Seasonal influenza vaccine performance and the potential benefits of mRNA vaccines.

Influenza remains a public health threat, partly due to suboptimal effectiveness of vaccines. One factor impacting vaccine effectiveness is strain mismatch, occurring when vaccines no longer match circulating strains due to antigenic drift or the incorporation of inadvertent (eg, egg-adaptive) mutations during vaccine manufacturing. In this review, we summarize the evidence for antigenic drift of circulating viruses and/or egg-adaptive mutations occurring in vaccine strains during the 2011-2020 influenza seasons. Evidence suggests that antigenic drift led to vaccine mismatch during four seasons and that egg-adaptive mutations caused vaccine mismatch during six seasons. These findings highlight the need for alternative vaccine development platforms. Recently, vaccines based on mRNA technology have demonstrated efficacy against SARS-CoV-2 and respiratory syncytial virus and are under clinical evaluation for seasonal influenza. We discuss the potential for mRNA vaccines to address strain mismatch, as well as new multi-component strategies using the mRNA platform to improve vaccine effectiveness.

Understanding barriers to vaccination against invasive meningococcal disease: a survey of the knowledge gap and potential solutions.

INTRODUCTION: Invasive meningococcal disease (IMD) is a leading cause of life-threatening bacterial meningitis and septicemia. Evidence points to a knowledge gap among parents, teenagers, and healthcare providers (HCPs) regarding IMD and available vaccines, including those against the highly prevalent serogroup B. AREAS COVERED: An online survey was conducted between March 27 and 12 April 2019, to gather insights into the knowledge that parents/guardians have about IMD vaccines. The children were aged 2 months to 10 years in Australia, Brazil, Germany, Greece, Italy, and Spain, 5-20 years in the UK, and 16-23 years in the USA. The findings were discussed in the context of the available literature and solutions were proposed to minimize the knowledge gap and the barriers to vaccination against IMD. EXPERT OPINION: The survey demonstrated that parents have a good understanding of IMD but a limited understanding of the different serogroups and vaccines. The available literature highlighted multiple barriers to IMD vaccine uptake; these may be reduced through education of HCPs, clear recommendations to parents by HCPs, the use of technology, and disease-awareness initiatives that engage parents through physical and digital channels. Further studies are warranted to assess the impact of the COVID-19 pandemic on IMD vaccination.

Evidence of an Annexin A4 mediated plasma membrane repair response to biomechanical strain associated with glaucoma pathogenesis.

Glaucoma is a common neurodegenerative blinding disease that is closely associated with chronic biomechanical strain at the optic nerve head (ONH). Yet, the cellular injury and mechanosensing mechanisms underlying the resulting damage have remained critically unclear. We previously identified Annexin A4 (ANXA4) from a proteomic analyses of human ONH astrocytes undergoing pathological biomechanical strain that mimics glaucomatous conditions. Annexins are a family of calcium-dependent phospholipid binding proteins with key functions in plasma membrane repair (PMR); an active mechanism to limit and mend cellular injury that involves membrane and cytoskeletal reorganizations. However, a role for direct membrane damage and PMR has not been well studied in the context of biomechanical strain, such as that associated with glaucoma. Here we report that this moderate strain surprisingly damages cell membranes to increase permeability in a calcium-dependent manner, and induces rapid aggregation of ANXA4 at injury sites. ANXA4 loss-of-function increases permeability, while exogenous ANXA4 reduces it. Furthermore, ANXA4 aggregation is associated with F-actin dynamics in vitro, and remarkably this interaction and aggregation signature is also observed in the glaucomatous ONH in patient samples. Together these studies link moderate biomechanical strain with direct membrane damage and actin dynamics, and identify an active PMR role for ANXA4 in new model of cell injury associated with glaucoma pathogenesis.

Meningococcal Disease Outbreaks: A Moving Target and a Case for Routine Preventative Vaccination.

Outbreaks of invasive meningococcal disease (IMD) are unpredictable, can be sudden and have devastating consequences. We conducted a non-systematic review of the literature in PubMed (1997-2020) to assess outbreak response strategies and the impact of vaccine interventions. Since 1997, IMD outbreaks due to serogroups A, B, C, W, Y and X have occurred globally. Reactive emergency mass vaccination campaigns have encompassed single institutions (schools, universities) through to whole sections of the population at regional/national levels (e.g. serogroup B outbreaks in Saguenay-Lac-Saint-Jean region, Canada and New Zealand). Emergency vaccination responses to IMD outbreaks consistently incurred substantial costs (expenditure on vaccine supplies, personnel costs and interruption of other programmes). Impediments included the limited pace of transmission of information to parents/communities/healthcare workers; issues around collection of informed consents; poor vaccine uptake by older adolescents/young adults, often a target age group; issues of reimbursement, particularly in the USA; and difficulties in swift supply of large quantities of vaccines. For serogroup B outbreaks, the need for two doses was a significant issue that contributed substantially to costs, delayed onset of protection and non-compliance with dose 2. Real-world descriptions of outbreak control strategies and the associated challenges systematically show that reactive outbreak management is administratively, logistically and financially costly, and that its impact can be difficult to measure. In view of the unpredictability, fast pace and potential lethality of outbreak-associated IMD, prevention through routine vaccination appears the most effective mitigation tool. Highly effective vaccines covering five of six disease-causing serogroups are available. Preparedness through routine vaccination programmes will enhance the speed and effectiveness of outbreak responses, should they be needed (ready access to vaccines and need for a single booster dose rather than a primary series).

Biomechanical insult switches PEA-15 activity to uncouple its anti-apoptotic function and promote erk mediated tissue remodeling.

Biomechanical insult contributes to many chronic pathological processes, yet the resulting influences on signal transduction mechanisms are poorly understood. The retina presents an excellent mechanotransduction model, as mechanical strain on sensitive astrocytes of the optic nerve head (ONH) is intimately linked to chronic tissue remodeling and excavation by matrix metalloproteinases (MMPs), and apoptotic cell death. However, the mechanism by which these effects are induced by biomechanical strain is unclear. We previously identified the small adapter protein, PEA-15 (phosphoprotein enriched in astrocytes), through proteomic analyses of human ONH astrocytes subjected to pathologically relevant biomechanical insult. Under resting conditions PEA-15 is regulated through phosphorylation of two key serine residues to inhibit extrinsic apoptosis and ERK1/2 signaling. However, we surprisingly observed that biomechanical insult dramatically switches PEA-15 phosphorylation and function to uncouple its anti-apoptotic activity, and promote ERK1/2-dependent MMP-2 and MMP-9 secretion. These results reveal a novel cell autonomous mechanism by which biomechanical strain rapidly modifies this signaling pathway to generate altered tissue injury responses.

Cholinergic manipulations bidirectionally regulate object memory destabilization.

Consolidated memories can become destabilized and open to modification upon retrieval. Destabilization is most reliably prompted when novel information is present during memory reactivation. We hypothesized that the neurotransmitter acetylcholine (ACh) plays an important role in novelty-induced memory destabilization because of its established involvement in new learning. Accordingly, we investigated the effects of cholinergic manipulations in rats using an object recognition paradigm that requires reactivation novelty to destabilize object memories. The muscarinic receptor antagonist scopolamine, systemically or infused directly into the perirhinal cortex, blocked this novelty-induced memory destabilization. Conversely, systemic oxotremorine or carbachol, muscarinic receptor agonists, administered systemically or intraperirhinally, respectively, mimicked the destabilizing effect of novel information during reactivation. These bidirectional effects suggest a crucial influence of ACh on memory destabilization and the updating functions of reconsolidation. This is a hitherto unappreciated mnemonic role for ACh with implications for its potential involvement in cognitive flexibility and the dynamic process of long-term memory storage.