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Journal of Colloid and Interface Science Jan 2021The micellization behavior of nonionic surfactants is significantly influenced by substituting ethylene oxide (EO) units with CO in the head group of nonionic CEO...
HYPOTHESIS
The micellization behavior of nonionic surfactants is significantly influenced by substituting ethylene oxide (EO) units with CO in the head group of nonionic CEO surfactants. Incorporating hydrophobic units has a major effect on the driving forces of the micellization process by a reduced hydration affinity. Hence, the incorporation of CO moieties is favoring micellization and thereby adding a further tuning parameter.
EXPERIMENTS
The micellization of the surfactants was characterized in terms of thermodynamics and the assembly properties on the water/air interface by isothermal titration calorimetry (ITC) and surface tension measurements. The incorporation of CO moieties was compared to the effect of propylene oxide (PO) and propiolactone (PL) over the temperature range of 25-50 °C. From ITC measurements and the van't Hoff relation, we determined the thermodynamic parameters of micellization: enthalpy (ΔH), entropy (ΔS), and Gibbs free energy (ΔG).
FINDINGS
The incorporation of CO moieties reduces the critical micellization concentration (cmc) and a transfer energy of -0.36 kT/CO unit quantifies favored micellization for CO surfactants. The presence of PO or CO in the head group has a similar effect on the cmc, but for CO ΔH is substantially decreased, resulting in a largely reduced temperature sensitivity of the micellization process and indicating a reduced hydration affinity. This thermodynamic analysis reveals that CO and PO behave very differently concerning their effect on the micellization process.
PubMed: 32818681
DOI: 10.1016/j.jcis.2020.07.141 -
JAMA Sep 2020A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
A vaccine against coronavirus disease 2019 (COVID-19) is urgently needed.
OBJECTIVE
To evaluate the safety and immunogenicity of an investigational inactivated whole-virus COVID-19 vaccine in China.
INTERVENTIONS
In the phase 1 trial, 96 participants were assigned to 1 of the 3 dose groups (2.5, 5, and 10 μg/dose) and an aluminum hydroxide (alum) adjuvant-only group (n = 24 in each group), and received 3 intramuscular injections at days 0, 28, and 56. In the phase 2 trial, 224 adults were randomized to 5 μg/dose in 2 schedule groups (injections on days 0 and 14 [n = 84] vs alum only [n = 28], and days 0 and 21 [n = 84] vs alum only [n = 28]).
DESIGN, SETTING, AND PARTICIPANTS
Interim analysis of ongoing randomized, double-blind, placebo-controlled, phase 1 and 2 clinical trials to assess an inactivated COVID-19 vaccine. The trials were conducted in Henan Province, China, among 96 (phase 1) and 224 (phase 2) healthy adults aged between 18 and 59 years. Study enrollment began on April 12, 2020. The interim analysis was conducted on June 16, 2020, and updated on July 27, 2020.
MAIN OUTCOMES AND MEASURES
The primary safety outcome was the combined adverse reactions 7 days after each injection, and the primary immunogenicity outcome was neutralizing antibody response 14 days after the whole-course vaccination, which was measured by a 50% plaque reduction neutralization test against live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
RESULTS
Among 320 patients who were randomized (mean age, 42.8 years; 200 women [62.5%]), all completed the trial up to 28 days after the whole-course vaccination. The 7-day adverse reactions occurred in 3 (12.5%), 5 (20.8%), 4 (16.7%), and 6 (25.0%) patients in the alum only, low-dose, medium-dose, and high-dose groups, respectively, in the phase 1 trial; and in 5 (6.0%) and 4 (14.3%) patients who received injections on days 0 and 14 for vaccine and alum only, and 16 (19.0%) and 5 (17.9%) patients who received injections on days 0 and 21 for vaccine and alum only, respectively, in the phase 2 trial. The most common adverse reaction was injection site pain, followed by fever, which were mild and self-limiting; no serious adverse reactions were noted. The geometric mean titers of neutralizing antibodies in the low-, medium-, and high-dose groups at day 14 after 3 injections were 316 (95% CI, 218-457), 206 (95% CI, 123-343), and 297 (95% CI, 208-424), respectively, in the phase 1 trial, and were 121 (95% CI, 95-154) and 247 (95% CI, 176-345) at day 14 after 2 injections in participants receiving vaccine on days 0 and 14 and on days 0 and 21, respectively, in the phase 2 trial. There were no detectable antibody responses in all alum-only groups.
CONCLUSIONS AND RELEVANCE
In this interim report of the phase 1 and phase 2 trials of an inactivated COVID-19 vaccine, patients had a low rate of adverse reactions and demonstrated immunogenicity; the study is ongoing. Efficacy and longer-term adverse event assessment will require phase 3 trials.
TRIAL REGISTRATION
Chinese Clinical Trial Registry Identifier: ChiCTR2000031809.
Topics: Adjuvants, Immunologic; Adolescent; Adult; Aluminum Hydroxide; Antibodies, Neutralizing; Antibodies, Viral; Betacoronavirus; COVID-19; COVID-19 Vaccines; Coronavirus Infections; Dose-Response Relationship, Immunologic; Double-Blind Method; Female; Humans; Immunogenicity, Vaccine; Injections, Intramuscular; Male; Pandemics; Pneumonia, Viral; Propiolactone; SARS-CoV-2; Vaccines, Inactivated; Viral Vaccines; Young Adult
PubMed: 32789505
DOI: 10.1001/jama.2020.15543 -
Biomacromolecules Jul 2020The use of safe natural catalyst such as enzymes for ring opening polymerization (ROP) of β-substituted β-lactones such as benzyl malolactonate (MLABe) is an important...
The use of safe natural catalyst such as enzymes for ring opening polymerization (ROP) of β-substituted β-lactones such as benzyl malolactonate (MLABe) is an important objective considering the biomedical applications of the resulting (co)polymers. However, the preparation of well-defined polymeric materials using such systems requires an understanding of enzyme-substrate interactions. In this context, we investigated the mechanism of lipase-catalyzed ROP of MLABe, because it appears that it is probably not the same as the one widely described for other lactones such ε-caprolactone, propiolactone. and lactide. Enzymatic-catalyzed ROPs of MLABe in the presence of the lipase/acyltransferase CpLip2 and its serine knockout (serine KO) mutant (CpLip2_180A) have led to poly(benzyl malate) (PMLABe) terminated by a monobenzyl fumarate group with monomer conversion higher than 70% and weight-average molar mass of about 3600 g/mol ( = 1.42). On the other hand, only less than 7% of MLABe conversion and no polymer formation were observed when the polymerization reaction was conducted in the presence of inactivated CpLip2 (heated at 100 °C). Moreover, the ROP of MLABe in the presence of imidazole, a synthetic mimic of the catalytic histidine, led to a PMLABe terminated by a monobenzyl fumarate group. On the contrary, neither the enzymatic-catalyzed ROP of benzyl dimethylmalolactonate (diMeMLABe), a MLABe with two methyl groups instead of the two "acidic" protons on the lactone's ring, in the presence of CpLip2 and CpLip2_180A nor its chemical ROP in the presence of imidazole were successful. Together, all these results suggested that the lipase-catalyzed polymerization of malolactonates occurred through the abstraction of one of the two "acidic" protons of the lactone's ring by the histidine of the catalytic triad leading to the corresponding monobenzyl fumarate responsible for the polymerization of the remaining monomer. Finally, molecular modeling of the positioning of the monomer into the catalytic site of the CpLip2 and DFT quantum-chemical calculations highlighted an interaction of ()- and ()-MLABe with the catalytic histidine of the enzyme preferentially to serine, in the form of a strong hydrogen bond with one of the "acidic" protons of MLABe, thus, supporting the important role of the catalytic histidine in the polymerization of such cyclic lactones.
Topics: Catalysis; Lactones; Lipase; Molecular Weight; Polymerization; Polymers
PubMed: 32551525
DOI: 10.1021/acs.biomac.0c00593 -
Viruses Jun 2020In late 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, the capital of the Chinese province Hubei. Since then,...
In late 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, the capital of the Chinese province Hubei. Since then, SARS-CoV-2 has been responsible for a worldwide pandemic resulting in over 4 million infections and over 250,000 deaths. The pandemic has instigated widespread research related to SARS-CoV-2 and the disease that it causes, COVID-19. Research into this new virus will be facilitated by the availability of clearly described and effective procedures that enable the propagation and quantification of infectious virus. As work with the virus is recommended to be performed at biosafety level 3, validated methods to effectively inactivate the virus to enable the safe study of RNA, DNA, and protein from infected cells are also needed. Here, we report methods used to grow SARS-CoV-2 in multiple cell lines and to measure virus infectivity by plaque assay using either agarose or microcrystalline cellulose as an overlay as well as a SARS-CoV-2 specific focus forming assay. We also demonstrate effective inactivation by TRIzol, 10% neutral buffered formalin, beta propiolactone, and heat.
Topics: Animals; Betacoronavirus; COVID-19; Cellulose; Chlorocebus aethiops; Coronavirus Infections; Culture Media; Formaldehyde; Guanidines; HEK293 Cells; Humans; Pandemics; Phenols; Pneumonia, Viral; Propiolactone; SARS-CoV-2; Sepharose; Vero Cells; Viral Plaque Assay; Virus Inactivation
PubMed: 32517266
DOI: 10.3390/v12060622 -
Chemical Research in Toxicology Mar 2020The discovery that β-propiolactone (BPL), once a commercially important chemical, causes various tumors in experimental animals has led to a significant decrease in its...
The discovery that β-propiolactone (BPL), once a commercially important chemical, causes various tumors in experimental animals has led to a significant decrease in its use. However, owing to its efficacy this possible human carcinogen remains to be utilized in vaccines for inactivation of viruses. The focus of the current study was to uncover the mechanisms of β-propiolactone reactions with both nucleobases and glutathione (GSH) through computer simulations based on quantum chemical methods. Our results, in accordance with in vitro studies, show that among all nucleobases guanine most readily forms adducts with BPL through S2 reaction mechanism. Acquired activation energies with incorporated solvent effects reveal that alkylation represents an energetically more favorable reaction than acylation for all nucleobases. Comparison of activation free energies of glutathione and guanine reactions with BPL suggest that glutathione may represent an efficient natural scavenger of BPL. Therefore, glutathione present in the organism may provide protection to the DNA and thus prevent BPL's genotoxicity, mutagenicity, and possibly even carcinogenicity.
Topics: Carcinogenesis; Density Functional Theory; Humans; Models, Molecular; Molecular Structure; Propiolactone; Thermodynamics
PubMed: 32056425
DOI: 10.1021/acs.chemrestox.9b00389 -
International Journal of Molecular... Jan 2020[6]-Gingerol from ginger has received considerable attention as a potential cancer therapeutic agent because of its chemopreventive and chemotherapeutic effects, as well...
[6]-Gingerol from ginger has received considerable attention as a potential cancer therapeutic agent because of its chemopreventive and chemotherapeutic effects, as well as its safety. In the current study, we examined [6]-gingerol as a natural scavenger of nine ultimate chemical carcinogens to which we are frequently exposed: glycidamide, styrene oxide, aflatoxin B1 exo-8,9-epoxide, -propiolactone, ethylene oxide, propylene oxide, 2-cyanoethylene oxide, chloroethylene oxide, and vinyl carbamate epoxide. To evaluate [6]-gingerol efficacy, we expanded our research with the examination of glutathione-the strongest natural scavenger in human cells. The corresponding activation free energies were calculated using Hartree-Fock method with three flexible basis sets and two implicit solvation models. According to our results, [6]-gingerol proves to be an extremely effective scavenger of chemical carcinogens of the epoxy type. On the other hand, with the exception of aflatoxin B1 exo-8,9-epoxide, glutathione represents a relatively poor scavenger, whose efficacy could be augmented by [6]-gingerol. Moreover, our quantum mechanical study of the alkylation reactions of chemical carcinogens with [6]-gingerol and glutathione provide valuable insights in the reaction mechanisms and the geometries of the corresponding transition states. Therefore, we strongly believe that our research forms a solid basis for further computational, experimental and clinical studies of anticarcinogenic properties of [6]-gingerol as well as for the development of novel chemoprophylactic dietary supplements. Finally, the obtained results also point to the applicability of quantum chemical methods to studies of alkylation reactions related to chemical carcinogenesis.
Topics: Aflatoxin B1; Alkylation; Anticarcinogenic Agents; Carcinogens; Catechols; Cell Line; Chemoprevention; Epoxy Compounds; Ethylene Oxide; Fatty Alcohols; Zingiber officinale; Humans; Propiolactone; Urethane
PubMed: 31973096
DOI: 10.3390/ijms21030695 -
Fish & Shellfish Immunology Mar 2020As one of the most important fish in freshwater aquaculture, gibel carp (Carassius auratus gibelio) is easily susceptible to Cyprinid herpesvirus 2 (CyHV-2). Immersion...
As one of the most important fish in freshwater aquaculture, gibel carp (Carassius auratus gibelio) is easily susceptible to Cyprinid herpesvirus 2 (CyHV-2). Immersion vaccination has attracted many researchers due to its simple operation in preventing infectious diseases. However, the unavoidable disadvantage is that the immersion vaccine must be used with adjuvants to get a better performance. In this study, gibel carps were vaccinated by a 60 min bath in a β-propiolactone-inactivated Cyprinid herpesvirus 2, mixed with DTT, β-glucan, anisodamine and scopolamine, respectively. After immunization, the fishs were challenged by CyHV-2 in 2 weeks. By analyzing pathological section, we found that β-glucan, anisodamine and scopolamine groups protected the gibel carp compared to the control group, which was consistent with the trend of survival rate. Specifically, β-glucan group in serum appeared best on lysozyme, TSOD and complement C3. Real time quantitative RT-PCR results demonstrated that in both spleen and head kidney tissues, mRNA expressions of typical Th1 immune response cytokines IL-2 and IFN-γ2 in β-glucan group and anisodamine group were significantly higher than other groups and the level of immunoglobulins related to systemic immunity (IgM) and mucosal immunity (IgZ) were also enhanced in the immune period. DTT group slightly affected immune gene and serum enzyme activity, while did not show an adjuvant effect on survival rate. In addition, four adjuvant groups could obviously inhibit CyHV-2 replication. This study explored and proved the good efficiency of β-glucan or anisodamine as immersion immune adjuvant and also provided reference for improving the efficiency of immersion immunity.
Topics: Adjuvants, Immunologic; Animals; Aquaculture; Fish Diseases; Goldfish; Herpesviridae; Herpesviridae Infections; Immunity, Innate; Immunity, Mucosal; Immunization; Propiolactone; Scopolamine; Solanaceous Alkaloids; Survival Rate; Vaccines, Inactivated; Viral Vaccines; Virus Replication; beta-Glucans
PubMed: 31962149
DOI: 10.1016/j.fsi.2020.01.025 -
Food and Environmental Virology Mar 2020Influenza A virus (IAV) infection is perennially one of the leading causes of death worldwide. Effective therapy and vaccination are needed to control viral expansion....
Influenza A virus (IAV) infection is perennially one of the leading causes of death worldwide. Effective therapy and vaccination are needed to control viral expansion. However, current anti-IAV drugs risk inducing drug-resistant virus emergence. Although intranasal administration of whole inactivated virus vaccine can induce efficient protective immunity, formalin and β-propiolactone are the currently used and harmful inactivating agents. Here, we analyzed the antiviral activity of hibiscus (Hibiscus sabdariffa L.) tea extract against human IAV and evaluated its potential as a novel anti-IAV drug and a safe inactivating agent for whole inactivated vaccine. The in vitro study revealed that the pH of hibiscus tea extract is acidic, and its rapid and potent antiviral activity relied largely on the acidic pH. Furthermore, the mouse study showed that the acidic extract was not effective for either therapeutic or vaccination purposes. However, hibiscus tea extract and protocatechuic acid, one of the major components of the extract, showed not only potent acid-dependent antiviral activity but also weak low-pH-independent activity. The low-pH-independent activity did not affect the conformation of immunodominant hemagglutinin protein. Although this low-pH-independent activity is very limited, it may be suitable for the application to medication and vaccination because this activity is not affected by the neutral blood environment and does not lose antigenicity of hemagglutinin. Further study of the low-pH-independent antiviral mechanism and attempts to enhance the antiviral activity may establish a novel anti-IAV therapy and vaccination strategy.
Topics: Animals; Antiviral Agents; Female; Hibiscus; Humans; Hydrogen-Ion Concentration; Influenza A virus; Influenza, Human; Mice; Mice, Inbred BALB C; Plant Extracts
PubMed: 31620998
DOI: 10.1007/s12560-019-09408-x -
Reviews in Medical Virology Nov 2019Despite tremendous efforts toward vaccination, influenza remains an ongoing global threat. The induction of strain-specific neutralizing antibody responses is a common... (Review)
Review
Despite tremendous efforts toward vaccination, influenza remains an ongoing global threat. The induction of strain-specific neutralizing antibody responses is a common phenomenon during vaccination with the current inactivated influenza vaccines, so the protective effect of these vaccines is mostly strain-specific. There is an essential need for the development of next-generation vaccines, with a broad range of immunogenicity against antigenically drifted or shifted influenza viruses. Here, we evaluate the potential of whole inactivated vaccines, based on chemical and physical methods, as well as new approaches to generate cross-protective immune responses. We also consider the mechanisms by which some of these vaccines may induce CD8 T-cells cross-reactivity with different strains of influenza. In this review, we have focused on conventional and novel methods for production of whole inactivated influenza vaccine. As well as chemical modification, using formaldehyde or β-propiolactone and physical manipulation by ultraviolet radiation or gamma-irradiation, novel approaches, including visible ultrashort pulsed laser, and low-energy electron irradiation are discussed. These two latter methods are considered to be attractive approaches to design more sophisticated vaccines, due to their ability to maintain most of the viral antigenic properties during inactivation and potential to produce cross-protective immunity. However, further studies are needed to validate them before they can replace traditional methods for vaccine manufacturing.
Topics: Animals; Humans; Influenza A virus; Influenza B virus; Influenza Vaccines; Influenza, Human; Orthomyxoviridae Infections; Vaccines, Inactivated; Vaccinology
PubMed: 31334909
DOI: 10.1002/rmv.2074 -
Biologicals : Journal of the... Jul 2019The NIH assay is used to assess the potency of rabies vaccine and is currently a key measure required for vaccine release. As this test involves immunization of mice and...
The NIH assay is used to assess the potency of rabies vaccine and is currently a key measure required for vaccine release. As this test involves immunization of mice and subsequent viral challenge, efforts are being made to develop alternative analytical methods that do not rely on animal testing. Sanofi Pasteur has reported the development of a G-protein specific ELISA assay that has shown agreement with the NIH test. In this study we have generated several non-conform vaccine lots by an excessive inactivation with β-propiolactone (BPL) and assessed the capacity of both tests to detect the corresponding consequences. Excessive BPL inactivation causes G-protein unfolding, altering in turn viral morphology and the continuity of the G-protein layer in the viral particle. Both the NIH and the ELISA tests were able to monitor the consequences of excessive inactivation in a similar manner. Of note, the experimental error of the ELISA test was well below that of the NIH test. These results increase the prospect that the ELISA test could be considered a suitable candidate for the replacement of the NIH test.
Topics: Animals; Biological Assay; Enzyme-Linked Immunosorbent Assay; Mice; Rabies; Rabies Vaccines; Vaccination; Vaccine Potency; Vaccines, Inactivated
PubMed: 31105021
DOI: 10.1016/j.biologicals.2019.05.004