Study of the teratogenicity of the vaccine strain of the Rubella virus «Orlov-V¼ (Matonaviridae: Rubivirus: Rubella virus) in experience on rhesus macaques.

INTRODUCTION: Rubella virus has pronounced teratogenic properties that can cause generalized and persistent intrauterine infection of the fetus. As a result, the control of the loss of teratogenicity inherent in «wild-type¼ virus strains is a necessary stage of a preclinical study of the vaccine strain for a live attenuated rubella vaccine.The purpose of the study is to comprehensively study the teratogenic properties of the vaccine strain of rubella virus «Orlov-V¼ in the experiment on rhesus macaques. MATERIAL AND METHODS: Seronegative to rubella virus female rhesus macaques in early pregnancy at the age of 4-7 years (n = 13) were used in the experiment. Animals of the experimental group (n = 9) received single immunization intramuscularly with a preparation from the «Orlov-V¼ strain. The control group of the monkeys (n = 3) were immunized with a commercial vaccine containing Wistar RA27/3 strain. The female of the control group (n = 1) was injected with a solvent used in the rubella vaccine. Study of possible teratogenic properties of vaccine strains of rubella virus was carried out using a complex of clinical, immunological, pathomorphological and virological methods. Clinical observations were made within 3 months after the monkeys' birth. Determination of antibody titers in the blood serum of immunized monkeys was performed in HI test on the 28th-30th day after infection. The ELISA method was applied to determine IgM antibodies in the blood serum of newborns within the first month of life. Detection of rubella virus RNA was performed by PCR with electrophoretic detection of amplicons. RESULTS: No markers of congenital rubella infection were found in infants born from monkeys vaccinated during the pregnancy. It is shown that PCR can be an informative method to confirm the absence of teratogenic properties of vaccine strains of rubella virus. DISCUSSION: The obtained data demonstrated that vaccine strains of the «Orlov-V¼ rubella virus and Wistar RA27/3 have lost their teratogenic properties. The possibility of using an alternative strategy for preclinical assessment of specific safety of antiviral vaccines including a complex of clinical, immunological, pathologic and virological methods instead of the classical pathologic method is discussed. CONCLUSION: The results obtained in this study showed the absence of teratogenic properties and high immunogenic activity of the vaccine strain of rubella virus «Orlov-V¼.

Clinical Manifestations, Prognosis, and Vaccination Status of Patients With Rubella Virus-Associated Uveitis.

PURPOSE: To assess the clinical and laboratory manifestations and vaccination status of uveitis patients positive for rubella virus (RV) in aqueous humor and investigate its relationship to Fuchs uveitis syndrome (FUS). METHODS: Retrospective study of all uveitis patients, positive for RV in aqueous humor analysis (polymerase chain reaction [PCR] and/or Goldmann-Witmer coefficient [GWC]) between January 2010 and October 2016 at the ophthalmology departments in the Erasmus Medical Center (Rotterdam) and University Medical Center Utrecht. Outcomes of aqueous analyses of FUS patients during this period were assessed. RESULTS: We included 127 patients (144 eyes) positive for RV in aqueous fluid: 23 (20%) by PCR, 120 (97%) by GWC, and 16 (13%) by both. The average age at first presentation was 37 years. Patients typically complained of blurred vision and exhibited a combination of unilateral anterior uveitis, keratic precipitates, vitritis, and absence of posterior synechiae, but the classical FUS was observed in a minority. The main cause of untreatable visual loss was glaucoma. Cystoid macular edema (CME) before intraocular surgery was not encountered. None of the unilateral cases developed involvement of the other eye. None of the patients was vaccinated against RV. All FUS patients, except 2 (5%), were positive for RV. CONCLUSION: RV-associated uveitis and FUS are not exchangeable. Chronic anterior uveitis, vitritis, early development of cataract, and the absence of posterior synechiae and CME characterize RV-associated uveitis. Almost all FUS cases had documented intraocular RV infection, but only some of the patients with RV-associated uveitis presented with FUS.

RUBELLA--SHOULD IT BE A PRIORITY IN THE NATIONAL IMMUNIZATION PROGRAMMES?

Rubella is a mild infection of childhood and young adults with 75% of cases occurring in age group 15-45 years. In unvaccinated populations, rubella usually occurs in spring with epidemics in 6-9 years cycles. Rubella has devastating effects on growing foetus if contracted by women in the first trimester of pregnancy. Perinatal infection of Rubella contributes to 2-3% of all congenital anomalies. Over the past three decades many resource risk countries have introduced universal or selective immunization programs against rubella with evidence that such interventions reduce the incidence of congenital rubella syndrome. In Pakistan the schedules of the Expanded Program on Immunization (EPI) do not include immunization against rubella and evidence is needed to estimate the risk of congenital rubella with a view to start immunization programmes to combat the menace of Congenital Rubella Syndrome (CRS). Logistically it is easy to add rubella vaccine to the already existing EPI schedules as measles is given on 9th and 15 month with little implications for cost, resulting in great reduction in CRS.

Insights from epidemiological game theory into gender-specific vaccination against rubella.

Rubella is a highly contagious childhood disease that causes relatively mild symptoms. However, rubella can result in severe congenital defects, known as congenital rubella syndrome (CRS), if transmitted from a mother to a fetus. Consequently, women have higher incentive to vaccinate against rubella than men do. Within the population vaccination reduces transmission but also increases the average age of infection and possibly the risk of CRS among unvaccinated females. To evaluate how the balance among these factors results in optimal coverage of vaccination, we developed a game theoretic age-structured epidemiological model of rubella transmission and vaccination. We found that high levels of vaccination for both genders are most effective in maximizing average utility across the population by decreasing the risk of CRS and reducing transmission of rubella. By contrast, the demands for vaccines driven by self-interest among males and females are 0% and 100% acceptance, respectively, if the cost of vaccination is relatively low. Our results suggest that the rubella vaccination by males that is likely to be achieved on voluntary basis without additional incentives would have been far lower than the population optimum, if rubella vaccine were offered separately instead of combined with measles and mumps vaccination as the MMR vaccine.

Rubella eradication.

The virulence of rubella virus for the fetus was fully defined between 1963 and 1965 when an epidemic of rubella occurred in Europe and the US, followed by a wave of damaged babies. Attenuated live virus vaccines were developed in our and other laboratories and their use has already considerably changed the epidemiology of rubella. Nevertheless, only about half of the world's countries vaccinate against rubella. We argue for the combination of rubella vaccine with measles vaccine in all campaigns for the control of measles, and will discuss the strategies by which congenital rubella syndrome could be eradicated at little additional cost.

The effect of live measles vaccines on serum vitamin A levels in healthy children.

OBJECTIVE: Serum retinol levels have been shown to be depressed during measles infection. This study aims to demonstrate whether there is any decrease in serum vitamin A level following immunization with live viral vaccine and its relation with vaccine seroconversion in children with measles. Since many children receive measles vaccine alone or in combination with measles-mumps-rubella vaccine, we studied serum vitamin A levels and antibody levels in healthy, well-nourished children before and after immunization with monovalent and combined live attenuated measles vaccine. METHODS: The first group included 21 healthy children between the ages of 9-11 months who received live measles (Schwarz) vaccine. There were also 21 healthy children (range 14-20 months of age) who received measles-mumps-rubella Trimovax (Pasteur Merieux) vaccine. All children were tested for serum vitamin A levels before vaccination, on days 9-14 and 30-42 following both vaccinations. Measles specific antibody levels were also measured on admission and 30-42 days following vaccinations. RESULTS: In both vaccination groups, mean serum vitamin A levels reduced significantly on days 9-14, but increased slightly on days 30-42 in the measles-mumps-rubella vaccinated group (P < 0.05). The baseline and follow-up levels of mean serum vitamin A did not differ between seroconverted and nonseroconverted cases within the measles vaccinated group. CONCLUSION: Serum vitamin A levels are reduced following vaccination with monovalent and combined live attenuated measles vaccines.

WHO activities towards the three Rs in the development and control of biological products.

WHO supports the concept of replacement, reduction and refinement of the use of in vivo methods for biologicals production and control, and regularly conducts reviews of its recommended procedures to allow reduction in the use of animals. The coordination of collaborative studies, publication of standardized methods, and holding of workshops on the use of these methods contributes to their use. The neurovirulence test for oral poliovaccine is probably the single most visible animal test for which alternative methods are sought. Collaborative studies on alternative methods for screening products are currently being sponsored by WHO. The use of Vero cells rather than primary monkey kidney cells for poliovaccine production can avoid the use of many monkeys. Cell banks of Vero and HEp-2 cells have been developed by WHO, tested for virus sensitivity and freedom from adventitious agents, and are available for vaccine production and control, replacing primary animal cells. For the future, final product testing will increasingly be directed towards establishment of consistency of production rather than potency. By supporting the validation and use of this approach, WHO can effectively influence more rational animal use in biological production and control.

Quality standard for assurance of measles immunity among health care workers. Infectious Diseases Society of America.

OBJECTIVE: The objective of this quality standard is to prevent nosocomial transmission of measles by assuring universal measles-mumps-rubella (MMR) vaccination of all health care workers who lack immunity to measles. Although the primary emphasis is on health care workers in hospitals, those at other sites, such as clinics, nursing homes, and schools, are also included. It will be the responsibility of designated individuals at these institutions to implement the standard. OPTIONS: We considered advocating the use of measles vaccine rather than MMR vaccine but chose the latter because it also protects against mumps and rubella and because it is more readily available. OUTCOMES: The desired outcome is a reduction in the nosocomial transmission of measles. EVIDENCE: Although direct comparative studies are lacking, nosocomial outbreaks of measles have been reported (as recently as 1992) in institutions where measles immunization of nonimmune health care workers is not universal, whereas such outbreaks have not been reported in institutions with universal immunization. VALUES AND VALIDATION: We consulted more than 50 infectious-disease experts from the fields of epidemiology, government, medicine, nursing, obstetrics and gynecology, pediatrics, and surgery. In light of disagreement regarding the implementation of the standard, we used group discussions to reach a consensus. BENEFITS, HARMS, AND COSTS: The consequences of the transmission of measles (and of mumps and rubella) in a health care institution include not only the morbidity and mortality attributable to the disease but also the significant cost of evaluating and containing an outbreak and the serious disruption of regular hospital routines when control measures are instituted. The potential harm to health care workers after the implementation of the standard consists of untoward effects of MMR vaccine, although the reactions of vaccinees should be minimal with adherence to recommended vaccination procedures. Implementation of the standard should entail no expense to health care workers; the precise cost to institutions is unknown, but the expense would be mitigated by the prevention of measles outbreaks. RECOMMENDATIONS: We recommend MMR vaccination of all health care workers who lack immunity to measles. SPONSORS: The Quality Standards Subcommittee of the Clinical Affairs Committee of the Infectious Diseases Society of America (IDSA) developed the standard. The subcommittee was composed of representatives of the IDSA (P.A.G. and J.E.M.), the Society for Hospital Epidemiology of America (R.P.W.), the Surgical Infection Society (E.P.D.), the Pediatric Infectious Diseases Society (P.J.K.), the Centers for Disease Control and Prevention (W.J.M.), the Obstetrics and Gynecology Infectious Diseases Society (R.L.S.), and the Association of Practitioners of Infection Control (T.L.B.). Funding was provided by the IDSA and the other cooperating organizations. The standard is endorsed by the IDSA.

Influence of MPR revaccination on tuberculin and sensitin skin reactions in children.

Many viral diseases, as well as viral vaccines, have a transient effect in depressing cell-mediated immunity. The study group consisted of 52 children, aged 6.0-6.3 years. Thirty (57%) of them had been revaccinated against measles, parotitis and rubella (MPR vaccination). In MPR-revaccinated children, the mean skin reaction sizes were 4.7 mm, 4.1 mm, 4.3 mm and 2.1 mm to tuberculin, Mycobacterium avium, M. scrofulaceum and M. fortuitum sensitins, respectively. In non-revaccinated children (n = 22), the respective mean skin reaction sizes were 3.0 mm, 2.8 mm, 2.9 mm and 0.8 mm. The difference between re- and non-revaccinated children was statistically significant with regard to reactions to M. fortuitum sensitin (p < 0.05). These results suggest that the influence of viral revaccination is different from natural infection or primary vaccination. The mechanism of stimulation of cell-mediated immunity--either specific or non-specific--is unknown.

Prior infection by respiratory syncytial virus or parainfluenza viruses augments virus-specific IgG responses induced by the measles/mumps/rubella vaccine.

We found previously that immunizing cyclophosphamide-treated mice with one Paramyxoviridae virus mixed with dimethyl dioctadecyl ammonium bromide induces T cells which apparently also recognize other Paramyxoviridae viruses. This finding and the fact that respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) infect children early in life led us to ask if prior RSV or PIV infections influence the antibody response to measles and mumps vaccine viruses. Detection of virus-specific IgG in serum specimens collected randomly or at defined times after measles/mumps/rubella (MMR) vaccination was done with solid-phase enzyme immunoassays. The antibody-binding data obtained were converted to serum antibody titers by an immunoassay curve-fitting computer program. Prior infection by RSV and PIVs correlated with an augmented IgG response not only to measles and mumps virus, but also to rubella virus. Furthermore, the augmentation was greater for responders below the median response. These data show that common early childhood viral infections can influence immunity induced by the MMR vaccine.

Interference of immune globulin with measles and rubella immunization.

Passively acquired antibody may interfere with the active antibody response to live viral vaccines such as measles and rubella. To evaluate the duration of this inhibitory effect, we measured the measles and rubella antibody responses of Apache children immunized with measles, mumps, and rubella vaccine at varying intervals after administration of an immune globulin termed bacterial polysaccharide immune globulin (BPIG). This specific immune globulin contained measles and rubella antibody titers similar to those in standard intramuscularly and intravenously administered immune globulins. Antibody responses to measles vaccine were inhibited for up to 5 months after a BPIG dose of 80 mg IgG per kilogram of body weight, but responses to rubella vaccine were inhibited for only 2 months. Most children who had a decreased measles antibody response to primary measles, mumps, and rubella immunization given 1 1/2 to 4 months after BPIG administration responded to a booster immunization given 6 months after their last BPIG dose. We conclude that high doses of immune globulin (> 10 mg/kg) may inhibit the antibody response to measles for more than 3 months. We propose that the interval between administration of immune globulin and measles and rubella immunization be adjusted on the basis of the dose of immune globulin.

Vacunación antirrubéolica: la vacuna y las estrategias / Vaccination antimeasles: the vaccine and the strategies

Las primeras vacunas utilizadas para uso generalizado fueron las elaboradas con las cepas HPV77 y la Cendehill en 1969. A partir de entonces diversas vacunas han estado disponibles en el mercado, pero la de uso más generalizado es la preparada con la cepa RA27/3 cultivada en células diploides humanas que es más inmunogénica y estimula tanto la producción de anticuerpos humorales como secretorios, todo ello sin que se presente un incremento de los efectos colaterales indeseables. La vacuna antirrubéolica existe en tres presentaciones: sola o asociada con otras, la viral doble (rubéola-sarampión) y la viral triple (rubéola-sarampión-parotiditis). En las tres formas la dosis es de 0.5 mL, se prepara en forma liofilizada y debe guardarse en refrigeración (entre 2§C y 8§C) antes de su reconstrucción. Una vez reconstruida debe aplicarse antes de ocho horas. En relación con la vacunación antirrubéolica, existen varias posibles estrategias. Las más importantes son: 1.No incluir a la vacuna contra la rubéola en los programas nacionales de vacunación. 2.Vacunar a todos los suceptibles mayores de un año de edad con énfasis en niños, adolescentes y mujeres adultas. 3.Vacunar a todas las niñas de 11 a 14 años de edad. Y 4.vacunar a grupos específicos: mujeres adultas rubéola-seronegativas, mujeres en el post-parto y personal médico y paramédico principalmente

Interferon-gamma production closely related to antibody production in lymphocyte cultures stimulated with mumps virus.

Enzyme-linked immunosorbent assay (ELISA) antibody to mumps virus and virus specific interferon (IFN)-gamma production were investigated in lymphocyte cultures stimulated with mumps virus before and after immunization with live mumps vaccine. Synthesis of immunoglobulin (Ig) M but not Ig G was enhanced after vaccination. Spontaneous production of mumps ELISA antibodies in lymphocyte culture increased after vaccination and substantially higher levels of antibodies were produced when lymphocytes were stimulated with mumps virus after vaccination. The production of mumps ELISA antibodies was closely related to IFN-gamma production (r = 0.326, p less than 0.01) but not to IFN-alpha production (r = 0.084, p greater than 0.05).

2',5'-Oligoadenylate synthetase and interferon in peripheral blood after rubella, measles, or mumps live virus vaccine.

The temporal activation of the human interferon system by infection with virus was studied by serial measurements of both interferon in serum and activity of 2',5'-oligo adenylate synthetase in peripheral mononuclear leukocytes. A frequency distribution of baseline values of synthetase was established for normal individuals. Following subcutaneous inoculation of rubella vaccine virus, serum interferon rose briefly with a peak on Day 14. The peak concentration of synthetase also occurred on Day 14 but remained elevated for greater than 1 week. After measles virus, serum interferon did not rise above baseline, but synthetase peaked on Day 14 and remained elevated. Subcutaneous inoculation of mumps vaccine virus was associated with a brief period of elevation of the synthetase and no interferon in the serum. Thus, the determination of synthetase levels in tissue may be useful in some situations to reflect a small or transient elevation of endogenous interferon.

A comparison of the reactivity and immunogenicity of RA 27/3 strain rubella vaccine prepared in WI-38 or MRC5 human diploid cells.

The immunogenicity and clinical reactivity of rubella vaccine derived from WI-38 or MRC5 human diploid cells was compared in 125 seronegative adolescent females. Seroconversion rates, assessed by single radial haemolysis testing of paired pre- and post-vaccination samples exceeded 98% (56/57 and 68/68 vaccinees, respectively) for both vaccines. Quantitative assessment of rubella-specific antibodies in 53 post-vaccination sera by an ELISA technique also failed to reveal any difference in immunogenicity between the vaccines. Assessable calendar records documenting the occurrence of local and systemic signs and symptoms in the four weeks following vaccination were returned by 106 subjects. No important statistically significant difference in parameters of clinical reactivity between the vaccine groups was observed although the incidence of pain at the injection site was found to be significantly higher for vaccinees receiving WI-38 derived vaccine.

Influence of several bacterial and viral vaccines on hepatic drug metabolism in mice.

Pentobarbital-induced sleeping time was found to be significantly prolonged in mice within at least 4 days following either whooping cough, tetanus, rubella or poliomyelitis vaccination. By contrast, barbital-induced sleeping time remained unaffected, These findings provide further evidence of a correlation between inhibition of liver drug metabolizing enzymes and stimulation of the immune response.

Interferon-induced 2-5A synthetase activity in human peripheral blood mononuclear cells after immunization with influenza virus and rubella virus vaccines.

The interferon-induced enzyme 2-5A synthetase can be a sensitive indicator of activation of the human interferon system during viral infection or interferon therapy. To determine the response of the human interferon system to viral antigens, the level of 2-5A synthetase activity was monitored in peripheral blood mononuclear cells of healthy adults before and after immunization with influenza or rubella virus vaccine. The influenza virus-vaccinated individuals demonstrated increases in enzyme activity on days 1 and 11 in vivo, whereas those vaccinated with rubella virus vaccine showed an increase only on day 11. The difference in the day 1 in vivo 2-5A synthetase response in the two vaccinated groups could be demonstrated by in vitro incubations of peripheral blood mononuclear cells isolated approximately 90 days postvaccination with the two vaccines. The day 11 increase of enzyme activity in the rubella virus group showed a positive correlation with an increase in serum antibody titer, suggesting activation of the interferon system during antibody production in vivo after human exposure to virus antigens. The demonstration of increased 2-5A synthetase activity at specific times postimmunization in this investigation indicates that the interferon system is involved in the human in vivo response to virus vaccination.

[Studies on rubella vaccination in adult females. II: Hormonal influence on clinical reactions].

All rubella vaccines may, on occasion, cause mild and transient clinical reactions, especially joint symptoms, which occur most commonly in females with increase in frequency and severity with advancing age. These facts suggested the role of hormonal influences. To clarify the role of hormonal influences on the development of clinical reactions, 110 vaccinees, aged 18-30 years (mean age; 20.9 year), who received TO-336 vaccine were examined for their menstrual cycles and basal body temperature (BBT). Clinical reactions were noticed in 33 cases (30.0%), including 26 cases with joint symptoms, 12 cases with lymphadenopathy and 1 case with a rash. Clinical reactions, especially joint symptoms, were observed significantly more often in vaccinees when the vaccine was given at the high phase on BBT than in vaccinees when the vaccine was given at the low phase on BBT. Serum progesterones were radioimmunoassayed at an interval of 7 days for 6 weeks after vaccination in 88 vaccinees (80.0%) of 110. Clinical reactions, especially joint symptoms, occurred more commonly in vaccinees who received vaccine at the progestational stage than in vaccinees who received it at the estrogenic and menstrual stages. But there was not a significant difference of progesterone levels between the reaction group and non-reaction group who received vaccine at the progestational stage. These results mentioned above were confirmed at any age groups; 18-20, 21-25 and 26-30 year of age. But there was not a significant difference of antibody response by the stage when the vaccine was given. Initial clinical reaction occurred commonly at the menstrual stage. According to the periods of the hormonal stage, clinical reactions, especially joint symptoms, occurred more commonly at the menstrual stage, but least commonly at the progestational stage.

[Evaluation of the effects of active rubella vaccination. Comparative studies of the evaluation of seroconversion using the ELISA technic and the hemagglutination inhibition test]. / Zur Beurteilung des Impferfolgs nach aktiver Röteln-Impfung. Vergleichende Untersuchung zur Bewertung der Serokonversion mittels ELISA-Technik und Hämagglutinationshemmtest.

31 women were vaccinated with attenuated rubella-virus (RV) strains. According to the prevaccinal antibody status they were grouped as follows: I: HIT 1: less than 10, RV-specific IgG 1: less than 20; II: HIT 1: less than 10, RV-specific IgG 1: greater than 20; III: HIT 1: greater than or equal to 10, RV-specific IgG 1: greater than 30. The postvaccinal geometric mean titers for RV-ELISA-IgG were somewhat higher in group II compared to group I, eventually because of a weak booster effect based on low level prevaccinal RV-antibody titers--but the difference is not significant for 5%. The difference between RV-ELISA-IgG in group II and group I is significant. Within group II there is a low titer rise upon vaccination although elevated prevaccinal titers were already present. The quotient "RV-ELISA-IgG-titer: HIT-titer" is in the range of greater than or equal to 23:1 for the postvaccinal period (8-10 weeks after vaccination) compared to about 8:1 resp. in stationary sera of reconvalescent individuals. These quotients could be helpful for interpretation of suspicious elevated titers during pregnancy.