History of rubella virus

Postnatal rubella usually resolves without complication. Other complications of rubella, reported with much less frequency than arthritis, include encephalitis and thrombocytopenic purpura. Rubella infection acquired during pregnancy can result in stillbirth, spontaneous abortion, or several anomalies associated with the congenital rubella syndrome. The clinical features of congenital rubella vary and depend on the organ system s involved and the gestational age at the time of maternal infection Table The classic triad of congenital rubella syndrome includes cataracts, heart defects, and deafness, although many other abnormalities, as noted in the Table, may be seen.

Defects may occur alone or in combination and may be temporary or permanent. The risk of rubella-associated congenital defects is greatest during the first trimester of pregnancy. Some defects have been reported after maternal infections in the second trimester. Abnormalities Associated with Congenital Rubella Syndrome. Rubella virus is a spherical to nm, positive-sense, single-stranded RNA virus consisting of an electron-dense to nm core surrounded by a lipoprotein envelope. The virus particles are generally spherical with spiky hemagglutinin-containing surface projections.

Rubella virus is the single member of the genus Rubivirus in the family Togaviridae. It is serologically distinct from other members of the Togaviridae, and, unlike most other togaviruses, is not known to be transmitted by an arthropod.

Only one genetically stable serotype of rubella virus has been identified. Phylogenetic tree analysis of nine virus strains indicate the existence of at least three distinct genetic lineages. Rubella virus contains three major structural polypeptides: two membrane glycoproteins, E1 and E2 and a single nonglycosylated RNA-associated capsid protein, C, within the virion. One of the envelope proteins, E1, is responsible for viral hemagglutination and neutralization.

E2 has been found in two forms, E2a and E2b due to differences in glycosylation. The differences among strains of rubella viruses have been correlated with differences in the antigenicity of E2.

Humans are the only known reservoir of rubella virus, with postnatal person-to-person transmission occurring via direct or droplet contact with the respiratory secretions of infected persons. Although the early events surrounding infection are incompletely characterized, the virus almost certainly multiplies in cells of the respiratory tract, extends to local lymph nodes, and then undergoes viremic spread to target organs Fig.

Subsequent additional replication in selected target organs, such as the spleen and lymph nodes, leads to a secondary viremia with wide distribution of rubella virus. At this time approximately 7 days after infection and 7 to 10 days before the onset of rash the virus can be detected in the blood and respiratory secretions Fig. Viremia disappears shortly after the onset of rash; it is also associated with the appearance of circulating neutralizing antibodies. However, virus shedding from the respiratory tract may continue for up to 28 days following the onset of rash.

Rubella infection in the first 3 or 4 months of pregnancy provides opportunities during the period of maternal viremia for invasion of the placenta and subsequent fetal infection. Development of infection probably depends upon gestational age. It has been estimated that the fetus has a 40 to 60 percent chance of developing multiple rubella-associated defects if the mother is infected during the first 2 months of pregnancy, with the risk dropping to 30 to 35 percent during the third month of gestation and 10 percent during the fourth.

This difference in both risk for and severity of fetal infection seen with gestational age may be associated with immature host defenses during the first trimester of pregnancy. During fetal infection, the virus can multiply in and damage virtually any organ system. Pathogenesis of the congenital defects is not fully understood; however, a number of mechanisms have been proposed.

Cell culture studies show that the virus produces chromosomal abnormalities, slows cellular growth rates, and causes cell lysis and death in some cell types; these effects appear capable of producing the characteristic abnormalities of cell structure and function.

In the congenitally infected fetus and infant, virus persistence occurs in the presence of neutralizing antibodies; immunological tolerance does not develop. Postnatal infection rapidly induces a specific immune response which provides lifelong protection against the natural disease.

Neutralizing and hemagglutination-inhibiting antibodies appear shortly after the onset of rash and reach maximum levels in 1 to 4 weeks.

Specific antibodies persist after infection. Cell-mediated immunity also develops in convalescence and can be detected for years following infection. When exposed to rubella virus, individuals with neutralizing or hemagglutination-inhibiting antibodies are most often protected.

However, reinfection with rubella virus has been documented in individuals with demonstrated natural immunity and, more commonly, in vaccinees. The vast majority of such reinfections are asymptomatic, detectable only by a boost in antibody titer; however, a few cases of reinfection-associated rash and arthritis have been reported.

Rubella occurs worldwide. There have been no major epidemics in the United States since the licensure of the live attenuated rubella vaccine in However, limited sporadic outbreaks of rubella continue to occur each year, particularly in settings such as schools where susceptible individuals come into close contact.

The incidence of infection shows the same prominent seasonal pattern as for other respiratory diseases. The incidence increases in winter, peaks in spring, and then subsides to extremely low levels in summer and fall. Epidemiologic data suggest that maximum infectivity occurs from 3 days before the onset of rash until 3 days afterward. However, throat swabs from children with rubella have been reported to contain virus from as early as 10 days before the onset of rash to as late as 28 days afterward.

In addition, asymptomatic individuals have been reported to transmit rubella. In the prevaccine era, the disease usually affected children 5 to 9 years old. However, because rubella is less contagious than diseases such as measles and varicella, a significant proportion of the population 10 to 15 percent escaped rubella infection in childhood.

Widespread vaccine use has reduced rubella incidence by more than 99 percent overall Fig. Rubella is caused by a virus from the genus Rubivirus. Its symptoms include low-grade fever, respiratory problems, and most notably a rash of pink or light red spots that typically begins on the face and spreads downward. The rash occurs about two to three weeks after exposure to the virus. In children, illness from rubella infection is usually mild. Complications from rubella are more common in adults than children, and include arthritis, encephalitis, and neuritis.

A woman who contracts rubella infection during pregnancy can pass the infection to the developing fetus. Such pregnancies are at risk of spontaneous abortion or premature birth. If the fetus survives, the child may suffer from a wide range of birth defects, including deafness, eye defects, cardiac defects, mental retardation, bone lesions, and other abnormalities. The virus is spread by airborne respiratory droplets. Infected individuals may be contagious as early as a week before the appearance of the rubella rash, and for up to a week after it first appears.

It is most contagious at the time the rash first appears. Children born with CRS may transmit the virus to others for more than a year. There is no direct treatment for rubella. Supportive care may be provided, including efforts to lower fever. Rubella is not normally a serious illness in children, and, in fact, its symptoms are often mild. The chief danger of the disease is Congenital Rubella Syndrome.

From , before the development of a vaccine against the disease, a rubella epidemic swept the United States. During that short period there were Twenty thousand children were born with CRS: 11, were deaf, 3, blind, and 1, intellectually disabled.

There were 2, neonatal deaths and more than 11, abortions — some a spontaneous result of rubella infection in the mother, and others performed surgically after women were informed of the serious risks of rubella exposure during their pregnancy. Globally, about , rubella cases were reported for in the member states to the World Health Organization, though it is probable that the number of actual cases is much higher. The number of estimated CRS cases each year is more than , The first rubella vaccine—a live, attenuated vaccine—was licensed in It was developed by the prolific vaccine researcher Maurice Hilleman, using rubella virus obtained from Division of Biologics Standards scientists Paul Parkman and Harry Meyer.

Other companies in both the United States and Europe licensed their own rubella vaccines. Developed by Stanley A. It also replaced the original rubella vaccine in the MMR combined shot, and is still used today.

The World Health Organization encourages countries not currently using rubella vaccination to take advantage of widespread measles vaccination initiatives to introduce RCVs in order to advance rubella and CRS elimination. Vaccination against rubella is included on the U. This vaccine is given in two doses, the first at months of age and the second between years of age. Alternatively, rubella vaccination is available as part of the newer MMRV measles, mumps, rubella, and varicella combination vaccine, which also protects against chickenpox.

Women in the United States who are considering becoming pregnant may be tested for rubella immunity, especially if they were born in countries where rubella vaccination is not routinely performed. The cyclical nature of rubella is related to the buildup of susceptible persons in the population and contact rates.

A review of the epidemiology of rubella in Africa in the prevaccine era — found the median age of rubella IgM positive cases to be 7. Reprinted with permission from: Goodson JL, et al. Rubella epidemiology in Africa in the prevaccine era, — Journal of Infectious Diseases Suppl 1:S— Those that survive the neonatal period may face serious developmental disabilities e.

In fact, rubella is and should be considered a vaccine-preventable cause of autism. Countries with high rates of susceptibility to rubella among women of childbearing age are at highest risk for CRS. This risk varies between and within countries based on epidemiological and socioeconomic differences. Before the introduction of rubella vaccine, the incidence of CRS varied from 0.

This epidemic was associated with an estimated The basic reproductive rate R 0 for rubella has been estimated at between 3—8 in European countries and as high as 12 in crowded developing countries. This concept is supported by experience in the United Kingdom, where measles outbreaks continue to occur among adolescents born during the period of reduced public confidence in MMR vaccine due to the now disproven association between MMR and childhood autism.

While two doses are generally recommended, high coverage with a single dose appears to have been adequate to terminate transmission. Three of the six WHO regions have set control or elimination targets for rubella.

In , the WHO updated its guidance on rubella vaccine use with a clear recommendation that countries that have not yet introduced rubella vaccine should take the opportunity of accelerated measles control and elimination activities to include RCV in their immunization program. For countries newly introducing rubella vaccine, the preferred approach is to begin with a wide-age range MR campaign followed immediately with introduction of MR or MMR vaccine in the routine program — either one or two doses depending on the country schedule for measles vaccination.

This has the theoretical potential to result in an increased risk of CRS above the pre-vaccine era level. Because of their high efficacy and relatively low cost, rubella vaccines are highly cost-effective. Over the past 15 years there has been a gradual increase in the number of countries using rubella vaccine in their national immunization program. In other regions, the number of cases increased during this period in parallel with the increase in the number of countries reporting rubella cases.

Compared to model estimates, the number of reported CRS cases is very low, with reported CRS cases in versus a model-based estimate of , CRS cases in Estimates suggest that the burden of CRS in regions that had not yet introduced rubella-containing vaccination by may be very high.

For example, in , approximately 22, new cases of CRS were born in Africa uncertainty bounds: 6,—51, , and approximately 46, uncertainty bounds: 1,—, and 12, uncertainty bounds: 1,—21, new cases were born in South East Asia and the Western Pacific regions, respectively. Very few countries in these regions had introduced rubella-containing vaccination by the year , and therefore the current burden of CRS in these settings is likely to be similar to that estimated for GAVI support includes funding for an initial MR mass campaign for all children up to 15 years of age as well as a one-time grant to support introduction of RCV in the routine program.

In , six countries Bangladesh, Cambodia, Ghana, Rwanda, Senegal, Vietnam successfully applied for GAVI funding to introduce rubella vaccine and are in the process of introducing the vaccine. The new GAVI support for introduction of rubella vaccine offers the opportunity to accelerate progress toward both rubella and measles elimination by rapidly raising population immunity among children age 9 months up to 15 years who typically contribute most to virus transmission.

To ensure sufficient MR vaccine supply for the campaigns, and to allow countries not yet using RCV time to prepare for the switch to MR vaccine as part of their routine program, the roll-out is planned over an eight-year period — Full implementation of the roll-out will result in nearly 1 billion children receiving MR vaccine in the campaigns and an additional million infants receiving MR vaccine as a routine first dose Figure 3.

In measles, for example, most catch-up SIAs covered children 9 months through 14 years of age. For measles, this is usually 9 months through 4 years of age. Information is subject to change based on country decisions on when to introduce rubella vaccine in the WHO Member States. While rubella and CRS are potentially eradicable, lack of awareness and political commitment, in part due to the difficulty in documenting the true burden of CRS, as well as competing public health priorities, remain the major barriers.

At its November meeting, the Strategic Advisory Group of Experts SAGE concluded that, based on current trends and program performance, the current regional measles and rubella elimination targets except for the Americas will not be achieved on time.

Clinical specimens for the diagnosis of rubella by virus detection usually consist of throat swabs TS , oral fluids OF or nasopharyngeal secretions, and by antibody detection are usually sera or OF. The timing of specimen collection is important in postnatal rubella. Most rubella cases are virus positive on the day of rash and may be positive from seven to ten days post rash. Assays that can reliably detect 3 to 10 copies of rubella virus RNA are necessary since many specimens have small amounts of rubella RNA.

There is no cell type that reliably produces a cytopathic effect CPE in a single passage of wild-type viruses. Sequencing of the rubella virus nucleic acid amplified directly from specimens or from infected tissue culture cells can now provide useful information on vaccine versus wild-type viruses, on the likely origin of imported cases of rubella and CRS, and for the documentation of elimination.

If acute- and convalescent-phase sera are available, a four-fold rise in rubella virus-specific IgG usually by ELISA is also diagnostic for postnatal rubella infection. Avidity tests have now been developed that are useful for suspect case classification in certain situations e. Low avidity anti-rubella IgG suggests recent infection.

Laboratory tests supporting surveillance for rubella and CRS in control and elimination programs have largely been rubella virus specific IgM tests, supported for some suspect cases by techniques that amplify rubella virus RNA.

Specifically, advanced molecular techniques and point-of-care diagnostics for rubella may be used. Since the clinical symptoms of postnatal rubella and CRS are dramatically different, it is not surprising that there are significant differences in the immune responses of patients with these diseases. These differences can be observed on Western blots, in which antibodies in sera from CRS patients often demonstrate different reactivity to rubella proteins than those from postnatal rubella patients.

In many countries, much of the rubella testing is for immunity to rubella. Immunity testing is often done commercially. Monitoring of rubella vaccination programs by seroprevalence studies is used in some countries. However, this assay is no longer a common diagnostic test. Neutralization tests for virus specific antibodies have the advantages over other tests such as ELISA because they assess the biologic function of antibodies and can be used with any virus strain.

For some viruses e. The plaque reduction neutralization test PRN is performed when a quantitative assessment of the neutralizing capacity of an antiserum is necessary.

The assay follows a format common to many viruses. Such neutralization tests exist for laboratory-adapted rubella virus strains in a number of cell types, but an immunocolorimetric neutralization assay for rubella virus using a soluble substrate is a significant improvement over plaque development.

More than sera were titered a second time. These repeated assays suggested a good degree of reproducibility, with person-to-person differences being more than 8 times higher than the observed within-assay variability. Thus, laboratories bear a considerable burden in rubella and CRS diagnosis. For example, when primary rubella virus infection is suspected for a pregnant woman, false positives and false negatives may lead to incorrect clinical decisions.

It was first isolated from an infected fetus in the s 76 and further passaged for attenuation through either the WI or MRC-5 human diploid cell lines. Distinct patterns of cellular immunity to rubella virus are related to the time elapsed since vaccination. There are numerous factors that influence inter-individual variations in immune responses to rubella vaccine such as: genetics; age; race; gender; antigenic exposure history either infectious or through vaccination ; interference of maternal antibodies still present during vaccination; and other confounding environmental variables.

A successful model that allows for the control of genetic and certain environmental factors is to perform immunogenetic studies in twin subjects. Along with similar dizygotic or identical monozygotic genetic backgrounds, assumptions regarding environmental factors can be made that account for twins being raised in the same household. Twin studies also offer an exceptional model to study the heritability of immune response to live viral vaccines.

With this intention, in pairs of twins 45 monozygotic and 55 dizygotic , the heritability of rubella antibody levels after vaccination was calculated to be Polymorphisms in genetic elements controlling the immunity to rubella virus explain a significant degree of inter-individual variations in immune response.

These genetic elements include: HLA alleles; haplotypes; HLA supertypes; single-nucleotide polymorphisms in genes involved in innate and antiviral immunity; SNPs in genes not associated with classical viral response or immunity, but discovered through genome-wide association studies; and whole-genome transcription profiling, as well as other factors. The human leukocyte antigens HLA play a critical role in immune response to viruses.

The highly polymorphic nature of HLA genes highlights their importance in contributing to the heterogeneity of the immune response to rubella virus. HLA class I and II polymorphisms restrict the available repertoire of rubella antigens presented to T cells and therefore influence the subsequent immune response. Specific HLA alleles bind to unique motifs of rubella-derived epitopes. To investigate this relationship, extensive research has been performed in the discovery and replication of the association of HLA genes with inter-individual variations in immunity to rubella virus.

For example, there is a weak association between HLA-DR and transient arthritis-like joint manifestations after rubella vaccination. To investigate other genetic contributions, studies next focused on candidate genes with known involvement in innate immunity and response to viral infection or vaccination.

The contribution of inter-individual differences in gene expression in response to rubella virus can be assayed through whole-genome transcriptional profiling of peripheral blood mononuclear cells from subjects with extreme immunological phenotypes to rubella vaccine. The Mayo Clinic Vaccine Research Group is currently conducting a replication study of all HLA and candidate gene SNP associations and two unique GWAS studies in independent cohorts to elucidate novel gene polymorphisms associated with inter-individual variations in immune responses to rubella vaccine.

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