A real-world study on the changing characteristics of measles antibodies in premature infants in China.

The waning of maternal antibodies may cause infants to lose protection against measles before receiving measles-containing vaccine (MCV). The aim of this study is to investigate the changing characteristics and influencing factors of measles antibodies in preterm infants (PT), and to provide scientific basis for optimizing MCV vaccination strategy of the target population. Blood samples were collected from PT and full-term infants (FT) at the chronological age (CA) of 3, 6, and 12 months. Measles antibodies were quantitatively detected by enzyme-linked immunosorbent assay. Demographic and vaccination information were both collected. Kruskal-Wallis rank sum test was used to compare the measles antibodies among different gestation age (GA) groups, and multiple linear regression was performed to identify the correlative factors for the antibodies. Measles antibodies of PT decreased significantly with age increasing before MCV vaccination. The positive rates of antibodies of PT were 10.80% and 3.30% at the age of 3 and 6 months, respectively (p < .001). At 12 months, the measles antibodies and seropositive rate in the infants who received MCV vaccination increased sharply (p < .001). Regression analyzes showed that the younger the GA or the older the age, the lower the antibodies at 3 months(p < .001，p = .018); while the lower measles antibody levels at 3 months and older age predicted the lower antibodies at 6 months(p < .001, p = .029). PT were susceptible to measles due to the low level of maternally derived antibodies before MCV vaccination. More efforts should be considered to protect the vulnerable population during their early postnatal life.

Increased reports of measles in the Metropolitan City of Milan, northern Italy, September 2023 to March 2024.

Since late 2023, the Metropolitan City of Milan and surrounding areas (northern Italy) have been experiencing a resurgence of measles, with most cases detected starting from January 2024. During this brief period, we observed measles in travellers from endemic areas, participants in international events, vaccinees and healthcare workers. Indigenous cases have also been identified. Even though we have not yet identified large and disruptive outbreaks, strengthening surveillance and vaccination activities is pivotal to help limit the impact of measles spread.

Rapid molecular epidemiology investigations into two recent measles outbreaks in Israel detected from October 2023 to January 2024.

Between late 2023 and early 2024, two measles outbreaks occurred in Israel, each caused by importation of measles virus strains of respective B3 and D8 genotypes. In this study, we validate transmission pathways uncovered by epidemiological investigations using a rapid molecular approach, based on complete measles virus genomes. The presented findings support this rapid molecular approach in complementing conventional contact tracing and highlight its potential for informing public health interventions.

Measles - United States, January 1, 2020-March 28, 2024.

Measles is a highly infectious febrile rash illness and was declared eliminated in the United States in 2000. However, measles importations continue to occur, and U.S. measles elimination status was threatened in 2019 as the result of two prolonged outbreaks among undervaccinated communities in New York and New York City. To assess U.S. measles elimination status after the 2019 outbreaks and to provide context to understand more recent increases in measles cases, CDC analyzed epidemiologic and laboratory surveillance data and the performance of the U.S. measles surveillance system after these outbreaks. During January 1, 2020-March 28, 2024, CDC was notified of 338 confirmed measles cases; 97 (29%) of these cases occurred during the first quarter of 2024, representing a more than seventeenfold increase over the mean number of cases reported during the first quarter of 2020-2023. Among the 338 reported cases, the median patient age was 3 years (range = 0-64 years); 309 (91%) patients were unvaccinated or had unknown vaccination status, and 336 case investigations included information on ≥80% of critical surveillance indicators. During 2020-2023, the longest transmission chain lasted 63 days. As of the end of 2023, because of the absence of sustained measles virus transmission for 12 consecutive months in the presence of a well-performing surveillance system, U.S. measles elimination status was maintained. Risk for widespread U.S. measles transmission remains low because of high population immunity. However, because of the increase in cases during the first quarter of 2024, additional activities are needed to increase U.S. routine measles, mumps, and rubella vaccination coverage, especially among close-knit and undervaccinated communities. These activities include encouraging vaccination before international travel and rapidly investigating suspected measles cases.

Measles outbreak in the adult age group: Clinical, laboratory, and epidemiological features of the 11 patients admitted to the hospital.

The measles virus, also known as the morbillivirus, or MV, is a virus that infects humans. The goal of this research is to assess to adult cases of measles. Eleven patients thought to be confirmed cases of measles were enrolled in the investigation. Following the identification of symptoms of tiredness, fever, and rash in one soldier, the results of 10 more troops from the pertinent military group were assessed. The diagnosis was made based on the presence of serum immunoglobulin M (IgM) and positive polymerase chain reaction (PCR) results. When the control IgM, immunoglobulin G, and PCR findings were evaluated a fortnight after hospitalization, a cluster of 11 incidents was found. It is now necessary to address the issue of the cautious stance towards vaccination or the anti-vaccination sentiment that has grown increasingly popular, particularly in light of the COVID-19 pandemic, for both our nation and the entire world.

TDP-43 pathology in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a fatal, slowly progressive brain disorder caused by a mutated measles virus. Both subacute inflammatory and neurodegenerative mechanisms appear to play significant roles in the pathogenesis. TAR DNA-binding protein 43 (TDP-43) inclusions are a common co-pathology in several neurodegenerative disorders with diverse pathogenesis. In the present study, we examined brains of 16 autopsied SSPE patients for the presence of TDP-43 pathology and possible associations with tau pathology. Immunohistochemical staining identified TDP-43 inclusions in 31% of SSPE cases. TDP-43 pathology was widely distributed in the brains, most severely in the atrophied cerebral cortex (temporal and parietal), and most frequently as tangle- and thread-like neuronal cytoplasmic inclusions. It was associated with longer disease duration (>4 years) and tau pathology (all TDP-43-positive cases had tau-positive neurofibrillary tangles). This study demonstrates for the first time an association between TDP-43 pathology and SSPE. The co-occurrence of TDP-43 and tau aggregates and correlation with the disease duration suggest that both pathological proteins are involved in the neurodegenerative process induced by viral inflammation.

Ongoing measles outbreak, the Federation of Bosnia and Herzegovina, December 2023 to February 2024.

We report on an ongoing measles outbreak in the Federation of Bosnia and Herzegovina with 141 cases notified between week 52 2023 and week 6 2024. Among those with known vaccination status, 97% were unvaccinated and the most affected group is children under the age of 5 years (n = 87) who were not vaccinated during the pandemic years. Sixty-eight cases were hospitalised, the most common complications were measles-related pneumonia and diarrhoea. The sequenced measles viruses from four cases belonged to genotype D8.

Implications of Measles Inclusion by Commercial Syndromic Polymerase Chain Reaction Panels - United States, May 2022-April 2023.

Syndromic polymerase chain reaction (PCR) panels are used to test for pathogens that can cause rash illnesses, including measles. Rash illnesses have infectious and noninfectious causes, and approximately 5% of persons experience a rash 7-10 days after receipt of a measles, mumps, and rubella (MMR) vaccine. MMR vaccine includes live attenuated measles virus, which is detectable by PCR tests. No evidence exists of person-to-person transmission of measles vaccine virus, and illness does not typically result among immunocompetent persons. During September 2022-January 2023, the Tennessee Department of Health received two reports of measles detected by syndromic PCR panels. Both reports involved children (aged 1 and 6 years) without known risk factors for measles, who were evaluated for rash that occurred 11-13 days after routine MMR vaccination. After public health responses in Tennessee determined that both PCR panels had detected measles vaccine virus, six state health departments collaborated to assess the frequency and characteristics of persons receiving a positive measles PCR panel test result in the United States. Information was retrospectively collected from a commercial laboratory testing for measles in syndromic multiplex PCR panels. During May 2022-April 2023, among 1,548 syndromic PCR panels, 17 (1.1%) returned positive test results for measles virus. Among 14 persons who received a positive test result and for whom vaccination and case investigation information were available, all had received MMR vaccine a median of 12 days before specimen collection, and none had known risk factors for acquiring measles. All positive PCR results were attributed to detection of measles vaccine virus. Increased awareness among health care providers about potential measles detection by PCR after vaccination is needed. Any detection of measles virus by syndromic PCR testing should be immediately reported to public health agencies, which can use measles vaccination history and assessment of risk factors to determine the appropriate public health response. If a person recently received MMR vaccine and has no risk factors for acquiring measles, additional public health response is likely unnecessary.

Rational attenuation of canine distemper virus (CDV) to develop a morbillivirus animal model that mimics measles in humans.

Morbilliviruses are members of the family Paramyxoviridae and are known for their ability to cause systemic disease in a variety of mammalian hosts. The prototypic morbillivirus, measles virus (MeV), infects humans and still causes morbidity and mortality in unvaccinated children and young adults. Experimental infection studies in non-human primates have contributed to the understanding of measles pathogenesis. However, ethical restrictions call for the development of new animal models. Canine distemper virus (CDV) infects a wide range of animals, including ferrets, and its pathogenesis shares many features with measles. However, wild-type CDV infection is almost always lethal, while MeV infection is usually self-limiting. Here, we made five recombinant CDVs, predicted to be attenuated, and compared their pathogenesis to the non-attenuated recombinant CDV in a ferret model. Three viruses were insufficiently attenuated based on clinical signs, fatality, and systemic infection, while one virus was too attenuated. The last candidate virus caused a self-limiting infection associated with transient viremia and viral dissemination to all lymphoid tissues, was shed transiently from the upper respiratory tract, and did not result in acute neurological signs. Additionally, an in-depth phenotyping of the infected white blood cells showed lower infection percentages in all lymphocyte subsets when compared to the non-attenuated CDV. In conclusion, infection models using this candidate virus mimic measles and can be used to study pathogenesis-related questions and to test interventions for morbilliviruses in a natural host species.IMPORTANCEMorbilliviruses are transmitted via the respiratory route but cause systemic disease. The viruses use two cellular receptors to infect myeloid, lymphoid, and epithelial cells. Measles virus (MeV) remains an important cause of morbidity and mortality in humans, requiring animal models to study pathogenesis or intervention strategies. Experimental MeV infections in non-human primates are restricted by ethical and practical constraints, and animal morbillivirus infections in natural host species have been considered as alternatives. Inoculation of ferrets with wild-type canine distemper virus (CDV) has been used for this purpose, but in most cases, the virus overwhelms the immune system and causes highly lethal disease. Introduction of an additional transcription unit and an additional attenuating point mutation in the polymerase yielded a candidate virus that caused self-limiting disease with transient viremia and virus shedding. This rationally attenuated CDV strain can be used for experimental morbillivirus infections in ferrets that reflect measles in humans.

Rapid quantitative detection system for measles virus-neutralizing antibodies using HiBiT-tagged virus-like particles.

Immunological testing to detect neutralizing antibodies (NAbs) is important in measles (MV) infection control. Currently, the plaque reduction neutralization test is the only credible method for measuring actual virus NAbs; however, its feasibility is hampered by drawbacks, such as long turnaround times, low throughput, and the need for laboratory biosafety equipment. To solve these problems, we developed a simple and rapid MV-NAb detection system using lentivirus-based virus-like particles incorporated with the NanoLuc fragment peptide HiBiT comprising the MV fusion protein and hemagglutinin on their exterior surface. Overall, this simple, safe, and rapid method could be used to detect MV NAbs.

Forskolin Enhances Antitumor Effect of Oncolytic Measles Virus by Promoting Rab27a Dependent Vesicular Transport System.

The measles vaccine virus strain (MV-Edm) serves as a potential platform for the development of effective oncolytic vectors. Nevertheless, despite promising pre-clinical data, our comprehension of the factors influencing the efficacy of MV-Edm infection and intratumoral spread, as well as the interactions between oncolytic viruses and specific chemotherapeutics associated with viral infection, remains limited. Therefore, we investigated the potency of Forskolin in enhancing the antitumor effect of oncolytic MV-Edm by promoting the Rab27a-dependent vesicular transport system. After infecting cells with MV-Edm, we observed an increased accumulation of cytoplasmic vesicles. Our study demonstrated that MV-Edm infection and spread in tumors, which are indispensable processes for viral oncolysis, depend on the vesicular transport system of tumor cells. Although tumor cells displayed a responsive mechanism to restrain the MV-Edm spread by down-regulating the expression of Rab27a, a key member of the vesicle transport system, over-expression of Rab27a promoted the oncolytic efficacy of MV-Edm towards A549 tumor cells. Additionally, we found that Forskolin, a Rab27a agonist, was capable of promoting the oncolytic effect of MV-Edm in vitro. Our study revealed that the vesicle transporter Rab27a could facilitate the secretion of MV-Edm and the generation of syncytial bodies in MV-Edm infected cells during the MV-Edm-mediated oncolysis pathway. The results of the study demonstrate that a combination of Forskolin and MV-Edm exerts a synergistic anti-tumor effect in vitro, leading to elevated oncolysis. This finding holds promise for the clinical treatment of patients with tumors.

Probability of exposure to the wild measles virus in adult population - Estimation from seroepidemiology and historical data.

Vaccination against measles is one of the most effective public health interventions which has saved millions of lives and interrupted circulation of the natural virus in the population. However, it is widely accepted that the immunity after vaccination can wane, especially in those who have had no contact with the virus. This study aimed to classify the particular birth cohorts of adults with regard to their exposure to the wild measles virus in the population with a long history of mandatory vaccination. We introduced two methods. In the first, we estimated the probability of exposure to the wild virus through an analysis of antibody levels from the Immunologic Survey performed in the Slovak Republic in 2018, while the second was based on historical epidemiological data. Both methods resulted in similar estimations. Cohorts born in Slovakia before 1964 can be considered to be cohorts in which most people were exposed to the wild measles virus. Cohorts born after 1977 can be designated as cohorts that most likely did not come into the contact with the wild virus. Cohorts born between 1965 and 1976 are composed of a mixture, with a decreasing proportion of people exposed to the wild virus with increasing year of birth. The proposed methods can help identify potential immunity gaps in the adult population. They can be applied in other countries with high measles vaccination coverage to estimate the probability of exposure to the wild measles virus in particular birth cohorts.

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.

Vaccine-induced neutralizing antibodies bind to the H protein of a historical measles virus.

Measles is a highly contagious airborne viral disease. It can lead to serious complications and death and is preventable by vaccination. The live-attenuated measles vaccine (LAMV) derived from a measles virus (MV) isolated in 1954 has been in use globally for six decades and protects effectively by providing a durable humoral and cell-mediated immunity. Our study addresses the temporal stability of epitopes on the viral surface glycoprotein hemagglutinin (H) which is the major target of MV-neutralizing antibodies. We investigated the binding of seven vaccine-induced MV-H-specific monoclonal antibodies (mAbs) to cell-free synthesized MV-H proteins derived from the H gene sequences obtained from a lung specimen of a fatal case of measles pneumonia in 1912 and an isolate from a current case. The binding of four out of seven mAbs to the H protein of both MV strains provides evidence of epitopes that are stable for more than 100 years. The binding of the universally neutralizing mAbs RKI-MV-12b and RKI-MV-34c to the H protein of the 1912 MV suggests the long-term stability of highly conserved epitopes on the MV surface.

Identification of a measles variant displaying mutations impacting molecular diagnostics, Geneva, Switzerland, 2023.

Real-time PCR is one of the most widely used techniques to diagnose measles cases. Here we report measles virus variants with three genetic mutations in the reverse primer annealing site of a widely used PCR. The mutations result in a slight loss of the PCR sensitivity. Variants bearing the three mutations presently circulate in different countries since at least the end of 2021. Our findings highlight the usefulness of molecular surveillance in monitoring if oligonucleotides in diagnostic tests remain adequate.

Viral etiology of measles-like rash in Guinean children during the COVID epidemic in 2022.

Covid-19 in West Africa masked outbreaks of vaccine-preventable diseases such as the measles epidemic in children in Guinea in 2021-2022 characterized by a lack of confirmation of suspected clinical cases. During weeks 13-22 of 2022, saliva samples were collected from 213 children (3-60 months old) with measles-like symptoms within the St Gabriel dispensary in Conakry. Samples were processed in Virus Transport Medium (VTM) and tested on the same day by triplex reverse transcriptase -real-time polymerase chain reaction for Measles, Rubella and RNaseP. Samples were also tested for HHV6 and Parvovirus B19, viruses causing clinical signs similar to measles. We confirmed 146 (68.5%) measles cases, 27 (12.7%) rubella, 5 (2.3%) double-positive measles-rubella, 35 (16.4%) HHV-6 and 8 (3.75%) Parvovirus B19. To test the assay's robustness, 27 samples were kept at 26-30°C. Measles and rubella were still detected after 7 days at 26-30°C, and after 21 days measles and rubella were still detectable in all samples but one. Sequencing indicated the circulation of the B3 measles genotype, as expected in West Africa. This study highlights the robustness of the measles/rubella diagnostic test on saliva samples stored in VTM. The high level of rubella detection questioned the single valence measles vaccination strategy.

Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets.

Measles cases have surged pre-COVID-19 and the pandemic has aggravated the problem. Most measles-associated morbidity and mortality arises from destruction of pre-existing immune memory by measles virus (MeV), a paramyxovirus of the morbillivirus genus. Therapeutic measles vaccination lacks efficacy, but little is known about preserving immune memory through antivirals and the effect of respiratory disease history on measles severity. We use a canine distemper virus (CDV)-ferret model as surrogate for measles and employ an orally efficacious paramyxovirus polymerase inhibitor to address these questions. A receptor tropism-intact recombinant CDV with low lethality reveals an 8-day advantage of antiviral treatment versus therapeutic vaccination in maintaining immune memory. Infection of female ferrets with influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks pre-CDV causes fatal hemorrhagic pneumonia with lung onslaught by commensal bacteria. RNAseq identifies CDV-induced overexpression of trefoil factor (TFF) peptides in the respiratory tract, which is absent in animals pre-infected with IAV. Severe outcomes of consecutive IAV/CDV infections are mitigated by oral antivirals even when initiated late. These findings validate the morbillivirus immune amnesia hypothesis, define measles treatment paradigms, and identify priming of the TFF axis through prior respiratory infections as risk factor for exacerbated morbillivirus disease.

Surface-modified measles vaccines encoding oligomeric, prefusion-stabilized SARS-CoV-2 spike glycoproteins boost neutralizing antibody responses to Omicron and historical variants, independent of measles seropositivity.

Serum titers of SARS-CoV-2-neutralizing antibodies (nAbs) correlate well with protection from symptomatic COVID-19 but decay rapidly in the months following vaccination or infection. In contrast, measles-protective nAb titers are lifelong after measles vaccination, possibly due to persistence of the live-attenuated virus in lymphoid tissues. We, therefore, sought to generate a live recombinant measles vaccine capable of driving high SARS-CoV-2 nAb responses. Since previous clinical testing of a live measles vaccine encoding a SARS-CoV-2 spike glycoprotein resulted in suboptimal anti-spike antibody titers, our new vectors were designed to encode prefusion-stabilized SARS-CoV-2 spike glycoproteins, trimerized via an inserted peptide domain, and displayed on a dodecahedral miniferritin scaffold. Additionally, to circumvent the blunting of vaccine efficacy by preformed anti-measles antibodies, we extensively modified the measles surface glycoproteins. Comprehensive in vivo mouse testing demonstrated the potent induction of high titer nAbs in measles-immune mice and confirmed the significant contributions to overall potency afforded by prefusion stabilization, trimerization, and miniferritin display of the SARS-CoV-2 spike glycoprotein. In animals primed and boosted with a measles virus (MeV) vaccine encoding the ancestral SARS-CoV-2 spike, high-titer nAb responses against ancestral virus strains were only weakly cross-reactive with the Omicron variant. However, in primed animals that were boosted with a MeV vaccine encoding the Omicron BA.1 spike, antibody titers to both ancestral and Omicron strains were robustly elevated, and the passive transfer of serum from these animals protected K18-ACE2 mice from infection and morbidity after exposure to BA.1 and WA1/2020 strains. Our results demonstrate that by engineering the antigen, we can develop potent measles-based vaccine candidates against SARS-CoV-2.IMPORTANCEAlthough the live-attenuated measles virus (MeV) is one of the safest and most efficacious human vaccines, a measles-vectored COVID-19 vaccine candidate expressing the SARS-CoV-2 spike failed to elicit neutralizing antibody (nAb) responses in a phase-1 clinical trial, especially in measles-immune individuals. Here, we constructed a comprehensive panel of MeV-based COVID-19 vaccine candidates using a MeV with extensive modifications on the envelope glycoproteins (MeV-MR). We show that artificial trimerization of the spike is critical for the induction of nAbs and that their magnitude can be significantly augmented when the spike protein is synchronously fused to a dodecahedral scaffold. Furthermore, preexisting measles immunity did not abolish heterologous immunity elicited by our vector. Our results highlight the importance of antigen optimization in the development of spike-based COVID-19 vaccines and therapies.