A Novel Laser Vaccine Adjuvant Increases the Motility of Antigen Presenting Cells

Background Development of a potent vaccine adjuvant without introduction of any side effects remains an unmet challenge in the field of the vaccine research. Methodology/Principal Findings We found that laser at a specific setting increased the motility of antigen presenting cells (APCs) and immune responses, with few local or systemic side effects. This laser vaccine adjuvant (LVA) effect was induced by brief illumination of a small area of the skin or muscle with a nondestructive, 532 nm green laser prior to intradermal (i.d.) or intramuscular (i.m.) administration of vaccines at the site of laser illumination. The pre-illumination accelerated the motility of APCs as shown by intravital confocal microscopy, leading to sufficient antigen (Ag)-uptake at the site of vaccine injection and transportation of the Ag-captured APCs to the draining lymph nodes. As a result, the number of Ag+ dendritic cells (DCs) in draining lymph nodes was significantly higher in both the 1° and 2° draining lymph nodes in the presence than in the absence of LVA. Laser-mediated increases in the motility and lymphatic transportation of APCs augmented significantly humoral immune responses directed against a model vaccine ovalbumin (OVA) or influenza vaccine i.d. injected in both primary and booster vaccinations as compared to the vaccine itself. Strikingly, when the laser was delivered by a hair-like diffusing optical fiber into muscle, laser illumination greatly boosted not only humoral but also cell-mediated immune responses provoked by i.m. immunization with OVA relative to OVA alone. Conclusion/Significance The results demonstrate the ability of this safe LVA to augment both humoral and cell-mediated immune responses. In comparison with all current vaccine adjuvants that are either chemical compounds or biological agents, LVA is novel in both its form and mechanism; it is risk-free and has distinct advantages over traditional vaccine adjuvants.National Institutes of Health (U.S.) (grant AI070785)National Institutes of Health (U.S.) (grant RC1 DA028378)Bill & Melinda Gates Foundation (Grand Challenges Explorations grant # 53273)Boston BioCom (Firm) (Sponsored Research agreement grant #2008A25652

The curse of the Pharaoh revisited: evolutionary bi‐stability in environmentally transmitted pathogens

It is increasingly evident that for a number of high‐profile pathogens, transmission involves both direct and environmental pathways. Much of the distinguished evolutionary theory has, however, focused on each of transmission component separately. Herein, we use the framework of adaptive dynamics to study the evolutionary consequences of mixed transmission. We find that environmental transmission can select for increased virulence when direct transmission is low. Increasing the efficiency of direct transmission gives rise to an evolutionary bi‐stability, with coexistence of different levels of virulence. We conclude that the overlooked contribution of environmental transmission may explain the curious appearance of high virulence in pathogens that are typically only moderately pathogenic, as observed for avian influenza viruses and cholera.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86963/1/j.1461-0248.2011.01619.x.pd

A review of data needed to parameterize a dynamic model of measles in developing countries

<p>Abstract</p> <p>Background</p> <p>Dynamic models of infection transmission can project future disease burden within a population. Few dynamic measles models have been developed for low-income countries, where measles disease burden is highest. Our objective was to review the literature on measles epidemiology in low-income countries, with a particular focus on data that are needed to parameterize dynamic models.</p> <p>Methods</p> <p>We included age-stratified case reporting and seroprevalence studies with fair to good sample sizes for mostly urban African and Indian populations. We emphasized studies conducted before widespread immunization. We summarized age-stratified attack rates and seroprevalence profiles across these populations. Using the study data, we fitted a "representative" seroprevalence profile for African and Indian settings. We also used a catalytic model to estimate the age-dependent force of infection for individual African and Indian studies where seroprevalence was surveyed. We used these data to quantify the effects of population density on the basic reproductive number <it>R</it>₀.</p> <p>Results</p> <p>The peak attack rate usually occurred at age 1 year in Africa, and 1 to 2 years in India, which is earlier than in developed countries before mass vaccination. Approximately 60% of children were seropositive for measles antibody by age 2 in Africa and India, according to the representative seroprevalence profiles. A statistically significant decline in the force of infection with age was found in 4 of 6 Indian seroprevalence studies, but not in 2 African studies. This implies that the classic threshold result describing the critical proportion immune (<it>p</it>_c) required to eradicate an infectious disease, <it>p</it>_c= 1-1/<it>R</it>₀, may overestimate the required proportion immune to eradicate measles in some developing country populations. A possible, though not statistically significant, positive relation between population density and <it>R</it>₀for various Indian and African populations was also found. These populations also showed a similar pattern of waning of maternal antibodies. Attack rates in rural Indian populations show little dependence on vaccine coverage or population density compared to urban Indian populations. Estimated <it>R</it>₀values varied widely across populations which has further implications for measles elimination.</p> <p>Conclusions</p> <p>It is possible to develop a broadly informative dynamic model of measles transmission in low-income country settings based on existing literature, though it may be difficult to develop a model that is closely tailored to any given country. Greater efforts to collect data specific to low-income countries would aid in control efforts by allowing highly population-specific models to be developed.</p

The war of the wrongdoers: When are wrongdoers truly unequal?

© 2021 Maja CvjetanovicThe law relating to multiple wrongdoers for civil wrongs has a chequered history. For centuries, solidary liability, which applies where wrongdoers jointly or independently cause the same loss, indivisible loss, has ensured that the plaintiff is able to seek full recourse from any defendant who was a necessary ingredient or cause of the harm suffered. Undoubtedly, the system has led many “deep-pocketed” defendants – who are the obvious targets of any plaintiff - to question whether they should be left on the hook for loss which the law recognises as the shared and indivisible fault of multiple defendant parties. In the relatively recent spate of reforms, the system of attributing fault between multiple defendants has been overhauled by a myriad of reforms. The reforms achieve multiple ends in different contexts. What this paper will refer to as “contribution reforms” have achieved two main ends. Firstly, they have enabled courts to order defendants to ‘contribute’ in the context of tortious wrongs an area in which the law has previously disallowed contribution. Secondly, the reforms have enabled courts to attribute liability on a pro rata basis which reflects the defendants’ respective wrongdoing – whereas previously the courts were only able to attribute a pro rata percentage of liability. What the paper will call “proportionate liability” reforms have removed solidary liability from the law altogether – in certain legislatively defined contexts. Similar to the contribution reforms, the court is empowered to apportion blame based on the respective wrongdoings of the wrongdoers or defendants. Drawing on from the law of contributory negligence, both sets of reforms rely on the dual tests of “causal potency” and “moral blameworthiness” when assessing the proportion of liability that should be attributed to either of the defendants. The focus of this paper will be to draw from the learnings of each of the “contribution” and contribution-like regimes: contribution as it applies in the general law, the contribution reforms and the proportionate liability reforms, in search of a unified approach to the principle of contribution in the context of civil wrongs. Section [II] of the paper considers the principle of contribution. It argues that that “eligibility” limitation, which requires that the defendants each be liable for coordinate liabilities is difficult to apply and unsound in principle. The Section concludes by arguing that unjust enrichment provides an adequate and unifying “eligibility” criterion, in preference to the existing “coordinate liabilities,” test. However, unjust enrichment does not provide an adequate basis upon which the court can attribute liability between the defendants. (The pro rata attribution of liability is an outworking of contribution’s paradigmatic or early cases which arose from surety situation – something which cannot be readily applied in the context of torts and civil wrongs, more generally). Sections [III] and [IV] consider how both the contribution and proportionate liability reforms manage apportioning liability regarding the perceived or actual responsibility for the loss (rather than pro rata) and the lessons that could be learned from the dual tests of causal potency and moral blameworthiness, which the reforms apply in attributing liability between multiple wrongdoers. The section concludes that the dual tests of “causal potency” and “moral blameworthiness” are inadequate and present no better or legitimate alternative to the pro rata status quo that applies under the general law of contribution. Section [V] provides an alternative approach to the apportionment of responsibility by referencing criminal law principles applicable to sentencing. The argument is underpinned by the acknowledgement that, once the plaintiff’s loss is determined as a loss necessarily caused by either defendant, the question necessarily becomes one of comparing and adjudging blame – a task which the criminal law courts conduct expertly