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1.  Rubella epidemic caused by genotype 1E rubella viruses in Beijing, China, in 2007–2011 
Virology Journal  2013;10:122.
Background
A series of different rubella vaccination strategies were implemented to control rubella and prevent congenital rubella virus infection in Beijing, China. The rubella vaccine was available in 1995 in Beijing, and was introduced into the Beijing immunization program (vaccine recipients at their own expense vaccination) in 2000, and was introduced into the National Expanded Program on Immunization (vaccine recipients free vaccination) in 2006. Rubella virological surveillance started in Beijing in 2007.
Results
The reported rubella incidence rate has decreased dramatically due to the introduction of the vaccine in Beijing since 1995. However, rubella epidemics occurred regardless in 2001 and 2007. The incidence rate among the floating population has gradually increased since 2002, reaching 2 or more times that in the permanent resident population. The peak age of rubella cases gradually changed from <15 years of age to adults after 2005. Phylogenetic analysis was performed and a phylogenetic tree was constructed based on the World Health Organization standard sequence window for rubella virus isolates. All Beijing rubella virus isolates belong to genotype 1E/cluster1 and were clustered interspersed with viruses from other provinces in China. The effective number of infections indicated by a Bayesian skyline plot remained constant from 2007 to 2011.
Conclusions
The proportion of rubella cases among the floating population has increased significantly in Beijing since 2002, and the disease burden gradually shifted to the older age group (15- to 39-year olds), which has become a major group with rubella infection since 2006. Genotype 1E rubella virus continuously caused a rubella epidemic in Beijing in 2007–2011 and was the predominant virus, and all Beijing genotype 1E viruses belong to cluster 1, which is also widely circulated throughout the country.
doi:10.1186/1743-422X-10-122
PMCID: PMC3660283  PMID: 23596982
Rubella epidemics; Rubella virus; Genotype 1E, Beijing
2.  Rubella Epidemics and Genotypic Distribution of the Rubella Virus in Shandong Province, China, in 1999–2010 
PLoS ONE  2012;7(7):e42013.
Background
The rubella vaccine was introduced into the immunization program in 1995 in the Shandong province, China. A series of different rubella vaccination strategies were implemented at different stages of measles control in Shandong province.
Methodology/Principal Findings
The average reported incidence rate of rubella cases remained at a low level in Shandong province after 1999. However, rubella epidemics occurred repeatedly in 2001/2002, 2006, and 2008/2009. The age of the onset of rubella cases gradually increased during 1999–2010, which showed that most cases were found among the 10 years old in 1999 and among the 17 years old in 2010. Phylogenetic analysis was performed and a phylogenetic tree was constructed based on the World Health Organization standard sequence window for rubella virus isolates. All rubella viruses isolated in Shandong province were divided into 4 genotypes: 1E, 1F, 2A, and 2B. Genotype 1E viruses accounted for the majority (79%) of all these viruses. The similarity of nucleotide and amino acid sequences among genotype 1E viruses was 98.2–100% and 99.1–100%, respectively. All Shandong genotype 1E strains, differed from international genotype 1E strains, belonged to cluster 1 and interdigitated with the viruses from other provinces in mainland China. The effective number of infections indicated by a Bayesian skyline plot remained constant from 2001 to 2009.
Conclusions/Significance
The gradual shift of disease burden to an older age group occurred after a rubella-containing vaccine was introduced into the childhood immunization schedule in 1995 in Shandong province. Four genotypes, including 1E, 1F, 2A, and 2B, were found in Shandong province during 2000–2009. Genotype 1E, rather than genotype 1F, became the predominant genotype circulating in Shandong province from 2001. All Shandong genotype 1E viruses belong to the genotype 1E/cluster 1; they have constantly circulated, and co-evolved and co-circulated, with those from other provinces.
doi:10.1371/journal.pone.0042013
PMCID: PMC3404038  PMID: 22911874
3.  Rubella Virus Genotypes in the People's Republic of China between 1979 and 2007: a Shift in Endemic Viruses during the 2001 Rubella Epidemic▿ † 
Journal of Clinical Microbiology  2010;48(5):1775-1781.
The incidence of rubella cases in China from 1991 to 2007 was reviewed, and the nucleotide sequences from 123 rubella viruses collected during 1999 to 2007 and 4 viral sequences previously reported from 1979 to 1984 were phylogenetically analyzed. Rubella vaccination was not included in national immunization programs in China before 2007. Changes in endemic viruses were compared with incidences of rubella epidemics. The results showed that rubella epidemics occur approximately every 6 to 8 years (1993/1994, 2001, and 2007), and a shift of disease burden to susceptible young adults was observed. The Chinese rubella virus sequences were categorized into 5 of the 13 rubella virus genotypes, 1a, 1E, 1F, 2A, and 2B; cocirculations of these different genotypes were found in China. In Anhui province, a shift in the predominant genotype from 1F and 2B to 1E coincided with the 2001 rubella epidemic. This shift may have occurred throughout China during 2001 to 2007. This study investigated the genotype distribution of rubella viruses in China over a 28-year period to establish an important genetic baseline in China during its prevaccination era.
doi:10.1128/JCM.02055-09
PMCID: PMC2863877  PMID: 20351211
4.  Rubella antibody levels in school-aged children in Newfoundland: Implications for a two-dose rubella vaccination strategy 
OBJECTIVE:
To determine the prevailing levels of rubella immunity among school-aged children who received a single dose of measles-mumps-rubella (MMR) vaccine at one year of age.
DESIGN:
Cross-sectional study with a two stage cluster sampling of randomly picked schools across the province of Newfoundland.
STUDY POPULATION AND METHODS:
A total of 1053, five to 17-year-old children were enrolled; vaccination history was verified through official records; and a sample of blood was taken. Rubella immunity was determined by enzyme immunoassay based on a serum antibody protective cut-off titre of more than 10 IU.
RESULTS:
A total of 145 (13.8%) were found to be nonimmune. The rate of susceptibility ranged from 3.2% to 25.9% for different age groups. The proportion susceptible was significantly higher at 16.5% in the age group eight to 17 years old versus 3.9% for the age group five to eight years old (χ2=24.08; df=1, P<0.001). There was a significant regression of logarithm titre values on the age of children with an average decline in titre values of 8.1% per annum.
CONCLUSIONS:
A substantial number of those who were given a single dose of MMR II vaccine may not have protective immunity against rubella as they reach prime reproductive age. There is a definite need to consider a two-dose rubella vaccination strategy in Canada, and these data suggest the second dose given after eight years of age will be most beneficial. In the move towards a routine two-dose measles vaccination strategy in Canada, the MMR II vaccine is being used for the second dose and given either at 18 months of age or at school entry. While this approach will have an overall beneficial effect, the impact of the above timing of the second dose on long term rubella immunity cannot be predicted at this time. These data also underscore the continuing need for prenatal rubella screening program.
PMCID: PMC3327347  PMID: 22514481
Rubella immunity; Rubella seroscreening; Rubella vaccination
5.  Evolutionary analysis of rubella viruses in mainland China during 2010–2012: endemic circulation of genotype 1E and introductions of genotype 2B 
Scientific Reports  2015;5:7999.
Rubella remains a significant burden in mainland China. In this report, 667 viruses collected in 24 of 31 provinces of mainland China during 2010–2012 were sequenced and analyzed, significantly extending previous reports on limited numbers of viruses collected before 2010. Only viruses of genotypes 1E and 2B were found. Genotype 1E viruses were found in all 24 provinces. Genotype 1E viruses were likely introduced into mainland China around 1997 and endemic transmission of primarily one lineage became established. Viruses reported here from 2010–2012 are largely in a single cluster within this lineage. Genotype 2B viruses were rarely detected in China prior to 2010. This report documents a previously undetected 2B lineage, which likely became endemic in eastern provinces of China between 2010 and 2012. Bayesian analyses were performed to estimate the evolutionary rates and dates of appearance of the genotype 1E and 2B viral linages in China. A skyline plot of viral population diversity did not provide evidence of reduction of diversity as a result of vaccination, but should be useful as a baseline for such reductions as vaccination programs for rubella become widespread in mainland China.
doi:10.1038/srep07999
PMCID: PMC4303870  PMID: 25613734
6.  Difficulties in Eliminating Measles and Controlling Rubella and Mumps: A Cross-Sectional Study of a First Measles and Rubella Vaccination and a Second Measles, Mumps, and Rubella Vaccination 
PLoS ONE  2014;9(2):e89361.
Background
The reported coverage of the measles–rubella (MR) or measles–mumps–rubella (MMR) vaccine is greater than 99.0% in Zhejiang province. However, the incidence of measles, mumps, and rubella remains high. In this study, we assessed MMR seropositivity and disease distribution by age on the basis of the current vaccination program, wherein the first dose of MR is administered at 8 months and the second dose of MMR is administered at 18–24 months.
Methods
Cross-sectional serological surveys of MMR antibodies were conducted by collecting epidemiological data in Zhejiang province, China in 2011. In total, 1015 participants were randomly selected from two surveillance sites. Serum MMR-specific immunoglobulin G levels were tested by enzyme-linked immunosorbent assay. The geometric mean titers and seroprevalence with 95% confidence intervals (CIs) were calculated by age and gender. Proportions of different dose of vaccine by age by vaccine were also identified. Statistically significant differences between categories were assessed by the Chi-square test.
Results
Over 95% seroprevalence rates of measles were seen in all age groups except <7 months infants. Children aged 5–9 years were shown lower seropositivity rates of mumps while elder adolescences and young adults were presented lower rubella seroprevalence. Especially, rubella seropositivity was significantly lower in female adults than in male. Nine measles cases were unvaccinated or unknown vaccination history. Among them, 66.67% (6/9) patients were aged 20–29 years while 33.33% (3/9) were infants aged 8–12 months. In addition, 57.75% (648/1122) patients with mumps were children aged 5–9 years, and 50.54% (94/186) rubella cases were aged 15–39 years.
Conclusions
A timely two-dose MMR vaccination schedule is recommended, with the first dose at 8 months and the second dose at 18–24 months. An MR vaccination speed-up campaign may be necessary for elder adolescents and young adults, particularly young females.
doi:10.1371/journal.pone.0089361
PMCID: PMC3930734  PMID: 24586717
7.  Phylogenetic Analysis of Rubella Viruses Identified in Uganda, 2003–2012 
Journal of medical virology  2014;86(12):2107-2113.
Molecular data on rubella viruses are limited in Uganda despite the importance of congenital rubella syndrome (CRS). Routine rubella vaccination, while not administered currently in Uganda, is expected to begin by 2015. The World Health Organization recommends that countries without rubella vaccination programs assess the burden of rubella and CRS before starting a routine vaccination program. Uganda is already involved in integrated case-based surveillance, including laboratory testing to confirm measles and rubella, but molecular epidemiologic aspects of rubella circulation have so far not been documented in Uganda. Twenty throat swab or oral fluid samples collected from 12 districts during routine rash and fever surveillance between 2003 and 2012 were identified as rubella virus RNA positive and PCR products encompassing the region used for genotyping were sequenced. Phylogenetic analysis of the 20 sequences identified 19 genotype 1G viruses and 1 genotype 1E virus. Genotype-specific trees showed that the Uganda viruses belonged to specific clusters for both genotypes 1G and 1E and grouped with similar sequences from neighboring countries. Genotype 1G was predominant in Uganda. More epidemiological and molecular epidemiological data are required to determine if genotype 1E is also endemic in Uganda. The information obtained in this study will assist the immunization program in monitoring changes in circulating genotypes.
doi:10.1002/jmv.23935
PMCID: PMC4269980  PMID: 24700073
genotype; molecular characterization; sequences; rubella epidemiology
8.  Molecular Evolutionary and Epidemiological Dynamics of Genotypes 1G and 2B of Rubella Virus 
PLoS ONE  2014;9(10):e110082.
Rubella Virus (RV), which causes measles-like rashes in children, puts millions of infants at risk of congenital defects across the globe. Employing phylogenetic approaches to the whole genome sequence data and E1 glycoprotein sequence data, the present study reports the substitution rates and dates of emergence of all thirteen previously described rubella genotypes, and gains important insights into the epidemiological dynamics of two geographically widely distributed genotypes 1G and 2B. The overall nucleotide substitution rate of this non-vector-borne RV is in the order of 10−3 substitutions/site/year, which is considerably higher than the substitution rates previously reported for the vector-borne alphaviruses within the same family. Currently circulating strains of RV share a common ancestor that existed within the last 150 years, with 95% Highest Posterior Density values ranging from 1868 to 1926 AD. Viral strains within the respective genotypes began diverging between the year 1930 s and 1980 s. Both genotype 1G and 2B have shown a decline in effective number of infections since 1990 s, a period during which mass immunization programs against RV were adapted across the globe. Although both genotypes showed some extent of spatial genetic structuring, the analyses also depicted an inter-continental viral dispersal. Such a viral dispersal pattern could be related to the migration of infected individuals across the regions coupled with a low coverage of MMR vaccination.
doi:10.1371/journal.pone.0110082
PMCID: PMC4201520  PMID: 25329480
9.  Rubella and the Rubella Syndrome—New Epidemiologic and Virologic Observations 
California Medicine  1965;102(6):397-403.
The importance of rubella lies in the 15 to 20 per cent incidence of damage to the fetus when infection occurs in the first trimester of pregnancy. The “rubella syndrome” appears as various combinations of congenital defects, chiefly cardiac anomalies, cataracts and impaired hearing.
Now that the rubella virus has been isolated and grown in tissue culture, it is possible to study the spread of the disease, to determine apparent and inapparent infection rates and to investigate the nature of fetal infection. It has been found that the disease is a highly contagious one in the family setting, and that inapparent infections are more common than overt cases with rash. Infection of the fetus in the early weeks of intrauterine life may become chronic, and virus has been recovered from placenta and fetal specimens collected at induced abortions many weeks after the maternal disease. Infants born with the rubella syndrome are still shedding virus at birth and may continue to do so for at least several months.
Gamma globulin, which is effective in preventing measles and hepatitis, has not been highly effective in the prevention of rubella when given to those exposed to the disease. Successful control of the rubella problem will depend upon the development of an active vaccine, which is a possibility now that the virus can be grown in tissue culture.
PMCID: PMC1516135  PMID: 14298864
10.  Effect of selective vaccination on rubella susceptibility and infection in pregnancy. 
The effect of school and adult vaccination on susceptibility to rubella in women of childbearing age was assessed in the Manchester area, where the population attending antenatal clinics is over 40 000 a year. Between 1979 and 1984 the proportion susceptible fell from 6.4% to 2.7%. In 1984, 4.2% of nulliparous women were susceptible compared with 1.4% of women in their second or subsequent pregnancy. Eighty five per cent of pregnant women screened and found to be non-immune were vaccinated post partum before leaving hospital. Requests for prevaccination screening of non-pregnant women increased in response to a national campaign and at the time of local outbreaks of rubella but only two thirds of those found to be nonimmune were subsequently vaccinated. During 1983 and 1984 infection was confirmed in 57 pregnant women--2% of those non-immune. Selective vaccination has reduced susceptibility to rubella in the childbearing population, but it is suggested that mass vaccination of children of both sexes should be added to the existing policy to control circulation of wild rubella virus and reduce the risk of infection to pregnant women who remain susceptible.
PMCID: PMC1419038  PMID: 3933685
11.  Pregnant Women in and Around Dhaka City: Are Their Children at Risk of Developing Congenital Rubella Syndrome? 
Indian Journal of Microbiology  2011;50(4):443-448.
Rubella Virus (RUBV) is a common cause of childhood rash and fever in non-immunized populations, and its public health importance relates to teratogenic effects of primary rubella infection in women with early pregnancy. Infection of the fetus may lead to congenital rubella syndrome (CRS). This work aimed to assess the degree of risk associated in acquiring rubella virus infection by the women during pregnancy and developing CRS among their children in Bangladesh. The study population (n = 275) included pregnant mothers (15–38 years) from various socioeconomic backgrounds attending a women health care based hospital. All subjects were personally interviewed, clinically examined and a standardized questionnaire was filled up for each of them. From each participant 3 ml blood was taken and serum was separated. Commercially available ELISA kit was used for the qualitative and quantitative determination of IgM and IgG class antibodies against RUBV in collected serum samples. 209 women were found to contain detectable level of antiRUBV IgG antibodies, but did not possess IgM antibodies against rubella. Only 9% participants were vaccinated previously against rubella virus among the whole antenatal population studied. Ninety-two percent of these vaccinated pregnant women contained serum anti-rubella IgG antibody which was significantly (P = 0.05) higher than that of the nonvaccinated study population (75%). Pregnant women from lower middle and poor socioeconomic class had significantly (P = 0.05) more intra uterine growth retardation (IUGR) of fetus than the upper middle class. 20% of the women of child bearing age examined in this work were not yet exposed to RUBV and at risk of acquiring this virus during pregnancy and subsequently transmitting the virus to the fetus. Our work demonstrates rubella attack rate among antenatal population in Bangladesh as 14.5 in 1000 during pregnancy. A proper and reliable vaccination policy against rubella virus is not yet adopted at the national level in many developing countries including Bangladesh. This work identifies the requirement of detailed study for the identification of intrauterine rubella infection and its related influence on perinatal morbidity and mortality. Thorough epidemiological studies are also considered necessary prior to the development and acceptance of national immunization program against rubella virus in Bangladesh.
doi:10.1007/s12088-011-0094-5
PMCID: PMC3209850  PMID: 22282613
Rubella virus; Pregnancy; Congenital rubella syndrome
12.  Phylogenetic Analysis of Rubella Viruses Involved in Congenital Rubella Infections in France between 1995 and 2009▿  
Journal of Clinical Microbiology  2010;48(7):2530-2535.
Rubella is an acute infectious disease that normally has a mild clinical course. However, infections during pregnancy, especially before week 12 of gestation (WG), can cause severe birth defects known as congenital rubella syndrome (CRS). The aim of this study was to perform genotyping and molecular characterization of rubella viruses involved in congenital infections in France over the past 15 years (1995 to 2009). Amniotic fluid (AF) specimens (n = 80) from pregnant women with congenital rubella infections (CRI) before week 20 of gestation, and a few other samples available from children/newborns with CRS (n = 26), were analyzed. The coding region of the rubella virus E1 gene was amplified directly from clinical specimens by reverse transcriptase PCR, and the resulting DNA fragments were sequenced. Sequences were assigned to genotypes by phylogenetic analysis with rubella virus reference sequences. Sufficient E1 gene sequences were obtained from 56 cases. Phylogenetic analysis of the sequences showed that at least five different genotypes (1E, 1G, 1B, 2B, and 1h) were present in France and were involved in congenital infections, with a strong predominance of genotype 1E (87%). This is one of the very few comprehensive studies of rubella viruses involved in CRI. The results indicated that over the past 15 years, multiple introductions of the dominant genotype E caused most of the CRI cases in France. A few sporadic cases were due to other genotypes (1B, 1G, 1h, 2B).
doi:10.1128/JCM.00181-10
PMCID: PMC2897492  PMID: 20463161
13.  Characterization of Regional Influenza Seasonality Patterns in China and Implications for Vaccination Strategies: Spatio-Temporal Modeling of Surveillance Data 
PLoS Medicine  2013;10(11):e1001552.
Cécile Viboud and colleagues describe epidemiological patterns of influenza incidence across China to support the design of a national vaccination program.
Please see later in the article for the Editors' Summary
Background
The complexity of influenza seasonal patterns in the inter-tropical zone impedes the establishment of effective routine immunization programs. China is a climatologically and economically diverse country, which has yet to establish a national influenza vaccination program. Here we characterize the diversity of influenza seasonality in China and make recommendations to guide future vaccination programs.
Methods and Findings
We compiled weekly reports of laboratory-confirmed influenza A and B infections from sentinel hospitals in cities representing 30 Chinese provinces, 2005–2011, and data on population demographics, mobility patterns, socio-economic, and climate factors. We applied linear regression models with harmonic terms to estimate influenza seasonal characteristics, including the amplitude of annual and semi-annual periodicities, their ratio, and peak timing. Hierarchical Bayesian modeling and hierarchical clustering were used to identify predictors of influenza seasonal characteristics and define epidemiologically-relevant regions. The annual periodicity of influenza A epidemics increased with latitude (mean amplitude of annual cycle standardized by mean incidence, 140% [95% CI 128%–151%] in the north versus 37% [95% CI 27%–47%] in the south, p<0.0001). Epidemics peaked in January–February in Northern China (latitude ≥33°N) and April–June in southernmost regions (latitude <27°N). Provinces at intermediate latitudes experienced dominant semi-annual influenza A periodicity with peaks in January–February and June–August (periodicity ratio >0.6 in provinces located within 27.4°N–31.3°N, slope of latitudinal gradient with latitude −0.016 [95% CI −0.025 to −0.008], p<0.001). In contrast, influenza B activity predominated in colder months throughout most of China. Climate factors were the strongest predictors of influenza seasonality, including minimum temperature, hours of sunshine, and maximum rainfall. Our main study limitations include a short surveillance period and sparse influenza sampling in some of the southern provinces.
Conclusions
Regional-specific influenza vaccination strategies would be optimal in China; in particular, annual campaigns should be initiated 4–6 months apart in Northern and Southern China. Influenza surveillance should be strengthened in mid-latitude provinces, given the complexity of seasonal patterns in this region. More broadly, our findings are consistent with the role of climatic factors on influenza transmission dynamics.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, millions of people worldwide catch influenza, a viral disease of the airways. Most infected individuals recover quickly but seasonal influenza outbreaks (epidemics) kill about half a million people annually. These epidemics occur because antigenic drift—frequent small changes in the viral proteins to which the immune system responds—means that an immune response produced one year provides only partial protection against influenza the next year. Annual vaccination with a mixture of killed influenza viruses of the major circulating strains boosts this natural immunity and greatly reduces the risk of catching influenza. Consequently, many countries run seasonal influenza vaccination programs. Because the immune response induced by vaccination decays within 4–8 months of vaccination and because of antigenic drift, it is important that these programs are initiated only a few weeks before the onset of local influenza activity. Thus, vaccination starts in early autumn in temperate zones (regions of the world that have a mild climate, part way between a tropical and a polar climate), because seasonal influenza outbreaks occur in the winter months when low humidity and low temperatures favor the transmission of the influenza virus.
Why Was This Study Done?
Unlike temperate regions, seasonal influenza patterns are very diverse in tropical countries, which lie between latitudes 23.5°N and 23.5°S, and in the subtropical countries slightly north and south of these latitudes. In some of these countries, there is year-round influenza activity, in others influenza epidemics occur annually or semi-annually (twice yearly). This complexity, which is perhaps driven by rainfall fluctuations, complicates the establishment of effective routine immunization programs in tropical and subtropical countries. Take China as an example. Before a national influenza vaccination program can be established in this large, climatologically diverse country, public-health experts need a clear picture of influenza seasonality across the country. Here, the researchers use spatio-temporal modeling of influenza surveillance data to characterize the seasonality of influenza A and B (the two types of influenza that usually cause epidemics) in China, to assess the role of putative drivers of seasonality, and to identify broad epidemiological regions (areas with specific patterns of disease) that could be used as a basis to optimize the timing of future Chinese vaccination programs.
What Did the Researchers Do and Find?
The researchers collected together the weekly reports of laboratory-confirmed influenza prepared by the Chinese national sentinel hospital-based surveillance network between 2005 and 2011, data on population size and density, mobility patterns, and socio-economic factors, and daily meteorological data for the cities participating in the surveillance network. They then used various statistical modeling approaches to estimate influenza seasonal characteristics, to assess predictors of influenza seasonal characteristics, and to identify epidemiologically relevant regions. These analyses indicate that, over the study period, northern provinces (latitudes greater than 33°N) experienced winter epidemics of influenza A in January–February, southern provinces (latitudes less than 27°N) experienced peak viral activity in the spring (April–June), and provinces at intermediate latitudes experienced semi-annual epidemic cycles with infection peaks in January–February and June–August. By contrast, influenza B activity predominated in the colder months throughout China. The researchers also report that minimum temperatures, hours of sunshine, and maximum rainfall were the strongest predictors of influenza seasonality.
What Do These Findings Mean?
These findings show that influenza seasonality in China varies between regions and between influenza virus types and suggest that, as in other settings, some of these variations might be associated with specific climatic factors. The accuracy of these findings is limited by the short surveillance period, by sparse surveillance data from some southern and mid-latitude provinces, and by some aspects of the modeling approach used in the study. Further surveillance studies need to be undertaken to confirm influenza seasonality patterns in China. Overall, these findings suggest that, to optimize routine influenza vaccination in China, it will be necessary to stagger the timing of vaccination over three broad geographical regions. More generally, given that there is growing interest in rolling out national influenza immunization programs in low- and middle-income countries, these findings highlight the importance of ensuring that vaccination strategies are optimized by taking into account local disease patterns.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001552.
This study is further discussed in a PLOS Medicine Perspective by Steven Riley
The UK National Health Service Choices website provides information for patients about seasonal influenza and about influenza vaccination
The World Health Organization provides information on seasonal influenza (in several languages) and on influenza surveillance and monitoring
The US Centers for Disease Control and Prevention also provides information for patients and health professionals on all aspects of seasonal influenza, including information about vaccination; its website contains a short video about personal experiences of influenza.
Flu.gov, a US government website, provides access to information on seasonal influenza and vaccination
Information about the Chinese National Influenza Center, which is part of the Chinese Center for Disease Control and Prevention: and which runs influenza surveillance in China, is available (in English and Chinese)
MedlinePlus has links to further information about influenza and about vaccination (in English and Spanish)
A recent PLOS Pathogens Research Article by James D. Tamerius et al. investigates environmental predictors of seasonal influenza epidemics across temperate and tropical climates
A study published in PLOS ONE by Wyller Alencar de Mello et al. indicates that Brazil, like China, requires staggered timing of vaccination from Northern to Southern states to account for different timings of influenza activity.
doi:10.1371/journal.pmed.1001552
PMCID: PMC3864611  PMID: 24348203
14.  Rubella-associated arthritis. I. Comparative study of joint manifestations associated with natural rubella infection and RA 27/3 rubella immunisation. 
Annals of the Rheumatic Diseases  1986;45(2):110-114.
Joint manifestations observed during the course of a prospective RA 27/3 rubella immunisation trial were compared with those observed during an intercurrent wild rubella epidemic in an outlying community. Among 44 rubella haemagglutination inhibition (HAI) negative females ranging in age from 17 to 33 years who received rubella vaccine, six (13.6%) developed acute polyarticular arthritis within two to four weeks postvaccine and two (4.5%) had continuing or recurrent arthropathy lasting longer than 18 months. In contrast, among 23 females ranging in age from 11 to 39 years undergoing wild rubella infection, 12 (52.2%) developed acute polyarticular arthritis and seven (30.4%) had recurrent arthropathy 18 months postinfection. Among 23 males ranging in age from 13 to 54 years undergoing wild rubella infection, only two (8.7%) developed acute arthritis and both individuals had continuing joint manifestations 18 months postinfection. Wild rubella infection in adult populations is associated with a higher incidence, increased severity, and more prolonged duration of joint manifestations than is seen after RA 27/3 rubella immunisation.
PMCID: PMC1001829  PMID: 3947141
15.  Mutational Analysis, Using a Full-Length Rubella Virus cDNA Clone, of Rubella Virus E1 Transmembrane and Cytoplasmic Domains Required for Virus Release 
Journal of Virology  1999;73(6):4622-4630.
We report on the construction of a full-length cDNA clone, pBRM33, derived from wild-type rubella virus M33 strain. The RNA transcripts synthesized in vitro from pBRM33 are highly infectious, and the viruses produced retain the phenotypic characteristics of the parental M33 virus in growth rate and plaque size. This cDNA clone was used to study the role of E1 transmembrane and cytoplasmic domains in virus assembly by site-directed mutagenesis. Three different alanine substitutions were introduced in the transmembrane domain of E1. These included substitution of leucine 464, cysteine 466, cysteine 467, and both cysteines 466 and 467 to alanine. In the E1 cytoplasmic domain, cysteine 470 and leucine 471 were altered to alanine. We found that these mutations did not significantly affect viral RNA replication, viral structural protein synthesis and transport, or E2/E1 heterodimer formation. Except for the substitution of cysteine 470, these mutations did, however, lead to a reduction in virus release. Substitution of cysteine 467 in the transmembrane region and of leucine 471 in the cytoplasmic domain dramatically reduced virus yield, resulting in the production of only 1 and 10% of the parental virus yield, respectively, in a parallel infection. These data show that E1 transmembrane and cytoplasmic domains play an important role in late stages of virus assembly, possibly during virus budding, consistent with earlier studies indicating that the E1 cytoplasmic domain may interact with nucleocapsids and that this interaction drives virus budding.
PMCID: PMC112503  PMID: 10233921
16.  Sero-Surveillance to Assess Immunity to Rubella and Assessment of Immunogenicity and Safety of a Single dose of Rubella Vaccine in School Girls 
Background:
Rubella vaccination is not yet included in National Immunization Schedule in India. Serosurvey is frequently used to assess epidemiologic pattern of Rubella in a community. Serosurveys in different parts of India have found that 6–47% of women are susceptible for Rubella infection. The present serosurveillance was conducted in Jammu, India, in two public schools.
Objective:
To determine serological status of Rubella antibodies of school girls and assessment of immunogenicity and reactogenicity of Rubella immunization in seronegative girls.
Materials and Methods:
The current study was conducted to determine Rubella serostatus in peripubertal schoolgirls aged 11–18 years and also to assess immunogenicity and safety of Rubella vaccine (R-Vac) of Serum Institute of India Ltd., Pune, in seronegative girls. For screening, pre-vaccination serum Rubella IgG antibodies were determined and to assess immunogenicity of the vaccine, post-vaccination IgG antibodies were compared with pre-vaccination levels. Safety assessment was done for a period of 8 weeks, post-vaccination.
Results:
A total of 90 (32.7%) seronegative girls were vaccinated. All girls (100%) became seropositive, post-vaccination. Clinically relevant and statistically significant increase in anti-Rubella IgG titres was observed. The adverse events were mild and self-limiting.
Conclusions:
R-Vac vaccine used in the study demonstrated an excellent safety and immunogenicity profile.
doi:10.4103/0970-0218.62575
PMCID: PMC2888342  PMID: 20606938
Immunogenicity; Rubella; school girls; serosurveillance; India
17.  Rubella reimmunization: comparative analysis of the immunoglobulin G response to rubella virus vaccine in previously seronegative and seropositive individuals. 
Journal of Clinical Microbiology  1996;34(9):2210-2218.
Rubella virus (RV)-specific immunoglobulin G (IgG) antibodies were studied in military recruits undergoing unselected immunization with live attenuated measles, mumps, and rubella virus (MMR) vaccine. Three different whole-RV enzyme immunoassays (EIAs) and an epitope-specific EIA with a synthetic peptide (BCH-178c) representing a heutralization domain on the RV E1 envelope protein were used. Before vaccination, 84.2, 87.7, and 84.5% of the subjects tested (n = 399) were found to be seropositive (> 10 IU/ml or assay equivalent) by the three whole-RV EIAs, respectively, while only 82.5% were seropositive by the BCH-178c EIA. Although prevaccination seropositivity rates were similar for the whole-RV EIAs (sensitivity, 94 to 100%), many sera considered seropositive by the whole-RV EIAs had E1 peptide EIA antibody levels of < 10 IU/ml (sensitivity, 77.4 to 80.7%). One month after vaccination, 97.8, 97.2, and 93.5% of the subjects who were followed (n = 356) were seropositive by the three whole-RV EIAs, respectively, while 89% had BCH-178c peptide-specific IgG titers of > 10 IU/ml. After vaccination, depending on the assay used, up to 20.6% of initially seropositive individuals exhibited a greater than fourfold increase in RV-specific IgG, while up to 47.3% showed a greater than twofold increase. Increased antibody titers after vaccination (seroboosting) were most frequently associated with low levels of BCH-178c peptide-specific IgG before vaccination. RV protein-specific IgG was also studied by immunoblot assays in a subset (n = 56) of individuals receiving the MMR vaccine. Of these, 89.4 and 91.1% exhibited RV protein (E1, E2, and C protein)-specific IgG before and after vaccination, respectively. Seroboosting (two- to fourfold increase in EIA titers of individuals seropositive by the whole-RV EIA before vaccination) was usually accompanied by a shift in the IgG immunoblot pattern from a single (E1) to multiple (E1-E1, E1-C, or E1-E2-C) specificities, suggesting exposure of new epitopes as a result of viral replication.
PMCID: PMC229219  PMID: 8862587
18.  Analysis of whole genome sequences of 16 strains of rubella virus from the United States, 1961–2009 
Virology Journal  2013;10:32.
Rubella virus is the causative agent of rubella, a mild rash illness, and a potent teratogenic agent when contracted by a pregnant woman. Global rubella control programs target the reduction and elimination of congenital rubella syndrome. Phylogenetic analysis of partial sequences of rubella viruses has contributed to virus surveillance efforts and played an important role in demonstrating that indigenous rubella viruses have been eliminated in the United States. Sixteen wild-type rubella viruses were chosen for whole genome sequencing. All 16 viruses were collected in the United States from 1961 to 2009 and are from 8 of the 13 known rubella genotypes. Phylogenetic analysis of 30 whole genome sequences produced a maximum likelihood tree giving high bootstrap values for all genotypes except provisional genotype 1a. Comparison of the 16 new complete sequences and 14 previously sequenced wild-type viruses found regions with clusters of variable amino acids. The 5′ 250 nucleotides of the genome are more conserved than any other part of the genome. Genotype specific deletions in the untranslated region between the non-structural and structural open reading frames were observed for genotypes 2B and genotype 1G. No evidence was seen for recombination events among the 30 viruses. The analysis presented here is consistent with previous reports on the genetic characterization of rubella virus genomes. Conserved and variable regions were identified and additional evidence for genotype specific nucleotide deletions in the intergenic region was found. Phylogenetic analysis confirmed genotype groupings originally based on structural protein coding region sequences, which provides support for the WHO nomenclature for genetic characterization of wild-type rubella viruses.
doi:10.1186/1743-422X-10-32
PMCID: PMC3574052  PMID: 23351667
Rubella virus; Whole genome
19.  Influence of host genetic variation on rubella-specific T cell cytokine responses following rubella vaccination 
Vaccine  2009;27(25-26):3359-3366.
The variability of immune response modulated by immune response gene polymorphisms is a significant factor in the protective effect of vaccines. We studied the association between cellular (cytokine) immunity and HLA genes among 738 schoolchildren (396 males and 342 females) between the ages of 11 and 19 years, who received two doses of rubella vaccine (Merck). Cytokine secretion levels in response to rubella virus stimulation were determined in PBMC cultures by ELISA. Cell supernatants were assayed for Th1 (IFN-γ, IL-2, and IL-12p40), Th2 (IL-4, IL-5, and IL-10), and innate/proinflammatory (TNF-α, GM-CSF, and IL-6) cytokines. We found a strong association between multiple alleles of the HLA-DQA1 (global p-value 0.022) and HLA-DQB1 (global p-value 0.007) loci and variations in rubella-specific IL-2 cytokine secretion. Additionally, the relationships between alleles of the HLA-A (global p-value 0.058), HLA-B (global p-value 0.035), and HLA-C (global p-value 0.023) loci and TNF-α secretion suggest the importance of HLA class I molecules in innate/inflammatory immune response. Better characterization of these genetic profiles could help to predict immune responses at the individual and population level, provide data on mechanisms of immune response development, and further inform vaccine development and vaccination policies.
doi:10.1016/j.vaccine.2009.01.079
PMCID: PMC2693348  PMID: 19200845
Rubella vaccine; HLA alleles; Cellular responses; Cytokines; ELISA; ELISPOT
20.  Vaccination of schoolgirls against rubella. Assessment of serological status and a comparative trial of Wistar RA 27/3 and Cendehill strain live attenuated rubella vaccines in 13-year-old schoolgirls in Dudley. 
A total of 1525 schoolgirls aged 13 years from 21 schools in the County Borough of Dudley, were bled for titration of rubella haemagglutinating inhibiting antibody and then were immediately vaccinated with either Wistar RA 27/3 or Cendehill strain live attenuated. Both vaccines were administered subcutaneously by syringe and needle but the Wistar RA 27/3 vaccine was also given by multiple injection apparatus. Significnatly higher conversion rates and geometric mean haemagglutinating inhibiting antibody titres were obtained in girls initially seronegative given the Wister RA 27/3 than in those given the Cendehill vaccine, regardless of the method of vaccination. The RA 27/3 strain was associated with a small but significantly greater incidence of local pain immediately on injection. With this exception, differences in the occurrence of reactions were not found between vaccines, between those initially susceptible and immune or with the level of antibody response.
PMCID: PMC478923  PMID: 766879
21.  Residual susceptibility to measles among young adults in Victoria, Australia following a national targeted measles-mumps-rubella vaccination campaign 
BMC Public Health  2007;7:99.
Background
Past measles immunisation policies in Australia have resulted in a cohort of young adults who have been inadequately vaccinated, but who also have low levels of naturally acquired immunity because immunisation programs have decreased the circulation of wild virus. A measles-mumps-rubella (MMR) immunisation campaign aimed at addressing this susceptibility to measles among young adults was conducted in Australia in 2001–2. By estimating age-specific immunity, we aimed to evaluate the success of this campaign in the state of Victoria.
Methods
We conducted serosurveys after the young adult MMR program at state and national levels to estimate immunity among young adults born between 1968–82. We compared results of the Victorian (state) surveys with the Victorian component of the national surveys and compared both surveys with surveys conducted before the campaign. We also reviewed all laboratory confirmed measles cases in Victoria between 2000–4.
Results
The Victorian state serosurveys indicated no significant change in immunity of the cohort following the young adult MMR campaign (83.9% immune pre and 85.5% immune post campaign) while the Victorian component of the national serosurvey indicated a significant decline in immunity (91.0% to 84.2%; p = 0.006). Both surveys indicated about 15% susceptibility to measles among young Victorian adults after the campaign. Measles outbreaks in Victoria between 2000–4 confirmed the susceptibility of young adults. Outbreaks involved a median of 2.5 cases with a median age of 24.5 years.
Conclusion
In Victoria, the young adult MMR program appears to have had no effect on residual susceptibility to measles among the 1968–82 birth cohort. Young adults in Victoria, as in other countries where past immunisation policies have left a residual susceptible cohort, represent a potential problem for the maintenance of measles elimination.
doi:10.1186/1471-2458-7-99
PMCID: PMC1913916  PMID: 17555601
22.  Etiology of Maculopapular Rash in Measles and Rubella Suspected Patients from Belarus 
PLoS ONE  2014;9(10):e111541.
As a result of successful implementation of the measles/rubella elimination program, the etiology of more and more double negative cases remains elusive. The present study determined the role of different viruses as causative agents in measles or rubella suspected cases in Belarus. A total of 856 sera sent to the WHO National Laboratory between 2009 and 2011 were tested for specific IgM antibodies to measles virus (MV), rubella virus (RV) and human parvovirus B19 (B19V). The negatives were further investigated for antibodies to enterovirus (EV) and adenovirus (AdV). Children of up to 3 years were tested for IgM antibodies to human herpesvirus 6 (HHV6). A viral etiology was identified in 451 (52.7%) cases, with 6.1% of the samples being positive for MV; 2.6% for RV; 26.2% for B19V; 9.7% for EV; 4.6% for AdV; and 3.6% for HHV6. Almost all measles and rubella cases occurred during limited outbreaks in 2011 and nearly all patients were at least 15 years old. B19V, EV and AdV infections were prevalent both in children and adults and were found throughout the 3 years. B19V occurred mainly in 3–10 years old children and 20–29 years old adults. EV infection was most common in children up to 6 years of age and AdV was confirmed mainly in 3–6 years old children. HHV6 infection was mostly detected in 6–11 months old infants. Laboratory investigation of measles/rubella suspected cases also for B19V, EV, AdV and HHV6 allows diagnosing more than half of all cases, thus strengthening rash/fever disease surveillance in Belarus.
doi:10.1371/journal.pone.0111541
PMCID: PMC4214721  PMID: 25356680
23.  Evaluation of Rubella Immunity in a Community Prenatal Clinic 
ISRN Family Medicine  2013;2013:602130.
Since the introduction of the Rubella vaccine in 1969, prevalence of congenital Rubella syndrome (CRS) has greatly declined in the United States. However, reports of sporadic adult cases of the disease and frequent identification of non-Rubella immune (NRI) women in prenatal units may result in outbreak of CRS in susceptible communities. Identifying populations with high rates of NRI will assist in evidence-based public health intervention that may prevent epidemic of CRS in the United States. Method. This is a retrospective, cross-sectional study involving chart audit of Rubella screening results of 642 women who attended a high-risk prenatal care at a northwestern Iowa clinic between January 1 and December 31, 2007. Results. NRI was found in 6.9% of the study population. The highest prevalence rate of 10.2% was found among adolescents. NRI was highest among Native American women at 17.3%, compared to Whites 7.3%, African Americans 5.9%, and Hispanics 4.6%. Multivariate analysis demonstrated that Native Americans were 2.5 times more likely to be NRI compared to Whites (OR 2.7; 95% CI: 1.1, 6.6). Conclusion. This study demonstrated higher rate of non-Rubella immunity among adolescent pregnant women and supports Rubella booster immunization for all non-pregnant teenage women. The observed high rate of NRI among Native Americans may require further studies and evaluation of Rubella vaccination programs in tribal communities.
doi:10.5402/2013/602130
PMCID: PMC4041247  PMID: 24967326
24.  Rubella Immunity in Women of Childbearing Age, Eight Years After the Immunization Program in Iran 
Background:
Rubella is a viral disease with a worldwide distribution. Mass vaccination campaigns have increased the vaccine coverage in the world with substantial impact on reduction of rubella infections. In Iran, the national measles-rubella campaign, targeting individuals 5-25 years old, was initiated in 2003 and mass childhood vaccination against measles, rubella and mumps has continued ever since.
Objectives:
The aim of this study was to evaluate the efficacy of routine vaccination on rubella immunity among women of childbearing age in Babol, north of Iran.
Patients and Methods:
This cross-sectional study was conducted on 812 women of childbearing age living in Babol, north of Iran, in 2011. Twelve samples were excluded from the study because of inadequate sera amounts. Serum samples were examined for presence of rubella-specific IgG antibodies by means of quantitative ELISA.
Results:
From a total of 800 samples in this study, rubella IgG seropositivity was seen in 786 (98.3% [95% CI = %97.5-%99.1]) cases. The maximum IgG seropositivity (99.2%) was seen in the age group of 21-25 years old and the lowest immunity (87.7%) was in the group of above 30 years old.
Conclusions:
Our data indicated that the rate of seropositivity to rubella virus in our population was high, suggesting that vaccination has been successful in Babol, reducing the likelihood of congenital rubella infection.
doi:10.5812/ircmj.10431
PMCID: PMC4166081  PMID: 25237562
Rubella; Congenital Rubella Syndrome; Immunity; Vaccination
25.  Sero-positivity rate of rubella and associated factors among pregnant women attending antenatal care in Mwanza, Tanzania 
Background
Sero-positivity rates of the rubella virus among pregnant women vary widely throughout the world. In Tanzania, rubella vaccination is not included in the national immunization schedule and there is therefore no antenatal screening for this viral disease. So far, there are no reports on the sero-prevalence of rubella among pregnant women in Tanzania. As a result, this study was undertaken to establish the sero-positivity rate of rubella and rubella risk factors among pregnant women attending antenatal care clinics in Mwanza, Tanzania.
Methods
From November 2012 to May 2013 a total of 350 pregnant women were enrolled and their serum samples collected and analyzed using the AXSYM anti-rubella virus IgG/IgM-MEIA test. Demographic and clinical data were collected using a standardized data collection tool. Data analysis was done using STATA version 12.
Results
Of 342 pregnant women tested for rubella antibodies, 317 (92.6%) were positive for anti-rubella IgG while only 1 (0.3%) was positive for IgM. Higher sero-positivity rates were found in the age group of 25–44 years. Furthermore, it was observed that with each year increase in age, the risk of contracting rubella increases by 12% (OR = 1.12, 95% CI: 1.02-1.22, P = 0.019). Women involved in farming and business women were at a higher risk of contracting rubella infection compared to formally employed women (OR: 4.9, P = 0.011; OR 7.1, p = 0.003 respectively). In univariate analysis, the risk of contracting rubella virus infection was found to increase with gestational age with a statistical significance.
Conclusions
Sero-positivity rates of rubella are high in Mwanza and are significantly associated with an increase in age and being a farmer or a business woman. Screening of rubella and immunization of women at risk are highly recommended in this area with a high non-immune rate against rubella virus.
doi:10.1186/1471-2393-14-95
PMCID: PMC3975942  PMID: 24589180
Prevalence; Rubella; Pregnancy; Mwanza; Tanzania

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