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      Characterization of rubella-specific humoral immunity following two doses of MMR vaccine using proteome microarray technology

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          Abstract

          Introduction//Background

          The lack of standardization of the currently used commercial anti-rubella IgG antibody assays leads to frequent misinterpretation of results for samples with low/equivocal antibody concentration. The use of alternative approaches in rubella serology could add new information leading to a fuller understanding of rubella protective immunity and neutralizing antibody response after vaccination.

          Methods

          We applied microarray technology to measure antibodies to all rubella virus proteins in 75 high and 75 low rubella virus-specific antibody responders after two MMR vaccine doses. These data were used in multivariate penalized logistic regression modeling of rubella-specific neutralizing antibody response after vaccination.

          Results

          We measured antibodies to all rubella virus structural proteins (i.e., the glycoproteins E1 and E2 and the capsid C protein) and to the non-structural protein P150. Antibody levels to each of these proteins were: correlated with the neutralizing antibody titer (p<0.006); demonstrated differences between the high and the low antibody responder groups (p<0.008); and were components of the model associated with/predictive of vaccine-induced rubella virus-specific neutralizing antibody titers (misclassification error = 0.2).

          Conclusion

          Our study supports the use of this new technology, as well as the use of antibody profiles/patterns (rather than single antibody measures) as biomarkers of neutralizing antibody response and correlates of protective immunity in rubella virus serology.

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          Most cited references47

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          Rubella.

          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.
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            Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms.

            The flavivirus nonstructural protein NS1 is a highly conserved secreted glycoprotein that does not package with the virion. Immunization with NS1 elicits a protective immune response against yellow fever, dengue, and tick-borne encephalitis flaviviruses through poorly defined mechanisms. In this study, we purified a recombinant, secreted form of West Nile virus (WNV) NS1 glycoprotein from baculovirus-infected insect cells and generated 22 new NS1-specific monoclonal antibodies (MAbs). By performing competitive binding assays and expressing truncated NS1 proteins on the surface of yeast (Saccharomyces cerevisiae) and in bacteria, we mapped 21 of the newly generated MAbs to three NS1 fragments. Prophylaxis of C57BL/6 mice with any of four MAbs (10NS1, 14NS1, 16NS1, and 17NS1) strongly protected against lethal WNV infection (75 to 95% survival, respectively) compared to saline-treated controls (17% survival). In contrast, other anti-NS1 MAbs of the same isotype provided no significant protection. Notably, 14NS1 and 16NS1 also demonstrated marked efficacy as postexposure therapy, even when administered as a single dose 4 days after infection. Virologic analysis showed that 17NS1 protects at an early stage in infection through a C1q-independent and Fc gamma receptor-dependent pathway. Interestingly, 14NS1, which maps to a distinct region on NS1, protected through a C1q- and Fc gamma receptor-independent mechanism. Overall, our data suggest that distinct regions of NS1 can elicit protective humoral immunity against WNV through different mechanisms.
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              Molecular Biology of Rubella Virus

              Teryl Frey (1994)
              Publisher Summary This chapter summarizes the present medical significance of rubella virus. Rubella virus infection is systemic in nature and the accompanying symptoms are generally benign, the most pronounced being a mild rash of short duration. The most common complication of rubella virus infection is transient joint involvement such as polyarthralgia and arthritis. The primary health impact of rubella virus is that it is a teratogenic agent. The vaccination strategy is aimed at elimination of rubella and includes both universal vaccination of infants at 15 months of age with the trivalent measles, mumps, rubella (MMR) vaccine and specific targeting with the rubella vaccine of seronegative women planning pregnancy and seronegative adults who could come in contact with women of childbearing age, although it is recommended that any individual over the age of 12 months without evidence of natural infection or vaccination be vaccinated. Medically, the current challenge posed by rubella virus is to achieve complete vaccination coverage to prevent resurgences.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: SoftwareRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 November 2017
                2017
                : 12
                : 11
                : e0188149
                Affiliations
                [1 ] Mayo Vaccine Research Group, Mayo Clinic and Foundation, Rochester, MN, United States of America
                [2 ] Division of Biomedical Statistics and Informatics- Department of Health Science Research, Mayo Clinic and Foundation, Rochester, MN, United States of America
                Imperial College London, UNITED KINGDOM
                Author notes

                Competing Interests: Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland offers consultative advice on vaccine development to Merck & Co. Inc., Avianax, Dynavax, Novartis Vaccines and Therapeutics, Adjuvance Technologies, Seqirus, and Protein Sciences. Drs. Poland and Ovsyannikova hold three patents related to measles and vaccinia peptide research. Dr. Kennedy has received funding from Merck Research Laboratories to study waning immunity to measles and mumps after immunization with MMR-II. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0001-5057-4457
                Article
                PONE-D-17-18827
                10.1371/journal.pone.0188149
                5690594
                29145521
                b3e317c1-341d-4f87-b289-55022c60ea9d
                © 2017 Haralambieva et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 May 2017
                : 1 November 2017
                Page count
                Figures: 2, Tables: 2, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R37AI048793
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: R01AI033144
                Award Recipient :
                This work was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Numbers R37AI048793 and R01AI033144 (GAP). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                Biology and Life Sciences
                Physiology
                Immune Physiology
                Antibodies
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                Custom metadata
                The data has been deposited to the public repository Gene Expression Omnibus (GEO), study number GSE104148: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE104148.

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