Immunological landscape of human lymphoid explants during measles virus infection.

In humans, lymph nodes are the primary site of measles virus (MeV) replication. To understand the immunological events that occur at this site, we infected human lymphoid tissue explants using a pathogenic strain of MeV that expresses GFP. We found that MeV infected 5%-15% of cells across donors. Using single-cell RNA-Seq and flow cytometry, we found that while most of the 29 cell populations identified in the lymphoid culture were susceptible to MeV, there was a broad preferential infection of B cells and reduced infection of T cells. Further subsetting of T cells revealed that this reduction may be driven by the decreased infection of naive T cells. Transcriptional changes in infected B cells were dominated by an interferon-stimulated gene (ISG) signature. To determine which of these ISGs were most substantial, we evaluated the proteome of MeV-infected Raji cells by mass spectrometry. We found that IFIT1, IFIT2, IFIT3, ISG15, CXCL10, MX2, and XAF1 proteins were the most highly induced and positively correlated with their expression in the transcriptome. These data provide insight into the immunological events that occur in lymph nodes during infection and may lead to the development of therapeutic interventions.

Measles immunity status in Iranian infants and children and outbreak concerns: Time for reconsidering the vaccination schedule?

INTRODUCTION: Measles vaccination has greatly reduced the disease burden worldwide, but challenges remain due to variations in vaccine effectiveness across age groups. This study aimed to assess the serological profile of measles antibodies across different age groups, evaluate the impact of maternal immunity on antibody levels in infants under 12 months, and assess measles immunity in vaccinated individuals. MATERIAL AND METHODS: This cross-sectional study was conducted from June 2022 to January 2023 at the Children's Medical Center, a referral hospital in Iran. Serum samples were tested for measles-specific IgG and IgM antibodies using a commercial enzyme-linked immunosorbent assay (ELSA). An avidity assay was performed to assess measles virus-specific IgG antibodies on the samples that were positive and borderline for the measles IgG ELISA. RESULTS: The study included 969 participants across various age groups. Among them, 23% (221 out of 953) tested positive for measles IgM ELISA, and 52% (504 out of 969) for measles IgG ELISA. Regarding the avidity assay for measles virus-specific IgG, the majority (418 out of 573, 73%) showed high-avidity antibodies. Measles-specific IgG levels varied significantly across different age groups, with infants below 6 months old showing a mean IgG level of 477 mIU/mL, declining to 230 mIU/mL between 6 and 12 months, and increasing significantly to 683 mIU/mL in the 12 to 18 month age group, reaching a peak at 938 mIU/mL among children aged 18-72 months. CONCLUSION: The increasing IgM positivity among young Iranians suggests a rising risk of measles outbreaks, possibly due to vaccination gaps. Inadequate antibody levels in infants raise concerns about vaccination effectiveness. Considering declining maternal antibodies, vaccinating infants at 6-9 months could be beneficial. Boosters for adolescents and women may further mitigate outbreak risks.

Onward transmission of measles virus among vaccinated cases in a large community outbreak in Auckland, New Zealand, 2019.

BACKGROUND: Isolation of cases and quarantining of non-immune contacts are the mainstay of measles outbreak management in elimination settings. Serology testing of exposed contacts may not be feasible in large outbreaks; therefore, vaccination history is used as a proxy for determining immunity to measles and thus prevention of onward virus transmission. This study sought to investigate the risk of measles virus transmission from individuals with a history of one or two doses of measles-containing vaccine (MCV). METHODS:  Retrospective analysis of data from measles cases reported to Auckland Regional Public Health Service during the 2019 Auckland region measles outbreak. Vaccination history was verified using patient records and the New Zealand National Immunisation Register. Onward transmission was determined through case interviews and assessment of exposed contacts. RESULTS:  1451 measles cases were assessed as eligible for vaccination at the time of measles outbreak. Of these, 1015 (70.0%) were unvaccinated, 220 (15.2%) had unknown vaccination status, 139 (9.6%) had received only one dose of MCV and 77 (5.3%) had received two doses of the vaccine. Compared to unvaccinated cases, the odds of onward transmission were lower among those with one dose only (OR 0.41, 95% CI: 0.20-0.75) or two doses of MCV (OR 0.44, 95% CI: 0.17-0.95). Median time since vaccination was longer among those with onward transmission compared to those without onward transmission for one and two doses of the vaccine, suggesting a potential effect of waning immunity among this cohort. CONCLUSION:  These findings support the hypothesis that measles cases with a history of prior vaccination are less likely to transmit the virus to others compared to unvaccinated cases. Such information can be used to support decisions around quarantine requirements for vaccinated contacts in future measles outbreaks.

Immunogenicity of a peptide-based vaccine for measles: a pilot evaluation in a mouse model.

Although neutralizing antibody is an established correlate of protection for measles, T cell-mediated responses play at least two critical roles in immunity to measles: first, through provision of 'help' enabling robust humoral immune responses; and second, through clearance of measles virus-infected cells. Previously, we identified 13 measles-derived peptides that bound to human leukocyte antigen (HLA) molecules in Priess cells infected with measles virus. In this study, we evaluated the immunogenicity of these peptides in a transgenic mouse model. Our results demonstrated that these peptides induced Th1-biased immune responses at varying levels. Of the 13 peptides, the top four immunogenic peptides were further selected for a viral challenge study in mice. A vaccine based on a combination of these four peptides reduced morbidity and weight loss after viral challenge compared to placebo. Our results emphasize the potential of T cell-mediated, peptide-based vaccines against measles.

Onward Virus Transmission after Measles Secondary Vaccination Failure.

Measles in persons with secondary vaccination failure (SVF) may be less infectious than cases in unvaccinated persons. Our systematic review aimed to assess transmission risk for measles after SVF. We searched PubMed, Embase, and Web of Science databases from their inception dates. Inclusion criteria were articles describing persons who were exposed to measles-infected persons who had experienced SVF. Across the included 14 studies, >3,030 persons were exposed to measles virus from SVF cases, of whom 180 were susceptible, indicating secondary attack rates of 0%-6.25%. We identified 109 cases of SVF from the studies; 10.09% (n = 11) of case-patients transmitted the virus, resulting in 23 further cases and yielding an effective reproduction number of 0.063 (95% CI 0.0-0.5). These findings suggest a remarkably low attack rate for SVF measles cases, suggesting that, In outbreak situations, public health management of unvaccinated persons could be prioritized over persons with SVF.

Three SARS-CoV-2 spike protein variants delivered intranasally by measles and mumps vaccines are broadly protective.

As the new SARS-CoV-2 Omicron variants and subvariants emerge, there is an urgency to develop intranasal, broadly protective vaccines. Here, we developed highly efficacious, intranasal trivalent SARS-CoV-2 vaccine candidates (TVC) based on three components of the MMR vaccine: measles virus (MeV), mumps virus (MuV) Jeryl Lynn (JL1) strain, and MuV JL2 strain. Specifically, MeV, MuV-JL1, and MuV-JL2 vaccine strains, each expressing prefusion spike (preS-6P) from a different variant of concern (VoC), were combined to generate TVCs. Intranasal immunization of IFNAR1-/- mice and female hamsters with TVCs generated high levels of S-specific serum IgG antibodies, broad neutralizing antibodies, and mucosal IgA antibodies as well as tissue-resident memory T cells in the lungs. The immunized female hamsters were protected from challenge with SARS-CoV-2 original WA1, B.1.617.2, and B.1.1.529 strains. The preexisting MeV and MuV immunity does not significantly interfere with the efficacy of TVC. Thus, the trivalent platform is a promising next-generation SARS-CoV-2 vaccine candidate.

Measles outbreak in 2019: a warning for the post-COVID-19 pandemic period.

Introduction. At the end of 2019 and the year before, there was a significant spread of measles in the World Health Organization (WHO) European Region.Gap statement. Among the countries that reported, a measles outbreak was Bosnia and Herzegovina (BiH).Aim. To describe the measles outbreak in BiH (an entity of the Federation of BiH, FBiH) in 2019.Methodology. Confirmatory IgM serology, measles nucleic acid detection by real-time RT-PCR and virus genotyping were done in the WHO-accredited laboratory for measles and rubella at the Clinical Center of the University of Sarajevo, Unit for Clinical Microbiology. Genotype was determined in all measles-RNA-positive cases by sequence analysis of the 450 nt fragment coding the C-terminal of measles virus nucleoprotein (N).Results. From 1 January to 31 December 2019, 1332 measles cases were reported, with the peak observed in April 2019 (413/1332, 31.01 %). Sarajevo Canton had the highest incidence, number of cases and percentage (206.4; 868/1332; 65.17 %) of measles cases. Around four-fifths of infected persons were unvaccinated (1086/1332, 81.53 %), while 4.58 % of the patients (61/1332) were immunized with one dose of measles-containing vaccine. The highest proportion of cases was found in children 0-6 years of age (738/1332, 55.41 %). Measles IgM positivity was determined in 75.88 % (346/456), while virus RNA was detected in 82.46 % (47/57) of the swab samples. All measles virus sequences belonged to genotype B3. SNP (position 216: C=>T) was detected in 1 of the 40 sequences obtained during this outbreak.Conclusion. Due to suboptimal immunization coverage, BiH belongs to countries at a high risk for measles outbreaks. Post-COVID-19 (coronavirus disease 2019) pandemic, targeted and tailored strategies are required to ensure routine vaccination demand and acceptance and broad partner and stakeholder group participation.

What's going on with measles?

Measles is a highly transmissible systemic viral infection associated with substantial mortality primarily due to secondary infections. Measles induces lifelong immunity to reinfection but loss of immunity to other pathogens. An attenuated live virus vaccine is highly effective, but lapses in delivery have resulted in increasing cases worldwide. Although the primary cause of failure to control measles is failure to vaccinate, waning vaccine-induced immunity and the possible emergence of more virulent virus strains may also contribute.

Immunity Against Measles in Korean Autologous Hematopoietic Stem Cell Transplant Recipients.

The seropositivity of measles antibodies among 261 autologous stem cell transplant recipients (ASCTs) in Korea, assessed approximately 1-2 years after transplant (median, 11 months; interquartile range, 9-14), was significantly lower than age- and sex-matched control healthcare workers (83.1% [217/261] vs. 90.3% [539/597], P = 0.002). The findings underscore the vulnerability of adult ASCT recipients to measles. Clinicians should prioritize testing for measles IgG after ASCT and consider vaccination for ASCT recipients who remain seronegative 2 years after ASCT.

Measles in the vaccinated host.

A woman in her 40s known to have systemic lupus erythematosus presented with a maculopapular rash on her face, neck and chest following measles exposure. She had received a single-dose measles vaccine as a child in the 1970s and was therefore presumed to be immune, and thus not infectious. As a result, she was initially managed in an open bay. Measles virus IgM antibody in serum was undetectable; however, measles virus RNA was subsequently detected in throat swab by PCR, which is consistent with current infection. Measles is one of the most transmissible diseases in the world and cases are rising both in the UK and globally. Our case and literature review highlight the risk of vaccine failure in measles, especially in people who have not received two doses of the measles, mumps and rubella vaccine. It also highlights the challenges in diagnosing measles in previously vaccinated individuals.

A neutralizing antibody prevents postfusion transition of measles virus fusion protein.

Measles virus (MeV) presents a public health threat that is escalating as vaccine coverage in the general population declines and as populations of immunocompromised individuals, who cannot be vaccinated, increase. There are no approved therapeutics for MeV. Neutralizing antibodies targeting viral fusion are one potential therapeutic approach but have not yet been structurally characterized or advanced to clinical use. We present cryo-electron microscopy (cryo-EM) structures of prefusion F alone [2.1-angstrom (Å) resolution], F complexed with a fusion-inhibitory peptide (2.3-Å resolution), F complexed with the neutralizing and protective monoclonal antibody (mAb) 77 (2.6-Å resolution), and an additional structure of postfusion F (2.7-Å resolution). In vitro assays and examination of additional EM classes show that mAb 77 binds prefusion F, arrests F in an intermediate state, and prevents transition to the postfusion conformation. These structures shed light on antibody-mediated neutralization that involves arrest of fusion proteins in an intermediate state.

Antibody inhibition of measles virus entry.

An intermediate virus-cell fusion step is revealed by an antibody with therapeutic potential.

Measles Infection Dose Responses: Insights from Mathematical Modeling.

How viral infections develop can change based on the number of viruses initially entering the body. The understanding of the impacts of infection doses remains incomplete, in part due to challenging constraints, and a lack of research. Gaining more insights is crucial regarding the measles virus (MV). The higher the MV infection dose, the earlier the peak of acute viremia, but the magnitude of the peak viremia remains almost constant. Measles is highly contagious, causes immunosuppression such as lymphopenia, and contributes substantially to childhood morbidity and mortality. This work investigated mechanisms underlying the observed wild-type measles infection dose responses in cynomolgus monkeys. We fitted longitudinal data on viremia using maximum likelihood estimation, and used the Akaike Information Criterion (AIC) to evaluate relevant biological hypotheses and their respective model parameterizations. The lowest AIC indicates a linear relationship between the infection dose, the initial viral load, and the initial number of activated MV-specific T cells. Early peak viremia is associated with high initial number of activated MV-specific T cells. Thus, when MV infection dose increases, the initial viremia and associated immune cell stimulation increase, and reduce the time it takes for T cell killing to be sufficient, thereby allowing dose-independent peaks for viremia, MV-specific T cells, and lymphocyte depletion. Together, these results suggest that the development of measles depends on virus-host interactions at the start and the efficiency of viral control by cellular immunity. These relationships are additional motivations for prevention, vaccination, and early treatment for measles.

Adapting response to a measles outbreak in a context of high vaccination and breakthrough cases: an example from Vaud, Switzerland, January to March 2024.

A measles outbreak with 51 cases occurred in the canton of Vaud, Switzerland, between January and March 2024. The outbreak was triggered by an imported case, and 37 (72.5%) subsequent cases were previously vaccinated individuals. Epidemiological investigations showed that vaccinated measles cases were symptomatic and infectious. In a highly vaccinated population, it is important to raise awareness among healthcare professionals to suspect and test for measles virus when an outbreak is declared, irrespective of the vaccination status of the patients.

Seroprevalence of measles antibodies in the Italian general population in 2019-2020.

In Italy, the measles elimination target has not yet been reached despite a significant reduction in cases. A multicenter study was conducted to estimate the prevalence of anti-measles (MV) IgG antibodies in the Italian population by age, sex and geographical area. To determine the level of MV-specific antibodies in sera, the immunoenzymatic assay ELISA was used (Enzygnost Anti-VZV/IgG, Siemens Healthcare Diagnostic Products GmbH, Germany). Overall, 3746 serum samples collected in the years 2019-20 from healthy subjects aged 6-64 years residing in 13 Italian regions. The overall seroprevalence of anti-MV IgG was 91.2 % (90.6 % male, 91.7 % female). Significantly higher seroprevalence values (p < 0.05) were recorded for the extreme age groups of the study population (6-9 years: 94.2 %; 40-64 years: 97.6 %). Subjects 20-39 and 40-64 years old had significantly higher antibody titers suggesting a protection against measles mainly derived from natural infection. Seroprevalence was significantly higher in the South (93.2 %) than in the Northern-Central Italy (88.9 %). The results indicate an increase in the overall seroprevalence data compared to previous investigations. However, further efforts must be made to implement and maintain high measles vaccination coverage to avoid the risk of future epidemic outbreaks.

Dynamics of measles immunity from birth and following vaccination.

Measles remains a major threat to human health despite widespread vaccination. While we know that maternal antibodies can impair vaccine-induced immunity, the relative contributions of pre-existing immunity levels, maternal and infant characteristics on vaccine responses remain unclear, hampering evidence-based vaccination policy development. Here we combine serological data from 1,505 individuals (aged 0-12 years) in a mother-infant cohort and in a child cohort with empirical models to reconstruct antibody trajectories from birth. We show that while highly heterogeneous across a population, measles antibody evolution is strongly predictive from birth at the individual level, including following vaccination. Further, we find that caesarean section births were linked with 2.56 (95% confidence interval: 1.06-6.37) increased odds of primary vaccine failure, highlighting the long-term immunological consequences of birth route. Finally, we use our new understanding of antibody evolution to critically assess the population-level consequences of different vaccination schedules, the results of which will allow country-level evaluations of vaccine policy.

Measles Foci Reduction Neutralization Test (FRNT).

The plaque reduction neutralization test (PRNT) and the enzyme-linked immunosorbent assay (ELISA) are both widely used to assess immunity to infectious diseases such as measles, but they use two different measurement principles: ELISA measures the ability of antibodies to bind to virus components, while the PRNT detects the aptitude of antibodies to prevent the infection of a susceptible cell. As a result, detection of measles virus (MV) neutralizing antibodies is the gold standard for assessing immunity to measles. However, the assay is laborious and requires experience and excellent technical skills. In addition, the result is only available after several days. Therefore, the classical PRNT is not suitable for high-throughput testing. By using an immunocolorimetric assay (ICA) to detect MV-infected cells, the standard PRNT has been developed into a focus reduction neutralization test (FRNT). This assay is faster and has improved specificity. The FRNT described here is extremely useful when immunity to measles virus needs to be assessed in patients with a specific medical condition, such as immunocompromised individuals in whom presumed residual immunity needs to be assessed. The FRNT is not generally recommended for use with large numbers of specimens, such as in a seroprevalence study.

Measles IgG Avidity Assay.

Measles IgG avidity assays determine the overall strength of molecular binding between measles-specific IgG antibodies and measles virus antigens. Avidity results can distinguish recent from distant measles virus infections. Individuals who are immunologically naïve to measles virus develop low-avidity antibodies upon measles virus infection or first-time vaccination. Within 4-6 months, antibodies mature to high avidity. Measles avidity assays are most useful in the context of measles elimination. In such settings, avidity and epidemiological and clinical information are used to classify measles breakthrough infections for control and surveillance purposes and to assist in case confirmation when other laboratory results are inconclusive or nonexistent. We present a highly accurate end-titer measles avidity assay that delivers results based on IgG quality (avidity) that are independent of IgG concentration.