Attenuated Measles Virus Vaccine Research Articles

Tailoring Tfh profiles enhances antibody persistence to a clade C HIV-1 vaccine in rhesus macaques.

CD4 T follicular helper cells (Tfh) are essential for establishing serological memory and have distinct helper attributes that impact both the quantity and quality of the antibody response. Insights into Tfh subsets that promote antibody persistence and functional capacity can critically inform vaccine design. Based on the Tfh profiles evoked by the live attenuated measles virus vaccine, renowned for its ability to establish durable humoral immunity, we investigated the potential of a Tfh1/17 recall response during the boost phase to enhance persistence of HIV-1 Envelope (Env) antibodies in rhesus macaques. Using a DNA-prime encoding gp160 antigen and Tfh polarizing cytokines (interferon protein-10 (IP-10) and interleukin-6 (IL-6)), followed by a gp140 protein boost formulated in a cationic liposome-based adjuvant (CAF01), we successfully generated germinal center (GC) Tfh1/17 cells. In contrast, a similar DNA-prime (including IP-10) followed by gp140 formulated with monophosphoryl lipid A (MPLA) +QS-21 adjuvant predominantly induced GC Tfh1 cells. While the generation of GC Tfh1/17 cells with CAF01 and GC Tfh1 cells with MPLA +QS-21 induced comparable peak Env antibodies, the latter group demonstrated significantly greater antibody concentrations at week 8 after final immunization which persisted up to 30 weeks (gp140 IgG ng/ml- MPLA; 5500; CAF01, 2155; p<0.05). Notably, interferon γ+Env-specific Tfh responses were consistently higher with gp140 in MPLA +QS-21 and positively correlated with Env antibody persistence. These findings suggest that vaccine platforms maximizing GC Tfh1 induction promote persistent Env antibodies, important for protective immunity against HIV.

Tailoring Tfh profiles enhances antibody persistence to a clade C HIV-1 vaccine in rhesus macaques

CD4 T follicular helper cells (Tfh) are essential for establishing serological memory and have distinct helper attributes that impact both the quantity and quality of the antibody response. Insights into Tfh subsets that promote antibody persistence and functional capacity can critically inform vaccine design. Based on the Tfh profiles evoked by the live attenuated measles virus vaccine, renowned for its ability to establish durable humoral immunity, we investigated the potential of a Tfh1/17 recall response during the boost phase to enhance persistence of HIV-1 Envelope (Env) antibodies in rhesus macaques. Using a DNA-prime encoding gp160 antigen and Tfh polarizing cytokines (interferon protein-10 (IP-10) and interleukin-6 (IL-6)), followed by a gp140 protein boost formulated in a cationic liposome-based adjuvant (CAF01), we successfully generated germinal center (GC) Tfh1/17 cells. In contrast, a similar DNA-prime (including IP-10) followed by gp140 formulated with monophosphoryl lipid A (MPLA) +QS-21 adjuvant predominantly induced GC Tfh1 cells. While the generation of GC Tfh1/17 cells with CAF01 and GC Tfh1 cells with MPLA +QS-21 induced comparable peak Env antibodies, the latter group demonstrated significantly greater antibody concentrations at week 8 after final immunization which persisted up to 30 weeks (gp140 IgG ng/ml- MPLA; 5500; CAF01, 2155; p&lt;0.05). Notably, interferon γ+Env-specific Tfh responses were consistently higher with gp140 in MPLA +QS-21 and positively correlated with Env antibody persistence. These findings suggest that vaccine platforms maximizing GC Tfh1 induction promote persistent Env antibodies, important for protective immunity against HIV.

Tricistronic Plasmid Expressing the T7 RNA Polymerase and Measles Virus N and P Proteins for Rescue of Measles Virus AIK-C Strain

: Up to now, several attenuated measles virus vaccine strains derived from the Edmonston B vaccine consisting of Schwarz/Moraten, Zagreb, and AIK-C have been introduced for the rescue of their relative viruses through reverse genetics. In most studies, the measles virus rescue was done by supplying a cell line that expresses T7 RNA polymerase and measles virus N and P proteins as accessory proteins. The present study aimed to evaluate the rescue efficiency of the recombinant measles virus AIK-C vaccine strain by using a tricistronic expression plasmid. In this study, the rescue of the recombinant measles virus AIK-C vaccine strain was performed by co-transfection of three plasmids, including the cloned antigenomic cDNA of measles virus, a tricistronic expression plasmid that contained T7 RNA polymerase and measles virus N and P genes, and measles virus L polymerase expression plasmid. To increase the rescue efficiency, the transfected HEK-293 cells were co-cultured with Vero cells. As a result, the use of tricistronic expression plasmid that concomitantly encoded three necessary genes for the rescue of the measles virus led to the viral cytopathic effect with high efficacy five days post-transfection. Finally, the co-culture of transfected HEK-293 cells with Vero cells showed a relatively fast induction of viral cytopathic effect.

Attenuated measles vaccine strain have potent oncolytic activity against Iraqi patient derived breast cancer cell line.

BackgroundOne of the world's leading causes of death among females is breast cancer. Oncolytic viruses are promising anticancer therapy that can overcome resistance to current conventional therapies. Measles virus replicates in and destroys malignant cells without affecting healthy cells. The study aimed to evaluate the lives attenuated Measles virus vaccine against Iraqi patient derived breast cancer cells that have functional BRCA1/BRCA2 genes and compare its activity against international breast cancer MCF-7 and CAL-51 cell lines.MethodsThe virus was propagated in VERO-hSLAM slam cells. The MTT cytotoxicity assay used to test the virus's ability to kill three human breast cell lines (AMJ13), (MCF-7), and (CAL-51). The cytopathic effect of the measles virus was determined using an H&E stain. Immunocytochemistry assay using specific anti H protein monoclonal antibody for measles virus in the virally infected cells. Finally, apoptosis induction in the infected cells tested using double staining of acridine orange/propidium iodide.ResultsThe result shown that breast cancer cells are effectively infected and destroyed by live attenuated measles virus vaccine, and it caused a significant cytopathic effect in the infected cell lines after 48–72 h of infection with remarkable effect on AMJ13 cells (IC50 was 3.527 for AMJ13, when it was 5.079 and 9.171 for MCF-7 and CAL-51 respectively). Measles virus treatment induces apoptosis significantly in breast cancer cell lines compared with control cells.ConclusionMeV vaccine is useful and safe as anticancer therapy with a notable impact on the local Iraqi breast cancer AMJ13 cells.

Thermostability of attenuated measles virus vaccine in Pakistan

Thermostability of attenuated measles virus vaccine in Pakistan

Investigation of Live Attenuated Measles Virus Vaccine as Anti Tumor Agent

This study was carried out to evaluate the antitumor effect of live attenuated measles virus Schwarz (MV) vaccine strain on tumor cell lines in vitro. Live attenuated measles virus Schwarz vaccine strain was obtained from Aventis Pasteur, France. Live attenuated measles virus Schwarz strain was propagated on Vero, human Rhabdomyosarcoma (RD) and human Glioblastoma-Multiform (GBM) cell lines which were supplied by Iraqi Center for Cancer and Medical Genetic Researches (ICCMGR). Results revealed that cell fusion occurred after 24 h of infection. The infected confluent monolayer appeared to be covered with syncytia with granulation and vaculation of cells after 72 to 120 h. Moreover, the formation of large round empty plaque spaces was observed in infected cells. Results of oncolytic cytopathic effect showed that after 120 h of exposure alterations in morphology of Vero, RD and GBM cells. Cells were rounded, shrink, clustered cells and large empty space with cell debris as a result of cell lysis and death. Haemadsorption effect of MV was studied and result recorded that all cell lines infected with virus have the ability for haemadsorption human red blood cells after 72 h of infection. While uninfected cells gave negative results. Detection of MV H protein by monoclonal antibodies in infected cells of all cell lines by immunocytochemistry assay gave positive results (brown color) in cytoplasm of infected cells. Cell viability was measured after 72 h of infection by MTT assay. Results showed a significant cytotoxic effect for measles virus (P ≤0.05) on growth of RD and GBM cell lines at the first dilution and the second one after 72 h of infection. When the dilution increases, there was a significant decline in the inhibitory effect with a significant cytotoxic effect as compared with the control. Also, concentrated inoculums of measles virus showed a significant cytotoxic effect when compared with the control.

Comparative Studies on Prevalence of Maternal Antibodies Against Measles Virus in Children (0-36 Months) in Rawalpindi and Islamabad

Measles is one of the most prevalent and serious infectious disease among children in the third world countries contributing to a high degree of morbidity and mortality unless they are either protected by high maternal antibody titer or by vaccination. Some work is still required regarding the optimum age of measles vaccination in developing countries. The present study was undertaken to find out the age where maternal antibodies declined and indicate the appropriate age for vaccination. A total of 606 blood samples were collected. 449 including 39 cord samples were collected from unvaccinated children between 0-36 months. 157 samples were analyzed for antibody response to live attenuated measles virus vaccine in 10-36 months. Haemagglutination Inhibition test (HI) was used to obtain stable titers. The percentage of maternal antibodies varied in each group. The highest antibodies 100% were observed in cord blood and 0-1 months of age group while lowest 17.39% in 9 months. A large increase in active immune response after vaccination was observed. The geometric mean titer (GMT) being significantly different before and after vaccination. At 13-24 months GMT was 5.038% before and 77.25% after vaccination. At 25-36 months GMT was 5.038% before and 87.2% after vaccination. It is concluded from this study that optimal age of measles vaccination in children is 9 months.

PACT- and RIG-I-Dependent Activation of Type I Interferon Production by a Defective Interfering RNA Derived from Measles Virus Vaccine.

The live attenuated measles virus vaccine is highly immunostimulatory. Identification and characterization of its components that activate the innate immune response might provide new strategies and agents for the rational design and development of chemically defined adjuvants. In this study, we report on the activation of type I interferon (IFN) production by a defective interfering (DI) RNA isolated from the Hu-191 vaccine strain of measles virus. We found that the Hu-191 virus induced IFN-β much more potently than the Edmonston strain. In the search for IFN-inducing species in Hu-191, we identified a DI RNA specifically expressed by this strain. This DI RNA, which was of the copy-back type, was predicted to fold into a hairpin structure with a long double-stranded stem region of 206 bp, and it potently induced the expression of IFN-β. Its IFN-β-inducing activity was further enhanced when both cytoplasmic RNA sensor RIG-I and its partner, PACT, were overexpressed. On the contrary, this activity was abrogated in cells deficient in PACT or RIG-I. The DI RNA was found to be associated with PACT in infected cells. In addition, both the 5'-di/triphosphate end and the double-stranded stem region on the DI RNA were essential for its activation of PACT and RIG-I. Taken together, our findings support a model in which a viral DI RNA is sensed by PACT and RIG-I to initiate an innate antiviral response. Our work might also provide a foundation for identifying physiological PACT ligands and developing novel adjuvants or antivirals. The live attenuated measles virus vaccine is one of the most successful human vaccines and has largely contained the devastating impact of a highly contagious virus. Identifying the components in this vaccine that stimulate the host immune response and understanding their mechanism of action might help to design and develop better adjuvants, vaccines, antivirals, and immunotherapeutic agents. We identified and characterized a defective interfering RNA from the Hu-191 vaccine strain of measles virus which has safely been used in millions of people for many years. We further demonstrated that this RNA potently induces an antiviral immune response through cellular sensors of viral RNA known as PACT and RIG-I. Similar types of viral RNA that bind with and activate PACT and RIG-I might retain the immunostimulatory property of measles virus vaccines but would not induce adaptive immunity. They are potentially useful as chemically defined vaccine adjuvants, antivirals, and immunostimulatory agents.

Live attenuated measles virus vaccine therapy for locally established malignant glioblastoma tumor cells.

Glioblastoma multiforme is the most aggressive malignant primary brain tumor in humans, with poor prognosis. A new glioblastoma cell line (ANGM5) was established from a cerebral glioblastoma multiforme in a 72-year-old Iraqi man who underwent surgery for an intracranial tumor. This study was carried out to evaluate the antitumor effect of live attenuated measles virus (MV) Schwarz vaccine strain on glioblastoma multiforme tumor cell lines in vitro. Live attenuated MV Schwarz strain was propagated on Vero, human rhabdomyosarcoma, and human glioblastoma-multiform (ANGM5) cell lines. The infected confluent monolayer appeared to be covered with syncytia with granulation and vacuolation, as well as cell rounding, shrinkage, and large empty space with cell debris as a result of cell lysis and death. Cell lines infected with virus have the ability for hemadsorption to human red blood cells after 72 hours of infection, whereas no hemadsorption of uninfected cells is seen. Detection of MV hemagglutinin protein by monoclonal antibodies in infected cells of all cell lines by immunocytochemistry assay gave positive results (brown color) in the cytoplasm of infected cells. Cell viability was measured after 72 hours of infection by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Results showed a significant cytotoxic effect for MV (P≤0.05) on growth of ANGM5 and rhabdomyosarcoma cell lines after 72 hours of infection. Induction of apoptosis by MV was assessed by measuring mitochondrial membrane potentials in tumor cells after 48, 72, and 120 hours of infection. Apoptotic cells were counted, and the mean percentage of dead cells was significantly higher after 48, 72, and 120 hours of infection compared with control cells. This study concludes that live attenuated MV Schwarz vaccine induces the oncolytic effect in Iraqi tumor cell line ANGM5 and in the rhabdomyosarcoma cell line through syncytia in tumor cells, which is one of the causes of cell death. The MV vaccine strain has the ability to insert its hemagglutinin protein into the tumor cell surface, leading to modification of the antigenic surface of tumor cells that may induce an antitumor immune response, MV vaccine strain induced cell killing by direct cytolysis and apoptosis induction. These antitumor features may indicate the use of MV in the treatment of glioblastoma.

The golden anniversary of the measles vaccine

Developed in the Enders laboratory of Boston Children ’ s Hospital (Boston, MA, USA) and Harvard Medical School (Boston, MA, USA) from 1954 to 1963, the live attenuated measles virus vaccine, ‘ Edmonston ’ , was the product of multiple passages through varied cell culture systems and embryonated hens ’ eggs, and studies in susceptible cynomolgus monkeys prior to introduction to adult humans and then susceptible children. Successful results enabled widespread studies in American children, leading to licensure in March 1963. Extension of clinical investigations then proceeded in Nigeria among health-compromised susceptible children, demonstrating the safety and effectiveness of the Edmonston vaccine among these young people. With national and international adoption of routine vaccination, measles was reduced to an uncommon childhood infection in many countries and, with the progress to a two-dose schedule, was eliminated from the entire western hemisphere by 2002. The World Health Organization ’ s inclusion of measles vaccine in its Expanded Program of Immunization since 1974 has reduced global mortality from measles and its complications from several million annually to approximately 150000 by 2011. Leading the elimination efforts since 2001 has been the Measles Initiative, which was broadened in 2012 to include rubella vaccine. The vaccine induces enduring (lifelong) immunity and is effective against all 23 known measles virus genotypes.

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.

Attenuated Oncolytic Measles Virus Strains as Cancer Therapeutics

Attenuated measles virus vaccine strains have emerged as a promising oncolytic vector platform, having shown significant anti-tumor activity against a broad range of malignant neoplasms. Measles virus strains derived from the attenuated Edmonston-B (MV-Edm) vaccine lineage have been shown to selectively infect, replicate in and lyse cancer cells while causing minimal cytopathic effect on normal tissues. This review summarizes the preclinical data that led to the rapid clinical translation of oncolytic measles vaccine strains and provides an overview of early clinical data using this oncolytic platform. Furthermore, novel approaches currently under development to further enhance the oncolytic efficacy of MV-Edm strains, including strategies to circumvent immunity or modulate immune system responses, combinatorial approaches with standard treatment modalities, virus retargeting as well as strategies for in vivo monitoring of viral replication are discussed.

Double-Stranded RNA Adenosine Deaminase ADAR-1-Induced Hypermutated Genomes among Inactivated Seasonal Influenza and Live Attenuated Measles Virus Vaccines

We sought to examine ADAR-1 editing of measles and influenza virus genomes derived from inactivated seasonal influenza and live attenuated measles virus vaccines grown on chicken cells as the culture substrate. Using highly sensitive 3DI-PCR (R. Suspène et al., Nucleic Acids Res. 36:e72, 2008), it was possible to show that ADAR-1 could hyperdeaminate adenosine residues in both measles virus and influenza virus A genomes. Detailed analysis of the dinucleotide editing context showed preferences for 5'ArA and 5'UrA, which is typical of editing in mammalian cells. The hyperedited mutant frequency, including genomes and antigenomes, was a log greater for influenza virus compared to measles virus, suggesting a greater sensitivity to restriction by ADAR-1.

Dry powder measles vaccine: Particle deposition, virus replication, and immune response in cotton rats following inhalation

A stable and high potency dry powder measles vaccine with a particle size distribution suitable for inhalation was manufactured by CO2-Assisted Nebulization with a Bubble Dryer® (CAN-BD) process from bulk liquid Edmonston-Zagreb live attenuated measles virus vaccine supplied by the Serum Institute of India. A novel dry powder inhaler, the PuffHaler® was adapted for use in evaluating the utility of cotton rats to study the vaccine deposition, vaccine virus replication, and immune response following inhalation of the dry powder measles vaccine. Vaccine deposition in the lungs of cotton rats and subsequent viral replication was detected by measles-specific RT-PCR, and viral replication was confined to the lungs. Inhalation delivery resulted in an immune response comparable to that following injection. The cotton rat model is useful for evaluating new measles vaccine formulations and delivery devices.

A highly attenuated measles virus vaccine strain encodes a fully functional C protein.

The P, V, and C proteins of measles virus are encoded in overlapping reading frames of the P gene, which makes it difficult to analyze the functions of the individual proteins in the context of virus infection. We established a system to analyze the C protein independently from the P and V proteins by placing its gene in an additional transcription unit between the H and L genes. Analyses with this system indicated that a highly attenuated Edmonston lineage vaccine strain encodes a fully functional C protein, and the P and/or V protein is involved in the attenuated phenotype.

Impfmasern/vakzineinduzierte Masern

With a worldwide annual incidence of 31 million cases resulting in 614,000 fatalities in 2002, measles is a main cause of childhood death which could be prevented by vaccination. Since the introduction of immunization with attenuated measles virus vaccine, which led to a decrease in measles cases with a low incidence of 0.2/100,000 inhabitants in Germany in 2004, the population's awareness of the risks of measles has faded. Instead public interest has increasingly focussed on the possible but mostly harmless complications of vaccination. There is concern that the number of those not immunized will increase to such an extent that endemic outbreaks of measles will again occur.

HIV's Challenge to Measles Control

Scott et al. have investigated an important and challenging aspect of the continuingly increasing efforts to reduce global measles-associated morbidity and mortality. What are the factors that may accelerate receptivity to attenuated measles virus vaccine by HIV-infected infants and thereby reduce their early susceptibility to wild-type measles virus? In early 2001 the American Red Cross initiated a program that developed a collaboration of the International Red Cross and Red Crescents the World Health Organization the United Nations Childrens Fund the United Nations Foundation the Centers for Disease Control and Prevention and later the Church of Latter Day Saints the Canadian International Development Agency and the Gates Foundation. As Rotary International had accepted the challenge of global polio eradication the Red Cross chose to focus on measles. Before a vaccine was available the World Health Organization estimated that nearly 8 million children died each year as a result ofmeasles and its complications. Although a vaccine had been available for 38 years when the Red Cross program was launched in early 2001 it was estimated that there were still nearly 900000 measles-associated deaths annually. The initial goal of this consortium now identified as the Measles Initiative or Measles Partnership was to reduce measles-associated mortality by 50% by 2005. Indeed the consortium exceeded their goal with the vaccination of 1360 million children in sub-Saharan Africa from 2001 through 2005 resulting in a 60% reduction of deaths to 345000 from the previously calculated 873000. In Africa it is estimated that 506000 deaths had been reduced to 126000. In addition to measles vaccination the campaigns of the consortium have provided polio vaccine tetanus toxoid (to women of childbearing age) antihelminthics vitamin A oral rehydration solution soap and insecticide-treated bed nets. Their next expressed goal is a global 90% reduction in measles-associated mortality by 2010.Preliminary data suggest they may have already achieved an 85% reduction by the end of 2006. (excerpt)

A Vaccine‐Preventable Infectious Disease Kills Half a Million Children Annually

The study by Bellini et al. [1] in this issue of the Journal of Infectious Diseases pro vides a reassuring affirmation that what previously had been only a clinical/epi demiologic observation is indeed factual: measles vaccine viruses do not cause sub acute sclerosing panencephalitis (SSPE). Bellini and colleagues have also revealed that the incidence of SSPE is much higher after natural measles than previously had been appreciated. Using sophisticated lab oratory technology that was not available when SSPE was previously reported in the United States, these investigators exam ined brain tissue specimens obtained dur ing the resurgence of measles in the United States during 1989-1991, confirmed the diagnosis of SSPE, and, by use of genotype analysis, established wild-type measles vi ruses as the responsible etiologic agents. The authors demonstrated, by use of data gathered during the measles outbreak of 1989-1991, as well as by use of data col lected during earlier outbreaks, that the true incidence of SSPE was ~7-ll cases of SSPE/100,000 cases of measles, rather than the previously cited estimate of 1 case of SSPE/100,000 cases of measles. When a live attenuated measles virus vaccine was first licensed in the United States in 1963 [2], the etiology of SSPE was unknown. It was not until 1967-1969 that measles viruses were demonstrated to

Measles vaccines, new developments and immunization strategies

The development of an attenuated measles virus vaccine gave us a tool to combat a disease which has ravaged the child population throughout the centuries. Three decades later the vaccine has shown its qualities and its problems. Using this vaccine the WHO have decided on a measles eradication policy. This article discusses some of the issues which are being addressed and possible solutions.

Immunocompromised might face vaccine risks

Live attenuated measles virus vaccine is currently recommended by the 1994 Red Book and the U.S. Public Health Service for administration to children, adolescents and adults with known HIV infection. However, a 21-year-old college student has provided the first indication of potential harmful consequence of administering the measles vaccine to a severely immunocompromised HIV-infected person. These recommendations attempted to prevent the occurrence of severe measles in symptomatic HIV-infected children, since no data previously existed to indicate serious or unusual reactions to measles, mumps and rubella (MMR) immunization. The case fatality rate for measles in HIV-infected individuals is reportedly as high as 40 percent. The immune status of HIV-infected children declines as disease progresses, prompting recommendation that HIV-exposed/infected children receive MMR vaccine routinely between ages 12 months to 15 months. HIV-infected children exposed to wild type measles virus should receive passive immunoglobulin (IG) whether or not they have been immunized; immunity may have declined and/or they may not have responded to the vaccine. Several studies have substantiated the less than optimal and unpredictable response to measles vaccines in HIV-infected infants.