Congenital Rubella Syndrome Following Rubella Vaccination During Pregnancy.

Rubella vaccine is usually given in combination with measles and mumps vaccines as a measles-mumps-rubella vaccination. Because it contains live attenuated virus, its use is contraindicated during pregnancy. However, since the introduction of rubella vaccine, no cases of congenital rubella syndrome have been reported following vaccination during pregnancy. We report a case of a female infant, born to a woman inadvertently vaccinated with measles-mumps-rubella vaccination early in pregnancy, who manifested a phenotype of cardiac and neurologic defects, neurodevelopmental delay, and lymphocytopenia consistent with congenital rubella syndrome.

Study protocol for a phase 1/2, single-centre, double-blind, double-dummy, randomized, active-controlled, age de-escalation trial to assess the safety, tolerability and immunogenicity of a measles and rubella vaccine delivered by a microneedle patch in healthy adults (18 to 40 years), measles and rubella vaccine-primed toddlers (15 to 18 months) and measles and rubella vaccine-naïve infants (9 to 10 months) in The Gambia [Measles and Rubella Vaccine Microneedle Patch Phase 1/2 Age De-escalation Trial].

BACKGROUND: New strategies to increase measles and rubella vaccine coverage, particularly in low- and middle-income countries, are needed if elimination goals are to be achieved. With this regard, measles and rubella vaccine microneedle patches (MRV-MNP), in which the vaccine is embedded in dissolving microneedles, offer several potential advantages over subcutaneous delivery. These include ease of administration, increased thermostability, an absence of sharps waste, reduced overall costs and pain-free administration. This trial will provide the first clinical trial data on MRV-MNP use and the first clinical vaccine trial of MNP technology in children and infants. METHODS: This is a phase 1/2, randomized, active-controlled, double-blind, double-dummy, age de-escalation trial. Based on the defined eligibility criteria for the trial, including screening laboratory investigations, 45 adults [18-40 years] followed by 120 toddlers [15-18 months] and 120 infants [9-10 months] will be enrolled in series. To allow double-blinding, participants will receive either the MRV-MNP and a placebo (0.9% sodium chloride) subcutaneous (SC) injection or a placebo MNP and the MRV by SC injection (MRV-SC). Local and systemic adverse event data will be collected for 14 days following study product administration. Safety laboratories will be repeated on day 7 and, in the adult cohort alone, on day 14. Unsolicited adverse events including serious adverse events will be collected until the final study visit for each participant on day 180. Measles and rubella serum neutralizing antibodies will be measured at baseline, on day 42 and on day 180. Cohort progression will be dependent on review of the unblinded safety data by an independent data monitoring committee. DISCUSSION: This trial will provide the first clinical data on the use of a MNP to deliver the MRV and the first data on the use of MNPs in a paediatric population. It will guide future product development decisions for what may be a key technology for future measles and rubella elimination. TRIAL REGISTRATION: Pan-African Clinical Trials Registry 202008836432905 . CLINICALTRIALS: gov NCT04394689.

Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity.

BACKGROUND: Rubella virus-induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. OBJECTIVE: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas. METHODS: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays. RESULTS: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses. CONCLUSIONS: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine-induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.

Congenital Rubella Syndrome Surveillance After Measles Rubella Vaccination Introduction in Yogyakarta, Indonesia.

BACKGROUND: Congenital rubella syndrome (CRS) is a fatal disease causing severe congenital defects. Indonesia had the highest CRS cases in the world in 2016 with a commitment to achieve elimination of rubella disease by 2020, through the campaign and introduction of measles rubella (MR) national vaccination program in 2017 and 2018. This study aimed to describe the impact of the national vaccination campaign by conducting surveillance of CRS cases and comparing the incidence of new CRS cases before and after the MR vaccination campaign. METHODS: From July 2015 to July 2020, we conducted surveillance of CRS in Yogyakarta. Suspected patients underwent complete clinical examinations. Serology was tested for the presence of IgM and IgG antibodies against rubella. Descriptive analysis was used to characterize the demographic and clinical characteristics of the cases before and after the MR vaccination campaign. RESULTS: The study involved 229 infants who were suspected for CRS. Laboratory-confirmed cases were found in 47 of them (20.86%). Most of the laboratory-confirmed cases (55.3%) were reported among 1-5 months old infants. Common clinical features among laboratory-confirmed cases included structural heart defects in 43 (91.4%). There was a significant decrease (60.9%) of CRS incidence from 0.39 per 1000 live births in the precampaign era to 0.08 in the postcampaign era (P = 0.00). CONCLUSION: There has been a significant declining number of CRS cases based on pre- and post-MR vaccination campaign in Yogyakarta, Indonesia. An effective surveillance system will help monitor the number of CRS cases.

Immunogenicity, duration of protection, effectiveness and safety of rubella containing vaccines: A systematic literature review and meta-analysis.

BACKGROUND: Rubella containing vaccines (RCV) prevent rubella virus infection and subsequent congenital rubella syndrome (CRS). To update the evidence on immunogenicity, duration of protection, effectiveness and safety of RCV, we conducted a systematic literature review. METHODS: We searched EMBASE and SCOPUS, using keywords for rubella vaccine in combination with immunogenicity (seroconversion and seropositivity), duration of protection, efficacy/effectiveness, and safety. Original research papers involving at least one dose of RCV (at any age), published between 1-1-2010 and 17-5-2019 were included. Where appropriate, meta-analyses were performed. Quality of included studies was assessed using GRADE methodology. RESULTS: We included 36 papers (32 randomized controlled trials (RCTs) and 4 observational studies) on immunogenicity (RA27/3 strain) in children and adolescent girls, 14 papers (5 RCTs and 9 observational studies) on duration of protection, one paper on vaccine effectiveness (VE) (BRDII strain), and 74 studies on safety, including three on safety in pregnancy. Meta-analysis of immunogenicity data showed 99% seroconversion (95% CI: 98-99%) after a single dose of RCV in children, independent of co-administration with other vaccines. Seroconversion after RCV1 below 9 months of age (BRDII strain, at 8 months) was 93% (95% CI: 92-95%). For duration of protection, the included studies showed a seropositivity of 88%-100% measured 1-20 years after one or two RCV doses. The single study on VE of BRDII strain, reported 100% VE after one and two doses. Among 34,332 individuals participating in the RCTs, 140 severe adverse events (SAEs) were reported as possibly related to RCV. Among the case reports on SAEs, the association with RCV was confirmed in one report (on fulminant encephalitis). Among 3,000 pregnant women who were inadvertently vaccinated, no SAEs were reported. CONCLUSIONS: One and two doses of RCV are highly immunogenic for a long period of time, effective in preventing rubella and CRS, and safe.

Vaccine-associated Rubella - a report of two cases and a review of the literature.

We report the clinical characteristics of two adult patients, presenting with a typical erythematous rash consistent with rubella disease after MMR vaccination. Both patients had an uncomplicated clinical course and recovered uneventfully. One patient was confirmed to have vaccine-associated rubella via sequencing of virus isolated in viral culture. The other patient had a pharyngeal swab positive for rubella virus PCR, with sequencing matching the vaccine strain. There are few reports of clinical disease from rubella vaccine-strains in the literature. Previous authors have reported severe disseminated vaccine-associated rubella in both immunodeficient and immunocompetent patients. Further study is required to ascertain the incidence, risk factors, and clinical characteristics of this condition; as well as investigate the extent of horizontal transmission to guide infection control recommendations.

Rubella Vaccine Persistence Within Cutaneous Granulomas in Common Variable Immunodeficiency Disorder.

Common variable immunodeficiency disorder is a primary immunodeficiency disorder characterized by reduced levels of serum immunoglobulins and impaired antibody response. This condition may be associated with development of noninfectious granulomatous dermatitis of the skin which may be disfiguring and destructive. There are no published guidelines for the treatment of cutaneous granulomas in this patient population. In recent studies, rubella virus-positive cells in granulomas were localized to M2 macrophages which have an important role in wound healing and the secretion of immunoregulatory cytokines. We present a case of treatment-refractory, disfiguring common variable immunodeficiency disorder-associated granulomatous dermatitis. Immunofluorescence microscopy of the biopsy specimen confirmed the presence of rubella vaccine capsid proteins in M2 macrophages within the granuloma, a newly recognized phenomenon in this patient population. This knowledge may serve to identify future therapeutic targets or preventative strategies for granulomatous dermatitis in patients with primary immunodeficiency disorder.

Safety profile of rubella vaccine administered to pregnant women: A systematic review of pregnancy related adverse events following immunisation, including congenital rubella syndrome and congenital rubella infection in the foetus or infant.

BACKGROUND: Data on the safety of inadvertent rubella vaccination in pregnancy is important for rubella vaccination programs aimed at preventing congenital rubella syndrome. METHODS: The association between monovalent rubella or combination vaccinations in or shortly before pregnancy and potential harm to the foetus was examined by conducting a systematic review and meta-analysis using fixed effect methods and simulation. RESULTS: Four cohort studies of inadvertently vaccinated and unvaccinated women were found, 15 cohorts of pregnant women who were rubella susceptible at time of inadvertent vaccination and 9 cohort studies with no information on susceptibility and case series. No case of vaccine associated congenital rubella syndrome (CRS) was identified. Cohort studies with an unvaccinated comparison group were limited in number and size, and based on these only a theoretical additional risk of 6 or more cases of CRS per 1000 vaccinated women (0% observed, upper 95% CI 0.6%) could be excluded. Based on cohorts of vaccinated rubella susceptible pregnant women a maximum theoretical risk of 1 CRS case in 1008 vaccinated women (0% observed, upper 95% CI 0.099%) was estimated. Asymptomatic rubella vaccine virus infection of the neonate was also noted (fixed effects estimate of risk overall 1.74%, 95% CI 1.21, 2.28). CONCLUSION: There is no evidence that CRS is caused by rubella-containing vaccines but transplacental vaccine virus infection can occur. CRS is effectively prevented by vaccination, thus the risk/benefit balance is unequivocally in favour of vaccination. The data confirm previous recommendations that inadvertent vaccination during pregnancy is not an indication for termination of pregnancy.

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.

Bilateral Deafness as a Complication of the Vaccination-A Case Report.

The vaccination has much profit for an infectious disease. On the other hand, there is little frequency, side effects may appear. It includes severe complication. We reported the case that resulted in bilateral acute profound hearing loss after mumps alone and measles and rubella (MR) vaccination. The case was a 5 years old girl. She inoculated mumps alone and MR vaccine. After 18days later, both sides profound hearing loss occurred in her. The hearing loss was not improved by the intravenous feeding of the steroid. Three months later, cochlea implantation was carried out to her right ear. She got hearing again. As for the hearing loss, mumps vaccine was considered as a cause from a latency period until the onset. The bilateral profound hearing loss that was a very rare complication was occurred by vaccination. The care of the hearing is important, but the mental care of an affected child and the parent is important, too.

Acute Bilateral Photoreceptor Degeneration in an Infant After Vaccination Against Measles and Rubella.

Importance: Ocular inflammation is occasionally observed after vaccinations, and most of them resolve without permanent visual disturbances. However, there are some rare cases of severe ocular complications following vaccinations. Objective: To report the findings in an infant boy who developed an acute loss of vision bilaterally after Haemophilus influenzae type b, Pneumococcal conjugate vaccination, and measles and rubella vaccination. His vision did not recover. Design, Setting, and Participant: A retrospective review of the medical records of a 13-month-old Japanese boy. Main Outcomes and Measures: Fundus and fluorescein angiographic findings, ultrasonographic and optical coherence tomographic images, and electroretinographic findings. Results: A healthy 13-month-old boy had an acute loss of vision in both eyes 31 days after Haemophilus influenzae type b and Pneumococcal conjugate vaccinations and 24 days after a measles and rubella vaccination. He also developed a common cold 10 days before the vision loss. Ultrasonography showed an exudative retinal detachment 1 day after the onset of the visual reduction; however, his fundi appeared normal 4 days later. His eyes did not pursue objects, and pupillary light reflexes were not present. No signs of anterior uveitis were noted. He was treated with corticosteroids, but his vision did not improve. The retinal vessels gradually attenuated, and diffuse small white punctate lesions appeared in the deep retina. Optical coherence tomography showed a thinner outer nuclear layer and an absent ellipsoid zone. The electroretinograms were nonrecordable. These findings suggested a severe impairment of the photoreceptors, especially their outer segments. Western blot analysis of the patient's sera detected an antibody against recoverin, a calcium-binding protein of photoreceptors. Conclusions and Relevance: We hypothesize that an infection induced severe chorioretinitis with an exudative retinal detachment, which then produced an autoantibody against recoverin. The autoantibody then altered the function of the photoreceptors very rapidly. The initial infection may have been caused by the measles and rubella vaccination. However, because to our knowledge this has not been reported previously, the visual loss after the vaccinations may have been an extremely rare event that was coincidental or may have been related to the vaccination.

Cutaneous and Visceral Chronic Granulomatous Disease Triggered by a Rubella Virus Vaccine Strain in Children With Primary Immunodeficiencies.

Persistence of rubella live vaccine has been associated with chronic skin granuloma in 3 children with primary immunodeficiency. We describe 6 additional children with these findings, including 1 with visceral extension to the spleen.

Seasonal variation in rates of emergency room visits and acute admissions following recommended infant vaccinations in Ontario, Canada: a self-controlled case series analysis.

OBJECTIVES: To determine if birth month has an effect on the incidence of adverse events following the 2- and 12-month recommended vaccinations. STUDY DESIGN: Using health administrative databases, we conducted a population-based retrospective cohort study and employed a self-controlled case series analysis approach. We included children born in Ontario, Canada between April 1st 2002 and March 31st 2010 who received the diphtheria, tetanus, pertussis, inactivated poliovirus and Haemophilus influenzae type b (DTaP-IPV-Hib) vaccine recommended at 2 months and/or the measles, mumps, and rubella vaccine recommended at 12 months. We calculated the relative incidence (RI) of hospitalizations and emergency room visits within a pre-specified risk period compared to a control period following vaccination. We measured the effect of birth month using relative incidence ratios (RIRs) to compare the RI for infants born in each month to that for the month having the lowest RI. RESULTS: For the 2-month vaccination, we observed the lowest and highest RIs for infants born in October and April, respectively. The RIR (95% CI) for April compared to October was 2.06 (1.59-2.67, p<0.0001), consistent with a strong seasonal effect. For the 12-month vaccination, November births had the lowest RI, whereas August births had the highest. The RIR (95% CI) for August compared to November was 1.52 (1.30-1.77, p<0.0001). CONCLUSIONS: Our findings suggest a seasonal effect on susceptibility to adverse events following vaccination exists. Further study will be important to elucidate potential biological and/or behavioral explanations for the seasonal effect we observed.