A vaccinia-based single vector construct multi-pathogen vaccine protects against both Zika and chikungunya viruses

Zika and chikungunya viruses have caused major epidemics and are transmitted by Aedes aegypti and/or Aedes albopictus mosquitoes. The "Sementis Copenhagen Vector" (SCV) system is a recently developed vaccinia-based, multiplication-defective, vaccine vector technology that allows manufacture in modified CHO cells. Herein we describe a single-vector construct SCV vaccine that encodes the structural polyprotein cassettes of both Zika and chikungunya viruses from different loci. A single vaccination of mice induces neutralizing antibodies to both viruses in wild-type and IFNAR-/- mice and protects against (i) chikungunya virus viremia and arthritis in wild-type mice, (ii) Zika virus viremia and fetal/placental infection in female IFNAR-/- mice, and (iii) Zika virus viremia and testes infection and pathology in male IFNAR-/- mice. To our knowledge this represents the first single-vector construct, multi-pathogen vaccine encoding large polyproteins, and offers both simplified manufacturing and formulation, and reduced "shot burden" for these often co-circulating arboviruses.Natalie A. Prow, Liang Liu, Eri Nakayama, Tamara H. Cooper ... Kerrilyn R. Diener ... John D. Hayball .. et al

Independent repeated mutations within the alphaviruses Ross River virus and Barmah Forest virus indicates convergent evolution and past positive selection in ancestral populations despite ongoing purifying selection

Ross River virus (RRV) and Barmah Forest virus (BFV) are arthritogenic arthropod-borne viruses (arboviruses) that exhibit generalist host associations and share distributions in Australia and Papua New Guinea (PNG). Using stochastic mapping and discrete-trait phylogenetic analyses, we profiled the independent evolution of RRV and BFV signature mutations. Analysis of 186 RRV and 88 BFV genomes demonstrated their viral evolution trajectories have involved repeated selection of mutations, particularly in the nonstructural protein 1 (nsP1) and envelope 3 (E3) genes suggesting convergent evolution. Convergent mutations in the nsP1 genes of RRV (residues 248 and 441) and BFV (residues 297 and 447) may be involved with catalytic enzyme mechanisms and host membrane interactions during viral RNA replication and capping. Convergent E3 mutations (RRV site 59 and BFV site 57) may be associated with enzymatic furin activity and cleavage of E3 from protein precursors assisting viral maturation and infectivity. Given their requirement to replicate in disparate insect and vertebrate hosts, convergent evolution in RRV and BFV may represent a dynamic link between their requirement to selectively ‘fine-tune’ intracellular host interactions and viral replicative enzymatic processes. Despite evidence of evolutionary convergence, selection pressure analyses did not reveal any RRV or BFV amino acid sites under strong positive selection and only weak positive selection for nonstructural protein sites. These findings may indicate that their alphavirus ancestors were subject to positive selection events which predisposed ongoing pervasive convergent evolution, and this largely supports continued purifying selection in RRV and BFV populations during their replication in mosquito and vertebrate hosts

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Commensal viruses of mosquitoes: Host restriction, transmission, and interaction with arboviral pathogens

Recent advances in virus detection strategies and deep sequencing technologies have enabled the identification of a multitude of new viruses that persistently infect mosquitoes but do not infect vertebrates. These are usually referred to as insect-specific viruses (ISVs). These novel viruses have generated considerable interest in their modes of transmission, persistence in mosquito populations, the mechanisms that restrict their host range to mosquitoes, and their interactions with pathogens transmissible by the same mosquito. In this article, we discuss studies in our laboratory and others that demonstrate that many ISVs are efficiently transmitted directly from the female mosquito to their progeny via infected eggs, and, moreover, that persistent infection of mosquito cell cultures or whole mosquitoes with ISVs can restrict subsequent infection, replication, and transmission of some mosquito-borne viral pathogens. This suggests that some ISVs may act as natural regulators of arboviral transmission. We also discuss viral and host factors that may be responsible for their host restriction

Statement in Support of: "Virology under the Microscope-a Call for Rational Discourse"

Letter to the Editor. Published 25 April 2023Peter Speck, Jason Mackenzie, Rowena A. Bull, Barry Slobedman, Heidi Drummer, Johanna Fraser, Lara Herrero, Karla Helbig, Sarah Londrigan, Gregory Moseley, Natalie Prow, Grant Hansman, Robert Edwards, Chantelle Ahlenstiel, Allison Abendroth, David Tscharke, Jody Hobson-Peters, Robson Kriiger-Loterio, Rhys Parry, Glenn Marsh, Emma Harding, David A. Jacques, Matthew J. Gartner, Wen Shi Lee, Julie McAuley, Paola Vaz, Frank Sainsbury, Michelle D. Tate, Jane Sinclair, Allison Imrie, Stephen Rawlinson, Andrew Harman, Jillian M. Carr, Ebony A. Monson, Merilyn Hibma, Timothy J.Mahony, Thomas Tu, Robert J. Center, Lok Bahadur Shrestha, Robyn Hall, Morgyn Warner, Vernon Ward, Danielle E. Anderson, Nicholas S. Eyre, Natalie E. Netzler, Alison J. Peel, Peter Revill, Michael Beard, Alistair R. Legione, Alexandra J. Spencer, Adi Idris, Jade Forwood, Subir Sarker, Damian F. J. Purcell, Nathan Bartlett, Joshua M. Deerain, Bruce J. Brew, Sassan Asgari, Helen Farrell, Alexander Khromykh, Daniel Enosi Tuipulotu, David Anderson, Sevim Mese, Yaman Tayyar, Kathryn Edenborough, Jasim Muhammad Uddin, Abrar Hussain, Connor J. I. Daymond, Jacinta Agius, Karyn N. Johnson, Paniz Shirmast, Mahdi Abedinzadeshahri, Robin MacDiarmid, Caroline L. Ashley, Jay Laws, Lucy L. Furfaro, Thomas D. Burton, Stephen M. R. Johnson, Zahra Telikani, Mary Petrone, Justin A. Roby, Carolyn Samer, Andreas Suhrbier, April Van Der Kamp, Anthony Cunningham, Celeste Donato, Jackie Mahar, Wesley D. Black, Subhash Vasudevan, Roman Lenchine, Kirsten Spann, Daniel J. Rawle, Penny Rudd, Jessica Neil, Richard Kingston, Timothy P. Newsome, Ki Wook Kim, Johnson Mak, Kym Lowry, Nathan Bryant, Joanne Meers, Jason A. Roberts, Nigel McMillan, Larisa I. Labzin, Andrii Slonchak, Leon E. Hugo, Bennett Henzeler, Natalee D. Newton, Cassandra T. David, Patrick C. Reading, Camille Esneau, Tatiana Briody, Najla Nasr, Donna McNeale, Brian McSharry, Omid Fakhri, Bethany A. Horsburgh, Grant Logan, Paul Howley, Paul Youn

Statement in Support of: "Virology under the Microscope-a Call for Rational Discourse".

Letter to the Editor OnlinePublPeter Speck ... Michael Beard ... et al

Supportive and symptomatic management of amyotrophic lateral sclerosis

The main aims in the care of individuals with amyotrophic lateral sclerosis (ALS) are to minimize morbidity and maximize quality of life. Although no cure exists for ALS, supportive and symptomatic care provided by a specialist multidisciplinary team can improve survival. The basis for supportive management is shifting from expert consensus guidelines towards an evidence-based approach, which encourages the use of effective treatments and could reduce the risk of harm caused by ineffective or unsafe interventions. For example, respiratory support using noninvasive ventilation has been demonstrated to improve survival and quality of life, whereas evidence supporting other respiratory interventions is insufficient. Increasing evidence implicates a causal role for metabolic dysfunction in ALS, suggesting that optimizing nutrition could improve quality of life and survival. The high incidence of cognitive dysfunction and its impact on prognosis is increasingly recognized, although evidence for effective treatments is lacking. A variety of strategies are used to manage the other physical and psychological symptoms, the majority of which have yet to be thoroughly evaluated. The need for specialist palliative care throughout the disease is increasingly recognized. This Review describes the current approaches to symptomatic and supportive care in ALS and outlines the current guidance and evidence for these strategies