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      Burden of congenital rubella syndrome (CRS) in India based on data from cross-sectional serosurveys, 2017 and 2019–20

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          Abstract

          Background

          India has set a goal to eliminate measles and rubella/Congenital Rubella Syndrome (CRS) by 2023. Towards this goal, India conducted nationwide supplementary immunization activity (SIA) with measles-rubella containing vaccine (MRCV) targeting children aged between 9 months to <15 years and established a hospital-based sentinel surveillance for CRS. Reliable data about incidence of CRS is necessary to monitor progress towards the elimination goal.

          Methods

          We conducted serosurveys in 2019–20 among pregnant women attending antenatal clinics of 6 hospitals, which were also sentinel sites for CRS surveillance, to estimate the prevalence of IgG antibodies against rubella. We systematically sampled 1800 women attending antenatal clinics and tested their sera for IgG antibodies against rubella. We used rubella seroprevalence data from the current survey and the survey conducted in 2017 among antenatal women from another 6 CRS surveillance sites to construct a catalytic models to estimate the incidence and burden of CRS.

          Result

          The seroprevalence of rubella antibodies was 82.3% (95% CI: 80.4–84.0). Rubella seropositivity did not differ by age group and educational status. Based on the constant and age-dependent force of infection models, we estimated that the annual incidence of CRS in India was 225.58 per 100,000 live births (95% CI: 217.49–232.41) and 65.47 per 100,000 live births (95% CI: 41.60–104.16) respectively. This translated to an estimated 14,520 (95% CI: 9,225–23,100) and 50,028 (95% CI: 48,234–51,543) infants with CRS every year based on age-dependent and constant force of infection models respectively.

          Conclusions

          Our findings indicated that about one fifth of women in the reproductive age group in India were susceptible for rubella. The estimates of CRS incidence will serve as a baseline to monitor the impact of MRCV SIAs, as well progress towards the elimination goal of rubella/CRS.

          Author summary

          Rubella infection during the first trimester of pregnancy can affect fetus, resulting in spontaneous abortion, stillbirth or birth of a baby with a combination of birth defects known as congenital rubella syndrome (CRS). Vaccination with rubella containing vaccine (RCV) is recommended as one of the strategies for eliminating rubella/CRS. The Southeast Asia region has set a target to eliminate rubella/CRS by 2023. Towards this goal, India completed nationwide immunization campaigns using measles-rubella vaccine during 2017–19, targeting children aged 9 months to <15 years. A case-based surveillance for CRS was initiated in five sentinel hospitals (Phase-1) in 2016 and later expanded to additional 6 sites (Phase-2) in 2019, to estimate burden of CRS and monitor its trend. As an adjunct to CRS surveillance, periodic serologic surveys were also planned to monitor the rubella seroprevalence among the pregnant women. A serosurvey conducted in 2017 indicated that 83.4% pregnant women attending antenatal clinics of Phase-1 sentinel hospitals had IgG antibodies against rubella. The second serosurvey conducted during 2019–20 in 6 Phase-2 sites indicated a comparable seroprevalence of 82.3%. Using seroprevalence data from these two serosurveys, we estimated that the annual incidence of CRS in India was 225.58 per 100,000 live births with constant force of infection and 65.47 per 100,000 live births with age-dependent force of infection models. This incidence rates translated to an estimated 14,520 to 50,028 infants with CRS every year. The estimates of CRS incidence will serve as a baseline to monitor the progress towards the elimination goal of rubella/CRS in India.

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          Most cited references17

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          Using Seroprevalence and Immunisation Coverage Data to Estimate the Global Burden of Congenital Rubella Syndrome, 1996-2010: A Systematic Review

          Background The burden of Congenital Rubella Syndrome (CRS) is typically underestimated in routine surveillance. Updated estimates are needed following the recent WHO position paper on rubella and recent GAVI initiatives, funding rubella vaccination in eligible countries. Previous estimates considered the year 1996 and only 78 (developing) countries. Methods We reviewed the literature to identify rubella seroprevalence studies conducted before countries introduced rubella-containing vaccination (RCV). These data and the estimated vaccination coverage in the routine schedule and mass campaigns were incorporated in mathematical models to estimate the CRS incidence in 1996 and 2000–2010 for each country, region and globally. Results The estimated CRS decreased in the three regions (Americas, Europe and Eastern Mediterranean) which had introduced widespread RCV by 2010, reaching <2 per 100,000 live births (the Americas and Europe) and 25 (95% CI 4–61) per 100,000 live births (the Eastern Mediterranean). The estimated incidence in 2010 ranged from 90 (95% CI: 46–195) in the Western Pacific, excluding China, to 116 (95% CI: 56–235) and 121 (95% CI: 31–238) per 100,000 live births in Africa and SE Asia respectively. Highest numbers of cases were predicted in Africa (39,000, 95% CI: 18,000–80,000) and SE Asia (49,000, 95% CI: 11,000–97,000). In 2010, 105,000 (95% CI: 54,000–158,000) CRS cases were estimated globally, compared to 119,000 (95% CI: 72,000–169,000) in 1996. Conclusions Whilst falling dramatically in the Americas, Europe and the Eastern Mediterranean after vaccination, the estimated CRS incidence remains high elsewhere. Well-conducted seroprevalence studies can help to improve the reliability of these estimates and monitor the impact of rubella vaccination.
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            Increase in congenital rubella occurrence after immunisation in Greece: retrospective survey and systematic review.

            To describe the events leading to the epidemic of congenital rubella syndrome in Greece in 1993 after a major rubella epidemic. Retrospective survey and systematic review. Greece (population 10 million), 1950-95. Children, adolescents, and women of childbearing age. Around 1975 in Greece the measles, mumps, and rubella vaccine started being given to boys and girls aged 1 year without policies to attain high vaccination coverage and to protect adolescents and young women. During the 1980s, vaccination coverage for rubella remained consistently below 50%, and the proportion of pregnant women susceptible to rubella gradually increased. In 1993 the incidence of rubella in young adults was higher than in any previous epidemic year. The epidemic of congenital rubella that followed, with 25 serologically confirmed cases (24.6 per 100 000 live births), was probably the largest such epidemic in Greece after 1950. With low vaccination coverage, the immunisation of boys and girls aged 1 year against rubella carries the theoretical risk of increasing the occurrence of congenital rubella. This phenomenon, which has not been previously reported, occurred in Greece.
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              Rubella immunity. Defining the level of protective antibody.

              L Skendzel (1996)
              The Rubella Subcommittee of the National Committee for Clinical Laboratory Standards has proposed lowering the breakpoint to define rubella immunity from 15 to 10 IU/mL. This recommendation stems from epidemiologic studies on vaccinated persons with low levels of antibody and anecdotal reports. Additional support comes from Centers for Disease Control and Prevention studies and reports. The effectiveness of rubella vaccination is well documented and the 10 IU/mL antibody level is protective in the vast majority of persons. Sporadic reports of viremia and/or reinfection among previously immunized persons with low antibody levels have been reported but proven cases of reinfection have also occurred in persons with titers greater than or equal to the 15 IU/mL cut-off. Despite the occasional occurrence of rubella reinfection in persons with low titers, the theoretical risks are small especially as compared with significantly greater risk in persons who have not been vaccinated. Immunity in a given patient is a clinical decision and the results of antibody tests for rubella, like other laboratory tests, must be evaluated in the context of the clinical setting.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Project administrationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: Data curationRole: Supervision
                Role: Data curationRole: Formal analysisRole: Software
                Role: ConceptualizationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                23 July 2021
                July 2021
                : 15
                : 7
                : e0009608
                Affiliations
                [1 ] ICMR–National Institute of Epidemiology, Chennai, Tamil Nadu, India
                [2 ] King George Medical University, Lucknow, Uttar Pradesh, India
                [3 ] All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
                [4 ] Govt Medical College, Thiruvananthapuram, Kerala, India
                [5 ] Mahatma Gandhi Institute of Medical Sciences, Sewagram, Maharashtra, India
                [6 ] All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
                [7 ] Nilofer Hospital, Hyderabad, Telangana, India
                [8 ] ICMR–National Institute of Virology, Pune, Maharashtra, India
                [9 ] All India Institute of Medical Sciences, Bibinagar, Telangana
                [10 ] Indian Council of Medical Research, New Delhi, India
                Beijing Children’s Hospital, Capital Medical University, CHINA
                Author notes

                The authors have declared that no competing interests exist.

                ‡ AA, RB, SJ, SKJ, JP, and KP also contributed equally to this work.

                ‡ SA, DB, AJ, RN, and SM also contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-1254-9802
                https://orcid.org/0000-0002-5318-6836
                https://orcid.org/0000-0001-8905-9292
                https://orcid.org/0000-0002-6264-4800
                https://orcid.org/0000-0001-6335-3805
                https://orcid.org/0000-0002-2178-9763
                https://orcid.org/0000-0003-0805-7370
                https://orcid.org/0000-0002-1517-0454
                https://orcid.org/0000-0002-4616-177X
                https://orcid.org/0000-0002-1041-3541
                https://orcid.org/0000-0002-6310-4232
                https://orcid.org/0000-0003-3195-0220
                https://orcid.org/0000-0001-9973-5311
                https://orcid.org/0000-0003-3587-8895
                https://orcid.org/0000-0003-2742-0366
                https://orcid.org/0000-0002-9431-2042
                https://orcid.org/0000-0003-1803-9977
                https://orcid.org/0000-0002-1720-7628
                Article
                PNTD-D-20-01940
                10.1371/journal.pntd.0009608
                8376255
                34297716
                d8c14d74-57a8-4579-b7e0-a102793f282d
                © 2021 Shanmugasundaram 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
                : 4 November 2020
                : 29 June 2021
                Page count
                Figures: 2, Tables: 3, Pages: 12
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100007334, ministry of health and family welfare;
                Award ID: 00101970
                Award Recipient :
                The study was funded by the Ministry of Health and Family Welfare, Govt of India, through Gavi, the Vaccine Alliance (MVM) (Grant Number: 00101970). 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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                2021-08-19
                All relevant data are within the manuscript and its Supporting Information files.

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                Infectious disease & Microbiology

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