Vaccines For Infectious Diseases Research Articles

Enhancing vaccination of key populations

Vaccination is effective in preventing the increase of disease, especially emerging infectious diseases (EIDs), and it is particularly important for people in close contact with infected sources and susceptible populations who are at increased risk of getting infectious diseases due to behavior, occupation or health. Despite targeted vaccination guidelines, inadequate vaccination of the key populations fails to receive widespread attention, resulting in a high-risk transition of disease from key populations to general populations. Strengthening the vaccination of the susceptible groups can effectively block the spread of pathogens to general populations, and reduce the consumption of medical resources in universal vaccination, which has significant economic value. In this review, we describe the prevalence of EIDs, analyze the experience and lessons of infectious disease vaccination in key populations through several cases, and further explore the causes for the decline in vaccination rates of key populations. According to the trends of EIDs, a plan to strengthen the vaccination of key populations is proposed to effectively prevent the transition of EIDs from key populations to general populations.

The Development of mRNA Vaccines for Infectious Diseases: Recent Updates.

mRNA-based technologies have been of interest for the past few years to be used for therapeutics. Several mRNA vaccines for various diseases have been in preclinical and clinical stages. With the outbreak of the COVID-19 pandemic, the emergence of mRNA vaccines has transformed modern science. Recently, two major mRNA vaccines have been developed and approved by global health authorities for administration on the general population for protection against SARS-CoV-2. They have been proven to be successful in conferring protection against the ongoing SARS-CoV-2 and its emerging variants. This will draw attention to various mRNA vaccines against infectious diseases that are in the early stages of clinical trials. mRNA vaccines offer several advantages ranging from rapid design, generation, manufacturing, and administration and have strong potential to be used against various diseases in the future. Here, we summarize the mRNA-based vaccines in development against various infectious diseases.

An introduction of the Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) Project

The vaccine benefit-risk assessment entails comprehensive and systematic evaluation of the major benefits and risks of vaccine based on information after a marketing authorization. In 2009, the influenza A (H1N1) pandemic led to the licensing of new H1N1 vaccines in many countries including Europe. The post-marketing evaluation and monitoring of H1N1 vaccines was carried out based on a project previously conducted in Europe. In 2013, the Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) project was launched with the support of Innovative Medicines Initiative (IMI) to address the limitations reported in the previous project. ADVANCE consisted of seven Work Packages (WPs), each indicating the vaccine benefitrisk monitoring readiness across four areas: Governance, Data source, Methods, and Study. First, a model for vaccine surveillance and governance with various functions such as decision making, quality management, execution, and financial administration was established. Also, the project developed a tool to identify, collect, and link the data sources available for vaccine surveillance. In addition, various methodologies were reviewed to assess the infectious disease burden, vaccine coverage, and benefit-risk based on linked data sources in Europe. Guidelines were proposed for real-world vaccine surveillance studies. Accordingly, a variety of tools and programs were developed, including a code of conduct related to the benefit-risk assessment of vaccines, ADVANCE International Research Readiness (AIRR), CodeMapper, and VaccO. Since the end of the ADVANCE project in 2019, the Vaccine Monitoring Collaboration for Europe (VAC4EU) has been conducting effective and sustainable vaccine benefit-risk monitoring programs based on the vision and ideology of ADVANCE. This study explains the contents and findings of ADVANCE with emphasis on WPs and proposes directions for establishing a vaccine benefit-risk assessment system in Korea.

Role of Damage-Associated Molecular Pattern/Cell Death Pathways in Vaccine-Induced Immunity.

Immune responses induced by natural infection and vaccination are known to be initiated by the recognition of microbial patterns by cognate receptors, since microbes and most vaccine components contain pathogen-associated molecular patterns. Recent discoveries on the roles of damage-associated molecular patterns (DAMPs) and cell death in immunogenicity have improved our understanding of the mechanism underlying vaccine-induced immunity. DAMPs are usually immunologically inert, but can transform into alarming signals to activate the resting immune system in response to pathogenic infection, cellular stress and death, or tissue damage. The activation of DAMPs and cell death pathways can trigger local inflammation, occasionally mediating adaptive immunity, including antibody- and cell-mediated immune responses. Emerging evidence indicates that the components of vaccines and adjuvants induce immunogenicity via the stimulation of DAMP/cell death pathways. Furthermore, strategies for targeting this pathway to enhance immunogenicity are being investigated actively. In this review, we describe various DAMPs and focus on the roles of DAMP/cell death pathways in the context of vaccines for infectious diseases and cancer.

Effect of Serial Passage on the Pathogenicity and Immunogenicity of Vaccinia Virus LC16m8 Strain.

Simple SummaryThere is great current interest in vaccines for use in the coronavirus disease 2019 (COVID-19) pandemic. Safety and efficacy are particularly important in vaccine development, and these depend on the properties of the vaccine and the response in the vaccinated person. Some vaccines produce a strong immune response but may also cause adverse events in certain individuals. It is particularly important to predict if a person may be vulnerable to these adverse events, and this is one of the purposes of the field of vaccinomics. In this review, we examine recent studies on vaccinia virus (VACV) vaccine, which is the key vaccine responsible for eradicating smallpox. In particular, we consider the different individual responses to this vaccine, and we discuss future research directions in this area.The phenotype of an attenuated live vaccine depends on gene mutation achieved by, for example, many passages in cultured cells. Viral clones with preferable phenotypes are selected and the causative genetic mutation(s) are later identified. LC16m8 is an example of a highly attenuated smallpox vaccine that was developed and licensed in Japan in the 1970s. LC16m8 was obtained by the passaging of Lister strain, with indicators of small plaque formation and temperature sensitivity as virus phenotypes. This strain can replicate in mammalian cells and provides robust cellular and humoral immunity, as well as long-term immune memory. Recent studies using proteome-wide antigen arrays have revealed that antibody production against LC16m8 and other VACVs differs largely among individuals. Moreover, associations between SNPs in immune-related genes and immune outcomes have been increasingly found. These results lead to predicting adverse events of a vaccine, which is a purpose of vaccinomics. Studies on VACV will continue to contribute to the understanding of host-pathogen interactions and to development of a vaccine for other infectious and non-infectious diseases. Here, we review studies of VACV, including our recent research on LC16m8, with a focus on the phenotype and genotype, and we discuss future research directions.

RNA Vaccines against Infectious Diseases: Vital Progress with Room for Improvement.

mRNA vaccines have amassed a strong interest from scientists and nonscientists alike for their potential in treating cancer and curbing the spread of infectious diseases. Their success has been bolstered by the COVID-19 pandemic as mRNA vaccines for the SARS-CoV-2 virus showed unrivaled efficiency and success. The strategy relies on the delivery of an RNA transcript that carries the sequence of an antigenic molecule into the body’s cells where the antigen is manufactured. The lack of use of infectious pathogens and the fact that they are made of nucleic acids render these vaccines a favorable alternative to other vaccination modalities. However, mRNA vaccination still suffers from a great deal of hurdles starting from their safety, cellular delivery, uptake and response to their manufacturing, logistics and storage. In this review, we examine the premise of RNA vaccination starting from their conceptualization to their clinical applications. We also thoroughly discuss the advances in the field of RNA vaccination for infectious diseases. Finally, we discuss the challenges impeding their progress and shed light on potential areas of research in the field.

Lipid Nanoparticles for Organ-Specific mRNA Therapeutic Delivery.

Advances in the using in vitro transcribed (IVT) modRNA in the past two decades, especially the tremendous recent success of mRNA vaccines against SARS-CoV-2, have brought increased attention to IVT mRNA technology. Despite its well-known use in infectious disease vaccines, IVT modRNA technology is being investigated mainly in cancer immunotherapy and protein replacement therapy, with ongoing clinical trials in both areas. One of the main barriers to progressing mRNA therapeutics to the clinic is determining how to deliver mRNA to target cells and protect it from degradation. Over the years, many different vehicles have been developed to tackle this issue. Desirable vehicles must be safe, stable and preferably organ specific for successful mRNA delivery to clinically relevant cells and tissues. In this review we discuss various mRNA delivery platforms, with particular focus on attempts to create organ-specific vehicles for therapeutic mRNA delivery.

Aggregation-Induced Emission-Based Vaccine Improves Potential Antitumor Immunotherapy.

Recently, immunomodulation based on biomaterials has held great promise for preventing and treating cancer. Tumor vaccination can be considered as one of promising immunotherapies, compared with the vaccines for infectious disease, it still stays in its infant. Herein, we designed a near-infrared-emitting AIEgens (named TPE-Ph-DCM) based vaccine as an adjuvant in enhancing immune response. AIE-based photodynamic vaccine exhibited efficiently enhancement of the DC?s antigen prestation and elicited antigen-specific cytotoxic T lymphocyte functionality, and significantly inhibited B16-OVA tumor growth prophylactically and therapeutically in mice model. This study is expected to provide a scientific basis for developing effective and safe tumor vaccines.

Self-assembled polymeric micelle as a novel mRNA delivery carrier

mRNA-based therapy has been evaluated in preclinical and clinical studies for the treatment of a wide variety of disease such as cancer immunotherapies and infectious disease vaccines. However, it remains challenging to development safe and efficient delivery system. Here, we have designed a novel self-assembled polymeric micelle based on vitamin E succinate modified polyethyleneimine copolymer (PVES) to delivery mRNA. In vitro, PVES could transfect mRNA into multiple cell lines such as HEK-293T, HeLa and Vero and the transfection efficiencies were much higher than PEI 25 k. In addition, the cytotoxicity of PVES was much lower than PEI 25 k. Furthermore, mice administered intramuscularly with PVES/SARS-CoV-2 mRNA vaccine induced potent antibody response and show no obvious toxicity. These results demonstrated the potential of PVES as a safe and effective delivery carrier for mRNA.

MRNA vaccines for infectious diseases: principles, delivery and clinical translation.

Over the past several decades, messenger RNA (mRNA) vaccines have progressed from a scepticism-inducing idea to clinical reality. In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts. Although it is now clear that mRNA vaccines can rapidly and safely protect patients from infectious disease, additional research is required to optimize mRNA design, intracellular delivery and applications beyond SARS-CoV-2 prophylaxis. In this Review, we describe the technologies that underlie mRNA vaccines, with an emphasis on lipid nanoparticles and other non-viral delivery vehicles. We also overview the pipeline of mRNA vaccines against various infectious disease pathogens and discuss key questions for the future application of this breakthrough vaccine platform.

UniCoVac Position Paper: Considerations for University Campus-Based Programmes for COVID-19 and Other Infectious Disease Vaccines

This position paper sets out the rationale, logistics and limitations for delivery of COVID-19, MMR and meningitis vaccines to university students. Key aspects considered are ascertainment of vaccine status and campus-based delivery of vaccines. The approaches described in this position paper require an inter-disciplinary approach. There will be a requirement for data analysts to enable personalised, secure access to vaccination records, for social media experts and sociologists to design appropriate pathways and literature for disseminating information and for public health experts to oversee literature outputs and delivery of campus-based immunisation programmes. Contributions from vaccinologists, economists and modellers will also be required for monitoring and assessing the utility of implemented recommendations.

​US Tropical Disease Priority Review Vouchers: Lessons In Promoting Drug Development And Access.

The COVID-19 global pandemic has devastated lives and economies. It has served as a reminder of how critical it is to invest in preventing and treating infectious diseases. Until the COVID-19 pandemic, the largest US government-sponsored reward for infectious disease drug and vaccine development was the Tropical Disease Priority Review Voucher program. Under this program, the Food and Drug Administration awards a priority review voucher to the sponsor of a new drug or vaccine for tropical infectious diseases. The voucher then can be exchanged for the faster review of one drug. We provide case studies for tropical disease voucher recipients between 2007 and 2018, examine the effects of the voucher program on product innovation and access, and recommend that policy makers protect the voucher program while creating complementary incentives.

Immune stimulation and antibody response of chicks to different doses/units of the Nigerian live infectious bursa disease vaccine

Vaccination failure is one of the major constraints to disease control in poultry. To investigate Infectious bursa disease (IBD)-vaccination failures (frequently/globally reported), batches of the Nigerian live-vaccine were tested for viral units before vaccinating following chick-groups: 16 doses (65,536 units), 8 doses (32,768 units), 4 doses (6,384 units), 2 doses (8,192 units), 1 dose (4,096 units), 1:2 dose (2,048 units), 1:4 dose (1,024 units), 1:8 dose (512 units), 1:16 dose (256 units) and control. Each batch gave 4,096 viral units. Mean bursa weight/body weight ratios (immune stimulation) and mean antibody titres of the chick-groups were 47.40 ±5.45 and 51.20 ±7.83; 44.25 ±7.28 & 48.00 ±9.24; 45.25 ± 4.28 and 64.00 ± 0.00; 43.00 ±7.58 and 101.60 ± 35.05; 44.60 ± 5.51 and 128.00 ± 0.00; 42.60 ± 6.23 and 268.80 ± 16.00; 40.50 ± 1.76 and 80.00 ±16.00; 31.40 ± 3.80 and 80.00 ± 27.71; 37.18 ± 4.07 and 89.60 ± 15.68 and 26.20 ± 3.31 and 19.20 ± 5.99, respectively. Half (2,048 units) of the recommended 1-dose gave optimal antibody-titre. The higher doses gave lower antibody-titres like the lower doses but immune stimulation continued to increase as doses/units increased. Both over-stimulating the immune system (too high vaccine-doses/viral-units/viral-virulence) and under-stimulation cause vaccination failure.

Nonhuman Adenoviral Vector-Based Platforms and Their Utility in Designing Next Generation of Vaccines for Infectious Diseases.

Several human adenoviral (Ad) vectors have been developed for vaccine delivery owing to their numerous advantages, including the feasibility of different vector designs, the robustness of elicited immune responses, safety, and scalability. To expand the repertoire of Ad vectors for receptor usage and circumvention of Ad vector immunity, the use of less prevalent human Ad types or nonhuman Ads were explored for vector design. Notably, many nonhuman Ad vectors have shown great promise in preclinical and clinical studies as vectors for vaccine delivery. This review describes the key features of several nonhuman Ad vector platforms and their implications in developing effective vaccines against infectious diseases.

From COVID-19 to Cancer mRNA Vaccines: Moving From Bench to Clinic in the Vaccine Landscape.

Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.

Abstract 1556: Retinoid X receptor agonists enhances Th1 antigen-specific and polyfunctional T cells with the HER2-IGFBP2-IGF1R vaccine

Abstract Bexarotene and 9cUAB30 are highly selective oral retinoid X receptor (RXR) agonists with anti-proliferative activity in breast cancer. We have demonstrated that bexarotene enhances efficacy of a multi-antigen vaccine to prevent breast cancer in the TgMMTV-neu model and increases CD8 T-cell tumor infiltration. We further have shown that RXRα expression is in 24.9±13% of macrophages, 38.6 ±14% of plasmacytic dendritic cells (pDC), and 33.1 ± 16% of monocytic dendritic cells (mDC). Furthermore, the RXR agonists increased Th1 pDC and mDC. We therefore evaluated whether RXR agonists could enhance the vaccine antigen-specific immunogenicity and polyfunctional T cells in the transgenic mouse mammary tumor model TgMMTV-neu. Vaccination with the 150 µg HER2-IGFBP2-IGF1R vaccine and 5 ug GMCSF adjuvant every 2 weeks for four doses significantly increased antigen-specific IFN-γ T cells, but not antigen-specific IL10 T cells, as compared to control vaccination with empty vector. Interestingly, daily oral administration of 30 mg/kg bexarotene for 5 days prior to the HER2-IGFBP2-IGF1R vaccination series increased the IFN-γ immune responses to HER2, IGFBP2, and IGF1R by 1.2, 2.4 and 2.2 fold, respectively, as compared to the HER2-IGFBP2-IGF1R vaccine alone. Daily administration of a higher dose (200 mg/kg) 9cUAB30 for 5 days prior to the HER2-IGFBP2-IGF1R vaccination series increased the IFN-γ immune responses to HER2, IGFBP2, and IGF1R by 2.0, 2.3 and 1.7 fold, respectively, as compared to the HER2-IGFBP2-IGF1R vaccine alone. Control vaccination with either 9cUAB30 or bexarotene had no impact on antigen-specific IFN-γ T cell response. Type I DCs are important for producing polyfunctional CD4+ T cells that release not only IFN-γ but also TNF-α and IL-2. Polyfunctional T cells induce a longer lasting and more effective immune response in vaccines both for infectious diseases and cancer. We demonstrated the addition of bexarotene or 9cUAB30 increased antigen-specific polyfunctional T cells in the TgMMTV-neu (n=15 mice) transgenic mouse mammary tumor model while vaccination alone did not. There were an average of 1.3±0.2% antigen-specific CD4 polyfunctional T cells and 2.7±0.7 antigen-specific CD8 polyfunctional T cells with empty vector and vehicle control (sesame oil). HER2-IGFBP2-IGF1R vaccination following 30 mg/kg bexarotene treatment increased polyfunctional T cells to an average of 6.1±2.0% antigen-specific CD4 polyfunctional T cells (p=0.07) and 20.3±4.1% antigen-specific CD8 polyfunctional T cells (p=0.0003). HER2-IGBP2-IGF1R vaccination after 200 mg/kg 9cUAB30 increased antigen-specific polyfunctional T cells to 7.6±2.0% (p=0.01) and antigen-specific CD8 polyfunctional T cells to 17.6±4.1% (p=0.003). These data indicate that RXR agonists have an immunostimulatory role with multi-antigen cancer vaccines and may augment the anti-tumor activity of vaccines. Citation Format: Sasha Elizabeth Stanton, Erin Rodmaker, Nicholas Drovetto, Lauren Corulli, Flonia Levy, Venkatram Atigadda, Clinton Grubbs, Romaine Fernando, Shizuko Sei, Mary L. Disis. Retinoid X receptor agonists enhances Th1 antigen-specific and polyfunctional T cells with the HER2-IGFBP2-IGF1R vaccine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1556.

Hunting for better biomarkers of response: where is real progress being made in understanding why patients do and don’t respond to I-O therapeutics?

Adil DaudProfessor of Medicine and Dermatology, University of California; and Director of the Melanoma program, Helen Diller Family Cancer Center, UCSFDr Adil Daud is an expert in immunotherapy and has pioneered the development of novel immunotherapeutics and targeted therapies. His fellowship in medical oncology was at the Memorial Sloan Kettering Cancer Center and was a faculty member at the Moffitt Cancer Center in Tampa, Fl. He is currently Professor of Medicine and Dermatology at the University of California, San Francisco. He is the director of the Melanoma Program and melanoma clinical research at the Helen Diller Family Cancer Center at UCSF. He led the development of IL-12 in melanoma and has developed novel technology to deliver it in vivo. He has played a major role in developing PD-1 antibodies in cancer therapy. Recently he has developed novel assays to determine immune responsiveness in vivo. These assays can determine the likelihood of response to immune therapy and provide novel insights into immune drug development. He has collaborated on numerous clinical and translational clinical trials that have yielded insights into the use of immunotherapy.Steven FlingSenior Staff Scientist, Fred Hutchinson Cancer Research Center; and Lab Director, Central Immune Monitoring LabSteven Fling, PhD serves as Lab Director for Central Immune Monitoring Lab (CIML), overseeing correlative biomarker studies for the NCI funded CITN (Cancer Immunotherapy Trials Network) and the industry funded ION (Immune Oncology Network). CITN/ION conducts early-stage, multicenter IO clinical trials, with a focus on agents/combinations to potentiate effective immune responses. Dr. Fling has >24 years research experience in T cell immunobiology, cancer vaccine and immunotherapeutic discovery, including ~13 years managing immunology research labs and directorship of collaborative research networks and consortia. Previously Dr. Fling served as Project Director for the IAVI’s Neutralizing Antibody Consortium, an international consortium working to develop a vaccine for HIV and in 2009 established lab operations at IAVI’s Neutralizing Antibody Center at the Scripps Research Institute (La Jolla, CA). In biotech R&D, Dr. Fling worked on vaccines for cancer and infectious diseases including adjuvant development at Corixa Corp (Seattle, WA) and as an Investigator in the Adjuvant Group for GSK Biologicals.John RossiSenior Director, Department of Translational Medicine, KiteI joined Kite in 2015 after 13 years at Amgen. I am currently a Senior Director in the Department of Translational Medicine at Kite and lead all pharmacology activities related to the clinical development of Kite’s cell therapy pipeline. At Kite, I have built an effective translational team to support the clinical development of axicabtagene ciloleucel (Yescarta®) and KTE-X19 (Tecartus®). My team has contributed directly to the regulatory approval of these products through pharmacokinetic and pharmacodynamic evaluation. Among many achievements at Kite, I have represented the organization through external scientific presentations and collaborative manuscripts with leading academic researchers such as Steven Rosenberg and James Kochenderfer at the NCI. Accomplishments include the discovery of metrics to characterize CAR T based on functionality, novel biomarker knowledge of how CARs work in the clinic, mechanistic information on toxicities and insights into the biology of the TME, including immune checkpoints, and the role of IL-15 in the context of CAR T-cell function.Majid GhoddusiSenior Director, Clinical Biomarkers, Poseida TherapeuticsDr Ghoddusi has over 15 years of experience in some of the most challenging areas of oncology with focus on drug discovery and clinical development. Dr Ghoddusi has broad and overarching insights into unmet therapeutic areas with expertise in translational sciences and clinical biomarker development which allows him to provide unique perspective on how to propel therapeutic projects from discovery to approval. Trained as a translational pathologist he has held numerous positions at large pharmaceutical and small biotech companies including Novartis, Celgene and Juno Therapeutics. His current focus at Poseida Therapeutic is Gene and Cellular Therapy.

Hunting for better biomarkers of response: where is real progress being made in understanding why patients do and don’t respond to I-O therapeutics?

Adil DaudProfessor of Medicine and Dermatology, University of California; and Director of the Melanoma program, Helen Diller Family Cancer Center, UCSFDr Adil Daud is an expert in immunotherapy and has pioneered the development of novel immunotherapeutics and targeted therapies. His fellowship in medical oncology was at the Memorial Sloan Kettering Cancer Center and was a faculty member at the Moffitt Cancer Center in Tampa, Fl. He is currently Professor of Medicine and Dermatology at the University of California, San Francisco. He is the director of the Melanoma Program and melanoma clinical research at the Helen Diller Family Cancer Center at UCSF. He led the development of IL-12 in melanoma and has developed novel technology to deliver it in vivo. He has played a major role in developing PD-1 antibodies in cancer therapy. Recently he has developed novel assays to determine immune responsiveness in vivo. These assays can determine the likelihood of response to immune therapy and provide novel insights into immune drug development. He has collaborated on numerous clinical and translational clinical trials that have yielded insights into the use of immunotherapy.Steven FlingSenior Staff Scientist, Fred Hutchinson Cancer Research Center; and Lab Director, Central Immune Monitoring LabSteven Fling, PhD serves as Lab Director for Central Immune Monitoring Lab (CIML), overseeing correlative biomarker studies for the NCI funded CITN (Cancer Immunotherapy Trials Network) and the industry funded ION (Immune Oncology Network). CITN/ION conducts early-stage, multicenter IO clinical trials, with a focus on agents/combinations to potentiate effective immune responses. Dr. Fling has >24 years research experience in T cell immunobiology, cancer vaccine and immunotherapeutic discovery, including ~13 years managing immunology research labs and directorship of collaborative research networks and consortia. Previously Dr. Fling served as Project Director for the IAVI’s Neutralizing Antibody Consortium, an international consortium working to develop a vaccine for HIV and in 2009 established lab operations at IAVI’s Neutralizing Antibody Center at the Scripps Research Institute (La Jolla, CA). In biotech R&D, Dr. Fling worked on vaccines for cancer and infectious diseases including adjuvant development at Corixa Corp (Seattle, WA) and as an Investigator in the Adjuvant Group for GSK Biologicals.John RossiSenior Director, Department of Translational Medicine, KiteI joined Kite in 2015 after 13 years at Amgen. I am currently a Senior Director in the Department of Translational Medicine at Kite and lead all pharmacology activities related to the clinical development of Kite’s cell therapy pipeline. At Kite, I have built an effective translational team to support the clinical development of axicabtagene ciloleucel (Yescarta®) and KTE-X19 (Tecartus®). My team has contributed directly to the regulatory approval of these products through pharmacokinetic and pharmacodynamic evaluation. Among many achievements at Kite, I have represented the organization through external scientific presentations and collaborative manuscripts with leading academic researchers such as Steven Rosenberg and James Kochenderfer at the NCI. Accomplishments include the discovery of metrics to characterize CAR T based on functionality, novel biomarker knowledge of how CARs work in the clinic, mechanistic information on toxicities and insights into the biology of the TME, including immune checkpoints, and the role of IL-15 in the context of CAR T-cell function.Majid GhoddusiSenior Director, Clinical Biomarkers, Poseida TherapeuticsDr Ghoddusi has over 15 years of experience in some of the most challenging areas of oncology with focus on drug discovery and clinical development. Dr Ghoddusi has broad and overarching insights into unmet therapeutic areas with expertise in translational sciences and clinical biomarker development which allows him to provide unique perspective on how to propel therapeutic projects from discovery to approval. Trained as a translational pathologist he has held numerous positions at large pharmaceutical and small biotech companies including Novartis, Celgene and Juno Therapeutics. His current focus at Poseida Therapeutic is Gene and Cellular Therapy.

Genesis of Antibiotic Resistance LXVI: Mechanism(s) of a Minimum Antibiotic Footprint (AF) Wane Prospective Infectious Diseases Pandemic, A critical appraisal with a global perspective

Antibiotic Footprint (AF) is a cumulative measure of the amount of antibiotics consumed by the general population inclusive of healthcare, educational activities, and agrochemical – livestock industries reported by each country. The principal objective of AF is to limit intentional and unintentional misuse/overuse curbing the resistance in bacteria (https://amr-review.org/). Defined Daily Dosage (DDD)/1,000 people/day and milligrams per Population Correction Unit (PCU) are utilized for comparison of consumption rate for specific antibiotics in general population and agricultural - livestock industries. The AF is calculated as the total amount (tones) / country in which the antibiotic usage ‘per person's lifetime’ or ‘per consumer product inclusive of antibiotics’ could be derived. According to the Antibiotic Footprint.net Thailand reported that a personal level as Human consumption 2,162.1 tonnes (32%) and Consumption in animal agriculture (ANIM) as 4,688.4 tonnes (68%). Whereas France reported that Human consumption in the community (Including the primary care sector) (COMM)860.7 tonnes (93%), Human consumption in the hospitals (HOSP) 62.7 tonnes (7%). U.S. reported that consumption in animal agriculture (ANIM) as 5,559.2 tonnes. Also, per person consumption was 99.2 grams/person. Though a detailed ESAC-Net Reporting Protocol 2020 and classes of antimicrobials are presented on ESAC-Net home page, it is our contention that the reporting method is flawed as it failed to factor in the number of unused antibiotics/antimicrobials collected each year which should be part of reporting as presented in our earlier work. As an effective means of instilling personal responsibility in each and every human being across the globe to minimize the AF has been presented by the https://www.antibioticfootprint.net/infobox.aspx?pageID=102 to track each individual's AF. In addition to well know measures such as vaccination for infectious diseases with imminent potential for pandemic as identified by CDC, better personal hygiene antibiotic stewardship in healthcare facilities, antibiotic prescription based on the clinical antibiogram of each patient, clean toilet facilities, clean portable water. In addition to that, we have found that the following specific objective measures were compelling as they are pivotal in reducing the AF: i. When was the last time you took antibiotics? ii. Was that possibly overuse? iii. How many times have you had antibiotics since birth? iv. How many times were possibly overuse? v. Do you know how many grams of antibiotics were used to raise the chicken that you are eating? vi. Which meat has a low Antibiotic Footprint? vii. How can you reduce your own and your country's Antibiotic Footprint to a minimum? Taken together, effective implementation of regulatory measures across the globe curbing the misuse and overuse of antibiotics in humans and animals would suffice to minimize the morbidity and mortality rate of a prospective incidence of infectious diseases pandemic inflicted by antibiotic-resistant bacterial pathogens which in turn reduce the consumption of antibiotics.

Lipid A mimetics BECC438 and BECC470 potentiate durable and balanced immune responses using an ovalbumin murine vaccine model.

Abstract The need for effective infectious disease vaccines has become an inescapable topic over the past year. Continued development of next-generation vaccines that provide robust protective immunity is imperative. Such vaccines will likely include an adjuvant that avoids excessive adverse reactions and allows for dose and antigen sparing. Bacterial lipid A mimetics BECC438 and BECC470 have recently emerged as lead adjuvant candidates across several experimental models of infectious disease including Yersinia pestis (plague), human papilloma virus (HPV), and influenza-A (flu). To further define BECC438 and BECC470 as immuno-adjuvants, even without antigen from an infectious pathogen, studies presented here use ovalbumin (Ova) as a model antigen in a murine prime-boost vaccine model. Higher magnitude and more balanced production of antibody isotypes IgG1 and IgG2 are observed when BECC adjuvants are compared to classic adjuvants alum and PHAD. This optimal antibody response is durable and maintained for at least 12 weeks post-vaccination. Initial experiments use C57BL6 mice and are expanded to include BALBc and CD-1 (outbred) mice. Observed immune metrics maintained similar trends across male and females, and genetic backgrounds tested. Biacore immunogenicity analysis of C57BL6 serum found an increased half-life of Ova-specific antibodies in BECC438-adjuvanted animals potentially indicative of a higher antigen binding affinity. Toxicity studies conducted in New Zealand White rabbits report that BECC438 was well tolerated with no significant reactogenicity after 50μg and 100μg intra-muscular adjuvant injection. These studies provide continued evidence supporting development of BECC adjuvants in vaccines for human use.