scholarly journals Modern Development and Production of a New Live Attenuated Bacterial Vaccine, SCHU S4 ΔclpB, to Prevent Tularemia

Pathogens ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 795
Author(s):  
J. Wayne Conlan ◽  
Anders Sjöstedt ◽  
H. Carl Gelhaus ◽  
Perry Fleming ◽  
Kevan McRae ◽  
...  
Keyword(s):  
Virulent Strain ◽  
Scale Up ◽  
Live Vaccine ◽  
High Dose ◽  
Production Scale ◽  
Stage Of Development ◽  
Modern Development ◽  
Select Group ◽  
Schu S4 ◽  
The U.S

Inhalation of small numbers of Francisella tularensis subspecies tularensis (Ftt) in the form of small particle aerosols causes severe morbidity and mortality in people and many animal species. For this reason, Ftt was developed into a bona fide biological weapon by the USA, by the former USSR, and their respective allies during the previous century. Although such weapons were never deployed, the 9/11 attack quickly followed by the Amerithrax attack led the U.S. government to seek novel countermeasures against a select group of pathogens, including Ftt. Between 2005–2009, we pursued a novel live vaccine against Ftt by deleting putative virulence genes from a fully virulent strain of the pathogen, SCHU S4. These mutants were screened in a mouse model, in which the vaccine candidates were first administered intradermally (ID) to determine their degree of attenuation. Subsequently, mice that survived a high dose ID inoculation were challenged by aerosol or intranasally (IN) with virulent strains of Ftt. We used the current unlicensed live vaccine strain (LVS), first discovered over 70 years ago, as a comparator in the same model. After screening 60 mutants, we found only one, SCHU S4 ΔclpB, that outperformed LVS in the mouse ID vaccination-respiratory-challenge model. Currently, SCHU S4 ΔclpB has been manufactured under current good manufacturing practice conditions, and tested for safety and efficacy in mice, rats, and macaques. The steps necessary for advancing SCHU S4 ΔclpB to this late stage of development are detailed herein. These include developing a body of data supporting the attenuation of SCHU S4 ΔclpB to a degree sufficient for removal from the U.S. Select Agent list and for human use; optimizing SCHU S4 ΔclpB vaccine production, scale up, and long-term storage; and developing appropriate quality control testing approaches.

International Competition and the Decline of U.S. Manufacturing

2018 ◽  
Author(s):  
William B. Bonvillian ◽  
Peter L. Singer
Keyword(s):  
Scale Up ◽  
Innovation System ◽  
The United States ◽  
First Century ◽  
New Production ◽  
Production Scale ◽  
Short Period ◽  
Production Stages ◽  
Distributed Production ◽  
The U.S

This chapter reviews the U.S. manufacturing decline in the first decade of the twenty-first century, examining this from a series of dimensions, including the critical relationship between the production stage and the other parts of its innovation system. The profound challenge to U.S. production in the 1970s and 1980s from Japan's quality manufacturing model and its accompanying technology and process advances, which dramatically disrupted U.S. production practices, is the first issue that must be understood. The chapter then explores the rise of China's manufacturing economy; its innovative new production scale-up approaches knocked the United States into second place in world manufacturing output in a remarkably short period. Accompanying that rise was a parallel and related rise in distributed production by U.S. firms, with outsourcing of production stages and corresponding issues of “innovate here/produce there,” which could lead to “produce there/innovate there.”

scholarly journals Reduced Virulence of a Bordetella bronchiseptica Siderophore Mutant in Neonatal Swine

2001 ◽  
Vol 69 (4) ◽  
pp. 2137-2143 ◽  
Author(s):  
Karen B. Register ◽  
Thomas F. Ducey ◽  
Susan L. Brockmeier ◽  
David W. Dyer
Keyword(s):  
Nasal Cavity ◽  
Resistance Gene ◽  
Parent Strain ◽  
Virulent Strain ◽  
Clinical Signs ◽  
Kanamycin Resistance ◽  
Live Vaccine ◽  
Bordetella Bronchiseptica ◽  
Kanamycin Resistance Gene ◽  
Phosphate Buffered Saline

ABSTRACT One means by which Bordetella bronchiseptica scavenges iron is through production of the siderophore alcaligin. A nonrevertible alcaligin mutant derived from the virulent strain 4609, designated DBB25, was constructed by insertion of a kanamycin resistance gene into alcA, one of the genes essential for alcaligin biosynthesis. The virulence of the alcA mutant in colostrum-deprived, caesarean-delivered piglets was compared with that of the parent strain in two experiments. At 1 week of age, piglets were inoculated with phosphate-buffered saline, 4609, or DBB25. Two piglets in each group were euthanatized on day 10 postinfection. The remainder were euthanatized at 21 days postinfection. Clinical signs, including fever, coughing, and sneezing, were present in both groups. Nasal washes performed 7, 14, and 21 days postinoculation demonstrated that strain DBB25 colonized the nasal cavity but did so at levels that were significantly less than those achieved by strain 4609. Analysis of colonization based on the number of CFU per gram of tissue recovered from the turbinate, trachea, and lung also demonstrated significant differences between DBB25 and 4609, at both day 10 and day 21 postinfection. Mild to moderate turbinate atrophy was apparent in pigs inoculated with strain 4609, while turbinates of those infected with strain DBB25 developed no or mild atrophy. We conclude from these results that siderophore production by B. bronchiseptica is not essential for colonization of swine but is required for maximal virulence. B. bronchiseptica mutants with nonrevertible defects in genes required for alcaligin synthesis may be candidates for evaluation as attenuated, live vaccine strains in conventionally reared pigs.

The USA: New Stage of Development

2014 ◽  
pp. 88-97
Author(s):  
N. Zagladin
Keyword(s):  
Tax Policy ◽  
Political System ◽  
The State ◽  
Military Force ◽  
Ruling Elite ◽  
Stage Of Development ◽  
The Us ◽  
The Usa ◽  
Democratic Parties ◽  
The U.S

In today’s world the U.S. ruling elite has proved unable to maintain its claim to world leadership by relying on military force. It was also necessary to make corrections in the budget and tax policy and to limit further increase of the state debt. The problems of choosing political alternatives, however, have provoked a serious conflict between the republican and the democratic parties, involving public movements. In fact, the US political system is in the state of crisis that exerts influence on Russian-American relations.

scholarly journals Nanotechnology in Personalized Medicine: A Promising Tool for Alzheimer’s Disease Treatment

2018 ◽  
Vol 25 (35) ◽  
pp. 4602-4615 ◽  
Author(s):  
Laura De Matteis ◽  
Rafael Martín-Rapún ◽  
Jesús M. de la Fuente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Personalized Medicine ◽  
Adverse Effects ◽  
Metabolic Response ◽  
Scale Up ◽  
High Sensitivity ◽  
Production Scale ◽  
Patient Response ◽  
Detection Techniques

Background: Alzheimer’s disease (AD) is a public health priority all over the world. The difficulty of fighting the disease consists mostly in the complexity of symptoms and causes, in the still poor knowledge of its mechanisms and in the existence of a latent, asymptomatic, preclinical stage. Although many drugs are continuously screened in clinical studies for the treatment of Alzheimer’s disease, the unexpected lack of patient response and sometimes the important adverse effects make it a potential field of application for personalized medicine. Objective: This perspective review proposes nanotechnology as a valuable tool for the application of personalized medicine to AD. Methods: The aim of personalized medicine is the development of more patient-precise treatments based mostly on the knowledge of individual genetics as well as of disease progress, and of pharmacokinetics and metabolic response to available drugs. The optimization of new and more sensitive detection techniques is an important tool for obtaining the pool of data needed for prediction and understanding of patient response. Results: Research in bionanosensors is already providing examples with high sensitivity for core and new biomarkers for AD. In therapy the functionalization of nanoparticle surface can add specificity for biological recognition or for improving the bioavailability. This would allow the administration of lower doses with less adverse effects due to the local targeting. Conclusion: Taking into account the promising characteristics of nanoparticles as excellent candidate tools for precision medicine development, the establishment of better standard methods for safety assessment and production scale up would be desirable for the nanomaterial fruitful employment.

Sign in / Sign up

Export Citation Format

Share Document