Polyvalent Vaccine Research Articles

Polyvalent therapeutic vaccine for type 2 diabetes mellitus: Immunoinformatics approach to study co-stimulation of cytokines and GLUT1 receptors

BackgroundType 2 diabetes mellitus (T2DM) is a worldwide disease that have an impact on individuals of all ages causing micro and macro vascular impairments due to hyperglycemic internal environment. For ultimate treatment to cure T2DM, association of diabetes with immune components provides a strong basis for immunotherapies and vaccines developments that could stimulate the immune cells to minimize the insulin resistance and initiate gluconeogenesis through an insulin independent route.MethodologyImmunoinformatics based approach was used to design a polyvalent vaccine for T2DM that involved data accession, antigenicity analysis, T-cell epitopes prediction, conservation and proteasomal evaluation, functional annotation, interactomic and in silico binding affinity analysis.ResultsWe found the binding affinity of antigenic peptides with major histocompatibility complex (MHC) Class-I molecules for immune activation to control T2DM. We found 13-epitopes of 9 amino acid residues for multiple alleles of MHC class-I bears significant binding affinity. The downstream signaling resulted by T-cell activation is directly regulated by the molecular weight, amino acid properties and affinity of these epitopes. Each epitope has important percentile rank with significant ANN IC50 values. These high score potential epitopes were linked using AAY, EAAAK linkers and HBHA adjuvant to generate T-cell polyvalent vaccine with a molecular weight of 35.6 kDa containing 322 amino acids residues. In silico analysis of polyvalent construct showed the significant binding affinity (− 15.34 Kcal/mol) with MHC Class-I. This interaction would help to understand our hypothesis, potential activation of T-cells and stimulatory factor of cytokines and GLUT1 receptors.ConclusionOur system-level immunoinformatics approach is suitable for designing potential polyvalent therapeutic vaccine candidates for T2DM by reducing hyperglycemia and enhancing metabolic activities through the immune system.

Prevalence of dengue virus serotypes in the 2017 outbreak in Peshawar, KP, Pakistan.

BackgroundDengue is a viral disease, transmitted by infected Aedes aegypti and Aedes albopictus female mosquitoes. Worldwide, 96 million infections were estimated in 2010. The dengue virus comprises four distinct serotypes (DENV‐1, DENV‐2, DENV‐3, and DENV‐4) which belong to the genus Flavivirus. Determining the serotypes during dengue outbreaks is crucial for its effective management in terms of diagnostics improvement and polyvalent vaccine development. The aim of the present study is to determine the prevalence rate of dengue virus serotypes in the samples collected from patients during the 2017 outbreak in Khyber Pakhtunkhwa, Pakistan.MethodsA total of 800 ELISA‐positive samples were collected, of which 513 (290 males, 223 females) samples were confirmed positive by PCR.ResultsOut of 513, 25 were found serotype 1 (5%), 196 were serotype 2 (38%), 192 were serotype 3 (37%), 56 were serotype 4 (11%), and 44 (8%) were found to have mix serotypes.ConclusionWe can conclude that serotypes 2 and 3 of dengue virus were the predominated serotypes of dengue virus in the 2017 outbreak in Peshawar, capital city of Khyber Pakhtunkhwa, Pakistan.

Atypical Aeromonas salmonicida vapA type V and Vibrio spp. are predominant bacteria recovered from ballan wrasse Labrus bergylta in Scotland.

Healthy and/or moribund farmed and wild ballan wrasse Labrus bergylta (>0.5 to 900 g) were sampled from hatcheries (n = 2) and Atlantic salmon Salmo salar cage sites (n = 8) in Scotland between February 2016 and October 2018. Less than half of the sampled individuals (n = 43; 32.3%) had been vaccinated (autogenous polyvalent vaccine; dip and/or injection) against atypical furunculosis (type V and VI), while 20 (15.0%) fish were not vaccinated, and the rest (70 individuals, 52.7%) were of unknown vaccination status. Swab samples from skin lesions, gill, liver, spleen and kidney were inoculated onto a variety of bacteriological agar plates, and bacteriology identification and sequencing analysis was performed on significant bacterial colonies. Atypical Aeromonas salmonicida (aAs) vapA type V was the predominant bacterial species (70/215 bacterial isolates, 32.5% of bacterial samples; 43/117 positive individual fish, 36.8%) isolated in this survey followed by Vibrio species, which were the most geographically prevalent bacteria. Photobacterium indicum/profundum was also isolated from L. bergylta for the first time during this study. The collection of these bacterial isolates provides useful information for disease management. Identifying the aAs isolates involved in disease in ballan wrasse could provide vital information for improving/updating existing autogenous vaccines.

Influencia del tabaquismo en la resistencia bacteriana después de la profilaxis frente a infecciones urinarias recurrentes con antibiótico o con vacuna

IntroductionThe influence of tobacco on the microbiological spectrum, resistance-sensitivity pattern and evolution in patients with recurrent urinary tract infections (RUTI) is analyzed. Evaluation of the effect of polyvalent bacterial vaccine on the prevention of RUTI and smoking status. Material and methodsRetrospective multicenter study of 855 women with RUTI receiving suppressive antibiotic treatment or bacterial vaccine between 2009 and 2013. Group A (GA): Antibiotic (n=495); Subgroups: GA1 non-smoker (n=417), GA2 smoker (n=78). Group B (GB): Vaccine (n=360); Subgroups: GB1 non-smoker (n=263), GB2 smoker (n=97). Variables: Age, pre-treatment UTI, disease-free time (DFT), microbial species, sensitivity and resistance. Follow-up at 3, 6 and 12 months with culture and SF-36 questionnaire. ResultsMean age 56.51 years (18-75), similar between groups (P=.2257). No difference in the number of pretreatment UTIs (P=.1329) or in the distribution of the bacterial spectrum (P=.7471). DFT was higher in subgroups B compared with A. Urine cultures in GA1: E. coli 62.71% with 8.10% resistance (33% quinolones; 33% cotrimoxazole; 33% quinolones + cotrimoxazole); in GA2 E. coli 61.53% with 75% resistance (16.66% quinolones; 33.33% quinolones + cotrimoxazole; 16.66% amoxicillin-clavulanate; 16.66% erythromycin + phosphomycin + clindamycin) (P=.0133). There were no differences between patients of GA treated with cotrimoxazole and nitrofurantoin (P=.8724). Urine cultures in GB1: E. coli 47.36% with 22.22% resistance (5.55% ciprofloxacin; 5.55% cotrimoxazole; 5.55% ciprofloxacin + cotrimoxazole; 5.55% amoxicillin/clavulanic acid). In GB2 E. coli 70.02% with 61.90% resistances (30.76% quinolones; 30.76% cotrimoxazole; 30.76% quinolones + cotrimoxazole; 17.69% amoxicillin-clavulanic acid) (P=.0144). ConclusionsThe development of bacterial resistance is more frequent among women with smoking habits and recurrent urinary infections. This could influence a worse response to preventive treatments, either with antibiotics or vaccines.

Epidemiology and Regional Programs on Meningococcal Disease Prevention in Tyumen Region and Yamalo-Nenets Autonomous District

Meningococcal disease is the urgent problem of healthcare due to its widespread prevalence, high incidence, severe course and high risk of mortality. Vaccination of Russian Federation population with polyvalent meningococcal vaccine for serogroups A, C, W, Y has not been studied before within the framework of regional immunization programs. The article presents the results of epidemiological analysis of the situation on meningococcal disease in Tyumen region and Yamalo-Nenets autonomous district (YNAD) in 2014-2019. The obtained data were used to develop the immunization strategy against meningococcal disease within the framework of the regional immunization calendar in Tyumen region and regional immunization programs in YNAD. The clinical case of severe course of meningococcemia with complications is presented in the article. Clinical conditions and syndromes which are common for practice of therapists during the management of patients with generalized forms of meningococcal disease are described.

Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung.

Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during Streptococcus pneumoniae infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 × 102 PFU). Control and influenza-infected mice were instilled with PBS or S. pneumoniae (1 × 103 CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as IL6 and IL1β. Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFҡB expression; however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with S. pneumoniae.

Reduction of foot-and-mouth disease virus transmission in cattle vaccinated one or two weeks before challenge using a commercial polyvalent vaccine

Immediate vaccination of the most susceptible and epidemiological relevant animals is a crucial part of control measures that facilitate virus elimination in case of entry of foot-and-mouth disease (FMD). The objective of this study was to evaluate the effect of cattle vaccination 7 and 14 days prior challenge using a vaccine commonly applied in systematic vaccination campaigns against transmission of FMD virus (FMDV). Transmission of FMDV was investigated in three groups of ten cattle each: one non-vaccinated group and two groups that were either vaccinated 7 days (−7/vaccinated group) or 14 days (−14/vaccinated group) before intranasal (IN) inoculation. Five cattle heads from each group were inoculated using the IN-route with the A/Argentina/2001 FMDV strain, while the remaining five cattle heads of each group were contact-exposed to inoculated cattle. Clinical signs were recorded; virus isolation and genome detection by RT-PCR were carried out on oesophageal–pharyngeal fluid (OPF) and blood. Neutralizing antibody titers and antibodies against non-structural proteins (NSP) of FMDV were also determined. Results suggest that the experimental design, virus challenge dose, and virus infectivity were appropriate and that the virus had been transmitted to naïve calves. Under the outlined experimental conditions, vaccination 7 and 14 days prior to challenge induced full clinical protection against virus inoculation. Moreover, −7/ or −14/vaccinated calves that had been contact-exposed to −7/ or −14/vaccinated IN-challenged calves, did not become infected. Consequently, no virus transmission occurred from vaccinated and subsequently infected calves to cohabitating vaccinated calves (R = 0). According to our results, early vaccination during an outbreak is effective as virus transmission can be significantly reduced using a vaccine commercially available, routinely applied in systematic vaccination campaigns.

Comparison of antibody repertories against Staphylococcus aureus in healthy and infected dairy cows with a distinct mastitis history and vaccinated with a polyvalent mastitis vaccine

Staphylococcus aureus is one of the pathogens most frequently isolated from cases of mastitis worldwide. To decrease the effect of S. aureus mastitis in dairy farming, alternative strategies for controlling mastitis are needed that depend on a better knowledge of cow-to-cow variations in S. aureus antibody production. The present study sought to explore the diversity of S. aureus antibodies produced by dairy cows with a distinct mastitis history and vaccinated with a polyvalent mastitis vaccine. We obtained protein extracts from S. aureus isolates derived from persistent subclinical mastitis. Proteins were fractionated using 2-dimensional gel electrophoresis and Western blotting. Then, Western blotting membranes were exposed to sera from 24 dairy cows that had been divided into the following groups: vaccinated dairy cows that were infected with S. aureus, further subdivided according to whether they (a) remained infected by S. aureus or (b) recovered from the intramammary infection; unvaccinated dairy cows infected with S. aureus; and vaccinated healthy dairy cows with no history of S. aureus mastitis. Proteins found to be reactive by Western blot were identified by mass spectrometry (MALDI/TOF-TOF). Our most important finding was that F0F1 ATP synthase subunit α, succinyl-diaminopimelate desuccinylase, and cysteinyl-tRNA synthetase were potential candidate proteins for the prevention of S. aureus mastitis. This study strengthens the notion that variations among animals should not be ignored and shows that the heterogeneity of antibody production against anti-staphylococcal antigens in animals may enable the identification of new immunotherapy targets.

Assessment of a poly-epitope candidate vaccine against Hepatitis B, C, and poliovirus in interaction with monocyte-derived dendritic cells: An ex-vivo study

Design and application of epitope-based polyvalent vaccines have recently garnered attention as an efficient alternative for conventional vaccines. We previously have reported the in silico design of HHP antigen which encompasses the immune-dominant epitopes of Hepatitis B surface antigen (HBsAg), Hepatitis C core protein (HCVcp) and Poliovirus viral proteins (VPs). It has been shown that the HHP has desirable conformation to expose the epitopes, high antigenicity and other desired physicochemical and immunological properties. To confirm the accuracy of these predictions, the ex-vivo immunogenicity of the HHP was assessed. The HHP gene was chemically synthesized in pET28a and expressed in E. coli (BL21). The expressed protein was purified and its immunological potency was evaluated on dendritic cells (DCs) as antigen presenting cells (APCs). Functional analysis was assessed in co-cultivation of autologous T-cells with matured DCs (mDCs). T-cell activation, proliferation and cytokines secretion were evaluated using flowcytometry and ELISA methods. Our results indicated that the HHP could induce the DC maturation. The mDCs were able to trigger T-cell activation and proliferation.In silico design and ex-vivo confirmation of immunological potential could pave the way to introduce efficient immunogens for further analysis. The ability of HHP in DC maturation and T-cell activation makes it an amenable vaccine candidate for further in-vivo studies.

Effect and Analysis of Bacterial Lysates for the Treatment of Recurrent Urinary Tract Infections in Adults.

Urinary tract infection (UTI) is a relevant public health problem, economically and socially affecting the lives of patients. The increase of antimicrobial bacterial resistance significantly hinders the treatment of UTIs, raising the need to search for alternative therapies. Bacterial lysates (BL) obtained from Escherichia coli and other pathogens have been used to treat different infectious diseases with promising results. This work aims to evaluate the effect and composition of an autologous BL for the treatment and control of recurrent UTIs in adults. The results show remission in 70% of the patients within the first three months after the administration of BL, while the infection is maintained under control for 6–12 months. The analysis by liquid chromatography–mass spectrometry (LC-MS) of the BL fractions recognized by the sera of patients shows the presence of cytosolic proteins, fimbriae, OMPs, and LPS. Our study demonstrates that the autologous BL contributed to the treatment and control of recurrent UTIs in adults, and its composition shows that different surface components of E. coli are potential immunogens that could be used to create a polyvalent protective vaccine.

A review of combined immunization: current research situation and its promising future

Combined immunization consists of combined vaccines (including polyvalent vaccines) and simultaneous administration of vaccines, aiming to reduce unnecessary inoculating times for children, and to broaden immunization coverage and a significant larger group of population would be benefit from the Expanded Program on Immunization. In this review, we have summarized a list of research papers focused on combined immunization. By scrutinizing the safety and effectiveness outcomes of combined immunization, we provide some suggestions about upgrading the current immunization program as well as research and development of new combined vaccines.

Maternal immunity of tilapia broodstock vaccinated with polyvalent vaccine and resistance of their offspring againstStreptococcus agalactiae

This study aimed to examine the use of Streptococcus agalactiae polyvalent vaccine in tilapia broodstock and the effect of maternal immunity and resistance on their offspring against S. agalactiae strain. The broodstock was injected with polyvalent vaccine of S. agalactiae at a dose of 108 CFU per fish at 2nd gonadal maturity until spawning. Challenge test was carried out on the offspring at the 5, 10, 15 and 20 days after hatching using NK1, N17O, N14G, N3M, N4M strain respectively and combination of them. We observed immunological parameters in broodstock, eggs and larvae and relative per cent survival (RPS) of larvae after challenged with pathogenic S. agalactiae. The results showed that the leukocytes, phagocytic activity, respiratory burst, lysozyme activity and antibody levels of vaccinated broodstock had higher level compared with unvaccinated broodstock. The high level of the lysozyme activity, antibody levels and recombination activating gene 1 (RAG1) were also observed in eggs and larvae from vaccinated broodstock. Larvae produced from vaccinated broodstock when challenged with variety strain of pathogenic S. agalactiae had RPS value more than 50% until 20 days after hatching. In conclusion, polyvalent vaccine of S. agalactiae administrated in the broodstock could enhance immunity in the broodstock and protect their offspring from pathogenic S. agalactiae.

MEASLES VIRUS ELIMINATION: RESOLVED ISSUES AND FUTURE CHALLENGES

Measles is a highly contagious infectious disease caused by an RNA−containing virus of the family Paramyxoviridae and Morbillivirus genus. The most proper way to stop it is a total vaccination. At the moment, live attenuated strains of the Enders − Schwartz measles virus are used to conduct it. Although they were developed more than 50 years ago, the vaccines in use today are effective enough to create a proper immune protection that can defend against an infection for decades, if the vaccination schedule is followed. The vast majority of measles outbreaks that have been reported in Europe over the last seven years have been caused by a lack of an immune response resulting from the unprecedented coverage of the population with vaccination. The measles outbreak observed in the adult and child population of Ukraine since December 2018 indicates the need and urgency of additional efforts to curb the spread and complete elimination of the measles virus. It has been determined that more than 95 % of the population should be vaccinated to ensure an elimination of measles virus and prevent the disease outbreaks after the virus has been imported from the countries that are still endemic to measles. It is noted that as a result of successful implementation of vaccination programs, the public's attention to measles is diminished even among physicians who sometimes have a rather dubious understanding of the disease symptoms. Ensuring a complete elimination of the measles virus requires the development and implementation of additional laboratory tests for immunity, development and realization of new, more polyvalent vaccines that are more readily accepted by population, increased awareness on safety and necessity of vaccination, as well as regulation. Key words: measles, immunity, elimination, epidemiological control, vaccination.

The Influence of an Elevated Production of Extracellular Enveloped Virions of the Vaccinia Virus on Its Properties in Infected Mice.

The modern approach to developing attenuated smallpox vaccines usually consists in targeted inactivation of vaccinia virus (VACV) virulence genes. In this work, we studied how an elevated production of extracellular enveloped virions (EEVs) and the route of mouse infection can influence the virulence and immunogenicity of VACV. The research subject was the LIVP strain, which is used in Russia for smallpox vaccination. Two point mutations causing an elevated production of EEVs compared with the parental LIVP strain were inserted into the sequence of the VACV A34R gene. The created mutant LIVP-A34R strain showed lower neurovirulence in an intracerebral injection test and elevated antibody production in the intradermal injection method. This VACV variant can be a promising platform for developing an attenuated, highly immunogenic vaccine against smallpox and other orthopoxvirus infections. It can also be used as a vector for designing live-attenuated recombinant polyvalent vaccines against various infectious diseases.

Respuesta inmune humoral contra toxoides de Clostridium perfringens en vaquillonas Holando seropositivas al virus de la Leucosis Bovina Enzoótica

Enzootic bovine leukosis is the main virosis that affects dairy cattle in Uruguay. The subclinical infection causes importants dysfunctions in the immune system impacting directly in the animal health. The aim of this study was to evaluate the immune response of Holstein heifers with positive serology against Leukosis bovine virus (BLV) when they were ordinary immunized against Clostridium perfringens. It was evaluated a seropositive group to BLV animals (n=29) and other seronegative group (n=19) during twelve months. The animals recived three immunizations with a commercial polyvalent vaccine against several Clostridios (days 0, 30, 173). Blood samples were taken in days 0, 30, 60, 90, 180 y 360 post vaccination and then the humoral immune response was analyzed through the use of the ELISA technique to quantify total antibodies against C. perfringens toxins alfa, beta and epsilon. Besides it was in vitro analyzed the amount of neutralizing antibodies against epsilon toxin using the reference technique, seroneutralization. The results demonstrated a low response of neutralizing antibodies to epsilon toxin by SN technique showing no correlation with the results obtained by the commercial ELISA kit. Total antibodies response evaluated using commercial ELISA Kit was variable according to the studied toxoid. No significant differences were found in the immune response against Clostridium perfringens vaccination between BLV seropositive and seronegative animals using the techniques mentioned. The commercial ELISA kit use to analyze the response to vaccination against Clostridiosis, must be discussed and analyzed according to the results of this work.

DDIS-23. CMV-BASED PLASMID DNA VACCINE FOR GBM USING THE UNITE PLATFORM

Abstract Glioblastoma (GBM) is an aggressive form of brain cancer with a median survival of 15 months, remaining unchanged in spite of technological advances in the standard of care. The presence of the partial CMV genome, specifically in GBM cells, provides a great opportunity for a targeted therapy. We have utilized our UNITE (UNiversal Intracellular Targeted Expression) platform to build a polyvalent DNA vaccine which includes HCMV proteins, pp65, gB and IE-1. The UNITE platform is based, in part, on a lysosomal targeting technology which can result in increased antigen presentation, a balanced T cell response, and subsequent immunologic benefit. Using an orthotopic GBM mouse model expressing CMV proteins in the CT2A cell line, we have shown up to 45% survival when treated therapeutically with the pp65-IE-1 vaccine. In order to further improve the vaccine’s efficacy, and also to understand the mechanism of action, we are evaluating the post-vaccination tumor microenvironment and testing combination therapies with immune checkpoint inhibitors. Preliminary data on treated tumors suggest an increase in the PD-1 immune checkpoint regulator and a higher number of regulatory T cells. Our immune response evaluation of the polyvalent vaccine in naïve mice showed generation of robust antigen specific T cell activation. The use of multiple antigens in this vaccine makes it better suited to prevent antigen escape by tumor cells. Encouraged by our non-clinical data and the promising outcomes from our collaborators’ clinical trials using pp65 mRNA transfected autologous dendritic cells (ATTAC and ATTAC-II), we are moving forward with a phase I trial. We believe that the immune boost from our UNITE platform combined with deactivation of the immunosuppressive microenvironment by checkpoint inhibition holds a promising treatment against GBM.

Cross-protective immune responses against African horse sickness virus after vaccination with protein NS1 delivered by avian reovirus muNS microspheres and modified vaccinia virus Ankara

African horse sickness virus (AHSV) is an insect-borne pathogen that causes acute disease in horses and other equids. In an effort to improve the safety of currently available vaccines and to acquire new knowledge about the determinants of AHSV immunogenicity, new generation vaccines are being developed. In this work we have generated and tested a novel immunization approach comprised of nonstructural protein 1 (NS1) of AHSV serotype 4 (AHSV-4) incorporated into avian reovirus muNS protein microspheres (MS-NS1) and/or expressed using recombinant modified vaccinia virus Ankara vector (MVA-NS1). The protection conferred against AHSV by a homologous MS-NS1 or heterologous MS-NS1 and MVA-NS1 prime/boost was evaluated in IFNAR (−/−) mice. Our results indicate that immunization based on MS-NS1 and MVA-NS1 afforded complete protection against the infection with homologous AHSV-4. Moreover, priming with MS-NS1 and boost vaccination with MVA-NS1 (MS-MVA-NS1) triggered NS1 specific cytotoxic CD8 + T cells and prevented AHSV disease in IFNAR (−/−) mice after challenge with heterologous serotype AHSV-9. Cross-protective immune responses are highly important since AHS can be caused by nine different serotypes, which means that a universal polyvalent vaccination would need to induce protective immunity against all serotypes.

Infections Due to Streptococcus pneumoniae

Pneumococci, or Streptococcus pneumoniae, are gram-positive, lancet-shaped diplococci but may also grow in short chains. The polysaccharide polymer that forms the outer capsule of S pneumoniae is chemically and antigenically unique and is crucial to virulence. There are at least 90 distinct serotypes. The capsule allows the bacteria to resist phagocytosis by leukocytes unless the organisms have been opsonized by antibody or serum complement components. Certain pneumococcal serotypes, such as the heavily encapsulated type 3 pneumococcus, are particularly virulent. In fact, only 23 serotypes account for 80% of bacteremic pneumococcal infections in the United States; capsular polysaccharides from these 23 serotypes are incorporated into the polyvalent polysaccharide pneumococcal vaccine (PPSV23), which has been available since 1983. This review covers the epidemiology and pathogenesis of pneumococcal infections, clinical pneumococcal infections, and prevention of pneumococcal infections. Adverse outcomes in pneumococcal pneumonia, antibiotic treatment for penicillin-resistant S pneumoniae, and Centers for Disease Control and Prevention child and adolescent immunization schedules are discussed. This review contains 1 figure, 6 tables, and 41 references. Key words: bacterial pneumonia, PCV13, penicillin-resistant Streptococcus pneumoniae, pneumococcal pneumonia, pneumococcus, PPSV23, pneumonia vaccine, Streptococcus pneumoniae

A phase II randomized, double-blind trial of a polyvalent Vaccine-KLH conjugate (NSC 748933 IND# 14384) + OPT-821 versus OPT-821 in patients with epithelial ovarian, fallopian tube, or peritoneal cancer who are in second or third complete remission: An NRG Oncology/GOG study

ObjectiveEarly-phase data have demonstrated induction of antibody responses to a polyvalent vaccine conjugate (Globo-H, GM2, MUC1-TN, TF) with adjuvant OPT-821. We sought to determine if this combination decreases the hazard of progression or death compared to OPT-821 alone in patients with ovarian cancer in second/third clinical complete remission following chemotherapy. Secondary and translational objectives were overall survival (OS), safety, and immunogenicity. MethodsFrom 2010-2013, patients were randomized (1:1) to receive OPT-821±vaccine-KLH conjugate subcutaneously at weeks 1, 2, 3, 7, 11, and then every 12 weeks (total 11). Dose delay or reduction was not permitted. Patients were removed for pre-defined dose-limiting toxicity. ResultsOf 171 patients randomized, 170 were treated. Most had disease of serous histology (85%), stage 3 disease at diagnosis (77%), and had received 2 prior regimens (68%). 32% received >6 treatment cycles [median 6, each arm (p = 0.33)]. 77% discontinued due to progression, 4% due to toxicity, and 1 due to myeloid dysplastic syndrome (MDS). Maximum toxicities included grade 4 MDS and depression/personality change (1 each, unlikely related), as well as grade 3 gastrointestinal disorders and others (n = 21, 4 related). Lesser adverse events were injection site reactions (82%) and fever (11%). Estimated HR for progression-free survival (PFS) of the vaccine + OPT-821 to OPT-821 arm was 0.98 (95% CI: 0.71–1.36). At a median follow-up of 60 months, median OS was 47 and 46 months, respectively. ConclusionsVaccine + OPT-821 compared to OPT-821 alone was modestly immunogenic and did not prolong PFS or OS. Multi-remission patients are a viable, well-defined population for exploring innovative consolidation and maintenance approaches. Trial registrationNCT00857545.

1180PD - Active immunization with immune checkpoint inhibitors-mimotope elicits strong anti-tumour effect against HER-2/neu-expressing tumours

BackgroundApplication of monoclonal antibodies (mAbs) as immune checkpoint inhibitors (ICIs) has demonstrated remarkable activity in cancer immunotherapy. Active immunization with mimotopes (B cell epitopes) of ICIs rather than application of the corresponding mAbs for passive immunotherapy may, however, provide advantages such as induction of antibodies by the patient’s own immune system and overcoming the costly treatment of the mAbs. MethodsAn established platform involving bacterial surface-display of overlapping peptides spanning the extracellular domains of human/mouse PD1 (h/mPD1), as well as in vitro assays based on T cells expressing h/mPD1 and h/mPDL1, were applied to identify and characterize mimotopes of an anti-human PD1 mAb as well as an anti-mouse PD1 mAb (as a proof of principle). ResultsThe PD1-mimotopes were shown to specifically inhibit the binding of the corresponding mAbs and also the mAbs capacity in blocking the respective PD1-PDL1 interactions. Applying a syngeneic mouse model with human Her-2/neu-expressing tumors, a significant tumor growth reduction by passive immunization with specific rabbit IgG against the mPD1-derived mimotope, comparable to the corresponding mAb, was shown. More importantly, active immunization with the mPD1-mimotope resulted in a significant tumor growth reduction associated with a marked increase of PD1 expressing lymphocytes in the tumors. Furthermore, a 68% homology between hPD1 and mPD1 sufficiently facilitated a significant induction of tumor growth reduction in the mice also by IgG against hPD1-derived mimotopes. ConclusionsOur results demonstrate in vivo anti-tumor effect following active immunization with PD1-derived mimotope in syngeneic mice with tumors expressing human Her-2/neu, implying the use of ICIs mimotopes for cancer immunotherapy. Evaluation of efficacy and safety of our second generation of anti-Her-2/neu vaccine (HerVAXX; Tobias et al, 2017, BMC Cancer) in combination with mimotopes of ICIs as adjuvants is now being carried out. Use of ICI mimotopes may, thus, pave the way for construction of monovalent as well as polyvalent vaccines in combination with tumor specific antigens against different malignancies. Legal entity responsible for the studyMedical University of Vienna and Ursula Wiedermann. FundingThe study was supported by the Medical University of Vienna and by a research grant from Imugene (Australia) to the Medical University of Vienna. DisclosureM. Preusser: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Gerson Lehrman Group; Honoraria (self), Advisory / Consultancy: CMC Contrast; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy: Mundipharma; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Medahead; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dome; Research grant / Funding (institution): Böhringer-Ingelheim. C.C. Zielinski: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): MSD; Honoraria (self), Advisory / Consultancy, Scientific Advisory Board member, Until June 2018: Imugene; Honoraria (self), Advisory / Consultancy: Ariad; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): Pfizer; Honoraria (self), Advisory / Consultancy: Merrimack; Honoraria (self), Advisory / Consultancy: Merck KGaA; Honoraria (self), Advisory / Consultancy: Fibrogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institution (CECOG): AstraZeneca; Honoraria (self), Advisory / Consultancy: Tesaro; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Shire; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Athenex. P. Steinberger: Non-remunerated activity/ies, Reports personal fees from Bristol-Myers Squibb outside the submitted work: Bristol-Myers Squibb. U. Wiedermann: Officer / Board of Directors, CSO, until Sept 2018: Imugene; Research grant / Funding (institution): Phizer; Research grant / Funding (institution): GSK ; Research grant / Funding (institution): Themis. All other authors have declared no conflicts of interest.