Abnormal Development - Rubella Virus

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Child with Measles back rash day 3
Child with Measles back rash day 3 (CDC)
Rubella Virus EM
Rubella Virus, transmission electron micrograph (Image: CDC USA)

Rubella virus (Latin, rubella = little red), also known as "German Measles" (due to early citation in German medical literature), infection during pregnancy can cause congenital rubella syndrome (CRS) with serious malformations of the developing fetus. The type and degree of abnormality relates to the time of maternal infection.

Rubella peaked in 1964 and 1965, when 12.5 million cases were reported (USA). As a result, 20,000 babies were born with birth defects, 6,200 babies were stillborn, and an estimated 5,000 births were aborted, both naturally and assisted. At that time no treatment by vaccination existed and this only became available in 1969. The disease was dangerous because in children it was almost unnoticable and pregnant women often did not know that they had been exposed. Initial vaccination strategies varied between countries, in the United States infants were first to be vaccinated, while in the United Kingdom adolescent girls were first to be vaccinated.

Pregnancy effects of measles results in a higher risk of premature labor, spontaneous abortion, low-birth-weight, and possibly rare cases of birth defects with no definable pattern of malformation.[1]

Children infected with rubella before birth (a condition known as congenital rubella) are at risk for the following: growth retardation; malformations of the heart, eyes, or brain; deafness; and liver, spleen, and bone marrow problems.

The complete genomic sequence of Rubella is now known.[2] Rubella is a 9755 bp single stranded RNA positive-strand virus with no DNA stage (Togaviridae; Rubivirus) encoding nonstructural protein, capsid protein, glycoproteins E1 and E2. (More? Rubella Genome)

Tinycc Rubella Virus page - http://tiny.cc/Rubella_Virus

Viral Links: TORCH Infections | Cytomegalovirus | Hepatitis Virus | HIV | Parvovirus | Polio Virus | Rubella Virus | Chickenpox | Lymphocytic Choriomeningitis Virus | Zika Virus | Vaccination | Environmental
| Category:Rubella
File:USA Measles cases and outbreaks graph
USA Measles cases and outbreaks graph

Some Recent Findings

  • Americas region is declared the world’s first to eliminate rubella 29 April 2015 (PAHO/WHO) "The Americas region has become the first in the world to be declared free of endemic transmission of rubella, a contagious viral disease that can cause multiple birth defects as well as fetal death when contracted by women during pregnancy. Before mass-scale rubella vaccination, an estimated 16,000 to more than 20,000 children were born with CRS each year in Latin America and the Caribbean, while more than 158,000 rubella cases were reported in 1997 alone. In the United States, 20,000 infants were born with CRS during the last major rubella outbreak (1964-65)." PAHO
  • Rubella[3] "Rubella remains an important pathogen worldwide, with roughly 100 000 cases of congenital rubella syndrome estimated to occur every year. Rubella-containing vaccine is highly effective and safe and, as a result, endemic rubella transmission has been interrupted in the Americas since 2009. Incomplete rubella vaccination programmes result in continued disease transmission, as evidenced by recent large outbreaks in Japan and elsewhere. In this Seminar, we provide present results regarding rubella control, elimination, and eradication policies, and a brief review of new laboratory diagnostics. Additionally, we provide novel information about rubella-containing vaccine immunogenetics and review the emerging evidence of interindividual variability in humoral and cell-mediated innate and adaptive immune responses to rubella-containing vaccine and their association with haplotypes and single-nucleotide polymorphisms across the human genome."
  • Rubella and congenital rubella syndrome control and elimination - global progress, 2000-2012[4] "Rubella virus usually causes a mild fever and rash in children and adults. However, infection during pregnancy, especially during the first trimester, can result in miscarriage, stillbirth, or infants with congenital malformations, known as congenital rubella syndrome (CRS). In 2011, the World Health Organization (WHO) updated guidance on the preferred strategy for introduction of rubella-containing vaccine (RCV) into national routine immunization schedules with an initial wide-age-range vaccination campaign that includes children aged 9 months-15 years. WHO also urged all member states to take the opportunity offered by accelerated measles control and elimination activities as a platform to introduce RCVs. The Global Measles and Rubella Strategic Plan (2012-2020) published by the Measles Rubella Initiative partners in 2012 and the Global Vaccine Action Plan endorsed by the World Health Assembly in 2012 include milestones to eliminate rubella and CRS in two WHO regions by 2015, and eliminate rubella in five WHO regions by 2020. This report summarizes the global progress of rubella and CRS control and elimination during 2000-2012. As of December 2012, a total of 132 (68%) WHO member states had introduced RCV, a 33% increase from 99 member states in 2000. A total of 94,030 rubella cases were reported to WHO in 2012 from 174 member states, an 86% decrease from the 670,894 cases reported in 2000 from 102 member states."
  • Results of the rubella elimination program in Catalonia (Spain), 2002-2011[5] "Rubella is usually a mild disease with nonspecific symptoms, but can cause congenital rubella syndrome (CRS) when infection occurs during pregnancy. The objective of this study was to evaluate the sensitivity and positive predictive value of different data sources used for surveillance purposes in the Rubella Elimination Program of Catalonia between 2002 and 2011. The Urgent Notification to the Statutory Disease Reporting System, the Individualized Disease Reporting System, screening for other viruses included in the Measles Elimination Program, the Microbiological Reporting System and the Minimum Hospital Discharge Data were evaluated. 100 suspected cases of postnatal rubella and 6 suspected cases of CRS were detected. ... Most confirmed postnatal cases (25 cases, 48.1%) were in the 25-44 y age group followed by the 15-24 y age group (11 cases, 21.2%)."
  • Controlling rubella and preventing congenital rubella syndrome – global progress, 2009 [6] "In 2009, a total of 121,344 rubella cases were reported to WHO from 167 countries, a 82% decrease from 2000"
  • An update on cardiovascular malformations in congenital rubella syndrome (CRS) [7] "We searched the English literature from 1941 through 2008 to identify studies that used cardiac catheterization or echocardiography to evaluate the cardiovascular malformations in CRS. Although published studies of CVMs in CRS have in general reported patent ductus arteriosus (PDA) as the CVM phenotype most commonly associated with CRS, among CRS cases evaluated by catheterization, branch pulmonary artery stenosis was actually more common than PDA. Moreover, although the combination of branch pulmonary artery stenosis and PDA was more common than either branch pulmonary artery stenosis or PDA alone, isolated branch pulmonary artery stenosis was twice as common as isolated PDA. ...Among children with suspected CRS, clinical evaluations for the presence of cardiovascular malformations should include examinations for both branch pulmonary artery stenosis and PDA."
More recent papers
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

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Search term: Abnormal Development Rubella Virus

L D Frenkel, F Gomez, F Sabahi The pathogenesis of microcephaly resulting from congenital infections: why is my baby's head so small? Eur. J. Clin. Microbiol. Infect. Dis.: 2017; PubMed 28980148

Yanna K M Nóbrega, Bruna C de Carvalho, Nadjar Nitz, Tamires E Vital, Franco B Leite, Inês J Sequeira, Elsa E Moreira, Juliana K B de Andrade, Lenora Gandolfi, Riccardo Pratesi, Mariana M Hecht Rubella Seropositivity in Pregnant Women After Vaccination Campaign in Brazil's Federal District. Viral Immunol.: 2017; PubMed 28972455

Nathalie Auger, Caroline Quach, Jessica Healy-Profitós, Anne-Marie Lowe, Laura Arbour Congenital microcephaly in Quebec: baseline prevalence, risk factors and outcomes in a large cohort of neonates. Arch. Dis. Child. Fetal Neonatal Ed.: 2017; PubMed 28676560

Adolfo Martinez-Palomo Revisiting Zika (and Rubella). J Public Health Policy: 2016, 37(3);273-276 PubMed 28615701

Juan B Yepez, Felipe A Murati, Michele Pettito, Carlos F Peñaranda, Jazmin de Yepez, Gladys Maestre, J Fernando Arevalo, Johns Hopkins Zika Center Ophthalmic Manifestations of Congenital Zika Syndrome in Colombia and Venezuela. JAMA Ophthalmol: 2017; PubMed 28418539

Search term: Congenital Rubella Syndrome

Iêda M Orioli, Helen Dolk, Jorge S Lopez-Camelo, Daniel Mattos, Fernando A Poletta, Maria G Dutra, Flavia M Carvalho, Eduardo E Castilla Prevalence and clinical profile of microcephaly in South America pre-Zika, 2005-14: prevalence and case-control study. BMJ: 2017, 359;j5018 PubMed 29162597

Progress in rubella and congenital rubella syndrome control and elimination – worldwide, 2000–2016. [Progrès réalisés pour combattre et éliminer la rubéole et le syndrome de rubéole congénitale dans le monde, 2000-2016.]  Wkly. Epidemiol. Rec.: 2017, 92(46);707-15 PubMed 29148274

Gavin B Grant, Susan E Reef, Minal Patel, Jennifer K Knapp, Alya Dabbagh Progress in Rubella and Congenital Rubella Syndrome Control and Elimination - Worldwide, 2000-2016. MMWR Morb. Mortal. Wkly. Rep.: 2017, 66(45);1256-1260 PubMed 29145358

Eduardo Jucá, André Pessoa, Erlane Ribeiro, Rafaela Menezes, Saile Kerbage, Thayse Lopes, Luciano Pamplona Cavalcanti Hydrocephalus associated to congenital Zika syndrome: does shunting improve clinical features? Childs Nerv Syst: 2017; PubMed 29086073

Noriyuki Otsuki, Masafumi Sakata, Kyoko Saito, Kiyoko Okamoto, Yoshio Mori, Kentaro Hanada, Makoto Takeda Both sphingomyelin and cholesterol in the host cell membrane are essential for Rubella virus entry. J. Virol.: 2017; PubMed 29070689

Virus Structure

Identical genotype B3 sequences from measles patients in 4 countries
Identical genotype B3 sequences from measles patients in 4 countries, 2005.[8]

Lineage: Viruses; ssRNA viruses; ssRNA negative-strand viruses; Mononegavirales; Paramyxoviridae; Paramyxovirinae; Morbillivirus; Measles virus

  • ssRNA; linear; Length: 15,894 nt Measles virus, complete genome
  • virus replication involves a viral RNA-dependent RNA polymerase (vRdRp), using as a template a nucleocapsid (NC) made of a single strand of RNA in tight complex with the nucleoprotein (N).[9]
  • negative-strand genome contains six transcription units encoding the N, phospho (P), matrix (M), fusion (F), hemagglutinin (H), and large (L) or polymerase protein.
  • each N protein binds to 6 nucleotides.
  • the N polymer entirely covers the 15,894-nucleotide genome.
  • 23 known measles genotypes.
Rubella virus 01.jpg Rubella virus 03.jpg
This transmission electron micrograph (TEM) shows the presence of Rubella virus virions, as they were in the process of budding from the host cell surface to be freed into the host’s system. Inside the capsid lies the Rubella virus’ positive-sense single-stranded RNA ((+)ssRNA) genome. (Image: CDC) The spherical virions' icosahedral capsid is enclosed in the host cell membrane, budding and producing an enveloped virus particle. (Image: CDC)

Model of cell virus RNA accumulation

The following 5 -step model has been described for cell virus accumulation following hours post-infection (hpi)[9]

  1. 0 to ~5 hpi - incoming viral RNA-dependent RNA polymerase (vRdRp) initiated primary transcription from every gene with no detectable lag phase.
  2. ~5 to ~12 hpi - mRNA accumulates exponentially.
  3. ~12 to ~24 hpi - mRNAs, genomes, and antigenomes accumulate exponentially because of the increase of both newly available template and vRdRp.
  4. ~24 to ~30 hpi - genomes and antigenomes continue to accumulate exponentially at the same rate, whereas the accumulation of the transcripts slows down.
  5. 30+ hpi - genome and antigenome accumulation slows down, and the cell content in viral transcripts tends to decrease.


Rubella and measles elimination in the Americas
Rubella and measles elimination in the Americas

Japan - first introduced to Japan in 1966 and adopted in the national regular immunization program from 1978.

WHO Rubella Information

PAHO Countries reporting measles and rubella (2013-2014)
  • Causative agent - Virus
  • Reservoir - Humans
  • Spread - Close respiratory contact and aerosolized droplets
  • Transmission period - A few days before to seven days after rash; up to one year of age in congenitally infected
  • Subclinical infection - Common
  • Duration of natural immunity - Lifelong
  • Risk factors for infection (for unvaccinated individuals) - Highly transmissible; crowding; low socioeconomic status
  • Case-fatality rate - Less than 0.1 percent (dependent on care)
  • Vaccine (number of doses); route - Rubella (one or two); subcutaneous
  • Vaccine efficacy - 95 percent (at 12 months and up)
  • Duration of immunity after primary series - Lifelong in most; presumed rare cases of waning immunity after one dose, not two
  • Schedule - First dose at 12 to 15 months; when given, a second dose with measles vaccine
  • Status as of the end of 2001 - 110 countries in 2003
  • Comments - Lower efficacy when maternal antibody present

The World Health Organization recommends that the combination measles-rubella or measles-mumps-rubella vaccines be introduced only after careful evaluation of public health priorities within each country and following the establishment of an adequate program for measles control as demonstrated by high coverage rates as part of a well-functioning childhood immunization program.

Sources: WHO 2002, 2004.

Rubella History

Norman Gregg (1892-1966)


Norman Gregg (1892-1966) was a Sydney ophthalmologist who in 1941[10] identified the link between maternal rubella infection and developmental abnormalities (atypical congenital cataracts, congenital heart defects, infants small-for-gestational age) initially in his own practice. This had coincided with a rubella epidemic that occurred between 1940 to 1941.

Links: Norman Gregg


The rubella virus was initially isolated [11][12][13]


United States first licensed live, attenuated rubella vaccines introduced.

USA rubella and congenital rubella syndrome cases.jpg

United States Elimination of rubella and congenital rubella syndrome, 1969-2004[14]

  1. 1969 - First official recommendations are published for the use of rubella vaccine. Vaccination is recommended for children aged 1 year to puberty.
  2. 1978 - Recommendations for vaccination are expanded to include adolescents and certain adults, particularly females.
  3. 1981 - Recommendations place increased emphasis on vaccination of susceptible persons in training and educational settings.
  4. 1984 - Recommendations are published for vaccination of workers in daycare centres, schools, colleges, companies, government offices, and industrial sites. Providers encouraged to conduct prenatal testing and postpartum vaccination of susceptible women. Recommendations for vaccination are expanded to include susceptible persons who travel abroad.
  5. 1990 - Recommendations include implementation of a new 2-dose schedule for measles-mumps-rubella vaccine.

Rubella and measles elimination in the Americas.jpg

Rubella and measles elimination in the Americas[15]


In 2014 a Philippines measles outbreak of over 50,000 cases occurred. Travellers to and from the Philippines during this period led to an increase in cases occurring in other countries. For example, the USA experienced the highest number of measles cases CDC had reported in 20 years, over 600, many of the people who got measles last year were linked to travelers who had gotten measles from the Philippines.

Links: CDC 2014 travel advisory | NSW Health


USA Measles cases and outbreaks graph 01.jpg

From January 1 to January 28, 2015, 84 people from 14 states were reported to have measles. Most of these cases are part of a large, ongoing outbreak linked to an amusement park in California. On January 23, 2015, CDC issued a Health Advisory to notify public health departments and healthcare facilities about this multi-state outbreak and to provide guidance for healthcare providers nationwide. For more information see CDC Press Briefing Transcript: Measles in the United States, 2015, January 29, 2015.

Congenital Rubella Syndrome Abnormalities

The following are some examples of abnormalities associated with Congenital Rubella Syndrome (CRS).


Congenital rubella syndrome retinopathy
Congenital rubella syndrome retinopathy[16]
  • retinopathy
  • cataracts
  • micropthalmia
  • glaucoma
  • retinitis
Links: Vision Abnormalities | Vision Development


  • sensorineural deafness
Links: Hearing Abnormalities | Hearing Development


  • mental retardation
  • meningoencephalitis
  • (rare) progressive rubella panencephalitis
  • microcephaly


  • patent ductus arteriosis
  • atrial septal defect
  • ventricular septal defect
  • peripheral pulmonic stenosis


  • insulin dependent diabetes mellitus
  • thyroiditis

Other Systems

  • general growth retardation
  • radiolucent bone disease
  • heptosplenomegaly
  • heamatologic abnormalities (thrombocytopenia, purpura)
  • pneumonitis


  1. Makiko Egashira Chiba, Masatoshi Saito, Nobuaki Suzuki, Yoshinobu Honda, Nobuo Yaegashi Measles infection in pregnancy. J. Infect.: 2003, 47(1);40-4 PubMed 12850161
  2. G Dominguez, C Y Wang, T K Frey Sequence of the genome RNA of rubella virus: evidence for genetic rearrangement during togavirus evolution. Virology: 1990, 177(1);225-38 PubMed 2353453
  3. Nathaniel Lambert, Peter Strebel, Walter Orenstein, Joseph Icenogle, Gregory A Poland Rubella. Lancet: 2015; PubMed 25576992
  4. Centers for Disease Control and Prevention (CDC) Rubella and congenital rubella syndrome control and elimination - global progress, 2000-2012. MMWR Morb. Mortal. Wkly. Rep.: 2013, 62(48);983-6 PubMed 24304830 | MMWR Morb Mortal Wkly Rep.
  5. Irene Barrabeig, Nuria Torner, Ana Martínez, Gloria Carmona, Pilar Ciruela, Joan Batalla, Josep Costa, Sergi Hernández, Luis Salleras, Angela Domínguez, Rubella Surveillance Group of Catalonia Results of the rubella elimination program in Catalonia (Spain), 2002-2011. Hum Vaccin Immunother: 2013, 9(3);642-8 PubMed 23299566
  6. No authors listed Controlling rubella and preventing congenital rubella syndrome – global progress, 2009 Wkly Epidemiol Rec. 2010 Oct 15;85(42):413-8. PMID20949700 | PDF
  7. Matthew E Oster, Tiffany Riehle-Colarusso, Adolfo Correa An update on cardiovascular malformations in congenital rubella syndrome. Birth Defects Res. Part A Clin. Mol. Teratol.: 2010, 88(1);1-8 PubMed 19697432
  8. Jennifer Rota, Luis Lowe, Paul Rota, William Bellini, Susan Redd, Gustavo Dayan, Rob van Binnendijk, Susan Hahné, Graham Tipples, Jeannette Macey, Rita Espinoza, Drew Posey, Andrew Plummer, John Bateman, José Gudiño, Edith Cruz-Ramirez, Irma Lopez-Martinez, Luis Anaya-Lopez, Teneg Holy Akwar, Scott Giffin, Verónica Carrión, Ana Maria Bispo de Filippis, Andrea Vicari, Christina Tan, Bruce Wolf, Katherine Wytovich, Peter Borus, Francis Mbugua, Paul Chege, Janeth Kombich, Chantal Akoua-Koffi, Sheilagh Smit, Henry Bukenya, Josephine Bwogi, Frederick Ndhoga Baliraine, Jacques Kremer, Claude Muller, Sabine Santibanez Identical genotype B3 sequences from measles patients in 4 countries, 2005. Emerging Infect. Dis.: 2006, 12(11);1779-81 PubMed 17283637 | Emerg Infect Dis.
  9. 9.0 9.1 Sébastien Plumet, W Paul Duprex, Denis Gerlier Dynamics of viral RNA synthesis during measles virus infection. J. Virol.: 2005, 79(11);6900-8 PubMed 15890929 | PMC1112129
  10. Gregg N. McA. Congenital cataract following German measles in the mother. Trans Ophthalmol Soc Aust 1941;3:35–46. | N M Gregg Congenital cataract following German measles in the mother. 1941. Epidemiol. Infect.: 1991, 107(1);iii-xiv; discussion xiii-xiv PubMed 1879476 | PMC2272051
  11. Weller, T. H., and Neva, F. A. Propagation in tissue culture of cytopathic agents from patients with rubella-like illnes . Proc. Soc. Exper. Biol. & Med. 111:215–225, 1962.
  12. P D PARKMAN, E L BUESCHER, M S ARTENSTEIN Recovery of rubella virus from army recruits. Proc. Soc. Exp. Biol. Med.: 1962, 111;225-30 PubMed 13941530 | see PMC1926918
  14. Elimination of rubella and congenital rubella syndrome--United States, 1969-2004. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2005 Mar 25;54(11):279-82. PMID 15788995 | MMWR Morb Mortal Wkly Rep.
  15. Progress Report: Elimination of Rubella and CRS in the Americas, 2007 Powerpoint slide on Elimination of Rubella and Congenital Rubella Syndrome in the Americas: Progress Report. Pan American Health Organization World Health Organization.
  16. Imran Jivraj, Chris J Rudnisky, Emmanuel Tambe, Graham Tipple, Matthew T S Tennant Identification of ocular and auditory manifestations of congenital rubella syndrome in mbingo. Int J Telemed Appl: 2014, 2014;981312 PubMed 25525427 | PMC4262751 | Int J Telemed Appl. 2



M De Santis, A F Cavaliere, G Straface, A Caruso Rubella infection in pregnancy. Reprod. Toxicol.: 2006, 21(4);390-8 PubMed 16580940

Kihei Terada Rubella and congenital rubella syndrome in Japan: epidemiological problems. Jpn. J. Infect. Dis.: 2003, 56(3);81-7 PubMed 12944671


Yan Feng, Sabine Santibanez, Hazel Appleton, Yiyu Lu, Li Jin Application of new assays for rapid confirmation and genotyping of isolates of rubella virus. J. Med. Virol.: 2011, 83(1);170-7 PubMed 21108356

Graham Tipples, Joanne Hiebert Detection of measles, mumps, and rubella viruses. Methods Mol. Biol.: 2011, 665;183-93 PubMed 21116802

M J Binnicker, D J Jespersen, J A Harring Multiplex detection of IgM and IgG class antibodies to Toxoplasma gondii, rubella virus, and cytomegalovirus using a novel multiplex flow immunoassay. Clin. Vaccine Immunol.: 2010, 17(11);1734-8 PubMed 20861325

Juan Fontana, Carmen López-Iglesias, Wen-Ping Tzeng, Teryl K Frey, José J Fernández, Cristina Risco Three-dimensional structure of Rubella virus factories. Virology: 2010, 405(2);579-91 PubMed 20655079

Stanley A Plotkin The history of rubella and rubella vaccination leading to elimination. Clin. Infect. Dis.: 2006, 43 Suppl 3;S164-8 PubMed 16998777

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Cite this page: Hill, M.A. 2017 Embryology Abnormal Development - Rubella Virus. Retrieved November 23, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Rubella_Virus

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