The Impact of Rubella Vaccine Introduction on Rubella Infection and Congenital Rubella Syndrome: A Systematic Review of Mathematical Modelling Studies

Abstract

Introduction: Rubella vaccines have been used to prevent rubella and congenital rubella syndrome (CRS) in several World Health Organization (WHO) regions. Mathematical modelling studies have simulated introduction of rubella-containing vaccines (RCVs), and their results have been used to inform rubella introduction strategies in several countries. This systematic review aimed to synthesize the evidence from mathematical models regarding the impact of introducing RCVs. Methods: We registered the review in the international prospective register of systematic reviews (PROSPERO) with registration number CRD42020192638. Systematic review methods for classical epidemiological studies and reporting guidelines were followed as far as possible. A comprehensive search strategy was used to identify published and unpublished studies with no language restrictions. We included deterministic and stochastic models that simulated RCV introduction into the public sector vaccination schedule, with a time horizon of at least five years. Models focused only on estimating epidemiological parameters were excluded. Outcomes of interest were time to rubella and CRS elimination, trends in incidence of rubella and CRS, number of vaccinated individuals per CRS case averted, and cost-effectiveness of vaccine introduction strategies. The methodological quality of included studies was assessed using a modified risk of bias tool, and a qualitative narrative was provided, given that data synthesis was not feasible. Results: Seven studies were included from a total of 1393 records retrieved. The methodological quality was scored high for six studies and very high for one study. Quantitative data synthesis was not possible, because only one study reported point estimates and uncertainty intervals for the outcomes. All seven included studies presented trends in rubella incidence, six studies reported trends in CRS incidence, two studies reported the number vaccinated individuals per CRS case averted, and two studies reported an economic evaluation measure. Time to CRS elimination and time to rubella elimination were not reported by any of the included studies. Reported trends in CRS incidence showed elimination within five years of RCV introduction with scenarios involving mass vaccination of older children in addition to routine infant vaccination. CRS incidence was higher with RCV introduction than without RCV when public vaccine coverage was lower than 50% or only private sector vaccination was implemented. Although vaccination of children at a given age achieved slower declines in CRS incidence compared to mass campaigns targeting a wide age range, this approach resulted in the lowest number of vaccinated individuals per CRS case averted. Conclusion and recommendations: We were unable to conduct data synthesis of included studies due to discrepancies in outcome reporting. However, qualitative assessment of results of individual studies suggests that vaccination of infants should be combined with vaccination of older children to achieve rapid elimination of CRS. Better outcomes are obtained when rubella vaccination is introduced into public vaccination schedules at coverage figures of 80%, as recommended by WHO, or higher. Guidelines for reporting of outcomes in mathematical modelling studies and the conduct of systematic reviews of mathematical modelling studies are required.

A retrospective 5-year review of rubella in South Africa prior to the introduction of a rubella-containing vaccine

“…Simply vaccinating young women only would not eradicate CRS unless 100% were immunised and is not recommended by the WHO. Recently various scenarios have been modelled [ 32 , 33 ]. Comparing different vaccine strategies and their relative costs, scenarios including mass campaigns resulted in more rapid elimination of rubella and CRS, however routine vaccination at 12 months of age coupled with vaccination of nine-year-old children was associated with the lowest cost per CRS case averted for a similar percentage reduction in CRS [ 33 ].…”

“…Recently various scenarios have been modelled [ 32 , 33 ]. Comparing different vaccine strategies and their relative costs, scenarios including mass campaigns resulted in more rapid elimination of rubella and CRS, however routine vaccination at 12 months of age coupled with vaccination of nine-year-old children was associated with the lowest cost per CRS case averted for a similar percentage reduction in CRS [ 33 ]. At 80% RCV coverage, all vaccine introduction scenarios modelled, would achieve rubella and CRS elimination in South Africa [ 32 ].…”

Epidemiological characteristic of rubella by age group during 12 years after the national introduction of rubella vaccine in Hangzhou, China

“…The combination of RCV coverage, serological investigation, rubella case surveillance, Rubella virological surveillance and mathematical modeling may provide support for routine CRS surveillance in the future. 14 , 21 , 25 …”

Low Susceptibility of Rubella Virus in First-Trimester Trophoblast Cell Lines

“…CRS occurs after the transplacental transmission of RuV during the first eight weeks of gestation in up to 90% of cases and during the second trimester in 25-35% [3]. CRS has severe medical and public health consequences with its typical symptoms, including cataracts, congenital heart disease, sensorineural hearing impairment, hepatosplenomegaly and microcephaly, underlining the need for and importance of rubella-containing vaccines in preventing rubella and CRS [4][5][6][7][8].…”