Cases of aseptic meningitis after vaccination against mumps in Russia (2009-2019).

OBJECTIVES: Mumps is a highly contagious viral infection prevented by immunization with live attenuated vaccines. Mumps vaccines have proven to be safe and effective; however, rare cases of aseptic meningitis (AM) can occur after vaccination. The range of meningitis occurrence varies by different factors (strain, vaccine producer, and so on). Monovaccines or divaccines (mumps-measles vaccine), prepared from the strain Leningrad-3 (L-3), are used in Russia. Meningitis occurrence after vaccination has been established previously as very low. Nevertheless, with the number of children being vaccinated every year, vaccine-associated AM cases still occur. There is no official statistics on AM incidence after mumps vaccines, and information on AM features as an adverse event of mumps vaccination is limited and mostly devoted to vaccines, prepared from strains other than L-3. STUDY DESIGN: The study included patients with AM who were vaccinated against mumps in the previous 30 days before the present disease onset during 2009-2019. METHODS: Patients admitted to Infectious Clinical Hospital No. 1, Moscow, Russia, with AM were observed by a pediatrician and were screened for etiological agents of meningitis. RESULTS: Seven patients were enrolled, and clinical features and the course of infection are presented. CONCLUSIONS: Detection of only 7 cases of AM associated with mumps vaccination during the 10-year period supports very low occurrence of this adverse event after immunization with the L-3 strain-based mumps vaccines. Nevertheless, the annual number of AM cases that occur after mumps vaccination remains unknown and poorly diagnosed in practice because of the low awareness of physicians of this adverse reaction. Detection and objective coverage of such cases can lead to a weakening of 'antivaccination' moods in a society and to restoration of confidence in the healthcare system.

ANALYSIS OF THE QUALITY OF NATIONAL VACCINE AGAINST RUBELLA.

Until recently Rubella has been a wide spread infection. Thanks to vaccination against rubella, taking part in the global elimination program of "manageable infections" of WHO and adoption of the program "Elimination of measles and rubella in Russian Federation" the morbidity index of rubella has reached the sporadic level. One of the determining conditions of rubella elimination is application of high-quality vaccines that satisfy international standards. In Russian Federation, foreign rubella vaccines certified in our country were used for several years. In 2008, the commercial production of domestic vaccine began. It is widely known that the required quality of immunobiological medications is achieved using adequate production conditions and standard technological process. That is why during the production of domestic rubella vaccine, all the rules and requirements of Russian regulatory authorities and international recommendations are followed. In this article, a retrospective analysis of domestic vaccine against rubella according to laboratory options of quality in 2012-2017 is given. The results of the analysis show that the medication demonstrates stable high quality that is indicative of secure production technologies.

Measles cases in highly vaccinated population of Novosibirsk, Russia, 2000-2005.

While the proportion of measles cases in vaccinees is expected to increase as vaccine coverage increases, such cases must be carefully investigated. The present study was conducted to examine possible contributions to vaccine failures (VFs) and to genetically characterize measles virus (MV) strains circulating in Novosibirsk, Russia during 2000-2005. Totally, 27 adult measles patients admitted to a regional hospital were prospectively enrolled in our study. Genetic characterization of the MV strains revealed circulation of genotypes A, D4 and D6 between 2000 and 2003 years; a genotype D6 MV was associated with the 2005 measles outbreak. Based on IgG avidity testing, half of the vaccinated patients demonstrated evidence of secondary vaccine failure (SVF). Patients, representing both levels of vaccine failure in our study were characterized by the lack of protective titers of neutralizing antibodies against circulating MVs, despite high IgG levels in many cases and high IgG avidity in SVF cases.

Pathogenesis of infectious disease of mice caused by H5N1 avian influenza virus.

The pathogenesis of a disease caused by Qinghai-like H5N1 influenza virus in BALB/c mice was studied. Clinical, morphological, and immunological characteristics of the experimental infection caused by highly pathogenic A/duck/Tuva/01/06/ (H5N1) virus are described.

Study of measles virus recombinant proteins and their immunobiological properties.

Recombinant proteins rN (nucleocapsid) and rH/Nh (hemagglutinin) of the measles virus strain NovO/96 of genotype A were obtained. The immunobiological properties of the proteins were studied in the reaction with a panel of positive and negative sera. BALB/c mice were immunized with recombinant proteins and native antigen of the measles virus strain NovO/96 in order to obtain hyperimmune serum and its analysis using ELISA (enzyme-linked immunosorbent assay) and PRN (plaque reduction neutralization). The hyperimmune sera against recombinant proteins and native antigen of the measles virus strain NovO/96 were found to be highly active in ELISA. The antibodies against the proteins rN and rH/Nh were found to be capable of neutralizing the virus in titer 1 : 13.5 and 1 : 22.9, respectively. The neutralization titer of the antibodies generated against native antigen of the measles virus strain NovO/96 was 1 : 25.7.

Mumps vaccine failure investigation in Novosibirsk, Russia, 2002-2004.

The aims of this study were to estimate the importance of vaccine failure (VF) in cases of mumps during 2002-2004 in the city of Novosibirsk, Western Siberia, Russia, and to genotype the responsible virus strain. Mumps virus-specific RT-PCR testing of saliva was performed for 18 cases of mumps. Sera were tested for IgM and IgG, IgG avidity, and the ability to neutralise a panel of mumps viruses, including the Leningrad-3 mumps vaccine virus. Of the 12 patients for whom vaccination status was positively determined, 11 showed serological evidence of primary VF. Sequence analysis of virus RNA amplified from saliva revealed a genotype C2 virus in 2002, a genotype H2 virus in 2003, and both genotypes in 2004. Although several vaccinated patients were positive for mumps virus IgG at the time of first sampling, only nominal levels of neutralising antibody were detected, and these were effective in neutralising the vaccine strain, but not genotype C and H mumps virus strains. These results suggest that the majority of cases of mumps in vaccinees are caused by primary VF, defined as either a lack of seroconversion or a lack of IgG maturity, as based on avidity testing. The results also support the hypothesis that sera of low neutralising antibody titre have a limited ability to neutralise heterologous mumps virus strains, suggesting that antigenic differences between circulating and mumps vaccine virus strains may play a role in cases of breakthrough infection. Consistent with previous reports, mumps virus genotypes C and H continue to circulate in Novosibirsk.

Horizontal transmission of the Leningrad-3 live attenuated mumps vaccine virus.

Here we describe symptomatic transmission of the Leningrad-3 mumps vaccine virus from healthy vaccinees to previously vaccinated contacts. Throat swab and serum samples were taken from six symptomatic mumps cases and from 13 family contacts. Assessment of serum IgG and IgM anti-mumps virus antibodies and IgG avidity testing was performed using commercial test kits. Sera neutralizing antibodies were measured by plaque reduction neutralization assay using the L-3 vaccine mumps virus as the target. All six of the symptomatic mumps cases and three contact subjects tested positive for mumps by RT-PCR. The genomic sequences tested (F, SH and HN genes) of all nine of these samples were identical to the L-3 mumps vaccine strain. All 13 contacts were asymptomatic; however clear serological evidence of mumps infection was found in some of them. The likely epidemiological source of the transmitted L-3 mumps virus was children who were recently vaccinated at the schools attended by the six symptomatic mumps patients described here. The L-3 mumps vaccine virus can be shed and transmitted horizontally, even to subjects previously vaccinated with the same virus.

Measles in Minsk, Belarus, 2001-2003: clinical, virological and serological parameters.

BACKGROUND: A number of cases of measles have been reported in the Republic of Belarus despite vaccine coverage of 98%. The absence of information on measles virus genotypes circulating in the Republic of Belarus has made it difficult to asses the situation. OBJECTIVES: The purpose of this study was to isolate and sequence measles virus strains from clinical cases in Minsk, Belarus, and to estimate the role of vaccine failure in those cases. STUDY DESIGN: Between 2001 and 2003 years, 14 measles cases admitted to the Hospital of Infectious Diseases of Minsk were enrolled in our study. Clinical, routine laboratory, as well as serological and virological examinations were carried out. Detection of measles antibodies and IgG avidity testing was performed using commercial test kits. All measles cases were confirmed by RT-PCR and phylogenetically characterized. RESULTS: Only 42.9% of the cases met the WHO laboratory criteria for measles, however, all cases were confirmed by RT-PCR. Most of the measles cases were attributed to secondary vaccine failure (SVF). Phylogenetic analysis revealed the presence of genotype A virus strains in 2001 and 2002 with D6 and D7 genotypes in 2003. CONCLUSIONS: For the first time, MVs were genetically characterized in Belarus. Our results suggest that in a highly vaccinated population, most of measles cases represent vaccine failures and are vaccine-modified. Our results also indicate that confirmation of a clinical diagnosis of vaccine-modified measles requires a combination of serological and virological tests.

Observation of neutronless fusion reactions in picosecond laser plasmas.

The yield of alpha particles in neutronless fusion reactions 11B +p in plasmas produced by picosecond laser pulses with the peak intensity of 2 x 10(18) W/cm2 has been observed. Experiments were carried out on the "Neodymium" laser facility at the pulse energy of 10-12 J and pulse duration of 1.5 ps. The composite targets 11B + (CH2)n were used. The yield of 10(3) alpha particles per pulse has been observed. The energy spectrum of alpha particles contains two maxima: at 3-4 MeV and at 6-10 MeV . The first of these peaks corresponds to the secondary alpha12 particles at the decay of the intermediate first excited state of 8Be, whereas the second peak demonstrates generation of alpha1 particles in the reaction 11B +p with the production of this excited state. Simultaneous measurements of neutrons result in zero yield, which proves the observation of neutronless fusion reactions in our experiments.

Acute infectious mononucleosis and coincidental measles virus infection.

BACKGROUND: Both Epstein-Barr and measles viruses (MV) cause immune suppression, and the association of the two viruses is evaluated as life threatening. The cell immune impairment caused by simultaneous Epstein-Barr and measles viral infections was responsible for the complicated course of the disease in all described previously reports and for unfavorable outcomes in most of the cases. Timely diagnosis of coincidental viral infections could be a useful predictor for the clinical course and complications. Diagnosis must be based on an accurate assessment of clinical, hematologic, serologic manifestations and supported by appropriate laboratory methods. Recognizing the infectious etiology of concomitant infections is important for both clinicians and epidemiologists. OBJECTIVE: To describe a case report of a 20-year-old woman previously vaccinated against measles infected with acute mononucleosis and coincidental measles virus infection. STUDY DESIGN: The clinical, routine laboratory, as well as serological and virologic findings of this patient were scrutinized. Special emphasis was placed on the use of RT-PCR/PCR for confirming the involvement of both measles virus and Epstein-Barr virus (EBV) in this patient's illness. RESULTS: Infectious mononucleosis was not suspected at admission to the hospital. The final diagnosis of a concomitant measles virus infection and acute infectious mononucleosis was facilitated using viral serology to detect virus-specific IgG and IgM antibodies and by RT-PCR for the detection of measles virus RNA and EBV DNA from peripheral blood monocyte cells (PBMC). CONCLUSION: The present report highlights the difficulty of diagnosing two coincidental virus infections on clinical grounds. Serological and molecular laboratory methods, specifically the PCR (RT-PCR) analysis, are found to be useful for confirming the concomitant viral infections and proper identification of the infecting pathogens.

Protective effect of exogenous recombinant mouse interferon-gamma and tumour necrosis factor-alpha on ectromelia virus infection in susceptible BALB/c mice.

The resistance to mousepox is correlated with the production of type I cytokines: interleukin (IL)-2, IL-12, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha. We intend to describe the modulation of generalized ectromelia virus (EV) infection with exogenous administration of mrIFN-gamma and mrTNF-alpha separately and in combination using susceptible BALB/c mice. The treatment schemes presented resulted in the localization of the generalized EV infection and its development into non-fatal sloughing of the infected limb. This was accompanied by low virus titres in the treated mice due to control of systemic virus replication and virus clearance. The balance of type I versus type II cytokines was dominated by a type I response in the treated groups. The group treated with the combination of IFN-gamma and TNF-alpha exhibited the best survival with Th1-dominant (IFN-gamma and IL-12) cytokine profiles, whereas the TNF-alpha-treated group of mice was less successful in clearance of virus and demonstrated the lowest survival rate. The successful cytokine treatment schemes in this orthopoxvirus model system may have important implications in the treatment of viral diseases in humans and, in particular, of variola virus infection.

Changes in immune parameters and their correction in human cases of tick-borne encephalitis.

Tick-Borne Encephalitis virus (TBEV) causes dangerous central nervous system diseases in humans. General infection leads to the development of meningitis or encephalitis, which is characterized by swelling of the brain due to inflammation. Tetracyclines may act locally to moderate inflammation in the CNS. In this study, we investigated the potential clinical benefits of administering tetracycline hydrochloride to patients hospitalized due to suspected TBEV infection presenting with fever and evidence of a recent tick bite. We also characterized an acute immune response to TBEV by profiling certain cytokines and soluble receptors in Tetracycline-treated and untreated patients. Increased serum levels of TNF-alpha, IL-1 alpha and IL-6 were found in all patients at admission. Soluble receptors presented in the serum of patients in a magnitude higher levels than the corresponding cytokines and were increasing during first weak of hospitalization. Levels of IL-10 were also rising during that period. In our study tetracycline hydrochloride acted as an immunomodulator, which was able to reduce manifestations of inflammation response during TBE course; this action led to quicker improvement of symptoms and, consequently, to a faster clinical recovery. The positive result of tetracycline hydrochloride treatment was accompanied by certain particularities in the dynamics of studied cytokines and receptors: the concentrations of IL-6, IL-1 beta, TNF-alpha dropped quicker and reached lower levels, and the concentrations of sIL-6R, IL-1RA, sTNFR1 increased faster and reached higher maximum levels in the tetracycline-treated groups. Children had the highest levels of IL-6, which were not neurotoxic.

Experimental study on the possibility of treatment of some hemorrhagic fevers.

After intracerebral challenge with 100 PFU of Lassa virus (strain Josiah), all infected mice (CBA/calac) died (control group). Production of pro-inflammatory cytokines (IL-1beta, TNF-alpha) significantly increased in the blood of these mice during the infection. For neutralization of increasing concentrations of these cytokines recombinant IL-1RA was used intraperitonealy at a dose 100 microg kg(-1), everyday, within 5 days from the third day after the challenge. Injections of IL-1RA decreased the concentration of IL-1beta and TNF-alpha and resulted in survival of all infected mice (treatment group). Marburg fever (strain Popp) caused in guinea pigs by 5 LD(50) of virus lead to the significant increase of TNF-alpha in the animal's blood and caused a lethal outcome (control group). Treatment of infected guinea pigs by IL-1RA or anti-TNF serum decreased the concentration of TNF-alpha and resulted in survival of half of the animals (treatment group). For the treatment recombinant IL-1RA was used at a dose 100 microg kg(-1), intramuscularly, everyday, within 6 days from the third day after the challenge or anti-TNF serum, intramuscularly 0.5 ml (2000 U ml(-1); 1 U of the antiserum neutralises 0.03 ng of TNF-alpha), everyday, within 6 days from the third day after the challenge.

Comparative investigation of the long non-coding M-F genome region of wild-type and vaccine measles viruses.

The sequence of the 300 nucleotides region of the measles virus genome was determined that includes a part of the 3'-untranslated region of the matrix (M) gene, the intergenic region and a part of the 5'-untranslated region of the fusion (F) gene [M-F region] for vaccine strain Leningrad-16 and 14 wild-type isolates. The data obtained demonstrate the variability of this long non-coding M-F region. No mutations in this region of the genome were found which seem to be specific for vaccine strains of measles virus (MV).

Immunization with recombinant vaccinia viruses expressing structural and part of the nonstructural region of tick-borne encephalitis virus cDNA protect mice against lethal encephalitis.

Three recombinant vaccinia viruses containing different fragments of tick-borne encephalitis virus (TBEV) cDNA representing the 5'-noncoding region (5'NCR), all structural and part of the nonstructural regions were constructed. Western blot analysis showed that E and NS1 proteins were expressed and processed correctly in cells infected with recombinant viruses vC-NS1 (coding for C-prM-E-NS1 region) and vC-NS3 (coding for C-prM-E-NS1-NS2A-NS2B-NS3 region). In contrast, in cells infected with recombinant virus v5'C-NS2A (coding for 5'NCR and C-prM-E-NS1-NS2A regions) expression of NS1 protein was greatly reduced and no E protein was detected. Immunization of mice with vC-NS3 induced high levels of TBEV-specific antibodies and protected them against intraperitoneal challenge with 10(7) LD50 of TBEV. The level of protection was very similar to the level of protection achieved by immunization with commercially available inactivated TBEV vaccine. Although the immunization of mice with recombinants vC-NS1 and v5'C-NS2A induced much lower levels of TBEV-specific antibodies, they were still protected against intraperitoneal challenge with 10(4) and 10(3.6) LD50 of TBEV, respectively. The high level of protection against TBEV infection achieved by the immunization of mice with the recombinant vaccinia virus vC-NS3 makes this virus a very attractive candidate for development of a live recombinant vaccine against TBEV.

Inactivated Marburg virus elicits a nonprotective immune response in Rhesus monkeys.

In the present work the kinetics of some indices of immunity (tumor necrosis factor (TNF), interferon (IFN), natural killer cells (NK), lymphocyte proliferation activity, virus-specific antibodies, CD4/CD8 ratio) in response to Marburg virus infection in Macaca mulatta were studied. The different kinetics of immunological parameters for animals which survived Marburg virus infection and for animals which died after infection are shown. A comparison of the indices of IFN, TNF and spontaneous lymphocyte proliferation activity in Macaca mulatta infected with Marburg virus at different stages of life shows the relationship between the increase of these indices and the decrease in the animals' lifespan. Marburg virus immunosuppressive properties were corroborated by studying lymphocyte proliferation activity in response to antigenic stimulation in vitro and the CD4/CD8 index during experimental Marburg virus infection in Macaca mulatta. We conclude that the disease outcome depends on the dynamics of certain immunologic indices such as TNF and IFN.