Live Attenuated Measles Vaccine Research Articles

B and T cell repertoire and gene expression differences in measles infection and vaccination revealed by longitudinal single-cell RNA/VDJ sequencing

Abstract While wild-type measles virus (WT MeV) was demonstrated to induce immune amnesia, it paradoxically still elicited high titers of measles-specific antibodies longitudinally; and much higher than the live-attenuated measles vaccine (LAMV). In order to further understand the longitudinal B and T repertoires, clonotype evolution and gene expression difference in WT MeV and LAMV, we conducted longitudinal single-cell RNA/VDJ sequencing of peripheral blood mononuclear cells (PBMC) from WT MeV and LAMV-infected rhesus macaques (RMs) (n = 3 in each WT MeV and LAMV groups, with 4 timepoints at D0, D11, D42/56, D168/176). Firstly, B cell subtypes (e.g. naïve, memory, activated and antibody-secreting B cells) were successfully annotated in PBMC based on key gene markers and immunogenetic information. Furthermore, preliminary analysis of 1 WT MeV and 1 LAMV revealed interesting differences in the B cell repertoire, including a more diverse usage of IGHV genes, greater isotype switching from IgD/M to IgGs, higher level of somatic hypermutation and later B cell clonal expansion peak in LAMV than WT-MeV infected RMs longitudinally. Interestingly, there was greater T cell clonotype expansion in the WT MeV than LAMV RMs. Our study highlights the differential humoral and adaptive immune responses between LAMV and WT MeV infections, uncovering important immunogenetic understanding in natural infection and vaccination.

Mechanistic insights into immune amnesia and immunity induced by measles infection and vaccination via comprehensive antiviral antibodies profiling

Abstract Measles is a disease known to induce acute immune amnesia and immunosuppression with increased susceptibility to other infections, while paradoxically conferring patients with life-long immunity to measles. However, it is not clear if the live-attenuated measles vaccine (LAMV) induces immunosuppression comparable to the wild-type measles (WT MeV) infection, nor how mechanistically LAMV and WT MeV affect antibodies specific to different pathogens. Therefore, we utilized VirScan, a phage-display immunoprecipitation and sequencing (PhIP-seq) technology for virome-wide detection of antibodies against viral epitopes, to compare longitudinal antibody diversity in plasma samples from WT MeV and LAMV-infected rhesus macaques (RMs) (n=10 and 6 respectively, with 5 longitudinal timepoints at D0, D14/15, D28, D84/89, D112/168/176). Preliminary analysis showed that WT MeV led to more long-term depletion of pre-existing antibodies to various viral peptides, while mounting a MeV-specific antibody response with greater intensity and breadth than LAMV-infected RM. Furthermore, in our sex difference analysis, male RMs elicited a stronger MeV response than female, particularly to N protein; also a more polyclonal MeV humoral response In summary, our work provided crucial mechanistic insights into immune amnesia and immunity induced by natural infection versus vaccination, highlighting the public health value of the measles vaccine in averting MeV-induced immune amnesia.

Inundative, Dry-Powder, Inhaled Measles Vaccination to Prevent Deaths of Young Children in War-torn Regions.

Children living in war-torn and geographically remote regions often die from measles due to undervaccination. Protective community immunity could be safely improved through the comprehensive use of small, inexpensive, easy-to-use, dry-powder aerosolized measles vaccination inhalers. Influential local community members could be engaged to provide risk counseling and inform their peers of measles risks to inspire vaccine uptake. Vaccination by inhaled live attenuated measles vaccine has been shown to be safe and protective among several million research subjects and omits (1) needles, syringes, glass vials, and specialized disposal systems; (2) deadly vaccine reconstitution errors; (3) cold chain technology to protect temperature-sensitive vaccine; (4) vaccine wastage associated with suboptimal use of multidose vials; (5) trained vaccinators; (6) food, housing, and transportation costs associated with centralized vaccination campaigns; and (7) risk of violence to vaccinators and associated staff. All elements for inhaler-based measles vaccination are readily available. Dry-powder measles vaccine inhalers can be assembled and distributed to save lives.

Mechanistic insight into immune amnesia and immunity induced by wild-type measles virus compared to live-attenuated measles vaccine

Abstract Despite the availability of a safe and effective vaccine, measles still causes significant mortality and morbidity among children in developing countries. As a disease that induces immune amnesia with increased susceptibility to other infections but also life-long immunity to measles, little is known about the immunogenetics of B cells that elicit measles-specific antibodies (Abs) in natural infection vs vaccination. We therefore conducted single-cell RNA sequencing (scRNA-seq) of longitudinal peripheral blood mononuclear cells (PBMC) and lymph node (LN) samples from wild-type (WT) measles virus (MeV) and live-attenuated measles vaccine (LAMV)-infected rhesus macaques (RMs) and characterized their gene expression, B cell repertoires and clonotype changes via bioinformatic pipelines. Preliminary analysis of two RMs across four timepoints (one WT MeV- and one LAMV-infected RM) revealed similarities and differences in immune cell populations and B cell repertoires, providing important mechanistic insights into B cell clonal development in natural infection as compared to vaccination. Supported by grants from NIH R01 AI153140 and the Jeffrey Richardson Fellowship

Adverse Reactions of Children Immunized with Live Attenuated Measles Vaccine and Nursing Countermeasures

Adverse Reactions of Children Immunized with Live Attenuated Measles Vaccine and Nursing Countermeasures

Assessment of Factors Associated with Low Measles Vaccine Effectiveness in Honkolo-Wabe District, Ethiopia

Background:-Measles is an acute illness and the most contagious childhood diseases. Almost all non-immune children contract this respiratory disease if exposed to the virus. The disease characterized by prodarmal fever, conjunctivitis, coryza and presence of Koplik spots. Prior to the introduction of vaccination programs, measles affected almost every child in the world. The expected sero conversion was estimated to 80-85% when 0.5ml live attenuated measles vaccine correctly administered subcutaneously at 9 months and more than 95% after 12months. This study was aimed to describe vaccine effectiveness and assess factors contributing to low measles vaccine effectiveness in Honkolo-Wabe district, Ethiopia. Methods:-Community based unmatched case-control study, involving 51 children who had previous measles illness were randomly selected and 153 controls were selected from the community three for each case in July, 2014. Vaccination status and other risk factors for the study children were ascertained through by interviewing mothers /care giver and observing the cold chain management. Epi-info version 7 was used for data analysis. Results:-Measles vaccine effectiveness was estimated at 70.9% [95% CI=65-79%]. Age of measles vaccine given, poor health seeking behavior of the community, number of dose and inappropriate vaccine transportation from district health office to health post, administration of reconstituted vaccine after 6hrs by HEW were identified as the contributing factors for low measles vaccine effectiveness in Honkolo-Wabe district. Contacting with laboratory confirmed or epidemiological linked measles cases statically significant regard to measles [OR=23.77, 95% CI=9.17-64.25]. Of the study participants 19.6%, 44.6% and 3.9% were received one, two and three doses of measles vaccine respectively. About 3.9%, 45.1% and 12.3% of the participants were received first dose of measles vaccination before, at 9month and after nine month respectively. However 18.6% of the study participants were not received 2nd does. Only 35.3% of the participants were received their second doses after 12month their birth. Conclusions:-Measles vaccine effectiveness was low. Age of children, number of dose, inappropriate vaccine transportation and utilization of reconstituted vaccine after 6hrs were contributing factors for low measles vaccine effectiveness. Regular monitoring and ensure of all birth cohort have received at least 2 doses of measles vaccine at 9month of their birth and above. Improve cold chain management at health post and use reconstituted vaccine within 6 hours.

Measles Vaccines Designed for Enhanced CD8+ T Cell Activation.

Priming and activation of CD8+ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8+ T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8+ epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8+ T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8+ responses against pathogens and tumor antigens.

Adverse effects of single-component measles vaccine in school children.

Measles is a highly contagious viral infection potentially with serious complications and the principal method of protection from the disease is vaccination. Measles vaccination resulted in a 79% drop in measles deaths between 2000 and 2015 worldwide. There has long been a debate about the necessity and benefit-loss ratio of routine MMR vaccination due to possible AE of MMR vaccine. Especially in developed countries which are thought to be free of measles there is an increasing tendency towards hesitation for vaccination though there have been continued outbreaks of measles in countries in which measles is considered to be eliminated. Considering those facts, we decided to publish our data about measles vaccination and adverse effects (AE) during national catch-up measles vaccination programme which took place December 8-26, 2003. A total of 152.648 children aged between seven and fourteen were vaccinated by a live attenuated measles vaccine of which 148.064 (97%) had received measles vaccine by age nine or twelve months. During one month follow-up the AE were recorded. Totally 30.302 AE were reported in 24.209 children, of which 52% of them were local and pain and swelling at injection side were the most common AE. Fever and headache were the most commonly observed systemic side effects. All AE were mild and transient except in four children in whom encephalitis was diagnosed during the one month observation period. Further investigation of the etiology of those cases revealed that they were not related to measles or measles vaccine. In conclusion, single-component measles vaccine was found to be safe in previously MMR vaccinated children in short term and long term effects may be need to be clarified by further studies.

Safety of measles-containing vaccines in post-marketing surveillance in Anhui, China.

The safety of measles vaccination is of great interest and importance to public health practice and the general society. We have analyzed the adverse events following immunization (AEFIs) of currently used measles-containing vaccines (including live attenuated measles vaccine, live attenuated measles and rubella combined vaccine, live attenuated measles and mumps combined vaccine, live attenuated Measles, Mumps and Rubella Combined Vaccine) in Anhui Province, China. From 2009 to 2014, 9.9 million doses of measles-containing vaccines were administrated and 1893 AEFIs were found (191.4 per million doses), of which, 33 serious AEFIs (3.3 per million vaccine doses) were reported. 59.4% (1124 cases) were male cases, and 85.1% (1611 cases) occurred in persons aged < 1 year. 93.3% (1766 cases) occurred at the first dose of vaccination and 95.9% (1815 cases) were found within 3 days after vaccination. This study presents up-to-date data and suggests that the measles-containing vaccines used in Anhui Province of China are safe.

Measles virus infection of human keratinocytes: Possible link between measles and atopic dermatitis

BackgroundMeasles virus (MV) infection is marked with a skin rash in the acute phase of the disease, which pathogenesis remains poorly understood. Moreover, the association between measles and progression of skin diseases, such as atopic dermatitis (AD), is still elusive. ObjectiveWe have thus analysed the susceptibility of human keratinocytes to MV infection and explore the potential relationship between MV vaccination and the pathogenesis the AD. MethodsWe performed immunovirological characterisation of MV infection in human keratinocytes and then tested the effect of live attenuated measles vaccine on the progression of AD in adult patients, in a prospective, double-blind study. ResultsWe showed that both human primary keratinocytes and the keratinocyte cell line HaCaT express MV receptors and could be infected by MV. The infection significantly modulated the expression of several keratinocyte-produced cytokines, known to be implicated in the pathogenesis of inflammatory allergic diseases, including AD. We then analysed the relationship between exposure to MV by vaccination and the progression of AD in 20 adults during six weeks. We found a significant decrease in CCL26 and thymic stromal lymphopoietin (TSLP) mRNA in biopsies from acute lesions of vaccinated patients, suggesting MV-induced modulation of skin cytokine expression. Clinical analysis revealed a transient improvement of SCORAD index in vaccinated compared to placebo-treated patients, two weeks after vaccination. ConclusionsAltogether, these results clearly demonstrate that keratinocytes are susceptible to MV infection, which could consequently modulate their cytokine production, resulting with a beneficial effect in the progression of AD. This study provides thus a proof of concept for the vaccination therapy in AD and may open new avenues for the development of novel strategies in the treatment of this allergic disease.

Development of Recombinant Measles Virus-Based Vaccines.

This chapter describes the development of recombinant measles virus (MV)-based vaccines starting from plasmid DNA. Live-attenuated measles vaccines are very efficient and safe. Since the availability of a reverse genetic system to manipulate MV genomes and to generate respective recombinant viruses, a considerable number of recombinant viruses has been generated that present antigens of foreign pathogens during MV replication. Thereby, robust humoral and cellular immune responses can be induced, which have shown protective capacity in a substantial number of experiments.For this purpose, the foreign antigen-encoding genes are cloned into additional transcription units of plasmid based full-length MV vaccine strain genomes, which in turn are used to rescue recombinant MV by providing both full-length viral RNA genomes respective anti-genomes together with all protein components of the viral ribonucleoprotein complex after transient transfection of the so-called rescue cells. Infectious centers form among these transfected cells, which allow clonal isolation of single recombinant viruses that are subsequently amplified, characterized in vitro, and then evaluated for their immunogenicity in appropriate preclinical animal models.

Measles in our time: the US experience.

Measles in our time: the US experience.

Vaccine-induced measles virus-specific T cells do not prevent infection or disease but facilitate subsequent clearance of viral RNA.

ABSTRACTInfection with wild-type measles virus (MeV) induces lifelong protection from reinfection, and parenteral delivery of the live attenuated measles vaccine (LAV) also provides protection from measles. The level of neutralizing antibody is a good indicator of protection, but the independent roles of MeV-specific antibody and T cells have not been identified. In this study, macaques immunized with LAV through a nebulizer and a mouthpiece developed MeV-specific T-cell responses but not neutralizing antibodies. Upon challenge with wild-type MeV, these animals developed rashes and viremias similar to those in naive animals but cleared viral RNA from blood 25 to 40 days faster. The nebulizer-immunized animals also had more robust MeV-specific CD4+ and CD8+ T-cell responses than the naive animals after challenge, characterized by a higher number and better durability of gamma interferon (IFN-γ)-producing cells. Induction of MeV-specific circulating CD4+ and CD8+ T cells capable of producing multiple cytokines correlated with clearance of viral RNA in the nebulizer-immunized macaques. These studies demonstrated that MeV-specific T-cell immunity alone did not prevent measles, but T-cell priming enhanced the magnitude, durability, and polyfunctionality of MeV-specific T cells after challenge infection and correlated with more rapid clearance of MeV RNA.

Co-administration of live measles and yellow fever vaccines and inactivated pentavalent vaccines is associated with increased mortality compared with measles and yellow fever vaccines only. An observational study from Guinea-Bissau

BackgroundStudies from low-income countries indicate that co-administration of inactivated diphtheria–tetanus–pertussis (DTP) vaccine and live attenuated measles vaccine (MV) is associated with increased mortality compared with receiving MV only. Pentavalent (DTP–H. Influenza type B–Hepatitis B) vaccine is replacing DTP in many low-income countries and yellow fever vaccine (YF) has been introduced to be given together with MV. Pentavalent and YF vaccines were introduced in Guinea-Bissau in 2008. We investigated whether co-administration of pentavalent vaccine with MV and yellow fever vaccine has similar negative effects. MethodsIn 2007–2011, we conducted a randomised placebo-controlled trial of vitamin A at routine vaccination contacts among children aged 6–23 months in urban and rural Guinea-Bissau. In the present study, we included 2331 children randomised to placebo who received live vaccines only (MV or MV+YF) or a combination of live and inactivated vaccines (MV+DTP or MV+YF+pentavalent). Mortality was compared in Cox proportional hazards models stratified for urban/rural enrolment adjusted for age and unevenly distributed baseline factors. ResultsWhile DTP was still used 685 children received MV only and 358 MV+DTP; following the change in programme, 940 received MV+YF only and 348 MV+YF+pentavalent. During 6 months of follow-up, the adjusted mortality rate ratio (MRR) for co-administered live and inactivated vaccines compared with live vaccines only was 3.24 (1.20–8.73). For MV+YF+pentavalent compared with MV+YF only, the adjusted MRR was 7.73 (1.79–33.4). ConclusionIn line with previous studies of DTP, the present results indicate that pentavalent vaccine co-administered with MV and YF is associated with increased mortality.

A recombinant measles vaccine expressing chikungunya virus-like particles is strongly immunogenic and protects mice from lethal challenge with chikungunya virus

Chikungunya virus (CHIKV), a mosquito-transmitted alphavirus, recently reemerged in the Indian Ocean, India and Southeast Asia, causing millions of cases of severe polyarthralgia. No specific treatment to prevent disease or vaccine to limit epidemics is currently available. Here we describe a recombinant live-attenuated measles vaccine (MV) expressing CHIKV virus-like particles comprising capsid and envelope structural proteins from the recent CHIKV strain La Reunion. Immunization of mice susceptible to measles virus induced high titers of CHIKV antibodies that neutralized several primary isolates. Specific cellular immune responses were also elicited. A single immunization with this vaccine candidate protected all mice from a lethal CHIKV challenge, and passive transfer of immune sera conferred protection to naïve mice. Measles vaccine is one of the safest and most effective human vaccines. A recombinant MV-CHIKV virus could make a safe and effective vaccine against chikungunya that deserves to be further tested in human trials.

Measles control strategies in India: Position paper of Indian academy of pediatrics

Measles continues to be a major cause of childhood morbidity and mortality in India. Recent studies estimate that 80,000 Indian children die each year due to measles and its complications, amounting to 4% of under-5 deaths. Immunization against measles directly contributes to the reduction of under five child mortality and hence to the achievement of Millennium Development Goal 4 (MDG 4). The live attenuated measles vaccines are safe, effective and provide long lasting protection. The key strategies being followed globally for measles mortality reduction are high coverage of measles first dose, sensitive laboratory supported surveillance, appropriate case management, and providing second dose of measles vaccine. Prior to 2010, India was the only country in the world that had not introduced a second dose of measles vaccine in its National immunization program. We herein discuss the current status of measles vaccination along with the rationale and challenges of providing a second opportunity for measles vaccination, and the principles of measles catch-up campaigns.

Heterologous ("Nonspecific") and Sex-Differential Effects of Vaccines: Epidemiology, Clinical Trials, and Emerging Immunologic Mechanisms

A growing body of evidence from epidemiologic, clinical, and immunologic studies indicates that vaccines can influence morbidity and mortality independent of vaccine-specific B-cell or T-cell immunity. For example, the live attenuated measles vaccine and BCG vaccine may reduce mortality from infections other than measles or tuberculosis, respectively. Immunologists call these heterologous effects and epidemiologists have called them nonspecific effects, indicating that they manifest against a broad range of pathogens/disease. These effects differ by sex, can be beneficial or detrimental, and appear to be mediated by mechanisms including innate immune memory (also known as "trained immunity") and cross-reacting lymphocytes. Herein we review recent studies in this emerging field based on a meeting of experts, the recent Optimmunize meeting, held in Copenhagen, Denmark, in August 2012. Further characterization of these effects is likely to expand the way vaccines are evaluated and alter the manner and sequence in which they are given.

The genetic basis for interindividual immune response variation to measles vaccine: new understanding and new vaccine approaches

The live-attenuated measles vaccine is effective, but measles outbreaks still occur in vaccinated populations. This warrants elucidation of the determinants of measles vaccine-induced protective immunity. Interindividual variability in markers of measles vaccine-induced immunity, including neutralizing antibody levels, is regulated in part by host genetic factor variations. This review summarizes recent advances in our understanding of measles vaccine immunogenetics relative to the perspective of developing better measles vaccines. Important genetic regulators of measles vaccine-induced immunity, such as HLA class I and HLA class II genotypes, single nucleotide polymorphisms in cytokine/cytokine receptor genes (IL12B, IL12RB1, IL2, IL10) and the cell surface measles virus receptor CD46 gene, have been identified and independently replicated. New technologies present many opportunities for identification of novel genetic signatures and genetic architectures. These findings help explain a variety of immune response-related phenotypes and promote a new paradigm of ‘vaccinomics’ for novel vaccine development.

The power of suggestion: Adverse events from inactivated vaccines mimic the disease

Journal of Paediatrics and Child HealthVolume 48, Issue 12 p. 1101-1102 Heads UpFree Access The power of suggestion: Adverse events from inactivated vaccines mimic the disease First published: 10 December 2012 https://doi.org/10.1111/jpc.12008_2AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat While it is well recognised that live attenuated measles vaccine can cause a mild measles-like illness due to viral replication, this cannot happen with inactivated vaccines excluding vaccine failures. People often report that they develop influenza-like symptoms following killed influenza vaccine. Plausible explanations include release of cytokines like interferon that can cause flu-like symptoms or a coincidental viral infection, even influenza occurring before the vaccine can induce protective antibodies. However, French authors say this can be part of a new phenomenon, ‘disease-specific adverse events following non-live vaccines’.1 They describe statistically disproportionate reporting of gynaecological symptoms by girls receiving human papillomavirus vaccine, hepatobiliary disorders with hepatitis B vaccine and trismus with tetanus vaccine. Strengthening their case that the symptoms are due to suggestion is the phenomenon that trismus was reported with the French monovalent tetanus vaccine (which had the word ‘tetanus’ in its proprietary name) but not tetanus-containing multivalent vaccines like diphtheria-tetanus-pertussis vaccine (which did not have ‘tetanus’ in the name). The authors ascribe this to a ‘paradoxical placebo effect’ (when a positive expectation for a medical intervention has a negative outcome) or a ‘nocebo phenomenon’ (when an expected negative effect does occur). Neither seemed to do full justice to what they were describing, but I love that vaccine symptoms mimic the disease being prevented and what this tells us about the human mind. Reference 1 Okaïs C et al. Vaccine 2011; 29: 6321– 6326. Reviewers: David Isaacs, david.isaacs@health.nsw.gov.au; Aditi Dey, Children's Hospital at Westmead Volume48, Issue12December 2012Pages 1101-1102 ReferencesRelatedInformation

Live attenuated measles virus vaccine induces apoptosis and promotes tumor regression in lung cancer

Although the treatment of lung carcinoma has improved, at least 65% of patients with this tumor succumb to progressive disease. Measles virus oncolytic therapy has been reported to be effective in reducing tumor burden in immunocompetent or nude mice; however, its potential to reduce tumor burden in lung carcinoma remains to be determined. Herein, we report the potent antitumor effects of a live attenuated measles vaccine virus Hu-191 strain (MV) against lung carcinoma. Immunocompetent C57BL/6 mice bearing Lewis lung carcinoma (LLC) cells were treated with MV (1x104 to 1x106 CCID50/ml) once every other day for 10 days. Our results showed that treatment with MV effectively suppressed tumor growth and significantly prolonged the survival time of tumor-bearing animals. Histological examination revealed that the antitumor effects of MV therapy may result from increased induction of apoptosis, tumor necrosis and elevated lymphocyte infiltration. Our data suggest that MV, one of the widely used vaccines in China, has the ability to inhibit the growth of mouse lung carcinoma and may prove useful in the further exploration of the application of this approach in the treatment of human advanced lung cancer.