Economic evaluation of Haemophilus influenzae type b vaccination in Moscow, Russian Federation.

OBJECTIVE: To estimate the cost-effectiveness of providing Haemophilus influenzae type b (Hib) vaccine to children in Moscow in routine immunization services. METHODS: The incidence of Hib meningitis among children aged <5 years in Moscow was obtained from a prospective surveillance study undertaken during October 1999-September 2001, with treatment cost data collected for all cases. Sequelae in surviving children were assessed in December 2002. The costs of Hib vaccination in Moscow were estimated assuming a vaccine price of US dollar 5 per dose and the same four-dose schedule and 97% coverage as for diphtheria-tetanus-pertussis vaccine. The most uncertain variables were varied in a sensitivity analysis. RESULTS: The annual incidence of Hib meningitis was 5.7 per 100,000 children <5 years. The average treatment cost for an acute Hib meningitis case was US dollar 1296. For a patient with sequelae, the average additional lifetime discounted treatment cost was US dollar 15,820. The total annual cost of Hib vaccination of infants in Moscow was estimated as US dollar 1.5 million per year. In the base case analysis, the cost-effectiveness ratios amount to US dollar 77,503 per Hib meningitis case averted and US dollar 10,842 per discounted disability adjusted life year averted. The break-even vaccine price, where the annual vaccination costs equal annual treatment costs averted, is only US dollar 0.04 per dose in the base case scenario. If discounted indirect costs are included, the break-even vaccine price is US dollar 0.5 per dose. CONCLUSION: In Moscow, the incidence of Hib meningitis is low and the costs of hospitalization and subsequent medical treatment are relatively inexpensive. Given these factors, Hib vaccine at US dollar 5 per dose would not be a cost-effective option in Moscow at the present time.

The WHO Vaccine Trial Registry.

The WHO Vaccine Trial Registry prospectively registers clinical vaccine studies supported by WHO. Through December 1999, the registry includes 103 studies from 43 countries, with nearly 80% in developing countries. The registry documents an expanding research capacity, with an average of 3.9 new studies per year during 1987-1993, rising to 10.7 per year during 1994-2000. The studies concern a broad spectrum of infectious organisms, including: Clostridium tetani (tetanus), dengue virus, enterotoxigenic Escherichia coli (ETEC), Haemophilus influenzae type b (Hib), hepatitis B virus, measles virus, Mycobacterium tuberculosis, Neisseria meningitidis (meningococcus), poliovirus, respiratory syncytial virus (RSV), rotavirus, Salmonella typhi, Shigella, Streptococcus pneumoniae (pneumococcus), and Vibrio cholerae.

Suppression of IL-2-induced T cell proliferation and phosphorylation of STAT3 and STAT5 by tumor-derived TGF beta is reversed by IL-15.

IL-2 responses are susceptible to suppression by TGFbeta, a cytokine widely implicated in suppression of inflammatory responses and secreted by many different tumor cell types. There have been conflicting reports regarding inhibition of IL-2-induced STAT3 and STAT5 phosphorylation by TGFbeta and subsequent suppression of immune responses. Using TGFbeta-producing multiple myeloma tumor cells we demonstrate that tumor-derived TGFbeta can block IL-2-induced proliferation and STAT3 and STAT5 phosphorylation in T cells. High affinity IL-2R expression was required for the suppression of IL-2 responses as a novel CD25(-) T cell line proliferated and phosphorylated STAT3 when cultured with tumor cells or rTGFbeta1. Activating T cells with IL-15, which does not use the high affinity IL-2R, completely restored the ability of T cells to phosphorylate STAT3 and STAT5 when cultured with tumor cells. IL-15-treated T cells proliferated normally when cocultured with tumor cells or rTGFbeta1, whereas IL-2 responses were consistently inhibited. Preincubation with IL-15 also restored the ability of T cells to respond to IL-2 by phosphorylating STAT3 and STAT5, and proliferating normally in the presence of tumor cells. IL-2 pretreatment did not restore T cell function. IL-15 also restored T cell responses by T cells from multiple myeloma patients, and against freshly isolated bone marrow tumor samples. Thus, activation of T cells by IL-15 renders T cells resistant to suppression by TGFbeta1-producing tumor cells and rTGFbeta1. This finding may be exploited in the design of new immunotherapy approaches that will rely on T cells avoiding tumor-induced suppression.

Trial of a supplemental dose of four poliovirus vaccines.

BACKGROUND: The immunogenicity of oral poliovirus vaccine (OPV), particularly the type 3 component, is lower in infants in most developing countries than in infants in industrialized countries. We conducted a multicenter trial in Oman to evaluate the response to a supplemental dose of four poliovirus vaccine formulations. METHODS: At nine months of age, infants were randomly assigned to receive inactivated-poliovirus vaccine (IPV), administered subcutaneously; trivalent OPV manufactured in the United States or in Europe; or monovalent type 3 OPV. Serum samples were collected at enrollment and 7 and 30 days later. All of the infants had previously received five doses of OPV. RESULTS: We enrolled 1025 infants; 785 (76.6 percent) met all the study requirements. At enrollment, 96.8 percent of the infants were seropositive for poliovirus type 1, 98.0 percent for type 2, and 88.0 percent for type 3. At 30 days there were no significant increases in type 3 seroprevalence or in the median antibody titer in the groups of infants who received OPV. Among the recipients of IPV, type 3 seroprevalence increased from 87.8 percent at enrollment to 97.1 percent at 30 days (P<0.001), and the median antibody titer increased from 1:228 to 1:1448 or higher (P<0.001). The rapid initial increase in the antibody titer suggests a secondary immune response. CONCLUSIONS: A supplemental dose of IPV has excellent immunogenicity and leads to increases in the titer of antibodies against type 3 poliovirus, whereas supplemental doses of the oral vaccines do not have these effects.

Genetic characterization of the 44D-45B region of the Drosophila melanogaster genome based on an F2 lethal screen.

We have performed an F2 genetic screen to identify lethal mutations that map to the 44D-45B region of the Drosophila melanogaster genome. By screening 8500 mutagenized chromosomes for lethality over Df(2R)Np3, a deficiency which encompasses nearly 1% of the D. melanogaster euchromatic genome, we recovered 125 lines with lethal mutations that represent 38 complementation groups. The lethal mutations have been mapped to deficiencies that span the 44D-45B region, producing an approximate map position for each complementation group. Lethal mutations were analyzed to determine the phase of development at which lethality occurred. In addition, we have linked some of the complementation groups to P element-induced lethals that map to 44D-45B, thus possibly providing new alleles of a previously tagged gene. Some of the complementation groups represent potentially novel alleles of previously identified genes that map to the region. Several genes have been mapped by molecular means to the 44D-45B region, but do not have any reported mutant alleles. This screen may have uncovered mutant alleles of these genes. The results of complementation tests with previously identified genes in 44D-45B suggests that over half of the complementation groups identified in this screen may be novel.

germ cell-less is required only during the establishment of the germ cell lineage of Drosophila and has activities which are dependent and independent of its localization to the nuclear envelope.

The germ cell precursors of Drosophila (pole cells) are specified by maternally supplied germ plasm localized to the posterior pole of the egg. One component of the germ plasm, germ cell-less (gcl) mRNA, encodes a novel protein which specifically localizes to the nuclear envelope of the pole cell nuclei. In addition to its maternal expression, gcl is zygotically expressed through embryonic development. In this report, we have characterized a null allele of germ cell-less to determine its absolute requirement during development. We have found that gcl activity is required only for the establishment of the germ cell lineage. Most embryos lacking maternal gcl activity fail to establish a germline. No other developmental defects were detected. Examination of germline development in these mutant embryos revealed that gcl activity is required for proper pole bud formation, pole cell formation, and pole cell survival. Using this null mutant we have also assayed the activity of forms of Gcl protein with altered subcellular distribution and found that localization to the nuclear envelope is crucial for promoting pole cell formation, but not necessary to initiate and form proper pole buds. These results indicate that gcl acts in at least two different ways during the establishment of the germ cell lineage.

Mumps and mumps vaccine: a global review.

Mumps is an acute infectious disease caused by a paramyxovirus. Although the disease is usually mild, up to 10% of patients can develop aseptic meningitis; a less common but more serious complication is encephalitis, which can result in death or disability. Permanent deafness, orchitis, and pancreatitis are other untoward effects of mumps. Based on data reported to WHO up to April 1998, mumps vaccine is routinely used by national immunization programmes in 82 countries/areas: 23 (92%) of 25 developed countries, 19 (86%) of 22 countries with economies in transition (mainly the Newly Independent States of the former Soviet Union), and 40 (24%) of 168 developing countries. Countries that have achieved high coverage have shown a rapid decline in mumps morbidity. Furthermore, in many of these countries, mumps-associated encephalitis and deafness have nearly vanished. This review considers the disease burden due to mumps; summarizes studies on the immunogenicity, efficacy, and safety of different strains of mumps vaccine; and highlights lessons learned about implementing mumps immunization in different countries. Countries already using mumps vaccine should monitor immunization coverage and establish routine mumps surveillance with investigation of outbreaks. Where mumps is targeted for elimination, countries need to add a second dose of mumps vaccine for children, keeping in mind that the disease may still occur in susceptible adults.

PIP: Mumps is an acute infectious disease caused by a paramyxovirus. While the disease is usually mild, up to 10% of patients can develop aseptic meningitis. A less common but more serious complication is encephalitis, which can result in death or disability. Permanent deafness, orchitis, and pancreatitis are other adverse effects of mumps. Based upon data reported to the World Health Organization (WHO) up to April 1998, mumps vaccine is routinely used by national immunization programs in 82 countries/areas: 23 of 25 developed countries, 19 of 22 countries with economies in transition, and 40 of 168 developing countries. Countries which have achieved high vaccine coverage have realized a rapid decline in mumps morbidity. Also in many such countries, mumps-associated encephalitis and deafness have almost vanished. The authors consider the disease burden due to mumps; summarize studies on the immunogenicity, efficacy, and safety of different strains of mumps vaccine; and note lessons learned about implementing mumps immunization in different countries. Countries already using mumps vaccine should monitor immunization coverage and establish routine mumps surveillance with investigation of outbreaks. Where mumps is targeted to be eliminated, countries need to add a second dose of mumps vaccine for children.

Registro de ensayos con vacunas del Programa Mundial de Vacunas e Inmunización de la OMS / The WHO Global Programme for Vaccines and Immunization Vaccine Trial Registry

En 1995, el Programa Mundial de Vacunas e Immunización de la OMS estableció un registro para ensayos con vacunas. En septiembre de 1996, este registro contenía 50 ensayos de vacunación patrocinados por la OMS, de los cuales 25 (50 por cien) eran estudios ya terminados. Las vacunas que se habían estudiado con mayor frecuencia fueron las de sarampión (9 ensayos), poliovirus (8 ensayos), cólera (8 ensayos), Escherichia coli enterotoxígena (4 ensayos) y neumococo (4 ensayos). Casi 80 por cien de estos ensayos se llevaron a cabo en países en desarrollo, principalmente en el Africa. En los 25 ensayos ya terminados, los resultados investigados fueron la respuesta inmunitaria (24 ensayos), las reacciones adversas (13 ensayos), la morbilidad (4 ensayos) y la mortalidad (1 ensayo). La OMS contribuyó a estos ensayos con el aporte indirecto de fondos, ayuda con el diseño metodológico, visitas a las localidades, el análisis de los datos, la adquisición de vacunas y la investigación de su potencia

Registro de ensayos con vacunas del Programa Mundial de Vacunas e Inmunización de la OMS / The WHO Global Programme for Vaccines and Immunization Vaccine Trial Registry

En 1995, el Programa Mundial de Vacunas e Immunización de la OMS estableció un registro para ensayos con vacunas. En septiembre de 1996, este registro contenía 50 ensayos de vacunación patrocinados por la OMS, de los cuales 25 (50 por cien) eran estudios ya terminados. Las vacunas que se habían estudiado con mayor frecuencia fueron las de sarampión (9 ensayos), poliovirus (8 ensayos), cólera (8 ensayos), Escherichia coli enterotoxígena (4 ensayos) y neumococo (4 ensayos). Casi 80 por cien de estos ensayos se llevaron a cabo en países en desarrollo, principalmente en el Africa. En los 25 ensayos ya terminados, los resultados investigados fueron la respuesta inmunitaria (24 ensayos), las reacciones adversas (13 ensayos), la morbilidad (4 ensayos) y la mortalidad (1 ensayo). La OMS contribuyó a estos ensayos con el aporte indirecto de fondos, ayuda con el diseño metodológico, visitas a las localidades, el análisis de los datos, la adquisición de vacunas y la investigación de su potencia

[Wide spread inflammation of the parotid glands (mumps): underestimated disease. I. Epidemiology of the mumps and its medical meaning in Poland]. / Nagminne zapalenie przyusznic (swinka)--niedoceniona choroba. I. Epidemiologia swinki i jej zdrowotne znaczenie w Polsce.

Mumps is commonly considered a "mild" infectious disease in children because death due to mumps is very rare. However, mumps causes a high rate of complications in young adults, and its burden should not be underestimated. Before the introduction of vaccine, mumps was a common infectious disease with high incidence rates which exceeded 100 per 100,000 population in most countries. Poland continues to belong to the group of countries, which do not use mumps vaccine. In Poland, the number of reported mumps cases per year ranges from 40,000 to 220,000, yielding an annual incidence rates of 110 and 570 per 100,000 population. It is estimated that each year in Poland, mumps causes 1000 cases of aseptic meningitis (range 400 to 2,200), 100 cases of encephalitis, 250 to 1375 cases of epidymo-orchitis in post-pubertal men, 50-275 cases of oophoritis in women. The age distribution of mumps cases is characteristic for a country that does not use mumps vaccine. For more that 20 years, the highest mumps incidence has occurred in children aged 5-9 years. In many countries the number of reported cases has declined significantly following the introduction of mumps vaccine, and in several countries the incidence has fallen to less than 1 per 100,000 population. Several countries using mumps vaccine have reported a shift in the age distribution of mumps cases, with an increased incidence in older children and young adults. Countries with high levels of coverage with measles-mumps-rubella (MMR) vaccine have nearly eliminated encephalitis associated with these diseases. A few countries using mumps vaccine have experienced relative resurgence of the disease, either due to incomplete vaccine coverage of certain age groups (USA) or problems with the long-term immunogenicity of mumps vaccine based on the Rubini strain (Portugal, Switzerland).

[Wide-spread inflammation of the parotid glands (mumps): an underestimated disease. II. Development, use, efficacy and safety of mumps vaccines]. / Nagminne zapalenie przyusznic (swinka)--niedoceniona choroba. II. Stosowanie, skutecznosc i bezpieczenstwo szczepionki przeciw swince.

Effective attenuated live virus mumps vaccines have been available for more than 30 years. Vaccine strains have been developed on various cell culture systems; the attenuated mumps virus strain most commonly used is the Jeryl Lynn strain. Various vaccines differ in their immunogenicity, efficacy and associated adverse events. It is estimated that the immunization coverage needed to block the transmission of mumps virus is at least 70%. Models indicate that low to moderate levels of mumps vaccine coverage may actually increase the number of susceptibles and the number of cases in older age groups. Benefit-cost analyses in a number of countries have found that the introduction of mumps vaccine is economically justifiable, as vaccination can avert the considerable medical and economic costs associated with mumps morbidity. Countries that do not immunize against mumps continue to register high mumps morbidity, and pay a high toll from neurological and other complications of mumps. Poland, which already has a high level of measles vaccine coverage, should make efforts to replace monovalent measles vaccine with trivalent measles-mumps-rubella (MMR) vaccine.

Spatial expression dynamics of Men-9 delineate the third floral whorl in male and female flowers of dioecious Silene latifolia.

Sex determination in Silene latifolia is controlled by heteromorphic sex chromosomes. Female flowers have five fused carpels and ten arrested stamen primordia. The male-determining Y chromosome overrides female development to suppress carpel formation and promote stamen development. The isolation and characterization of two S. latifolia. Male enhanced cDNAs, Men-9a and Men-9b, which probably represent different alleles of a novel gene are reported here. Men-9a and Men-9b share 91.8% coding sequence nucleotide identity, yet only 85.4% amino acid identity. The Men-9 cDNAs are related to the previously reported MROS3 cDNA from S. latifolia. However, MROS3 is not present in the S. latifolia population used in these studies and the expression dynamics of Men-9a and Men-9b contrast dramatically with those reported for MROS3. Men-9 cDNAs are expressed primarily in anthers of young male flowers, with highest expression in 1-2 mm buds. Men-9 expression is also observed at a low level in female flowers. In situ hybridization analysis reveals two phases of Men-9 expression. The first phase is during a common stage of early stamen development in male and female flowers prior to stamen arrest in female flowers. The second phase of Men-9 expression is maximal in the epidermis and endothecium of Y chromosome- and Ustilago violacea-induced stamens; expression in male and female flowers extends to the epidermis of the staminal nectaries with strict boundaries at the second and fourth whorls, Men-9 gene expression therefore delineates the boundaries of the third floral whorl in S. latifolia flowers.

Sex determination in dioecious Silene latifolia. Effects of the Y chromosome and the parasitic smut fungus (Ustilago violacea) on gene expression during flower development.

We have embarked on a molecular cloning approach to the investigation of sex determination in Silene latifolia Poiret, a dioecious plant species with morphologically distinguishable sex chromosomes. One of our key objectives was to define a range of genes that are up-regulated in male plants in response to Y chromosome sex-determination genes. Here we present the characterization of eight male-specific cDNA sequences and classify these according to their expression dynamics to provide a range of molecular markers for dioecious male flower development. Genetically female S. latifolia plants undergo a partial sex reversal in response to infection by the parasitic smut fungus Ustilago violacea. This phenomenon has been exploited in these studies; male-specific cDNAs have been further categorized as inducible or noninducible in female plants by smut fungus infection. Analysis of the organ-specific expression of male-specific probes in male and female flowers has also identified a gene that is regulated in a sex-specific manner in nonreproductive floral tissues common to both male and female plants. This observation provides, to our knowledge, the first molecular marker for dominant effect of the Y chromosome in nonreproductive floral organs.

Enhanced co-stimulatory ability of synovial fluid accessory cells in rheumatoid arthritis.

We have established in vitro assays that allow the examination of co-stimulatory function of rheumatoid arthritis (RA) antigen-presenting cells (APC). Synovial fluid (SF) and peripheral blood (PB) APC co-stimulatory ability was compared in the activation of peptide-specific human T-cell clones. T-cell receptor (TCR) stimulation by peptide or anti-CD3 antibody allowed the direct comparison of SF and PB APC co-stimulatory activity, separately from their ability to process antigen. SF APC from 15 RA patients consistently enhanced T-cell proliferation when compared to their PB counterparts. Moreover, increasing the numbers of PB APC present resulted in only a minor increase in T-cell proliferation, failing to achieve levels stimulated by SF APC. We propose that the enhanced co-stimulatory function of synovial APC may be a significant factor in the persistence of local immune responses in RA.

Sequential use of inactivated poliovirus vaccine followed by oral poliovirus vaccine in Oman.

Seroprevalence and geometric mean titers (GMTs) were compared at 6 and 10 months after vaccination with monovalent type 1 oral poliovirus vaccine (OPV) at 6 months and trivalent OPV at 7 and 9 months. Group 1 had received 4 doses of OPV, group 2 OPV at birth and 3 doses of OPV and inactivated poliovirus vaccine (IPV), and group 3 placebo at birth and 3 doses of IPV. A total of 547 infants completed the study. At 10 months, seroprevalence to poliovirus type 1 was 98%, 99%, and 98% in groups 1, 2, and 3; 100%, 100%, and 98% to poliovirus type 2; and 80%, 96%, and 91% to poliovirus type 3. Differences in seroprevalence among the groups were significant for poliovirus type 3 (P < .001). Between 6 and 10 months, significant increases in seroprevalence and GMTs occurred for poliovirus type 1 but not for types 2 and 3. Two OPV doses following 3 IPV doses did not significantly increase seroprevalence or raise GMTs for poliovirus types 2 and 3; however, significant increases were found for poliovirus type 1, which may have benefitted from monovalent type 1 administration.

Control of rubella and congenital rubella syndrome (CRS) in developing countries, Part 2: Vaccination against rubella.

In 1995-96 we conducted a review of rubella immunization strategies. Worldwide, 78 countries (more than one-third) reported a national policy of using rubella vaccine. This was closely related to country economic status. Based on the United Nations country classification, rubella vaccine is used in 92% of industrialized countries, 36% of those with economies-in-transition, and 28% of developing countries. Cases of congenital rubella syndrome (CRS) may be prevented as follows: by providing direct protection to women and/or schoolgirls (a selective vaccination strategy); by vaccinating boys and girls to provide indirect protection by reducing the transmission of rubella virus (a childhood vaccination strategy); or by a combination of these approaches (a combined strategy). A combined strategy was most commonly reported (60% of countries); seven countries (9%) reported a selective strategy; and 24 countries (31%) reported only childhood immunization. Experience has shown that it is essential to include vaccination of women of childbearing age in any rubella control strategy. Childhood vaccination alone may pose a risk of an increase in CRS cases. Although many countries have introduced rubella vaccine, few report any data on the impact of vaccination. Countries using rubella vaccine need to establish surveillance for rubella and CRS and monitor coverage in each of the target groups.