Vaccines for COVID-19.

Since the emergence of COVID-19, caused by the SARS-CoV-2 virus at the end of 2019, there has been an explosion of vaccine development. By 24 September 2020, a staggering number of vaccines (more than 200) had started preclinical development, of which 43 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socializing. Importantly, to effectively control the COVID-19 pandemic, production needs to be scaled-up from a small number of preclinical doses to enough filled vials to immunize the world's population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS-CoV-2 and the potential for vaccine-induced immunopathology. We describe the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising preclinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began we are at a point where preclinical and early clinical data are being generated for the vaccines; an overview of this important area will help our understanding of the next phases.

Political priorities and public health services in English local authorities: the case of tobacco control and smoking cessation services.

Background: Since 2013, local authorities in England have been responsible for public health including smoking cessation services. Methods: Online surveys of tobacco control leads in English local authorities were conducted in 2014 (76% response rate, n = 116), 2015 (82% response rate, n = 124) and 2016 (85% response rate, n = 129). Results: A high priority for tobacco control was reported in 17% of local authorities in 2014, rising to 27% in 2016. A low priority for tobacco control was reported in 4% of local authorities in 2014, rising to 11% in 2016. Budgets for smoking cessation services were cut in 16% of local authorities in 2014, 39% in 2015 and 59% in 2016. In 2016, budgets were cut in all local authorities where the priority given to tobacco control was perceived to be low and in 40% of the local authorities where it was perceived to be high. Cuts in smoking cessation budgets were principally due to cuts to the public health grant and wider cuts to local authority budgets. Conclusions: At a time of significant cost pressure, political support for tobacco control in English local authorities mitigates but does not remove the risk of cuts to budgets for smoking cessation services.

Electronic cigarette use in young people in Great Britain 2013-2014.

OBJECTIVES: The recent growth in the market for electronic cigarettes (e-cigarettes) has led to concerns over their use by young people. It is therefore important to examine trends in the perception and use of e-cigarettes and conventional cigarettes in this group. STUDY DESIGN: Two-wave cross-sectional survey design. METHODS: Young people aged 11-18 in Great Britain were surveyed online by YouGov in 2013 and 2014. Use of e-cigarettes, together with perceived health harms and intention to use were assessed and compared in relation to cigarette smoking history, age and gender. RESULTS: Ever-use of e-cigarettes increased significantly from 4.6% (95% CI 3.8-5.7) in 2013 to 8.2% (95% CI 7.0-9.6) in 2014. Monthly or more use of e-cigarettes increased from 0.9% (95% CI 0.5-1.5) to 1.7 (1.2-2.4), but remained rare in never-smokers at under 0.2%. The proportion of young people who perceived e-cigarettes to be less harmful to users than cigarettes fell from 73.4% (95% CI 71.0-75.8) to 66.9% (95% CI 64.5-69.2), while the proportion who considered e-cigarettes to cause similar levels of harm increased from 11.8% (95% CI 10.0-13.5) to 18.2% (95% CI 16.3-20.1). Of the 8.2% of e-cigarette ever-users in 2014, 69.8% (95% CI 62.2%-77.3%) had smoked a cigarette prior to using an e-cigarette, while 8.2% (95% CI 4.1%-12.2%) first smoked a cigarette after e-cigarette use. CONCLUSIONS: A growing proportion of young people in Great Britain believe e-cigarettes are as harmful as smoking tobacco. Use of e-cigarettes by young people is increasing, but is largely confined to those who smoke.

Airway T cells protect against RSV infection in the absence of antibody.

This corrects the article DOI: 10.1038/mi.2017.46.

Airway T cells protect against RSV infection in the absence of antibody.

Tissue resident memory T (Trm) cells act as sentinels and early responders to infection. Respiratory syncytial virus (RSV)-specific Trm cells have been detected in the lungs after human RSV infection, but whether they have a protective role is unknown. To dissect the protective function of Trm cells, BALB/c mice were infected with RSV; infected mice developed antigen-specific CD8+ Trm cells (CD103+/CD69+) in the lungs and airways. Intranasally transferring cells from the airways of previously infected animals to naïve animals reduced weight loss on infection in the recipient mice. Transfer of airway CD8 cells led to reduced disease and viral load and increased interferon-γ in the airways of recipient mice, while CD4 transfer reduced tumor necrosis factor-α in the airways. Because DNA vaccines induce a systemic T-cell response, we compared vaccination with infection for the effect of memory CD8 cells generated in different compartments. Intramuscular DNA immunization induced RSV-specific CD8 T cells, but they were immunopathogenic and not protective. Notably, there was a marked difference in the induction of Trm cells; infection but not immunization induced antigen-specific Trm cells in a range of tissues. These findings demonstrate a protective role for airway CD8 against RSV and support the need for vaccines to induce antigen-specific airway cells.

Substance P excitation of rat locus coeruleus neurones.

We have made extracellular recordings from locus coeruleus neurones contained in a pontine slice preparation. The in vitro technique permits application of known concentrations of drugs in the perfusion medium. Substance P excites locus coeruleus neurones in a concentration-dependent manner. The activity of substance P was found to reside in the C terminal region of the molecule. The relative potency of substance P and related peptides suggests that the substance P receptors present within the locus coeruleus are predominately of the substance P-P type. The synthetic analogue [D-Pro2,D-Trp7.9]substance P was not found to antagonise the action of substance P on locus coeruleus neurones.

Interaction of chlorpromazine with tea and coffee.

1 The interaction between phenothiazine neuroleptics with tea and coffee was studied in vitro. 2 Filtered infusions of tea and coffee caused precipitation of all the neuroleptics studied. Tea always caused a heavier precipitate than coffee. 3 The constituent or constituents of tea and coffee responsible for precipitating the neuroleptics was not identified. Solutions of caffeine, caffeine citrate and sodium chloride did not form a precipitate with chlorpromazine but precipitates were formed by sodium salicylate, sodium benzoate and trisodium citrate. 4 The interaction between chlorpromazine (CPZ) and tea was studied quantitatively using radiolabelled drug and it was found that the precipitation of [3H]-CPZ with a given quantity of tea was 'saturable'. The proportion of CPZ precipitated by a 'standard cup of tea' was 80% at low doses of the drug (10-40 mg) whilst at high doses (800 mg), the proportion of the drug precipitated was approximately 20%. 5 The interaction was further studied in vivo by the oral administration of tea and CPZ to rats. The cataleptic effect of CPZ was significantly reduced by the simultaneous administration of tea and this was apparently not due to the caffeine present in tea. 6 The results suggest that a substantial proportion of orally administered neuroleptic may be precipitated as a highly insoluble compound if coffee, or more especially tea, is taken close to drug administration. This interaction might affect the absorption of phenothiazines given orally to patients.

In vitro studies with UK-18,892, a new aminoglycoside antibiotic.

The antibacterial activity of UK-18,892, a new semisynthetic aminoglycoside, was examined against aminoglycoside-susceptible and aminoglycoside-resistant clinical isolates of gram-negative bacilli and Staphylococcus aureus. UK-18,892 had a similar degree of activity to those of amikacin and kanamycin A against aminoglycoside-susceptible bacteria but was less potent than gentamicin against all isolates except Providencia spp. UK-18,892 was highly active against aminoglycoside-resistant bacteria, inhibiting 93% of the 268 isolates examined at 12.5 mug/ml. Amikacin was similarly active, whereas gentamicin inhibited only 14% of these isolates at 12.5 mug/ml.

UK-18,892: resistance to modification by aminoglycoside-inactivating enzymes.

UK-18,892, a new semisynthetic aminoglycoside, was active against bacteria possessing aminoglycoside-inactivating enzymes, with the exception of some known to possess AAC(6') or AAD(4') enzymes. This activity has been rationalized by using cell-free extracts of bacteria containing known inactivating enzymes, where it was shown that UK-18,892 was not a substrate for the APH(3'), AAD(2''), AAC(3), and AAC(2') enzymes. It was also demonstrated that UK-18,892 protected mice against lethal infections caused by organisms possessing aminoglycoside-inactivating enzymes.

Pharmacological profile of UK-74,505, a novel and selective PAF antagonist with potent and prolonged oral activity.

UK-74505, a novel 1,4-dihydropyridine PAF antagonist, exhibited highly selective, time-dependent inhibition of PAF-induced aggregation of rabbit washed platelets (IC50 = 26.3 +/- 0.88 and 1.12 +/- 0.04 nM after 0.25 and 60 min preincubation, respectively), which became irreversible within 15 min, whereas inhibition by WEB-2086 was both independent of preincubation time (IC50 = 145.7 +/- 24.7 nM) and competitive (KI = 27.5 +/- 7.7 nM; Schild slope = 0.98 +/- 0.04). The selective inhibition of specific [3H]PAF binding by UK-74,505 exhibited a slower onset, the IC50 obtained without preincubation (14.7 +/- 2.6 nM) decreasing 2-fold at 45 min. UK-74,505 was 450-fold weaker as an antagonist of [3H]nitrendipine binding to bovine brain membranes and KCl-induced contraction of rat aorta. UK-74,505 was 10-30-fold more potent than WEB-2086 in vivo as an inhibitor of PAF-induced hypotension in rats (ED50 = 35 +/- 5.8 micrograms/kg, i.v.), cutaneous vascular permeability in guinea pigs (ED50 = 0.37 +/- 0.08 mg/kg, p.o.) and lethality in mice, with oral ED50 values of 0.26 +/- 0.03 and 1.33 +/- 0.19 mg/kg at 2 and 8 h, respectively. These data demonstrate that UK-74,505 is a potent, selective, long-acting irreversible PAF antagonist.