•Pregnant people are underrepresented in emergency vaccine clinical trials.•Incident pregnancies and related outcomes are underreported in vaccine clinical trials.•Public health emergencies often ...present disproportionate risk to pregnant people and neonates.•It is both ethical and feasible to enroll pregnant people safely into vaccine trials.•Plans for generating pregnancy-specific data during emergencies are needed.
Existing ethics guidance and regulatory requirements emphasize the need for pregnancy-specific safety and efficacy data during the development of vaccines in health emergencies. Our objective was to conduct a systematic review of vaccine clinical trials during active epidemic periods.
We searched for Phase II and Phase III vaccine clinical trials initiated during the H1N1 influenza, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Zika, and Ebola virus disease (EVD) outbreaks from 2009 to 2019. Data were extracted from clinical trial protocols identified in the following registries: ClinicalTrials.gov, Pan African Clinical Trial Registry (PACTR), and all primary registries indicated by the World Health Organization’s International Clinical Trials Registry Platform (ICTRP). Published studies from registered clinical trials were located through PubMed. Data was extracted on eligibility criteria and pregnancy outcomes. Data from this study is available in the Center for Open Science Data Repository: https://osf.io/nfk2p/?view_only=47deb3b206724af9b46c9c0c0083a267.
We identified 96 vaccine clinical trial protocols and included 84 in analysis. 5 records were excluded in screening for irrelevant abstracts, 7 were excluded in full-text assessment (1 for a therapeutic drug trial, 3 for enrolling elderly adults only, 3 for enrolling children/adolescents only). There were no eligible trials for MERS-CoV or Zika virus vaccines. Overall, 8 protocols explicitly included pregnant people; of these, 3 were completed trials with published results. Incidental pregnancies and outcomes of pregnant participants were reported in 2 studies, 10 studies reported serious adverse events related to pregnancy without mentioning total incidental pregnancies. A total of 411 recorded pregnancy outcomes were reported, with 293 from the 3 pregnancy-eligible studies with results. 71 serious adverse events pertaining to pregnancy were reported from all clinical trials with results.
Pregnant people are underrepresented in vaccine clinical trials conducted during outbreaks, resulting in underreporting of pregnancy-related outcomes and a lack of protection for pregnant people and neonates from infectious diseases.
Extracellular high mobility group box 1 protein (HMGB1) serves a central role in inflammation as a transporter protein, which binds other immune-activating molecules that are endocytosed via the ...receptor for advanced glycation end-products (RAGE). These pro-inflammatory complexes are targeted to the endolysosomal compartment, where HMGB1 permeabilizes the lysosomes. This enables HMGB1-partner molecules to avoid degradation, to leak into the cytosol, and to reach cognate immune-activating sensors. Lipopolysaccharide (LPS) requires this pathway to generate pyroptosis by accessing its key cytosolic receptors, murine caspase 11, or the human caspases 4 and 5. This lytic, pro-inflammatory cell death plays a fundamental pathogenic role in gram-negative sepsis. The aim of the study was to identify molecules inhibiting HMGB1 or HMGB1/LPS cellular internalization.
Endocytosis was studied in cultured macrophages using Alexa Fluor-labeled HMGB1 or complexes of HMGB1 and Alexa Fluor-labeled LPS in the presence of an anti-HMGB1 monoclonal antibody (mAb), recombinant HMGB1 box A protein, acetylcholine, the nicotinic acetylcholine receptor subtype alpha 7 (α7 nAChR) agonist GTS-21, or a dynamin-specific inhibitor of endocytosis. Images were obtained by fluorescence microscopy and quantified by the ImageJ processing program (NIH). Data were analyzed using student's t test or one-way ANOVA followed by the least significant difference or Tukey's tests.
Anti-HMGB1 mAb, recombinant HMGB1 antagonist box A protein, acetylcholine, GTS-21, and the dynamin-specific inhibitor of endocytosis inhibited internalization of HMGB1 or HMGB1-LPS complexes in cultured macrophages. These agents prevented macrophage activation in response to HMGB1 and/or HMGB1-LPS complexes.
These results demonstrate that therapies based on HMGB1 antagonists and the cholinergic anti-inflammatory pathway share a previously unrecognized molecular mechanism of substantial clinical relevance.
Abstract
Background
The COVID-19 pandemic, while unfortunately notable for immense strain and death throughout the world, has also shown great promise in the development of medical countermeasures. ...As the global scientific community shifted almost entirely towards vaccines, diagnostics and therapeutics, new trial designs most significantly adaptive platform trials, began to be used with greater speed and broader reach. These designs allowed for deploying and investigating new therapeutics, repurposing currently existing therapeutics and flexibly removing or adding additional medications as data appeared in real-time. Moreover, public–private sector partnering occurred at a level not seen before, contributing greatly to the rapid development and deployment of vaccines.
Objectives
To provide a brief overview of the advances in preventative and therapeutic medical countermeasure development for COVID-19.
Methods
A narrative review of relevant major medical countermeasure trials was conducted using the date range February 2020–December 2022, representing the period of greatest productivity in research to investigate COVID-19.
Results
Among the most influential trial designs are the adaptive platform designs, which have been applied to the development of initial COVID-19 antivirals, monoclonal antibodies, repurposing of existing immunomodulatory therapy and assisted in the disproof of ineffective medical therapies. Some of the most prominent examples include the REMAP-CAP, RECOVERY and TOGETHER trials.
Conclusions
Adaptive platform trial designs hold great promise for utility in future pandemics and mass casualty events. Additionally, public–private sectoring is essential for rapid medical countermeasure development and should be further enhanced for future biopreparedness.
The retrotrapezoid "nucleus" (RTN), located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 1000 glutamatergic noncatecholaminergic ...Phox2b-expressing propriobulbar neurons that are activated by CO(2) in vivo and by acidification in vitro. These cells are thought to function as central respiratory chemoreceptors, but this theory still lacks a crucial piece of evidence, namely that stimulating these particular neurons selectively in vivo increases breathing. The present study performed in anesthetized rats seeks to test whether this expectation is correct. We injected into the left RTN a lentivirus that expresses the light-activated cationic channel ChR2 (channelrhodopsin-2) (H134R mutation; fused to the fluorescent protein mCherry) under the control of the Phox2-responsive promoter PRSx8. Transgene expression was restricted to 423 +/- 38 Phox2b-expressing neurons per rat consisting of noncatecholaminergic and C1 adrenergic neurons (3:2 ratio). Photostimulation delivered to the RTN region in vivo via a fiberoptic activated the CO(2)-sensitive neurons vigorously, produced a long-lasting (t(1/2) = 11 s) increase in phrenic nerve activity, and caused a small and short-lasting cardiovascular stimulation. Selective lesions of the C1 cells eliminated the cardiovascular response but left the respiratory stimulation intact. In rats with C1 cell lesions, the mCherry-labeled axon terminals originating from the transfected noncatecholaminergic neurons were present exclusively in the lower brainstem regions that contain the respiratory pattern generator. These results provide strong evidence that the Phox2b-expressing noncatecholaminergic neurons of the RTN region function as central respiratory chemoreceptors.
The balance between plankton photosynthesis (GPP) and community respiration (CR) in the euphotic zone (net community production, NCP) is an essential driver of the biological carbon pump. Deficient ...datasets and a lack of knowledge of the mechanisms regulating CR cause poor empirical models and oversimplified parameterisations that maintain NCP as one of the most important unknowns for projections of the carbon pump. One important unresolved issue is the unexpected lack of empirical relationships between CR and the biomass or size-structure of the phytoplankton, which undermines the use of remotely sensed observations to predict net community metabolism. Here we analyse the spatial variation of plankton metabolism, chlorophyll a concentration (Chla), pico- and nanophytoplankton abundance and size-fractionated primary production (
14
CPP) along a latitudinal (49°N–46°S) transect of 73 stations across the Atlantic Ocean (AMT-22 cruise). The use of depth-weighted rates (rates integrated to the depth of 0.1% PAR, divided by the regionally varying depth of integration) markedly improved the depiction of latitudinal patterns and the significance of relationships, over volumetric or integrated rates. Depth-weighted CR showed clear and consistent latitudinal patterns with relevance for the distribution of NCP. Depth-weighted Chla and CR exhibited a significant relationship (CR
Z
=1.42Chla
Z
-0.21, r
2 =
0.69, N=37, p<0.001) with potential for the difficult prediction of CR. A general ratio of 1.42 mmolO
2
mgChla
-1
d
-1
and a threshold Chla for net heterotrophy of ca. 0.25 mgChla m
-3
can be tentatively proposed for the Atlantic, although further analyses of spatial and seasonal variation are necessary. We observed unusually positive NCP rates in the central part of the N gyre, due to a marked decrease of CR in a patch of high
Synechococcus
spp. abundance and high
14
CPP by large phytoplankton. However, no relationship was observed between size-fractionated
14
CPP and CR or the GPP : CR ratio during the cruise, contradicting the hypothesis that food web functioning is determined by the phytoplankton size structure. Such independence, together with the persistence of distinct GPP : CR and
14
CPP : NCP relationships in distinct biogeographic provinces suggest a resilience of trophic dynamics and the existence of alternative ecosystem states, whose implications for projections of the metabolic state of the ocean are discussed.
Anthropogenic climate change is exerting pressures on coastal ecosystems through increases in temperature, precipitation and ocean acidification. Phytoplankton community structure and ...photo-physiology are therefore adapting to these conditions. Changes in phytoplankton biomass and photosynthesis in relation to temperature and nutrient concentrations were assessed using a 14 yr dataset from a coastal station in the western English Channel (WEC). Dinoflagellate and coccolithophorid biomass exhibited a positive correlation with temperature, reaching the highest biomass between 15 and 17°C. Diatoms showed a negative correlation with temperature, with highest biomass at 10°C. Chlorophyll a (chl a) normalised maximum light-saturated photosynthetic rates (PB
m) exhibited a hyperbolic response to increasing temperature, with an initial linear increase from 8 to 11°C and reaching a plateau from 12°C. There was, however, no significant positive correlation between nutrients and phytoplankton biomass or PB
m, which reflects the lag time between nutrient input and phytoplankton growth at this coastal site. The major phytoplankton groups that occurred at this site occupied distinct thermal niches, which in turn modified PB
m. Increasing temperature and higher water column stratification were major factors in the initiation of dinoflagellate blooms at this site. Dinoflagellate blooms during summer also covaried with silicate concentration and acted as a tracer of dissolved inorganic nitrogen and phosphate from river run-off, which were subsequently reduced during these blooms. The data imply that increasing temperature and high river runoff during summer will promote dinoflagellate blooms in the WEC.
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