Vaccinia virus infections guide new vaccine designs

Posted on 13 July 2020 by mmmbitesizescience

If we mapped out the family tree of poxviruses, then vaccinia virus (the causative agent of cowpox) and variola virus (the causative agent of smallpox) would probably be sisters. Or at the very least, cousins. This close heritage allows the relatively benign vaccinia virus to confer variola virus-protective immune responses in vaccinated individuals.

A safely attenuated version of vaccinia virus, called modified vaccinia ankara (MVA), lies at the heart of the modern smallpox vaccine. Learning more about the biology of MVA helps us to understand why this vaccine is so great at protecting us from smallpox.

Scientists at Memorial Sloan-Kettering Cancer Centre in the USA have now discovered how MVA triggers innate immune responses during infection. They found that MVA DNA is detected by the immune sensors cGAS and STING, which activate secretion of type I interferons in a very specialised immune cell population – the conventional dendritic cells (cDCs).

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Yet vaccinia doesn’t passively accept the activation of these immune reactions that are designed to shut it down. Instead, it expresses a variety of virulence factors that inhibit these immune pathways and allow it to survive. This information could be used to improve the utility of MVA as a vaccine against other diseases, like cancer.

Image credit: Weltzin et al 2003

Repost from the Stojdl Lab blog.

Posted in Disease, Microorganisms, Science, Vaccines, Virology, Viruses | Leave a comment

Creating immune silent biotherapeutic proteins

Posted on 13 July 2020 by mmmbitesizescience

Our beautiful immune systems have evolved to efficiently recognise foreign objects – like bacteria and viruses – that aren’t supposed to be there. This activates a huge series of biological reactions that secure the threat and restore a safe environment.

Sometimes, though, the immune system reacts to things that it perceives as a theat, but are actually benign. This includes drugs and biotherapeutics that are being delivered to treat patients, but get blasted by immune responses before they get a chance to help.

Now, a team of scientists led by Chris King at the University of Washington in the USA have explored an interesting way to silence immune reactions against such foreign therapeutic proteins. They used computers to locate every immunogenic part of the protein (the T cell epitopes), and then predict a redesigned sequence that eliminated the immunogenicity but retained the protein activity.

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They used this method to successfully redesign two model proteins (GFP and Pseudomonas exotoxin A), and in future studies will use this approach to create immune silent proteins like factor VIII, a therapeutic protein for haemophilia A patients.

Image: The crystal structure of the factor VIII protein, Jacky Chi Ki Ngo

Repost from the Stojdl Lab blog.
Posted in Immunology, Medicine, Science | Leave a comment

Convection currents help to deliver oncolytic virus in the brain

Posted on 13 July 2020 by mmmbitesizescience

In a Phase I clinical trial for recurrent glioma run by the University of Alabama in the USA, 15 patients have received a steady stream of oncolytic reovirus (up to 10^10 TCID50) infused directly into their brain tumour. This novel method of infusion uses convection-enhanced delivery (continuous low-pressure catheter infusion) to deliver virus particles.

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The best responses were: 4 patient progressed, 10 patients had stable disease and 1 had a partial response. Some adverse events were reported, but none of these were considered serious.

Overall, reovirus was safe and well tolerated in the brain, and this newly tested method of delivery looks to improve how widely reovirus gets distributed across the tumour mass.

Image credit: NIAID via flickr

Repost from the Stojdl Lab blog.

Posted in Cancer Immunotherapy, Immunology, Oncolytic Virus, Science, Viruses | Leave a comment

From tumour biopsy to personalised cancer treatment in 16 days

Posted on 13 July 2020 by mmmbitesizescience

Every cancer patient essentially has a unique genetic disease. While certain key ‘driver’ mutations in genes such as TP53 and KRAS are almost always present, many other ‘passenger’ mutations are collected as tumours evolve that shape their genetic footprint.

These collections of mutations can lead to good or bad patient responses to treatment. Personalised cancer medicine aims to push a greater number of responses into the “good” category by using the genetic information from patient tumours to inform treatment choices. This strategy is already being used with some breast cancer drugs, such as Herceptin (Roche), where only ~30% of patient tumours express the right Her2 receptor target.

Whole exome sequencing (WES) is a computer-based method that catalogues patient tumour exomes – the part of their genetic information that gets translated into proteins. Yet WES has not been used extensively in the clinical setting.

Now, a team of researchers at Harvard Medical School, USA, have developed a clinical algorithm that translates the massive datasets generated by whole exome sequencing of tumour biopsies into a useful patient treatment plan. The algorithm is based on 121 target genes with potential relevance to tumour biology and clinical outcomes.

Your name hereAfter applying this algorithm across archived tumour biopsies from 511 patients, the team identified genetic alterations in their 121 target genes in 80% of patients. In a mini study to test the clinical utility of this approach, they generated personalised tumour genetic profiles for 16 cancer patients within 16 days, and used this information to siphon patients with certain exome mutations into matched clinical trials testing genetically complementary therapies. For example, one patient with metastatic lung adenocarcinoma exhibiting a KRAS-activating mutation (A146V) was enrolled in a phase I clinical trial of the CDK4 inhibitor, LY2835219 (preclinical data suggests a lethal relationship between activated KRAS and CDK4). This led to stable disease; the patient’s best and only clinical response to any cancer therapy.

Image credit: Swift Science Writing.

Repost from the Stojdl Lab blog.

Posted in Cancer Immunotherapy, Immunology, Mutations, Personalised Medicine, Science | Leave a comment

Blocking lethal viral haemorrhagic disease using interferons

Posted on 13 July 2020 by mmmbitesizescience

Genetics can have a big impact on immune responses, making some individuals more suspectible to infections than others. In the world of small mammals, the virus LCMV-Clone 13 establishes a chronic infection in one mouse strain without too much damage. Yet in another mouse strain, the same virus activates a host T cell response that reacts so vigorously against virally-infected tissues that it kills the animal. Such deaths are often characterised by haemorrhagic fevers, where blood vessels start to leak, the body loses its ability to form blood clots and organs start to fail. Pathogens such as Lassa fever virus, Ebola virus and Dengue virus can cause haemorrhagic fever in humans, and represent a serious health threat.

Now, a team of scientists at the Scripps Institute in California, USA, have found that the immune cascade that leads to virus-induced haemorrhagic fever requires the activation of type I interferon signalling in non-haematopoietic cells. They found that simply administering antibodies that block type I interferon receptors could protect susceptible infected mice from developing serious pathological conditions, even though virus still persisted long after the antibody treatment had finished.

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This could represent a basic but incredibly effective approach for preventing deaths due to haemorrhagic viral disease. The one caveat is that the type I interferon blockade must be administered relatively soon after infection, since treatment efficacy declines over time, with 100% efficacy at 24 hours, 30% at 60 hours and 0% at 72 hours post-infection.

Image credit: VirginPrune on DeviantArt

Repost from the Stojdl Lab blog.

Posted in Disease, Immunology, Microorganisms, Science, Virology, Viruses | Leave a comment