The impact of sub-national heterogeneities in demography and epidemiology on the introduction of rubella vaccination programs in Nigeria.

Rubella infection during pregnancy can result in miscarriage or infants with a constellation of birth defects known as congenital rubella syndrome (CRS). When coverage is inadequate, rubella vaccination can increase CRS cases by increasing the average age of infection. Thus, the World Health Organisation recommends that countries introducing rubella vaccine be able to vaccinate at least 80% of each birth cohort. Previous studies have focused on national-level analyses and have overlooked sub-national variation in introduction risk. We characterised the sub-national heterogeneity in rubella transmission within Nigeria and modelled local rubella vaccine introduction under different scenarios to refine the set of conditions and strategies required for safe rubella vaccine use. Across Nigeria, the basic reproduction number ranged from 2.6 to 6.2. Consequently, the conditions for safe vaccination varied across states with low-risk areas requiring coverage levels well below 80 %. In high-risk settings, inadequate routine coverage needed to be supplemented by campaigns that allowed for gradual improvements in vaccination coverage over time. Understanding local heterogeneities in both short-term and long-term epidemic dynamics can permit earlier nationwide introduction of rubella vaccination and identify sub-national areas suitable for program monitoring, program improvement and campaign support.

A measles and rubella vaccine microneedle patch in The Gambia: a phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial.

BACKGROUND: Microneedle patches (MNPs) have been ranked as the highest global priority innovation for overcoming immunisation barriers in low-income and middle-income countries. This trial aimed to provide the first data on the tolerability, safety, and immunogenicity of a measles and rubella vaccine (MRV)-MNP in children. METHODS: This single-centre, phase 1/2, double-blind, double-dummy, randomised, active-controlled, age de-escalation trial was conducted in The Gambia. To be eligible, all participants had to be healthy according to prespecified criteria, aged 18-40 years for the adult cohort, 15-18 months for toddlers, or 9-10 months for infants, and to be available for visits throughout the follow-up period. The three age cohorts were randomly assigned in a 2:1 ratio (adults) or 1:1 ratio (toddlers and infants) to receive either an MRV-MNP (Micron Biomedical, Atlanta, GA, USA) and a placebo (0·9% sodium chloride) subcutaneous injection, or a placebo-MNP and an MRV subcutaneous injection (MRV-SC; Serum Institute of India, Pune, India). Unmasked staff ransomly assigned the participants using an online application, and they prepared visually identical preparations of the MRV-MNP or placebo-MNP and MRV-SC or placebo-SC, but were not involved in collecting endpoint data. Staff administering the study interventions, participants, parents, and study staff assessing trial endpoints were masked to treatment allocation. The safety population consists of all vaccinated participants, and analysis was conducted according to route of MRV administration, irrespective of subsequent protocol deviations. The immunogenicity population consisted of all vaccinated participants who had a baseline and day 42 visit result available, and who had no protocol deviations considered to substantially affect the immunogenicity endpoints. Solicited local and systemic adverse events were collected for 14 days following vaccination. Unsolicited adverse events were collected to day 180. Age de-escalation between cohorts was based on the review of the safety data to day 14 by an independent data monitoring committee. Serum neutralising antibodies to measles and rubella were measured at baseline, day 42, and day 180. Analysis was descriptive and included safety events, seroprotection and seroconversion rates, and geometric mean antibody concentrations. The trial was registered with the Pan African Clinical Trials Registry PACTR202008836432905, and is complete. FINDINGS: Recruitment took place between May 18, 2021, and May 27, 2022. 45 adults, 120 toddlers, and 120 infants were randomly allocated and vaccinated. There were no safety concerns in the first 14 days following vaccination in either adults or toddlers, and age de-escalation proceeded accordingly. In infants, 93% (52/56; 95% CI 83·0-97·2) seroconverted to measles and 100% (58/58; 93·8-100) seroconverted to rubella following MRV-MNP administration, while 90% (52/58; 79·2-95·2) and 100% (59/59; 93·9-100) seroconverted to measles and rubella respectively, following MRV-SC. Induration at the MRV-MNP application site was the most frequent local reaction occurring in 46 (77%) of 60 toddlers and 39 (65%) of 60 infants. Related unsolicited adverse events, most commonly discolouration at the application site, were reported in 35 (58%) of 60 toddlers and 57 (95%) of 60 infants that had received the MRV-MNP. All local reactions were mild. There were no related severe or serious adverse events. INTERPRETATION: The safety and immunogenicity data support the accelerated development of the MRV-MNP. FUNDING: Bill & Melinda Gates Foundation.

Age-specific prevalence of IgG against measles/rubella and the impact of routine and supplementary immunization activities: A multistage random cluster sampling study with mathematical modelling.

BACKGROUND: Vietnam continues to have measles and rubella outbreaks following supplementary immunization activities (SIA) and routine immunization despite both having high reported coverage. To evaluate immunization activities, age-specific immunity against measles and rubella, and the number of averted Congenital Rubella Syndrome (CRS) cases, must be estimated. METHODS: Dried blood spots were collected from 2091 randomly selected individuals aged 1-39 years. Measles and rubella virus-specific immunoglobulin G (IgG) were measured by enzyme immunoassay. Results were considered positive at ≥120 mIU/mL for measles and ≥10 IU/mL for rubella. The number of CRS cases averted by immunization since 2014 were estimated using mathematical modelling. RESULTS: Overall IgG seroprevalence was 99.7% (95%CI: 99.2-99.9) for measles and 83.6% (95%CI: 79.3-87.1) for rubella. Rubella IgG seroprevalence was higher among age groups targeted in the SIA than in non-targeted young adults (95.4% [95%CI: 92.9-97.0] vs 72.4% [95%CI: 63.1-80.1]; P < 0.001). The estimated number of CRS cases averted in 2019 by immunization activities since 2014 ranged from 126 (95%CI: 0-460) to 883 (95%CI: 0-2271) depending on the assumed postvaccination reduction in the force of infection. CONCLUSIONS: The results suggest the SIA was effective, while young adults born before 1998 who remain unprotected for rubella require further vaccination.

Live attenuated rubella vectors expressing Plasmodium falciparum circumsporozoite protein (Pf-CSP) provide a novel malaria vaccine platform in the rhesus macaque.

There is an urgent need for a malaria vaccine that can prevent severe disease in young children and adults. Despite earlier work showing an immunological mechanism for preventing infection and reducing disease severity, there is currently no reliable vaccine that can provide durable protection. In part, this may reflect a limited number of ways that the host can respond to the NANP repeat sequences of circumsporozoite protein (CSP) in the parasite. In addition, it may reflect antigenic escape by the parasite from protective antibodies. To be successful, a vaccine must protect against repeated exposure to infected mosquitoes in endemic areas. We have created a series of live viral vectors based on the rubella vaccine strain that express multiple tandem repeats of NANP, and we demonstrate immunogenicity in a rhesus macaque model. We tested the vectors in a sequential immunization strategy. In the first step, the animals were primed with CSP-DNA vaccine and boosted with rubella/CSP vectors. In the second step, we gave rubella/CSP vectors again, followed by recombinant CSP protein. Following the second step, antibody titers were comparable to adult exposure to malaria in an endemic area. The antibodies were specific for native CSP protein on sporozoites, and they persisted for at least 1½ years in two out of three macaques. Given the safety profile of rubella vaccine in children, these vectors could be most useful in protecting young children, who are at greatest risk of severe malarial disease.

Factors Predicting Rubella Vaccination among Pregnant Women in Japan: an Interim Report from the Pregnant Women Health Initiative.

Following the 2018 rubella outbreak in Japan, this study aimed to assess rubella prevention measures based on the vaccination and immunization status of pregnant women in Japan. Our cohort study involved 3 local core hospitals in Yokohama City, and a total of 666 pregnant women were recruited between June 2018 and September 2019 and answered an online questionnaire. In total, 67.5% of the pregnant women had received rubella vaccination. The rate of rubella vaccination among pregnant women in the present survey was lower than that among age-matched female participants in a nationwide survey conducted in 2018. Overall, the study results showed that pregnant women in their 20s had a higher vaccination rate than those in their 40s, women who were nonsmokers before pregnancy had a higher vaccination rate than those who were smokers, and pregnant women who were aware that rubella may affect their fetuses had a higher vaccination rate than those who were unaware of this. This survey elucidated multiple predictive factors for rubella vaccination among pregnant women in Japan. Our results confirm the recommendation that women considering pregnancy should be vaccinated against rubella.

Safety and immunogenicity of co-administration of meningococcal type A and measles-rubella vaccines with typhoid conjugate vaccine in children aged 15-23 months in Burkina Faso.

OBJECTIVES: The World Health Organization pre-qualified single-dose typhoid conjugate vaccine (TCV) and requested data on co-administration with routine vaccines. The co-administration of Typbar TCV (Bharat Biotech International) with routine group A meningococcal conjugate vaccine (MCV-A) and measles-rubella (MR) vaccine was tested. METHODS: This was a double-blind, randomized controlled trial performed in Ouagadougou, Burkina Faso. Children were recruited at the 15-month vaccination visit and were assigned randomly (1:1:1) to three groups. Group 1 children received TCV plus control vaccine (inactivated polio vaccine) and MCV-A 28 days later; group 2 children received TCV and MCV-A; group 3 children received MCV-A and control vaccine. Routine MR vaccine was administered to all participants. Safety was assessed at 0, 3, and 7 days after immunization, and unsolicited adverse events and serious adverse events were assessed for 28 days and 6 months after immunization, respectively. RESULTS: A total of 150 children were recruited and vaccinated. Solicited symptoms were infrequent and similar for TCV and control recipients, as were adverse events (group 1, 61.2%; group 2, 64.0%; group 3, 68.6%) and serious adverse events (group 1, 2.0%; group 2, 8.0%; group 3, 5.9%). TCV generated robust immunity without interference with MCV-A vaccine. CONCLUSIONS: TCV can be safely co-administered at 15 months with MCV-A without interference. This novel study on the co-administration of TCV with MCV-A provides data to support large-scale uptake in sub-Saharan Africa.

Rubella Immunity among Italian Female Healthcare Workers: A Serological Study.

Rubella, also known as German measles or three-day measles, is an infectious disease caused by virus of the genus Rubivirus, which may be prevented by vaccination. The infection is potentially dangerous for non immune subjects, although 20-50% of infected subjects are asymptomatic. Healthcare workers (HCWs) have an increased potential exposure to rubella in comparison to the general population, putting them and their patients at risk of infection and its complications. In 2019, 20 cases of rubella have been reported in Italy. According to the Italian National Immunization and Prevention Plan, HCWs should provide a written certification of vaccination for rubella or serological evidence of protective antibodies. The aim of the study was to evaluate the rubella immunization status in female HCWs of the teaching hospital Policlinic Rome Tor Vergata (PTV) of childbearing age. For this purpose, we retrospectively checked the serologic values of rubella-specific IgG antibodies analyzing the clinical records of the HCWs of undergoing the occupational health surveillance program from January 1st to June1st 2020. Five hundred fourteen HCWs with a mean age of 23.19 (range 19-37, DS: 2.80) were included: 90.3% (464) showed a protective antibody titre. The mean value of the anti-rubella IgG was 49.59 IU/mL. Our study shows a non-protective anti rubella IgG titre in a substantial percentage of HCWs (9.7%). As vaccine protection decreases over the years and the risk of congenital rubella syndrome (CRS) in vaccinated subjects should not be underestimated, we suggest routine screening of the immunological status followed by the administration of a third dose of vaccine if the antibody titre becomes non-protective.

Rubella seroepidemiology among Korean women: Two decades after a combined vaccination strategy.

OBJECTIVES: The aim was to examine rubella seronegativity among women of childbearing age after the introduction of rubella-containing vaccine (RCV) among teenage girls and universal MMR programs in South Korea. METHODS: The serum IgG data of 72 114 women aged 20-49 years, who had undergone rubella antibody testing at the Gangnam CHA Medical Center between 2004 and 2018, were examined. A serum IgG level <10.0 IU/ml was considered negative. The study population was divided into three cohorts based on the vaccination policy: cohort 1, 1955-1976 (no national immunization program); cohort 2, 1977-1985 (national rubella only vaccination for high schoolers); cohort 3, 1986-1993 (combination strategy). We compared the rate of seronegativity and the adjusted odds ratio (OR) of seronegativity of each cohort. RESULTS: The overall proportion of seronegative women decreased significantly, from 6.1% in 2004 to 2.5% in 2018 (Kendall tau = -0.89, p < 0.001). The rate of seronegativity was highest among women who were not targeted for national immunization (born in 1955-1977, 5.2%), while it was lowest among candidates receiving routine and catch-up vaccinations (born in 1986-1993, 2.2%). When controlling for the effect of age and year of testing, the OR for seronegativity was lower for cohort 2 (adjusted OR 0.68, 95% confidence interval (CI) 0.60-0.76) and cohort 3 (OR 0.55, 95% CI 0.40-0.75) when compared to cohort 1. CONCLUSIONS: Women who were covered by either vaccination program were less susceptible to rubella infection, supporting the value of both approaches. The study findings will serve as empirical evidence for an immunization program targeted towards young women and children.

Rubella IgM epidemiology in the pre-rubella vaccination era in Uganda.

BACKGROUND: Control of Rubella and Congenital Rubella Syndrome using vaccination has shown great success in the America's. Uganda is due to introduce the Rubella vaccine however the magnitude of transmission is not well documented. Therefore this study was done to determine IgM sero-prevalance for Rubella in order to help monitor vaccine effectiveness post introduction of the vaccine in routine vaccination programme. METHODS: A retrospective review of suspected measles cases data for the reporting period January 2007 to December 2016 in Uganda was Done. rubella IgM testing was done on 15,296 of the cases and the data was analyzed using STATA version 13. RESULTS: In total 15,296 cases were tested and 4255 (27.8%) tested positive and among females aged 15-49 years 88 out of 322 (27%) tested positive. The age distribution range was 0-80 years, rubella IgM positivity was reported in all the 15 regions of Uganda and throughout the ten year period in every month. Age group 5-15 years had OR 2.5 p-value < 0.001 of being rubella IgM positive compared to age < 5 years and testing measles IgM negative OR 6.3 p-value < 0.001. CONCLUSION: Rubella is endemic in Uganda and although rubella IgM positivity is highest in the age 5-15 years even the younger, older and women of reprodutive age are affected. This means the risk of Congenital Rubella Syndrome is high hence the need to introduce the rubella vaccine for infants and pregnant mothers and continued surveillance to enhance its control.

Descriptive epidemiology of rubella disease and associated virus strains in Uganda.

Rubella virus causes a mild disease; however, infection during the first trimester of pregnancy may lead to congenital rubella syndrome (CRS) in over 80% of affected pregnancies. Vaccination is recommended and has been shown to effectively reduce CRS incidence. Uganda plans to introduce routine rubella vaccination in 2019. The World Health Organization recommends assessing the disease burden and obtaining the baseline molecular virological data before vaccine introduction. Sera collected during case-based measles surveillance from January 2005 to July 2018 were tested for rubella immunoglobulin M (IgM) antibodies. Sera from confirmed rubella outbreaks from January 2012 to August 2017 were screened using real-time reverse-transcription polymerase chain reaction (RT-PCR); for positive samples, a region within the E1 glycoprotein coding region was amplified and sequenced. Of the 23 196 suspected measles cases serologically tested in parallel for measles and rubella, 5334 (23%) were rubella IgM-positive of which 2710 (50.8%) cases were females with 2609 (96.3%) below 15 years of age. Rubella IgM-positive cases were distributed throughout the country and the highest number was detected in April, August, and November. Eighteen (18%) of the 100 sera screened were real-time RT-PCR-positive of which eight (44.4%) were successfully sequenced and genotypes 1G and 2B were identified. This study reports on the seroprevalence and molecular epidemiology of rubella. Increased knowledge of former and current rubella viruses circulating in Uganda will enhance efforts to monitor the impact of vaccination as Uganda moves toward control and elimination of rubella and CRS.

Determinants of Vaccination Coverage for the Second Dose of Measles-Rubella Vaccine in Tokyo, Japan.

In Japan, some measles outbreaks were initiated by a tourist from oversea and foreign workers recently. Moreover, rubella outbreak emerged since July 2018 mainly in the South Kanto, and the outbreak is currently ongoing in 2019. It is important to maintain a high measles-rubella combined vaccine (MR) coverage for measles-rubella control. Vaccination coverage for the second dose of MR (MR2) is 90.8% in Tokyo in 2016, which was the third worst among all prefectures in Japan. The purpose of this study was to clarify determinant factors of vaccination coverage for MR2 in Tokyo. Data were obtained for 49 wards and cities in Tokyo in 2016. We regressed vaccination coverage of MR2 on the times of notification by mail, the proportion of households receiving welfare payments, and the proportion of non-Japanese elementary school students. In addition to the simplest specification, five factors were included separately as explanatory variables: the proportion of public health nurses; the ratio of the number of pediatric medical facilities to the number of preschool and elementary school children; the moving-in rate; the proportion of households with a single parent; and the proportion of households with husband and wife both working. Results show that a high proportion of households receiving welfare payments, notification by two or more letters, and moving-in rate or a lower proportion of non-Japanese elementary school students improve coverage. In conclusion, the health authorities can exert efforts to reduce burden of time spent for vaccination and provide sufficient information to improve coverage.

Measles and rubella immunity in the population of Bhutan, 2017.

BACKGROUND: In 2017, measles elimination was verified in Bhutan, and the country appears to have sufficiently high vaccination coverage to achieve rubella elimination. However, a measles and rubella serosurvey was conducted to find if any hidden immunity gaps existed that could threaten Bhutan's elimination status. METHODS: A nationwide, three-stage, cluster seroprevalence survey was conducted among individuals aged 1-4, 5-17, and >20 years in 2017. Demographic information and children's vaccination history were collected, and a blood specimen was drawn. Serum was tested for measles and rubella immunoglobulin G (IgG). Frequencies, weighted proportions, and prevalence ratios for measles and rubella seropositivity were calculated by demographic and vaccination history, taking into account the study design. RESULTS: Of the 1325 individuals tested, 1045 (81%, 95% CI 78%-85%) were measles IgG seropositive, and 1290 (97%, 95% CI 95%-99%) were rubella IgG seropositive. Rubella IgG seropositivity was high in all three age strata, but only 47% of those aged 5-17 years were measles IgG seropositive. Additionally, only 41% of those aged 5-17 years who had documented receipt of two doses of measles- or measles-rubella-containing vaccine were seropositive for measles IgG, but almost all these children were rubella IgG seropositive. CONCLUSIONS: An unexpected measles immunity gap was identified among children 5-17 years of age. It is unclear why this immunity gap exists; however, it could have led to a large outbreak and threatened sustaining of measles elimination in Bhutan. Based on this finding, a mass vaccination campaign was conducted to close the immunity gap.

Biological view of vaccination described by mathematical modellings: from rubella to dengue vaccines.

The only rubella vaccine available in North America is the RA27/3 strain (isolated from the kidney of a rubella-infected fetus and attenuated) licensed in 1979, which substituted HPV77/DE5 strain vaccine due to concerns about waning immunity. The first dengue vaccine (Dengvaxia CYDTDV) was first registered in Mexico in December, 2015, which is a live recombinant tetravalent dengue vaccine. Rubella vaccine was applied since 1969, but tetravalent dengue vaccine is being used in large scale nowadays. In the past, based on unavailable information regarded to rubella vaccine, mathematical models were used to design vaccination schemes in order to avoid congenital rubella syndrome (CRS). Currently, knowing that vaccine does not result in CRS, rubella vaccination is modelled as usual childhood infection. This experience of updated biological knowledge that influenced mathematical modellings of rubella vaccination is taken into account to reflect about the tetravalent dengue vaccine. We also address a discussion about the security of vaccination strategies.

Rubella transmission and the risk of congenital rubella syndrome in Liberia: a need to introduce rubella-containing vaccine in the routine immunization program.

BACKGROUND: Rubella is an RNA virus in the genus Rubivirus within the Matonaviridae family. Rubella remains a leading vaccine-preventable cause of birth defects. Most African countries including Liberia do not currently provide rubella-containing vaccine (RCV) in their immunization program. We analyzed the existing surveillance data to describe rubella cases and identify the at-risk population. METHODS: We conducted a retrospective descriptive statistics on the suspected-measles case-based surveillance data that obtained from the national database. Suspected-measles cases who were negative and indeterminate for measles IgM and tested for rubella IgM were extracted from the database. We used only rubella IgM positive cases to calculate trends and percentages by person, place and time. The cumulative-percent curve was used to visually describe the age distribution of rubella cases. RESULTS: During 2017-2018, a total of 2027 suspected-measles cases with known laboratory results were reported; of which, 1307 were tested for rubella IgM. Among tested cases, 472 (36%) were positive, 769 (59%) were negative and 66 (5%) were indeterminate for rubella IgM. Female contributed 269 (57%) of the confirmed rubella cases respectively. The median age was 7 years with an interquartile range of 5-10 years. From the total rubella cases, 6 (1%) were under 1 year, 109 (23%) were 1-4 years, 207 (44%) were 5-9 years, 87 (18%) were 10-14 years and 56 (12%) were more than or equal to 15 years. Women in their reproductive-age contributed 23 (5%) of rubella cases with 17% positivity rate. Two-thirds or 307 (65%) of the cases were reported from February to May which is dry season in Liberia. CONCLUSIONS: Our analysis revealed that rubella was widely circulating in Liberia. Majority of the cases were reported among children < 15 years. However, rubella was also reported among women of reproductive age and infants < 1 year with no report of congenital rubella syndrome (CRS). Detail investigation of rubella cases among infants of < 1 year and women of reproductive age is important to uncover CRS. Establishment of CRS surveillance and the introduction of RCV in the immunization program are crucial to prevent rubella infection and avert the risk of CRS.

Estimating the immunogenicity of measles-rubella vaccination administered during a mass campaign in Lao People's Democratic Republic using multi-valent seroprevalence data.

Measles and rubella are important causes of morbidity and mortality globally. Despite high coverage reported for measles vaccination, outbreaks continue to occur in some countries. The reasons for these outbreaks are poorly understood. We apply Bayesian methods to multi-valent seroprevalence data for measles and rubella, collected 2 years and 3 months after a mass measles-rubella vaccination campaign in Lao PDR to estimate the immunogenicity and vaccination coverage. When the vaccination coverage was constrained to exceed 95% or 90%, consistent with officially-reported values, the immunogenicity of the measles vaccine component was unexpectedly low (75% (95% CR: 63-82%) and 79% (CR: 70-87%) respectively. The estimated immunogenicity increased after relaxing constraints on the vaccination coverage, with best-fitting values of 83% (95% CR: 73-91%) and 97% (95% CR: 90-100%) for the measles and rubella components respectively, with an estimated coverage of 83% (95% CR: 80-88%). The findings suggest that, if the vaccine coverage was as high as that reported, continuing measles outbreaks in Lao PDR, and potentially elsewhere, may be attributable to suboptimal immunogenicity attained in mass campaigns. Vaccine management in countries with high reported levels of coverage and ongoing measles outbreaks needs to be reviewed if measles elimination targets are to be achieved.

Preclinical study of safety and immunogenicity of combined rubella and human papillomavirus vaccines: Towards enhancing vaccination uptake rates in developing countries.

Rubella vaccine was not part of national immunization programs (NIP) in several countries in the Middle East and North Africa (MENA), South-East Asia (SEA), and South Africa regions until the year 2000. Therefore, immunization coverage of females older than 20 years old in these countries has been the focus of national campaigns for rubella elimination in developing countries. Vaccines against human papillomavirus (HPV) are not part of NIPs in developing countries. To enhance the advantages of rubella-directed immunization campaigns and to increase HPV vaccine uptake in developing countries, this study aimed to test the stability, potency, efficacy and safety of a combined rubella and HPV vaccine. Female BALB/c mice were immunized subcutaneously with proposed combined HPV16/HPV18 VLP and rubella vaccine at weeks (W) 0, 3 then with HPV vaccine at W 7. Immunized mice developed antigen-specific antibodies against rubella and HPV significantly higher than mice immunized with rubella or HPV vaccine alone. The combined vaccine induced significantly higher splenocyte proliferation than control groups. In addition, pro-inflammatory cytokines IL-4, IL-6, IL-2, and IFNγ levels were significantly higher in mice immunized with the combined vaccine than control groups. Overall, the combined vaccine was safe and immunogenic offering antibody protection as well as eliciting a cellular immune response against rubella and HPV viruses in a single vaccine. This combined vaccine can be of great value to females above 20 years old in the SEA, MENA and South Africa regions offering coverage to rubella vaccine and a potential increase in HPV vaccine uptake rates after appropriate clinical testing.