of EBV. We found that primary infection elicited oligoclonal expansions of TH1-like EBV-specific CD4+ T cells armed with cytotoxic proteins that responded immediately ex vivo to challenge with EBV-infected B cells. Importantly, these acutely generated cytotoxic CD4+ T cells were highly activated and transcriptionally distinct from classically described cytotoxic CD4+ memory T cells that accumulate during other persistent viral infections, including CMV and HIV. In contrast, EBV-specific memory CD4+ T cells displayed increased cytokine polyfunctionality but lacked cytotoxic activity. These findings suggested an important effector role for acutely generated cytotoxic CD4+ T cells that could potentially be harnessed to improve the efficacy of vaccines against EBV.

Infectious mononucleosis, immune genotypes, and non-Hodgkin lymphoma (NHL): an InterLymph Consortium study.

PURPOSE: We explored the interaction between non-Hodgkin lymphoma (NHL), infectious mononucleosis (IM) history, and immune-related genotypes in a pooled case-control analysis. METHODS: A total of 7,926 NHL patients and 10,018 controls from 12 case-control studies were included. Studies were conducted during various time periods between 1988 and 2008, and participants were 17-96 years of age at the time of ascertainment/recruitment. Self-reported IM history and immune response genotypes were provided by the InterLymph Data Coordinating Center at Mayo Clinic. Odds ratios (OR) were estimated using multivariate logistic regression, and interactions were estimated using the empirical Bayes method. PACT was used to account for multiple comparisons. RESULTS: There was evidence of an interaction effect between IM history and two variants on T-cell lymphoma (TCL) risk: rs1143627 in interleukin-1B (IL1B) (pinteraction = 0.04, ORinteraction = 0.09, 95% confidence interval [CI] 0.01, 0.87) and rs1800797 in interleukin-6 (IL6) (pinteraction = 0.03, ORinteraction = 0.08, 95% CI 0.01, 0.80). Neither interaction effect withstood adjustment for multiple comparisons. There were no statistically significant interactions between immune response genotypes and IM on other NHL subtypes. CONCLUSIONS: Genetic risk variants in IL1B and IL6 may affect the association between IM and TCL, possibly by influencing T-cell activation, growth, and differentiation in the presence of IM, thereby decreasing risk of immune cell proliferation.

Proteome-wide analysis of CD8+ T cell responses to EBV reveals differences between primary and persistent infection.

Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to a gamma1-herpesvirus, Epstein-Barr virus (EBV), and the first such proteome-wide analysis of primary versus memory CD8+ T cell responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor's individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response.

The promise of a prophylactic Epstein-Barr virus vaccine.

The worldwide burden of disease due to Epstein-Barr virus (EBV) infection is enormous. Diseases include endemic Burkitt lymphoma, infectious mononucleosis, cancers after transplantation, Hodgkin lymphoma, and nasopharyngeal carcinoma. A prophylactic EBV vaccine has the potential to significantly reduce the incidence and/or the severity of all these diseases. Infectious mononucleosis can be nasty and prolonged with a median duration of 17 days. Patients, especially children, undergoing bone marrow or solid organ transplantation may develop post-transplant lymphoproliferative disorder (PTLD). Preventing or modifying primary EBV infection could reduce the incidence PTLD, and also certain lymphomas and nasopharyngeal carcinoma. EBV is a major environmental risk factor for multiple sclerosis (MS). Contracting EBV is essential to getting MS, and having a childhood case of infectious mononucleosis increases that risk. Vaccinating against EBV could be vaccinating against MS.

Changes in mRNA expression of members of TGFB1-associated pathways in human leukocytes during EBV infection.

Transforming growth factor ß 1 (TGFB1) likely contributes to the pathogenesis of Epstein-Barr virus (EBV)-mediated cancer. A microarray containing 59 probes for detecting mRNA of members of TGFB1-associated pathways was developed. mRNA expression of TGFB1 receptors and members of connected pathways were examined in peripheral blood leukocytes of patients during acute EBV infection and after recovery. TGFB1 and TGFBR2 mRNA expression was increased in patients with EBV infection. Similarly, mRNA expression of protein kinase C (PRKCB), MAP3K7, PDLIM7, and other members of TGFB1 and NF-κB signaling pathways increased. A shift of mRNA transcript variant expression of some key members (TGFBR2, PRKCB, and NFKBIB) of involved signaling pathways was detected. After the patients' recovery, most of the altered mRNA expression has been normalized. We speculate that in patients with EBV infection, members of TGFB1-associated pathways contribute to the suppression of proapoptotic and induction of pro-survival factors in leukocytes. The modulation of TGFB1-associated pathways may be considered as a potential risk factor in the development of EBV-associated tumors in patients with acute EBV infection.

High Epstein-Barr Virus Load and Genomic Diversity Are Associated with Generation of gp350-Specific Neutralizing Antibodies following Acute Infectious Mononucleosis.

The Epstein-Barr virus (EBV) gp350 glycoprotein interacts with the cellular receptor to mediate viral entry and is thought to be the major target for neutralizing antibodies. To better understand the role of EBV-specific antibodies in the control of viral replication and the evolution of sequence diversity, we measured EBV gp350-specific antibody responses and sequenced the gp350 gene in samples obtained from individuals experiencing primary EBV infection (acute infectious mononucleosis [AIM]) and again 6 months later (during convalescence [CONV]). EBV gp350-specific IgG was detected in the sera of 17 (71%) of 24 individuals at the time of AIM and all 24 (100%) individuals during CONV; binding antibody titers increased from AIM through CONV, reaching levels equivalent to those in age-matched, chronically infected individuals. Antibody-dependent cell-mediated phagocytosis (ADCP) was rarely detected during AIM (4 of 24 individuals; 17%) but was commonly detected during CONV (19 of 24 individuals; 79%). The majority (83%) of samples taken during AIM neutralized infection of primary B cells; all samples obtained at 6 months postdiagnosis neutralized EBV infection of cultured and primary target cells. Deep sequencing revealed interpatient gp350 sequence variation but conservation of the CR2-binding site. The levels of gp350-specific neutralizing activity directly correlated with higher peripheral blood EBV DNA levels during AIM and a greater evolution of diversity in gp350 nucleotide sequences from AIM to CONV. In summary, we conclude that the viral load and EBV gp350 diversity during early infection are associated with the development of neutralizing antibody responses following AIM. IMPORTANCE: Antibodies against viral surface proteins can blunt the spread of viral infection by coating viral particles, mediating uptake by immune cells, or blocking interaction with host cell receptors, making them a desirable component of a sterilizing vaccine. The EBV surface protein gp350 is a major target for antibodies. We report the detection of EBV gp350-specific antibodies capable of neutralizing EBV infection in vitro The majority of gp350-directed vaccines focus on glycoproteins from lab-adapted strains, which may poorly reflect primary viral envelope diversity. We report some of the first primary gp350 sequences, noting that the gp350 host receptor binding site is remarkably stable across patients and time. However, changes in overall gene diversity were detectable during infection. Patients with higher peripheral blood viral loads in primary infection and greater changes in viral diversity generated more efficient antibodies. Our findings provide insight into the generation of functional antibodies, necessary for vaccine development.

The Effects of Epstein-Barr Virus Nuclear Antigen 2 (EBNA2) on B-Lymphocytic Activity.

BACKGROUND: Epstein-Barr virus is a worldwide disease that can cause a wide range of human diseases, the person will become a lifelong carrier of the virus once infected. To investigate the mechanism of Epstein-Barr virus nuclear antigen 2 (EBNA2) on B-lymphocytic activity, sera from 35 patients with infectious mononucleosis and from 34 cases without Epstein-Barr virus infection are collected for experimental analysis. METHODS: Quantitative real-time PCR, western blot, and MTT assays were used to evaluate the relative expression level of EBNA2 and to examine its impact on cell vitality. RESULTS: Research found that the average EBNA2 mRNA and protein levels in 35 patients with infectious mononucleosis were higher than that 34 cases without Epstein-Barr virus infection. The MTT assay indicates that EBNA2 can promote the growth and proliferation of B lymphocytes. CONCLUSIONS: Combining the above implies that EBNA2 plays an important role in diseases that are induced by the Epstein-Barr virus. Other experiments reveal that ATO promotes the degradation of EBNA2 protein and induces the apoptosis of B lymphocytes which are EBNA2-positive.

Infectious Mononucleosis and Lyme Disease as Confounding Diagnoses: A Report of 2 Cases.

Lyme disease and infectious mononucleosis are common illnesses that share similar clinical presentations. Significant cross-reactivity is known to occur between Lyme and EBV serologic assays complicating the diagnosis. To date, no prior cases of concurrent acute Lyme and EBV infections have been reported. We describe the clinical presentation of two children with confirmed early Lyme disease and features suggestive of infectious mononucleosis, including one case of probable Lyme and EBV co-infection.

Vaccine Development for Epstein-Barr Virus.

Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is associated with several malignancies, including nasopharyngeal carcinoma, gastric carcinoma, Hodgkin lymphoma, Burkitt lymphoma, and lymphomas in immunocompromised persons, as well as multiple sclerosis. A vaccine is currently unavailable. While monomeric EBV gp350 was shown in a phase 2 trial to reduce the incidence of infectious mononucleosis, but not the rate of EBV infection, newer formulations of gp350 including multimeric forms, viruslike particles, and nanoparticles may be more effective. A vaccine that also includes additional viral glycoproteins, lytic proteins, or latency proteins might improve the effectiveness of an EBV gp350 vaccine. Clinical trials to determine if an EBV vaccine can reduce the rate of infectious mononucleosis or posttransplant lymphoproliferative disease should be performed. The former is important since infectious mononucleosis can be associated with debilitating fatigue as well as other complications, and EBV infectious mononucleosis is associated with increased rates of Hodgkin lymphoma and multiple sclerosis. A vaccine to reduce EBV posttransplant lymphoproliferative disease would be an important proof of principle to prevent an EBV-associated malignancy. Trials of an EBV vaccine to reduce the incidence of Hodgkin lymphoma, multiple sclerosis, or Burkitt lymphoma would be difficult but feasible.

[Clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis].

OBJECTIVE: To study the clinical effect of pidotimod oral liquid as adjuvant therapy for infectious mononucleosis and its effect on T lymphocyte subsets. METHODS: A total of 76 children with infectious mononucleosis, who were admitted to the hospital between July 2016 and June 2017, were enrolled and randomly divided into two groups: conventional treatment and pidotimod treatment (n=38 each). The children in the conventional treatment group were given antiviral therapy with ganciclovir for injection and symptomatic treatment. Those in the pidotimod treatment group were given pidotimod oral liquid in addition to the treatment in the conventional treatment group. The course of treatment was two weeks for both groups. The two groups were compared in terms of the recovery of clinical indices and the changes in peripheral blood T lymphocyte subsets. RESULTS: Compared with the conventional treatment group, the pidotimod treatment group had significantly shorter fever clearance time, time to the disappearance of isthmopyra, time to the relief of lymph node enlargement, time to the relief of hepatosplenomegaly, and length of hospital stay (P<0.05). After treatment, the pidotimod treatment group had significant reductions in the percentages of CD3+ and CD8+ T cells and had significantly lower percentages of CD3+ and CD8+ T cells than the conventional treatment group (P<0.001). The pidotimod treatment group had significant increases in the percentage of CD4+ T cells and CD4+/CD8+ ratio after treatment, which was significantly higher than those in the conventional treatment group (P<0.001). The conventional treatment group had no significant changes in T lymphocyte subsets after treatment (P>0.05). CONCLUSIONS: Pidotimod oral liquid has a good clinical effect as the adjuvant therapy for infectious mononucleosis and can improve cellular immune function, so it holds promise for clinical application.

[CLINICAL AND IMMUNOLOGICAL CRITERIA FOR THE ADVERSE COURSE OF INFECTIOUS MONONUCLEOSIS IN CHILDREN].

The article presents the results of our own studies to determine the criteria for the adverse variants of the course of infectious mononucleosis (IM) in children. The study was conducted in the regional children's infectious clinical hospital in Kharkov. 161 children aged three to fifteen years were under observation with diagnosis of infectious moninucleosis. Out of 161 ill children, 140 (86.9%) had moderate severity of disease, and 21 (13.1%) had severe forms. All children were prescribed standard clinical and laboratory-instrumental examinations. The diagnosis of IM was verified by PCR (detection of VEB DNA in the blood) and ELISA (anti-VEB Ig M and Ig G). In 140 children (86.9%) IM proceeded sharply, smoothly (the first group), in 21 (13.1%) - unfavorably (wave and / or prolonged course) - the second group. The groups were comparable according to age, the severity of the disease and other parameters. All children received therapy according to approved protocols (Order of the Ministry of Health of Ukraine No. 354 of 09.07.2004). Immune status of children was assessed by determining the relative contents of CD3 +, CD4 +, CD8 +, CD16 +, CD19 + blood cells with appropriate monoclonal antibodies, serum IgA, IgM, IgG concentration by Mancini and interleukin (IL) -1ß cytokine response and - 4, tumor necrosis factor (TNF α) is a solid-phase enzyme-linked immunosorbent assay. Based on the results of observations, it was established that the prognostically unfavorable criteria of IМ at the stages of manifestation of disease include: generalized lymphadenopathy involving 5-6 groups of lymph nodes and a significant increasing of them, purulent tonsillitis, marked increasing of size of liver and spleen on the background of anemia, thrombocytopenia, neutropenia and the absence of atypical mononuclears in the complete blood count. There is a depression of the cellular link and an increase in the humoral mechanisms of immune responses in case of development of adverse course of IM.