- Short-term clinical safety profile of brincidofovir: A favorable benefit-risk proposition in the treatment of smallpox. [Journal Article]
- ARAntiviral Res 2017 Jan 13
- Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipient...
Brincidofovir (BCV, CMX001) is an orally available, long-acting, broad-spectrum antiviral that has been evaluated in healthy subjects in Phase I studies and in hematopoietic cell transplant recipients and other immunocompromised patients in Phase II/III clinical trials for the prevention and treatment of cytomegalovirus and adenovirus infections. BCV has also shown in vitro activity against orthopoxviruses such as variola (smallpox) virus, and is under advanced development as a treatment for smallpox under the US FDA's 'Animal Rule'. The anticipated treatment regimen for smallpox is a total weekly dose of 200 mg administered orally for 3 consecutive weeks. To assess the benefit-to-risk profile of BCV for the treatment of smallpox, we evaluated short-term safety data associated with comparable doses from Phase I studies and from adult and pediatric subjects in the cytomegalovirus and adenovirus clinical programs. When administered at doses and durations similar to that proposed for the treatment of smallpox, BCV was generally well tolerated in both adults and pediatric subjects. The most common adverse events were mild gastrointestinal events and asymptomatic, transient, and reversible elevations in serum transaminases. The data presented herein indicate a favorable safety profile for BCV for the treatment of smallpox, and support its continued development for this indication.
- The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar. [Journal Article]
- IBInflamm Bowel Dis 2017; 23(2):233-243
- CONCLUSIONS: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.
- Cutaneous Deficiency of Filaggrin and STAT3 Exacerbates Vaccinia Disease In Vivo. [Journal Article]
- PlosPLoS One 2017; 12(1):e0170070
- CONCLUSIONS: Our findings may point to a novel role for filaggrin in early antiviral responses in skin. In wounded skin with underlying barrier defects, chronically elevated activin A levels may contribute to skin remodeling and cutaneous pathogen persistence. Inhibition of ALK5/TGFβR1 signaling may provide a novel co-therapeutic approach, together with VIG, to limit cutaneous spread of vaccinia.
- Modified Vaccinia Virus Ankara: History, Value in Basic Research, and Current Perspectives for Vaccine Development. [Historical Article]
- AVAdv Virus Res 2017; 97:187-243
- Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infe...
Safety tested Modified Vaccinia virus Ankara (MVA) is licensed as third-generation vaccine against smallpox and serves as a potent vector system for development of new candidate vaccines against infectious diseases and cancer. Historically, MVA was developed by serial tissue culture passage in primary chicken cells of vaccinia virus strain Ankara, and clinically used to avoid the undesirable side effects of conventional smallpox vaccination. Adapted to growth in avian cells MVA lost the ability to replicate in mammalian hosts and lacks many of the genes orthopoxviruses use to conquer their host (cell) environment. As a biologically well-characterized mutant virus, MVA facilitates fundamental research to elucidate the functions of poxvirus host-interaction factors. As extremely safe viral vectors MVA vaccines have been found immunogenic and protective in various preclinical infection models. Multiple recombinant MVA currently undergo clinical testing for vaccination against human immunodeficiency viruses, Mycobacterium tuberculosis or Plasmodium falciparum. The versatility of the MVA vector vaccine platform is readily demonstrated by the swift development of experimental vaccines for immunization against emerging infections such as the Middle East Respiratory Syndrome. Recent advances include promising results from the clinical testing of recombinant MVA-producing antigens of highly pathogenic avian influenza virus H5N1 or Ebola virus. This review summarizes our current knowledge about MVA as a unique strain of vaccinia virus, and discusses the prospects of exploiting this virus as research tool in poxvirus biology or as safe viral vector vaccine to challenge existing and future bottlenecks in vaccinology.
- Humoral Immunity to Primary Smallpox Vaccination: Impact of Childhood versus Adult Immunization on Vaccinia Vector Vaccine Development in Military Populations. [Journal Article]
- PlosPLoS One 2017; 12(1):e0169247
- Modified Vaccinia virus has been shown to be a safe and immunogenic vector platform for delivery of HIV vaccines. Use of this vector is of particular importance to the military, with the implementati...
Modified Vaccinia virus has been shown to be a safe and immunogenic vector platform for delivery of HIV vaccines. Use of this vector is of particular importance to the military, with the implementation of a large scale smallpox vaccination campaign in 2002 in active duty and key civilian personnel in response to potential bioterrorist activities. Humoral immunity to smallpox vaccination was previously shown to be long lasting (up to 75 years) and protective. However, using vaccinia-vectored vaccine delivery for other diseases on a background of anti-vector antibodies (i.e. pre-existing immunity) may limit their use as a vaccine platform, especially in the military. In this pilot study, we examined the durability of vaccinia antibody responses in adult primary vaccinees in a healthy military population using a standard ELISA assay and a novel dendritic cell neutralization assay. We found binding and neutralizing antibody (NAb) responses to vaccinia waned after 5-10 years in a group of 475 active duty military, born after 1972, who were vaccinated as adults with Dryvax®. These responses decreased from a geometric mean titer (GMT) of 250 to baseline (<20) after 10-20 years post vaccination. This contrasted with a comparator group of adults, ages 35-49, who were vaccinated with Dryvax® as children. In the childhood vaccinees, titers persisted for >30 years with a GMT of 210 (range 112-3234). This data suggests limited durability of antibody responses in adult vaccinees compared to those vaccinated in childhood and further that adult vaccinia recipients may benefit similarly from receipt of a vaccinia based vaccine as those who are vaccinia naïve. Our findings may have implications for the smallpox vaccination schedule and support the ongoing development of this promising viral vector in a military vaccination program.
- Bob H. Reinhardt: The End of A Global Pox. America and the Eradication of Smallpox in the Cold War Era : The University of North Carolina Press, Chapel Hill, 2015, 268 pp., Hard cover, Illustrated, Figure, Maps, Table, Notes, Bibliography, Index., $39.95. [Journal Article]
- JCJ Community Health 2016 Dec 31
- This review examines in detail Bob H. Reinhardt's meticulous analyses of smallpox eradication within the broad context of American liberalism, Cold War politics, and the exercise of technological, me...
This review examines in detail Bob H. Reinhardt's meticulous analyses of smallpox eradication within the broad context of American liberalism, Cold War politics, and the exercise of technological, medical, and political power on the part of the United States. As a result, his book provides a unique perspective on the eradication of smallpox.
- Buccal viral DNA as a trigger for brincidofovir therapy in the mousepox model of smallpox. [Journal Article]
- ARAntiviral Res 2016 Dec 27; 139:112-116
- Orthopoxviruses continue to pose a significant threat to the population as potential agents of bioterrorism. An intentional release of natural or engineered variola virus (VARV) or monkeypox viruses ...
Orthopoxviruses continue to pose a significant threat to the population as potential agents of bioterrorism. An intentional release of natural or engineered variola virus (VARV) or monkeypox viruses would cause mortality and morbidity in the target population. To address this, antivirals have been developed and evaluated in animal models of smallpox and monkeypox. One such antiviral, brincidofovir (BCV, previously CMX001), has demonstrated high levels of efficacy against orthopoxviruses in animal models and is currently under clinical evaluation for prevention and treatment of diseases caused by cytomegaloviruses and adenoviruses. In this study we use the mousepox model of smallpox to evaluate the relationship between the magnitude of the infectious virus dose and an efficacious BCV therapy outcome when treatment is initiated concomitant with detection of ectromelia virus viral DNA (vDNA) in mouse buccal swabs. We found that vDNA could be detected in buccal swabs of some, but not all infected mice over a range of challenge doses by day 3 or 4 postexposure, when initiation of BCV treatment was efficacious, suggesting that detection of vDNA in buccal swabs could be used as a trigger to initiate BCV treatment of an entire potentially exposed population. However, buccal swabs of some mice did not become positive until 5 days postexposure, when initiation of BCV therapy failed to protect mice that received high doses of virus. And finally, the data suggest that the therapeutic window for efficacious BCV treatment decreases as the virus infectious dose increases. Extrapolating these findings to VARV, the data suggest that treatment should be initiated as soon as possible after exposure and not rely on a diagnostic tool such as the measurement of vDNA in buccal cavity swabs; however, consideration should be given to the fact that the behavior/disease-course of VARV in humans is different from that of ectromelia virus in the mouse.
- Modelling and Bayesian analysis of the Abakaliki smallpox data. [Journal Article]
- EEpidemics 2016 Dec 09
- The celebrated Abakaliki smallpox data have appeared numerous times in the epidemic modelling literature, but in almost all cases only a specific subset of the data is considered. The only previous a...
The celebrated Abakaliki smallpox data have appeared numerous times in the epidemic modelling literature, but in almost all cases only a specific subset of the data is considered. The only previous analysis of the full data set relied on approximation methods to derive a likelihood and did not assess model adequacy. The data themselves continue to be of interest due to concerns about the possible re-emergence of smallpox as a bioterrorism weapon. We present the first full Bayesian statistical analysis using data-augmentation Markov chain Monte Carlo methods which avoid the need for likelihood approximations and which yield a wider range of results than previous analyses. We also carry out model assessment using simulation-based methods. Our findings suggest that the outbreak was largely driven by the interaction structure of the population, and that the introduction of control measures was not the sole reason for the end of the epidemic. We also obtain quantitative estimates of key quantities including reproduction numbers.
- Anti-Proliferative Effects of Dendrophthoe pentandra Methanol Extract on BCR/ABL-Positive and Imatinib-Resistant Leukemia Cell Lines [Journal Article]
- APAsian Pac J Cancer Prev 2016 11 01; 17(11):4857-4861
- CONCLUSIONS: D. pentandra methanol extract exerts potent anti-proliferative effect on BCR/ABL positive K562 cells.
New Search Next
- Vector-based genetically modified vaccines: Exploiting Jenner's legacy. [Journal Article]
- VVaccine 2016 Oct 28
- The global vaccine market is diverse while facing a plethora of novel developments. Genetic modification (GM) techniques facilitate the design of 'smarter' vaccines. For many of the major infectious ...
The global vaccine market is diverse while facing a plethora of novel developments. Genetic modification (GM) techniques facilitate the design of 'smarter' vaccines. For many of the major infectious diseases of humans, like AIDS and malaria, but also for most human neoplastic disorders, still no vaccines are available. It may be speculated that novel GM technologies will significantly contribute to their development. While a promising number of studies is conducted on GM vaccines and GM vaccine technologies, the contribution of GM technology to newly introduced vaccines on the market is disappointingly limited. In this study, the field of vector-based GM vaccines is explored. Data on currently available, actually applied, and newly developed vectors is retrieved from various sources, synthesised and analysed, in order to provide an overview on the use of vector-based technology in the field of GM vaccine development. While still there are only two vector-based vaccines on the human vaccine market, there is ample activity in the fields of patenting, preclinical research, and different stages of clinical research. Results of this study revealed that vector-based vaccines comprise a significant part of all GM vaccines in the pipeline. This study further highlights that poxviruses and adenoviruses are among the most prominent vectors in GM vaccine development. After the approval of the first vectored human vaccine, based on a flavivirus vector, vaccine vector technology, especially based on poxviruses and adenoviruses, holds great promise for future vaccine development. It may lead to cheaper methods for the production of safe vaccines against diseases for which no or less perfect vaccines exist today, thus catering for an unmet medical need. After the introduction of Jenner's vaccinia virus as the first vaccine more than two centuries ago, which eventually led to the recent eradication of smallpox, this and other viruses may now be the basis for constructing vectors that may help us control other major scourges of mankind.