Functional properties of measles virus proteins derived from a subacute sclerosing panencephalitis patient who received repeated remdesivir treatments.

Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient's brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV in vitro. We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease.

Intralesional measles, mumps, and rubella vaccine after failure of intralesional Candida antigen for the treatment of recalcitrant pediatric warts.

Numerous studies have investigated the efficacy of intralesional immunotherapy for warts, but there are a lack of studies investigating the efficacy of alternative intralesional immunotherapies following failure of initial intralesional immunotherapy. In this retrospective study, we aimed to investigate the efficacy of intralesional measles, mumps, and rubella vaccine for the treatment of pediatric warts following failure of intralesional therapy with Candida antigen. Following intralesional measles, mumps, and rubella vaccine administration, 8/51 (15.5%) patients had complete resolution of their warts, 6/51 (12%) had near complete resolution, 19/51 (37%) had partial improvement, 12/51 (23.5%) had no change, and 6/51 (12%) had worsening. Although limited by retrospective nature and low sample size, our results demonstrate that intralesional immunotherapy with measles, mumps, and rubella vaccine provides an alternative therapeutic option for the treatment of recalcitrant pediatric warts in patients who fail to respond to intralesional Candida antigen.

Effect of remdesivir post-exposure prophylaxis and treatment on pathogenesis of measles in rhesus macaques.

Measles is a systemic disease initiated in the respiratory tract with widespread measles virus (MeV) infection of lymphoid tissue. Mortality can be substantial, but no licensed antiviral therapy is available. We evaluated both post-exposure prophylaxis and treatment with remdesivir, a broad-spectrum antiviral, using a well-characterized rhesus macaque model of measles. Animals were treated with intravenous remdesivir for 12 days beginning either 3 days after intratracheal infection (post-exposure prophylaxis, PEP) or 11 days after infection at the onset of disease (late treatment, LT). As PEP, remdesivir lowered levels of viral RNA in peripheral blood mononuclear cells, but RNA rebounded at the end of the treatment period and infectious virus was continuously recoverable. MeV RNA was cleared more rapidly from lymphoid tissue, was variably detected in the respiratory tract, and not detected in urine. PEP did not improve clinical disease nor lymphopenia and reduced the antibody response to infection. In contrast, LT had little effect on levels of viral RNA or the antibody response but also did not decrease clinical disease. Therefore, remdesivir transiently suppressed expression of viral RNA and limited dissemination when provided as PEP, but virus was not cleared and resumed replication without improvement in the clinical disease parameters evaluated.

MMR vaccination timing and long-term immunity among childhood cancer survivors.

Long-term seroprotection against the measles and mumps viruses has not been reported in childhood cancer survivor (CCS) who received two-lifetime doses of the measles, mumps, and rubella (MMR) vaccine. We performed a retrospective study of measles and mumps titers among 55 CCS who received standard chemotherapy and two MMR vaccinations at any time. Over 75% of CCS who received at least one MMR prior to their cancer diagnosis had a negative or equivocal titer to measles or mumps. In contrast, all CCS who received the MMR series following their cancer treatment demonstrated long-term seroprotection to both viruses at a mean of 8.2 years after their last vaccination.

A comparative evaluation of therapeutic response in warts to intralesional vitamin D3 versus intralesional measles, mumps, and rubella vaccine.

The infection of keratinocytes by human papilloma virus (HPV) causes warts. These are of different types based on morphological and anatomical grounds. This has led to the development of strategies involved in the treatment of warts by induction of delayed hypersensitivity reactions. The current study aims to compare the therapeutic response and side effect profile of intralesional vitamin D3 and measles, mumps, and rubella (MMR). The aim of this study is to study the therapeutic response of two intralesional immunotherapies in warts and compare their efficacies and side effects. A single-blind randomized control trial was conducted over 12 months on 100 patients using the purposive sampling technique. Randomly, half of the participants received one of the two immunotherapies. The clinical response was evaluated on the basis of decrease in wart size, wart number, wart distribution, and photographic comparison. The mean size of the largest wart in the vitamin D3 group was found to be 0.70 cm, and in the MMR group, it was 0.79 cm in breadth. The mean onset of first response was 3.55 weeks in the vitamin D3 group and 3.85 weeks in the MMR group. Complete response was seen in 54% and 62% of study participants in the vitamin D3 and MMR groups respectively. The study recommends that both intralesional vitamin D3 and MMR are efficacious in treating cutaneous warts, with MMR agents being moderately better compared to vitamin D3 in terms of warts clearance and side effects profile.

Innovations in vaccine delivery: increasing access, coverage, and equity and lessons learnt from measles and rubella elimination.

Disease eradication and elimination programs drive innovations based on progress toward measurable objectives, evaluations of new strategies and methods, programmatic experiences, and lessons learned from the field. Following progress toward global measles elimination, reducing measles mortality, and increasing introductions of measles and rubella vaccines to national programs, the measles and rubella immunization program has faced setbacks in recent years. Currently available vaccine delivery methods have complicated logistics and drawbacks that create barriers to vaccination; innovations for easier, more efficient, and safer vaccine delivery are needed. Progress can be accelerated by new technologies like microarray patches (MAPs) that are now widely recognized as a potential new tool for enhancing global immunizations efforts. Clinical trials of measles-rubella vaccine MAPs have begun, and several other vaccine MAPs are in the pre-clinical development pathway. MAPs could significantly contribute to Immunization Agenda 2030 priorities, including reaching zero-dose children; increasing vaccine access, demand, coverage, and equity; and achieving measles and rubella elimination. With strong partnerships between public health agencies and biotechnology companies, translational novel vaccine delivery systems can be developed to help solve public health problems and achieve global health priorities.

Favorable outcomes of interferon-α and ribavirin treatment for a male with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a slow virus infection associated with mutant measles virus (MeV). The long-term outcome of antiviral treatments remains to be determined. We herein present a Japanese boy who was diagnosed with SSPE at 10 years of age. Intraventricular infusions of interferon-α effectively prevented the progress of symptoms during 14 years of follow-up period. Flow-cytometric analysis demonstrated higher proportion of T helper 17 cells (Th17, 18.2%) than healthy controls (4.8-14.5%) despite the normal subpopulation of peripheral lymphocytes. These data suggest that a group of patients with SSPE may show favorable responses to intraventricular infusions of interferon-α.

Vitamin A in Children Hospitalized for Measles in a High-income Country.

BACKGROUND: Worldwide medical authorities recommend vitamin A supplementation for severe measles requiring hospitalization; however, evidence supporting its use in high-income countries is lacking. A nationwide vitamin A shortage reported in concomitance with a recent measles outbreak in Italy provided an opportunity to test the effectiveness of vitamin A in a high-income setting, approximating an unbiased allocation. METHODS: We conducted a prospective controlled cohort study involving children admitted for measles to a tertiary-care hospital in Southern Italy. The primary outcome was the duration of fever. Secondary outcomes included the length of hospitalization, rate of complications, need for antibiotic treatment and body temperature. RESULTS: A total of 108 inpatient children (36% female, median age 16.3 months) were enrolled; 36 received 2 doses of oil-based vitamin A according to age, and 72 matched controls received standard care. There were no significant differences between the study groups in the duration of fever (7.03 ± 2.67 vs. 6.82 ± 3.27, P = 0.72), length of hospitalization (median, 5.0 vs. 5.0 days, P = 0.50), maximum body temperature (median, 39°C in both groups, P = 0.23), rate of organ (69.4% vs. 63.9%, P = 0.72) and hematologic complications (41.7% vs. 59.7%, P = 0.12), or need for antibiotic treatment (66.7% vs. 61.1%, P = 0.72). Overall, vitamin A supplementation did not reduce the risk of any complications (relative risk, 1.33; 95% confidence intervals: 0.59-2.96). CONCLUSION: Vitamin A does not change the clinical course of measles infection or the rate of complications in children hospitalized in a high-income country. STUDY REGISTRATION NUMBER: EU PAS 31805.

Therapeutic targeting of measles virus polymerase with ERDRP-0519 suppresses all RNA synthesis activity.

Morbilliviruses, such as measles virus (MeV) and canine distemper virus (CDV), are highly infectious members of the paramyxovirus family. MeV is responsible for major morbidity and mortality in non-vaccinated populations. ERDRP-0519, a pan-morbillivirus small molecule inhibitor for the treatment of measles, targets the morbillivirus RNA-dependent RNA-polymerase (RdRP) complex and displayed unparalleled oral efficacy against lethal infection of ferrets with CDV, an established surrogate model for human measles. Resistance profiling identified the L subunit of the RdRP, which harbors all enzymatic activity of the polymerase complex, as the molecular target of inhibition. Here, we examined binding characteristics, physical docking site, and the molecular mechanism of action of ERDRP-0519 through label-free biolayer interferometry, photoaffinity cross-linking, and in vitro RdRP assays using purified MeV RdRP complexes and synthetic templates. Results demonstrate that unlike all other mononegavirus small molecule inhibitors identified to date, ERDRP-0519 inhibits all phosphodiester bond formation in both de novo initiation of RNA synthesis at the promoter and RNA elongation by a committed polymerase complex. Photocrosslinking and resistance profiling-informed ligand docking revealed that this unprecedented mechanism of action of ERDRP-0519 is due to simultaneous engagement of the L protein polyribonucleotidyl transferase (PRNTase)-like domain and the flexible intrusion loop by the compound, pharmacologically locking the polymerase in pre-initiation conformation. This study informs selection of ERDRP-0519 as clinical candidate for measles therapy and identifies a previously unrecognized druggable site in mononegavirus L polymerase proteins that can silence all synthesis of viral RNA.

Antiviral Effect of Favipiravir (T-705) against Measles and Subacute Sclerosing Panencephalitis Viruses.

Subacute sclerosing panencephalitis (SSPE) is a late-onset, intractable, and fatal viral disease caused by persistent infection of the central nervous system with a measles virus mutant (SSPE virus). In Japan, interferon-α and ribavirin are administered intracerebroventricularly to patients with SSPE. However, as the therapeutic effect is insufficient, more effective drugs are needed. Favipiravir, which is clinically used as an anti-influenza drug, demonstrates anti-viral effects against RNA viruses. In this study, the antiviral effect of favipiravir against measles virus (Edmonston strain) and SSPE virus (Yamagata-1 strain) was examined in vitro. The 50% effective concentration (EC50) of favipiravir (inhibiting viral plaque formation by 50%) against Edmonston and Yamagata-1 strains were 108.7 ± 2.0 µM (17.1 ± 0.3 µg/mL) and 38.6 ± 6.0 µM (6.1 ± 0.9 µg/mL), respectively, which were similar to those of ribavirin. The antiviral activity of favipiravir against the SSPE virus was demonstrated for the first time in this study.

Clinical characteristics and outcomes of measles outbreak in adults: A multicenter retrospective observational study of 93 hospitalized adults in Greece.

OBJECTIVES: Measles outbreaks are increasingly reported among countries that were close-to-eliminate measles infection. There are few reports of clinical characteristics of measles in adults in the contemporary literature. In this study we aim to describe the clinical characteristics and complications of measles infection in hospitalized adults during the recent epidemic in Greece. METHODS: A multicentre observational retrospective study was conducted in three tertiary hospitals in Greece. All adult hospitalized patients (≥18 years old) with serologically confirmed and/or clinical features compatible with measles were included. Pediatric patients and patients with missing data were excluded. RESULTS: In total, 93 patients, 40 males (43 %) and 53 females (57 %), mostly young patients were included. Most of them (87 %) had no past medical history. Among women, 4 were pregnant. 56 (60.2 %) and 25 (26.9 %) patients reported either unknown or incomplete vaccination for measles. Ribavirin was administered in 8 (8.6 %) patients. Pneumonitis and hepatic involvement were the most common complications, occurring in 43 (46.2 %) and 75 (80.6 %) patients respectively. Pneumonitis was significantly associated with male sex, older age, lower lymphocyte counts and higher C-reactive protein (CRP) on admission. One pregnant woman suffered spontaneous fetal miscarriage and one patient died due to acute respiratory distress syndrome (ARDS) and high-risk pulmonary embolism. CONCLUSION: Considerable proportions of incompletely vaccinated or unvaccinated adults have led to the re-emergence of measles in countries with reported close-to-elimination rates. Pneumonitis is a major complication among adults with measles. More studies are imperative in order to explore the role of immune paresis in measles.

[Ocular manifestations of measles in adults: About three cases]. / Manifestations oculaires de la rougeole chez l'adulte : à propos de trois cas.

Measles is a contagious viral infection that usually affects children. The disease is caused by morbillivirus, a virus of the family Paramyxoviridae. The clinical picture is characterized by four phases: incubation, invasion, eruption and desquamation. Ophthalmologic manifestations in measles are rare, dominated by conjunctivitis and keratitis. Corneal involvement is the main concern; it varies from simple superficial punctate keratitis to corneal perforation. We report three cases of acute keratitis in young adults during an epidemic. The epithelial involvement was peripheral, central or diffuse. The outcome was favorable under symptomatic topical treatment.

Diagnosing inborn error of immunity following the presentation of a complicated acquired infection after MMRV vaccine administration.

Live vaccine-acquired infection should attest for the occurrence of inborn errors of immunity. Autosomal recessive immunodeficiency 31B, a result of a signal transducer and activator of transcription 1 genetic mutation, results in defected interferon pathways: interferon alpha/beta and interferon gamma. These interferons are crucial for the defence against viral and mycobacterial infections. Recognition is important for preventive and therapeutic approaches. Herein, we report the presentation of a newly diagnosed 13-month-old child with immunodeficiency 31B after presenting with disseminated measles and varicella infection after Measles, Mumps, Rubella and Varicella vaccination.

Virucidal Activity of Gold Nanoparticles Synthesized by Green Chemistry Using Garlic Extract.

Measles virus (MeV) is a paramyxovirus that infects humans, principally children. Despite the existence of an effective and safe vaccine, the number of cases of measles has increased due to lack of vaccination coverage. The World Health Organization (WHO) reports that the number of cases worldwide multiplied fourfold between January and March 2019, to 112,000. Today, there is no treatment available for MeV. In recent years, it has been demonstrated that natural extracts (herbal or algal) with antiviral activity can also work as reducing agents that, in combination with nanotechnology, offer an innovative option to counteract viral infections. Here, we synthetized and evaluated the antiviral activity of gold nanoparticles using garlic extract (Allium sativa) as a reducing agent (AuNPs-As). These nanoparticles actively inhibited MeV replication in Vero cells at a 50% effective concentration (EC50) of 8.829 µg/mL, and the selectivity index (SI) obtained was 16.05. AuNPs-As likely inhibit viral infection by blocking viral particles directly, showing a potent virucidal effect. Gold nanoparticles may be useful as a promising strategy for treating and controlling the infection of MeV and other related enveloped viruses.

Measles Encephalitis: Towards New Therapeutics.

Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) infection leading to lethal neurological disease. Early following MeV infection some patients develop acute post-infectious measles encephalitis (APME), which is not associated with direct infection of the brain. MeV can also infect the CNS and cause sub-acute sclerosing panencephalitis (SSPE) in immunocompetent people or measles inclusion-body encephalitis (MIBE) in immunocompromised patients. To date, cellular and molecular mechanisms governing CNS invasion are still poorly understood. Moreover, the known MeV entry receptors are not expressed in the CNS and how MeV enters and spreads in the brain is not fully understood. Different antiviral treatments have been tested and validated in vitro, ex vivo and in vivo, mainly in small animal models. Most treatments have high efficacy at preventing infection but their effectiveness after CNS manifestations remains to be evaluated. This review describes MeV neural infection and current most advanced therapeutic approaches potentially applicable to treat MeV CNS infection.

Applying sequential surveillance methods that use regression adjustment or weighting to control confounding in a multisite, rare-event, distributed setting: Part 2 in-depth example of a reanalysis of the measles-mumps-rubella-varicella combination vaccine and seizure risk.

OBJECTIVE: In-depth example of two new group sequential methods for postmarket safety monitoring of new medical products. STUDY DESIGN AND SETTING: Existing trial-based group sequential approaches have been extended to adjust for confounders, accommodate rare events, and address privacy-related constraints on data sharing. Most adaptations have involved design-based confounder strategies, for example, self-controlled or exposure matching, while analysis-based approaches like regression and weighting have received less attention. We describe the methodology of two new group sequential approaches that use analysis-based confounder adjustment (GS GEE) and weighting (GS IPTW). Using data from the Food and Drug Administration's Sentinel network, we apply both methods in the context of a known positive association: the measles-mumps-rubella-varicella vaccine and seizure risk in infants. RESULTS: Estimates from both new approaches were similar and comparable to prior studies using design-based methods to address confounding. The time to detection of a safety signal was considerably shorter for GS IPTW, which estimates a risk difference, compared to GS GEE, which provides relative estimates of excess risk. CONCLUSION: Future group sequential safety surveillance efforts should consider analysis-based confounder adjustment techniques that evaluate safety signals on the risk difference scale to achieve greater statistical power and more timely results.

Measles in pregnancy.

Measles is becoming more prevalent; it can be difficult to diagnose, with severe complications in pregnancy. We report a case of measles in a 27-year-old, parainfluenza virus type 2-infected woman who was 32 weeks pregnant. She presented with fever, tachycardia, sore throat and a pruritic rash. She never had the measles, mumps, rubella vaccine. Serology showed raised inflammatory markers with lymphopoenia. Throat swab showed parainfluenza virus. Chest radiography was normal. Despite appropriate antimicrobial therapy, she developed worsening respiratory failure requiring premature delivery via caesarean section.Postoperatively, she was transferred to a tertiary centre for extracorporeal membrane oxygenation. She was decannulated and made a full recovery. Meanwhile, her husband was diagnosed with measles. She was then tested and measles was confirmed. The baby did not develop congenital measles.This case emphasises the importance of vaccine histories at booking of pregnancy and early multidisciplinary team input to facilitate delivery in rapidly deteriorating pregnant women.