Infectious #vaccine-derived #rubella viruses emerge, persist, and evolve in cutaneous #granulomas of #children with primary #immunodeficiencies (PLoS Pathog., abstract)

[Source: PLoS Pathogens, full page: (LINK). Abstract, edited.]


Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies

Ludmila Perelygina, Min-hsin Chen, Suganthi Suppiah, Adebola Adebayo, Emily Abernathy, Morna Dorsey, Lionel Bercovitch, Kenneth Paris, Kevin P. White, Alfons Krol, Julie Dhossche, Ivan Y. Torshin, Natalie Saini,  [ … ], Joseph Icenogle


Published: October 28, 2019 / DOI: / This is an uncorrected proof.



Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10−3 subs/site/year and 8.9 x 10−4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.


Author summary

Primary immunodeficiency diseases (PID) are caused by genetic defects and lead to serious problems including chronic granulomas (abnormal collections (nodules) of inflammatory cells), sometimes lasting for decades and sometimes leading to severe ulcers. Initial reports (2014–2016), including our report of a blinded study using ultrasensitive virus detection in biopsies, proved the association between granuloma of the skin in PID patients and rubella virus. The viruses in these reports and the current report were derived from a widely used vaccine strain of the rubella virus. Work reported here shows that these vaccine-derived viruses are biologically different from the vaccine virus and that their genomes have changed. Genomic changes could be analyzed largely because the exact sequence of starting vaccine virus genome was known. These genomic differences are likely generated via mechanisms similar to those occurring during normal circulation of wild type rubella. We present data that newly recognized mechanisms for generation of sequence diversity in viruses (because of cellular deaminases) likely occurs in the generation of these vaccine-derived rubella viruses. Thousands of PID patients in the United States are likely shedding these vaccine-derived rubella viruses. Our work presented here characterizing viruses in diagnostic specimens highlights at least two areas where insufficient work has been done: 1) research on the properties of rubella virus (limited understanding of the antibody binding sites on the virus); 2) controlled research studies to assess the public health impact of viruses in populations with high immunity.


Citation: Perelygina L, Chen M-h, Suppiah S, Adebayo A, Abernathy E, Dorsey M, et al. (2019) Infectious vaccine-derived rubella viruses emerge, persist, and evolve in cutaneous granulomas of children with primary immunodeficiencies. PLoS Pathog 15(10): e1008080.

Editor: Adam S. Lauring, University of Michigan, UNITED STATES

Received: April 24, 2019; Accepted: September 13, 2019; Published: October 28, 2019

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Data Availability: All sequences of iVDRV genomes are available from the GenBank database (accession number(s) MK787188 – MK787191 and MK780807- MK780812)

Funding: This work was supported by core funding from the Centers for Disease Control and Prevention, by a grant to K.E.S. from the National Institute of Health (R21-AI130967-01A1) and by the US National Institute of Health Intramural Research Program Project Z1AES103266 to D.A.G. K.E.S. was supported by the Wallace Chair of Pediatrics. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the United States Centers for Disease Control and Prevention. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have read the journal’s policy and have the following conflicts: Andrey Zharkikh is an employee of Myriad Genetics. This company works in cancer genetics and diagnostics without any relation to pathogen studies and treatments. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.

Keywords: Rubella; Vaccines; Rubivirus.


#Immunogenicity and #safety of #measles- #rubella #vaccine co-administered with attenuated Japanese #encephalitis SA 14–14–2 vaccine in infants aged 8 months in #China: a non-inferiority RCT (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Immunogenicity and safety of measles-rubella vaccine co-administered with attenuated Japanese encephalitis SA 14–14–2 vaccine in infants aged 8 months in China: a non-inferiority randomised controlled trial

Yan Li, MD, Susan Y Chu, PhD, Chenyan Yue, MD, Kathleen Wannemuehler, PhD, Shuyun Xie, MD, Fubin Zhang, MD, Yamin Wang, MD, Yuxi Zhang, MD, Rui Ma, MD, Yumin Li, MD, Zhiping Zuo, MD, Lance Rodewald, MD, Qiyou Xiao, MD, Zijian Feng, MD, Huaqing Wang, MD, Zhijie An, MD

Published: March 01, 2019 / DOI:




In China, measles-rubella vaccine and live attenuated SA 14–14–2 Japanese encephalitis vaccine (LJEV) are recommended for simultaneous administration at 8 months of age, which is the youngest recommended age for these vaccines worldwide. We aimed to assess the effect of the co-administration of these vaccines at 8 months of age on the immunogenicity of measles-rubella vaccine.


We did a multicentre, open-label, non-inferiority, two-group randomised controlled trial in eight counties or districts in China. We recruited healthy infants aged 8 months who had received all scheduled vaccinations according to the national immunisation recommendations and who lived in the county of the study site. Enrolled infants were randomly assigned (1:1) to receive either measles-rubella vaccine and LJEV simultaneously (measles-rubella plus LJEV group) or measles-rubella vaccine alone (measles-rubella group). The primary outcome was the proportion of infants with IgG antibody seroconversion for measles 6 weeks after vaccination, and a secondary outcome was the proportion of infants with IgG antibody seroconversion for rubella 6 weeks after vaccination. Analyses included all infants who completed the study. We used a 5% margin to establish non-inferiority. This trial was registered ( NCT02643433).


1173 infants were assessed for eligibility between Aug 13, 2015, and June 10, 2016. Of 1093 (93%) enrolled infants, 545 were randomly assigned to the measles-rubella plus LJEV group and 548 to the measles-rubella group. Of the infants assigned to each group, 507 in the measles-rubella plus LJEV group and 506 in the measles-rubella group completed the study. Before vaccination, six (1%) of 507 infants in the measles-rubella plus LJEV group and one (<1%) of 506 in the measles-rubella group were seropositive for measles; eight (2%) infants in the measles-rubella plus LJEV group and two (<1%) in the measles-rubella group were seropositive for rubella. 6 weeks after vaccination, measles seroconversion in the measles-rubella plus LJEV group (496 [98%] of 507) was non-inferior to that in the measles-rubella group (499 [99%] of 506; difference −0·8% [90% CI −2·6 to 1·1]) and rubella seroconversion in the measles-rubella plus LJEV group (478 [94%] of 507) was non-inferior to that in the measles-rubella group (473 [94%] of 506 infants; difference 0·8% [90% CI −1·8 to 3·4]). There were no serious adverse events in either group and no evidence of a difference between the two groups in the prevalence of any local adverse event (redness, rashes, and pain) or systemic adverse event (fever, allergy, respiratory infections, diarrhoea, and vomiting). Fever was the most common adverse event (97 [19%] of 507 infants in the measles-rubella plus LJEV group; 108 [21%] of 506 infants in the measles-rubella group).


The evidence of similar seroconversion and safety with co-administered LJEV and measles-rubella vaccines supports the co-administration of these vaccines to infants aged 8 months. These results will be important for measles and rubella elimination and the expansion of Japanese encephalitis vaccination in countries where it is endemic.


US Centers for Disease Control and Prevention, US Department of Health and Human Services; China–US Collaborative Program on Emerging and Re-emerging Infectious Diseases.

Keywords: Measles; Rubella; Japanese encephalitis; Vaccines; China.


#Seroprevalence of #Zika Virus and #Rubella Virus #IgG among #blood donors in #Rwanda and in #Sweden (J Med Virol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

J Med Virol. 2018 Apr 12. doi: 10.1002/jmv.25090. [Epub ahead of print]

Seroprevalence of Zika Virus and Rubella Virus IgG among blood donors in Rwanda and in Sweden.

Seruyange E1,2,3, Gahutu JB1, Muvunyi CM1, Katare S4, Ndahindwa V5, Sibomana H6, Nyamusore J7, Rutagarama F2, Hannoun C3, Norder H3, Bergström T3.

Author information: 1 Faculty of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Rwanda. 2 Rwanda Military Hospital, Kigali, Rwanda. 3 Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden. 4 National Centre for Blood Transfusion, Rwanda Biomedical Centre, Kigali, Rwanda. 5 School of Public Health, College of Medicine and Health Sciences, University of Rwanda, Rwanda. 6 Expanded Program on Immunization, Rwanda Biomedical Centre, Kigali, Rwanda. 7 Division of Epidemic Surveillance and Response, Rwanda Biomedical Centre, Kigali, Rwanda.



Statement of the problem

Seroprevalence studies provide information on the susceptibility to infection of certain populations, including women of childbearing age. Such data from Central Africa are scarce regarding two viruses that cause congenital infections: Zika virus (ZIKV), an emerging mosquito-borne infection, and rubella virus (RuV), a vaccine-preventable infection. We report on the seroprevalence of both ZIKV and RuV from Rwanda, a country without any known cases of ZIKV, but bordering Uganda where this virus was isolated in 1947.


Anti-ZIKV-specific and anti-RuV-specific immunoglobulin G (IgG) antibodies were analyzed by enzyme-linked immunosorbent assay (ELISA) in serum samples from 874 Rwandan and 215 Swedish blood donors. Samples positive for IgG antibodies against ZIKV were examined for viral RNA using real-time reverse transcription polymerase chain reaction (RT-qPCR).


The seroprevalence of ZIKV IgG in Rwanda was 1.4% (12/874), of which the predominance of positive findings came from the Southeastern region. All anti-ZIKV IgG-positive samples were PCR-negative. Among 297 female blood donors of childbearing age, 295 (99.3%) were seronegative and thus susceptible to ZIKV. All Swedish blood donors were IgG-negative to ZIKV. In contrast, blood donors from both countries showed high seroprevalence of IgG to RuV: 91.2% for Rwandan and 92.1% for Swedish donors. Only 10.5% (31/294) of female donors of childbearing age from Rwanda were seronegative for RuV.


In Rwanda, seroprevalence for ZIKV IgG antibodies was low, but high for RuV. Hence, women of childbearing age were susceptible to ZIKV. These data may be of value for decision-making regarding prophylactic measures.

This article is protected by copyright. All rights reserved.

KEYWORDS: ELISA; Rubella virus; Rwanda; Seroprevalence; Zika virus

PMID: 29645295 DOI: 10.1002/jmv.25090

Keywords: Zika Virus; Rubella; Rwanda; Sweden; Seroprevalence.


Características de la estructura molecular de las proteínas E del virus del #Zika y E1 del virus de la #rubéola y posibles implicaciones en el #neurotropismo y en las alteraciones del sistema nervioso (Biomedica, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Biomedica. 2017 Apr 1;37(0):121-132. doi: 10.7705/biomedica.v37i0.3807.

Características de la estructura molecular de las proteínas E del virus del Zika y E1 del virus de la rubéola y posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso.

[Article in Spanish]

Gómez LA1, Montoya G, Rivera HM, Hernández JC.

Author information: 1 Grupo de Fisiología Molecular, Subdirección de Investigación Científica y Tecnológica, Dirección de Investigación en Salud Pública, Instituto Nacional de Salud, Bogotá, D.C., Colombia Departamento de Ciencias Fisiológicas, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, D.C., Colombia.




El virus del Zika (ZIKV) es un flavivirus con envoltura, transmitido a los seres humanos principalmente por el vector Aedes aegypti. La infección por ZIKV se ha asociado con un gran neurotropismo y con efectos neuropáticos, como el síndrome de Guillain-Barré en el adulto y la microcefalia fetal y posnatal, así como con un síndrome de infección congénita similar al producido por el virus de la rubéola (RV).


Comparar las estructuras moleculares de la proteína de envoltura E del virus del Zika (E-ZIKV) y de la E1 del virus de la rubéola (E1-RV), y plantear posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso asociadas con el ZIKV.

Materiales y métodos.

La secuencia de aminoácidos de la proteína E-ZIKV (PDB: 5iZ7) se alineó con la de la glucopreteína E1 del virus de la rubéola (PDB: 4ADG). Los elementos de la estructura secundaria se determinaron usando los programas Vector NTI Advance®, DSSP y POSA, así como herramientas de gestión de datos (AlignX®). Uno de los criterios principales de comparación y alineación fue la asignación de residuos estructuralmente equivalentes, con más de 70 % de identidad.


La organización estructural de la proteína E-ZIKV (PDB: 5iZ7) fue similar a la de E1-RV (PDB: 4ADG) (70 a 80 % de identidad), y se observó una correspondencia con la estructura definida para las glucoproteínas de fusión de membrana de clase II de los virus con envoltura. E-ZIKV y E1-RV exhibieron elementos estructurales de fusión muy conservados en la región distal del dominio II, asociados con la unión a los receptores celulares de entrada del virus de la rubéola (glucoproteína de mielina del oligodendrocito, Myelin Oligodendrocyte Glycoprotein, MOG), y con los receptores celulares Axl del ZIKV y de otros flavivirus.


La comparación de las proteínas E-ZIKV y E1-RV es un paso necesario hacia la definición de otros factores moleculares determinantes del neurotropismo y la patogenia del ZIKV, el cual puede contribuir a generar estrategias de diagnóstico, prevención y tratamiento de las complicaciones neurológicas inducidas por el ZIKV.

KEYWORDS: estructura molecular; glucoproteína de la mielina del oligodendrocito; microcefalia; virus Zika; virus de la rubéola

PMID: 28527274

Keywords: Zika Virus; Rubella; Microcephaly.


#Cutaneous and #visceral chronic #granulomatous disease triggered by a #Rubella Virus #vaccine strain in #children with primary #immunodeficiencies (Clin Infect Dis., abstract)

[Source: Clinical Infectious Diseases Journal, full page: (LINK). Abstract, edited.]

Cutaneous and visceral chronic granulomatous disease triggered by a Rubella Virus vaccine strain in children with primary immunodeficiencies

Bénédicte Neven1,2,3,*, Philippe Pérot4,5,*, Julie Bruneau6, Marlene Pasquet7, Marie Ramirez4, Jean-Sébastien Diana1,2, Stéphanie Luzi8, Nicole Corre-Catelin9, Christophe Chardot10, Despina Moshous1,2,3, Stéphanie Leclerc Mercier6,11, Nizar Mahlaoui2,3, Nathalie Aladjidi12, Brigitte Le Bail13, Marc Lecuit1,3,4,14, Christine Bodemer11, Thierry Jo Molina1,6, Stéphane Blanche1,2,3, and Marc Eloit4,§

Author Affiliations: 1Sorbonne Paris Cité, Paris Descartes University, Institut Imagine, Paris-F; 2Paediatric Haemato-Immunology Unit, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris (AP-HP), Paris-F; 3National Reference Centre for Primary Immune Deficiencies (CEREDIH), Paris-F; 4Institut Pasteur, Inserm U1117, Biology of Infection Unit, Laboratory of Pathogen Discovery, Paris-F; 5Institut Pasteur, CITECH, Biomics, Paris-F; 6Department of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; 7Hematology and Immunology pediatric Department, CHU Toulouse, Center of Research in Cancerology of Toulouse (CRCT), Team 16, IUCT-Oncopole, Toulouse-F; 8Departement of radiology, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; 9ICAREB, Institut Pasteur, Paris-F; 10Department of Pediatric Surgery, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; 11Department of Dermatology, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France; 12Pediatric Oncology Hematology Unit / CEREVANCE / CIC 1401, Inserm CICP, University Hospital of Bordeaux, Pediatric Hospital, Bordeaux, France; 13Department of Pathology, Hopital des Enfants-Hôpital Pellegrin, Bordeaux-F; 14Department of Infectious Diseases, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France

§corresponding author : Institut Pasteur Inserm U1117, Biology of Infection Unit, Laboratory of Pathogen Discovery, 28 rue du Docteur Roux, 75015 Paris-F

* Bénédicte Neven and Philippe Pérot contributed equally to this work



Persistence of rubella live vaccine has been associated with chronic skin granuloma in three children with primitive immune deficiency (PID). We report here six additional children with PID and live rubella vaccine-associated chronic skin granuloma, one of them with visceral extension to the spleen.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail

Keywords: Research; Abstracts; Rubella; Vaccines.



[Source: Eurosurveillance, full page: (LINK). Abstract, edited.]

Eurosurveillance, Volume 21, Issue 38, 22 September 2016 / Research article


M Lazar 1 7 , E Abernathy 2 , M Chen 2 , J Icenogle 2 , D Janta 3 , A Stanescu 3 , A Pistol 3 , S Santibanez 4 , A Mankertz 4 , JM Hübschen 5 , G Mihaescu 7 , G Necula 1 6 , E Lupulescu 1

Author affiliations: 1. National Institute of Research-Development for Microbiology and Immunology “Cantacuzino”, Bucharest, Romania; 2. National Center for Immunizations and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States; 3. National Centre for Communicable Diseases Surveillance and Control, National Institute of Public Health, Bucharest, Romania; 4. WHO-EURO, Regional Reference Laboratory for Measles and Rubella, Robert Koch Institute, Berlin, Germany; 5. Department of Infection and Immunity, WHO-EURO Regional Reference Laboratory for Measles and Rubella, Luxembourg Institute of Health Esch-sur-Alzette, Grand-Duchy of Luxembourg; 6. Horia Hulubei National Institute for R&D in Physics and Nuclear Engineering, Bucharest, Romania; 7. University of Bucharest, Faculty of Biology, Department of Virology, Bucharest, Romania.

Correspondence: Mihaela Lazar (

Citation style for this article: Lazar M, Abernathy E, Chen M, Icenogle J, Janta D, Stanescu A, Pistol A, Santibanez S, Mankertz A, Hübschen JM, Mihaescu G, Necula G, Lupulescu E. Epidemiological and molecular investigation of a rubella outbreak, Romania, 2011 to 2012. Euro Surveill. 2016;21(38):pii=30345. DOI:

Received:02 June 2015; Accepted:16 June 2016



We describe a rubella outbreak that occurred in Romania between September 2011 and December 2012. During this period 24,627 rubella cases, 41.1% (n=10,134) of which female, were notified based on clinical criteria, and a total of 6,182 individuals were found serologically positive for IgM-specific rubella antibody. The median age of notified cases was 18 years (range: <1–65) and the most affected age group 15 to 19 years (n=16,245 cases). Of all notified cases, 24,067 cases (97.7%) reported no history of vaccination. Phylogenetic analysis of 19 sequences (739 nucleotides each), from 10 districts of the country revealed that the outbreak was caused by two distinct rubella virus strains of genotype 2B, which co-circulated with both temporal and geographical overlap. In addition to the 6,182 IgM-positive rubella cases, 28 cases of congenital rubella syndrome (CRS) were identified, including 11 neonatal deaths and one stillbirth. The outbreak underscores the need to encourage higher vaccination uptake in the population, particularly in women of reproductive age, and to strengthen epidemiological and laboratory investigations of suspected rubella cases. Genetic characterisation of wild-type rubella virus is an essential component to enhance surveillance and here we report rubella virus sequences from Romania.

Keywords: Research; Abstracts; Rubella; Romania.


#Invasion #Dynamics of #Teratogenic #Infections in Light of #Rubella #Control: Implications for #Zika Virus (PLoS Curr., abstract)

[Source: PLoS Currents Outbreaks, full page: (LINK). Abstract, edited.]

Invasion Dynamics of Teratogenic Infections in Light of Rubella Control: Implications for Zika Virus


AUTHORS: C. Jessica E. Metcalf, Alan Barrett




The greatest burden for a subset of pathogens is associated with infection during pregnancy. Evidence for teratogenic effects of Zika Virus have highlighted the importance of understanding the epidemiology of such pathogens. Rubella is perhaps the most classic example, and there is much to be learned from the long history of modelling associated with this virus.


We extended an existing framework for modeling age-specific dynamics of rubella to illustrate how the body of knowledge of rubella dynamics informs the dynamics of teratogenic infections more broadly, and particularly the impact of control on such infections in different transmission settings.


During invasion, the burden in women of childbearing age is expected to peak, but then fall to low levels before eventually levelling out. Importantly, as illustrated by rubella dynamics, there is potential for a paradoxical effect, where inadequate control efforts can increase the burden.


Drawing on the existing body of work on rubella dynamics highlights key knowledge gaps for understanding the risks associated with Zika Virus. The magnitude and impacts of sterilizing immunity, plus antigenic maps measuring cross-protection with other flaviviruses, and the magnitude of transmission, as well as likely impact of control efforts on transmission are likely to be key variables for robust inference into the outcome of management efforts for Zika Virus.


CJEM was funded by the Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Keywords: Research; Abstracts; Zika Virus; Zika Congenital Syndrome; Pregnancy; Rubella.