Natural history of nonhuman primates after conjunctival exposure to Ebola virus

Transmission of Ebola virus (EBOV) primarily occurs via contact exposure of mucosal surfaces with infected body fluids. Historically, nonhuman primate (NHP) challenge studies have employed intramuscular or small particle aerosol exposure, which are uniformly lethal routes of infection, but mimic worst-case scenarios such as a needlestick. When exposed by more likely routes of natural infection, limited NHP studies have shown delayed onset of disease and reduced mortality. Here we performed a series of systematic natural history studies in cynomolgus macaques with a range of conjunctival exposure doses. Challenge with 10,000 plaque forming units (PFU) of EBOV was uniformly lethal, whereas 5/6 subjects survived low and moderate dose challenges (100 or 500 PFU). Conjunctival challenge resulted in a protracted time-to death. Asymptomatic disease was observed in survivors with limited detection of EBOV replication. Inconsistent seropositivity in survivors may suggest physical or natural immunological barriers are sufficient to prevent widespread viral dissemination.

Comparative assessment of electronic nicotine delivery systems aerosol and cigarette smoke on endothelial cell migration: the Replica Project

Cigarette smoking is associated with impairment of repair mechanisms necessary for vascular endothelium homeostasis. Reducing the exposure to smoke toxicants may result in the mitigation of the harmful effect on the endothelium and cardiovascular disease development. Previous investigations performed by the tobacco industries evaluated in vitro the effect of electronic cigarette (e-cig) compared to cigarette smoke demonstrating a significant reduction in endothelial cell migration inhibition following e-cig aerosol exposure. In the present study, we replicated one of these studies, evaluating the effects of cigarette smoke on endothelial cell migration compared to e-cig and heated tobacco products. We used a multi-center approach (ring-study) to verify the robustness and reliability of the results obtained in the replicated study. Consistently with the original study, we observed a substantial reduction of the effects of e-cig and tobacco heated products on endothelial cell migration compared to cigarette smoke. In conclusion, our study further confirms the importance of e-cig and tobacco heated products as a possible harm reduction strategy for cardiovascular diseases development in smokers.

Efficacy of Ventilation, HEPA Air Cleaners, Universal Masking, and Physical Distancing for Reducing Exposure to Simulated Exhaled Aerosols in a Meeting Room

There is strong evidence associating the indoor environment with transmission of SARS-CoV-2, the virus that causes COVID-19. SARS-CoV-2 can spread by exposure to droplets and very fine aerosol particles from respiratory fluids that are released by infected persons. Layered mitigation strategies, including but not limited to maintaining physical distancing, adequate ventilation, universal masking, avoiding overcrowding, and vaccination, have shown to be effective in reducing the spread of SARS-CoV-2 within the indoor environment. Here, we examine the effect of mitigation strategies on reducing the risk of exposure to simulated respiratory aerosol particles within a classroom-style meeting room. To quantify exposure of uninfected individuals (Recipients), surrogate respiratory aerosol particles were generated by a breathing simulator with a headform (Source) that mimicked breath exhalations. Recipients, represented by three breathing simulators with manikin headforms, were placed in a meeting room and affixed with optical particle counters to measure 0.3–3 µm aerosol particles. Universal masking of all breathing simulators with a 3-ply cotton mask reduced aerosol exposure by 50% or more compared to scenarios with simulators unmasked. While evaluating the effect of Source placement, Recipients had the highest exposure at 0.9 m in a face-to-face orientation. Ventilation reduced exposure by approximately 5% per unit increase in air change per hour (ACH), irrespective of whether increases in ACH were by the HVAC system or portable HEPA air cleaners. The results demonstrate that mitigation strategies, such as universal masking and increasing ventilation, reduce personal exposure to respiratory aerosols within a meeting room. While universal masking remains a key component of a layered mitigation strategy of exposure reduction, increasing ventilation via system HVAC or portable HEPA air cleaners further reduces exposure.

A nucleic acid-based orthopoxvirus vaccine targeting the vaccinia virus L1, A27, B5 and A33 proteins protects rabbits against lethal rabbitpox virus aerosol challenge

In the age of COVID, nucleic acid vaccines have garnered much attention, at least in part, because of the simplicity of construction, production, and flexibility to adjust and adapt to an evolving outbreak. Orthopoxviruses remain a threat on multiple fronts, especially as emerging zoonosis. In response, we developed a DNA vaccine, termed 4pox, that protected nonhuman primates against monkeypox virus (MPXV) induced severe disease. Here, we examined the protective efficacy of the 4pox DNA vaccine delivered by intramuscular (i.m.) electroporation (EP) in rabbits challenged with aerosolized rabbitpox virus (RPXV), a model that recapitulates the respiratory route of exposure and low dose associated with natural smallpox exposure in humans. We found that 4pox vaccinated rabbits developed immunogen-specific antibodies, including neutralizing antibodies and did not develop any clinical disease, indicating protection against aerosolized RPXV. In contrast, unvaccinated animals developed significant signs of disease, including lesions, and were euthanized. These findings demonstrate that an unformulated, non-adjuvanted DNA vaccine delivered (i.m.) can protect against an aerosol exposure. Importance The eradication of smallpox and subsequent cessation of vaccination has left a majority of the population susceptible to variola virus or other emerging poxvirus. This is exemplified by human monkeypox, as evidenced by the increase in reported endemic and imported cases over the past decades. Therefore, a malleable vaccine technology that can be mass produced, and doesn’t require complex conditions for distribution and storage is sought. Herein, we show that a DNA vaccine, in the absence of a specialized formulation or adjuvant, can protect against a lethal aerosol insult of rabbitpox virus.

E-cigarette aerosol exacerbates cardiovascular oxidative stress in mice with an inactive aldehyde dehydrogenase 2 enzyme

Aims: E-cigarette aerosol containing aldehydes, including acetaldehyde, are metabolized by the enzyme aldehyde dehydrogenase 2 (ALDH2). However, little is known how aldehyde exposure from e-cigarettes, when coupled with an inactivating ALDH2 genetic variant, ALDH2*2 (present in 8% of the world population), affects cardiovascular oxidative stress. The aim of this study was to determine how e-cigarette aerosol exposure, when coupled with genetics, impacts cardiovascular oxidative stress in wild type ALDH2 and ALDH2*2 knock-in mice. Methods and Results: Using selective ion flow mass spectrometry, we determined that e-cigarette aerosol contains acetaldehyde that are 10-fold higher than formaldehyde or acrolein. Next, using wild type ALDH2 and ALDH2*2 knock-in rodents, we identified organ-specific differences in ALDH2 with the heart having 1.5-fold less ALDH2 enzyme activity relative to the liver and lung. In isolated cardiac myocytes, acetaldehyde exposure (30seconds, 0.1-1μM) caused a 4-fold greater peak in calcium levels for ALDH2*2 relative to ALDH2 cardiomyocytes. ALDH2*2 cardiomyocytes exposed to acetaldehyde also demonstrated a 2-fold increase in ROS production and 2.5-fold increase in 4HNE protein adducts relative to ALDH2 cardiomyocytes. For intact rodents, ALDH2*2 knock-in mice exposed to e-cigarette aerosol had an increased heart rate beginning 5 days after exposure compared to wild type ALDH2 mice (775±30bpm versus 679±33bpm, respectively, *p<0.01, n=7-8 per group). E-cigarette aerosol exposure also exacerbated oxidative stress in ALDH2*2 heart homogenates, including a 1.3-fold higher protein carbonyl level, a 1.7-fold higher lipid peroxide level and 1.5-fold greater phosphorylation of NF-κB relative to wild type ALDH2 homogenates. Conclusions: The increased oxidative stress from e-cigarette aerosol aldehydes triggers the proinflammatory NF-κB pathway. As ALDH2 expression and activity is lower in the heart relative to the lung, the heart could be more susceptible to increases in cardiovascular oxidative stress from e-cigarette aerosol; particularly for those carrying an ALDH2*2 genetic variant which limits acetaldehyde metabolism.

COVID-19 aerosol transmission simulation-based risk analysis for in-person learning

As educational institutions begin a school year following a year and a half of disruption from the COVID-19 pandemic, risk analysis can help to support decision-making for resuming in-person instructional operation by providing estiamtes of the relative risk reduction due to different interventions. In particular, a simulation-based risk analysis approach enables scenario evaluation and comparison to guide decision making and action prioritization under uncertainty. We develop a simulation model to characterize the risks and uncertainties associated with infections resulting from aerosol exposure in in-person classes. We demonstrate this approach by applying it to model a semester of courses in a real college with approximately 11,000 students embedded within a larger university. To have practical impact, risk cannot focus on only infections as the end point of interest, we estimate the risks of infection, hospitalizations, and deaths of students and faculty in the college. We incorporate uncertainties in disease transmission, the impact of policies such as masking and facility interventions, and variables outside of the college’s control such as population-level disease and immunity prevalence. We show in our example application that universal use of masks that block 40% of aerosols and the installation of near-ceiling, fan-mounted UVC systems both have the potential to lead to substantial risk reductions and that these effects can be modeled at the individual room level. These results exemplify how such simulation-based risk analysis can inform decision making and prioritization under great uncertainty.