AstraZeneca resumes trials of COVID vaccine halted by patient illness

AstraZeneca has resumed British clinical trials of its COVID-19 vaccine, one of the most advanced in development, after receiving the green light from safety watchdogs, the company said on Saturday.

The late-stage trials of the experimental vaccine, developed with researchers from the University of Oxford, were suspended this week after an illness in a study subject in Britain, casting doubts on an early rollout.

“On 6 September, the standard review process triggered a voluntary pause to vaccination across all global trials to allow review of safety data by independent committees, and international regulators,” AstraZeneca said.

It added that safety reviewers had recommended to Britain’s Medicines Health Regulatory Authority (MHRA) that it was safe to resume the UK trials.

The patient involved in the study had been reportedly suffering from neurological symptoms associated with a rare spinal inflammatory disorder called transverse myelitis.

AstraZeneca, based in Cambridge, said it could not disclose further medical information.

Governments around the world are desperate for a vaccine to help end the pandemic, which has caused more than 900,000 deaths and global economic turmoil. The World Health Organization (WHO) had flagged AstraZeneca’s as the most promising.

The pause of the trials came after reports that the United States was aiming for fast-track authorization or approval of a vaccine before November’s presidential election.

Leading U.S. and European vaccine developers have pledged to uphold scientific safety and efficacy standards for their experimental vaccines and not bow to political pressures to rush the process.

AstraZeneca has already agreed to supply close to three billion doses to governments across the globe – more than any other vaccine project.

The WHO’s chief scientist said the pause in the trial should serve as a “wake-up” call that there would be ups and downs in the development of a vaccine.

https://www.reuters.com/article/us-health-coronavirus-britain-vaccine/astrazeneca-resumes-trials-of-covid-vaccine-halted-by-patient-illness-idUSKBN2630O9

Lower Covid development in children reveals molecular checks, potential therapies

View ORCID ProfileJonathan Baruch Steinman, Fok Moon Lum, Peggy Pui-Kay Ho, View ORCID ProfileNaftali Kaminski, and Lawrence Steinman

doi: https://doi.org/10.1073/pnas.2012358117

PDF: https://scholar.google.com/scholar_url?url=https://www.pnas.org/content/pnas/early/2020/09/02/2012358117.full.pdf&hl=en&sa=T&oi=ucasa&ct=ufr&ei=rPZcX87AHM3pmQH3t5WwBA&scisig=AAGBfm1XTgzW4snF4AWfXJmVcfc3QociAg

Abstract

The reduced development of COVID-19 for children compared to adults provides some tantalizing clues on the pathogenesis and transmissibility of this pandemic virus. First, ACE2, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor, is reduced in the respiratory tract in children. Second, coronavirus associated with common colds in children may offer some protection, due to cross-reactive humoral immunity and T cell immunity between common coronaviruses and SARS-CoV-2. Third, T helper 2 immune responses are protective in children. Fourth, surprisingly, eosinophilia, associated with T helper 2, may be protective. Fifth, children generally produce lower levels of inflammatory cytokines. Finally, the influence of the downturn in the global economy, the impact of living in quarters among families who are the most at risk, and factors including the openings of some schools, are considered. Those most disadvantaged socioeconomically may suffer disproportionately with COVID-19.

Competing interest statement: N.K. has consulted with Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, RohBar, and reports a grant from Veracyte. N.K. has patents on New Therapies in Pulmonary Fibrosis and Peripheral Blood Gene Expression Biomarkers. All these consultations are outside of this work. L.S. has consulted with Roche, Novartis, Tolerion, Atreca, TG Therapeutics, and Atara Biopharma. All these consultations are outside of the scope of this work.

https://www.pnas.org/content/early/2020/09/02/2012358117#ack-1

Strict Social Distancing Linked to Much Lower Covid Infection

Using public transportation, visiting a place of worship, or otherwise traveling from the home is associated with a significantly higher likelihood of testing positive with the coronavirus SARS-CoV-2, while practicing strict social distancing is associated with a markedly lower likelihood, suggests a study from researchers at the Johns Hopkins Bloomberg School of Public Health.

For their analysis, the researchers surveyed a random sample of more than 1,000 people in the state of Maryland in late June, asking about their social distancing practices, use of public transportation, SARS-CoV-2 infection history, and other COVID-19-relevant behaviors. They found, for example, that those reporting frequent public transport use were more than four times as likely to report a history of testing positive for SARS-CoV-2 infection, while those who reported practicing strict outdoor social distancing were just a tenth as likely to report ever being SARS-CoV-2 positive.

The study is believed to be among the first large-scale evaluations of COVID-19-relevant behaviors that is based on individual-level survey data, as opposed to aggregated data from sources such as cellphone apps.

The results were published online on September 2 in Clinical Infectious Diseases.

“Our findings support the idea that if you’re going out, you should practice social distancing to the extent possible because it does seem strongly associated with a lower chance of getting infected,” says study senior author Sunil Solomon, MBBS, PhD, MPH, an associate professor in the Bloomberg School’s Department of Epidemiology and an associate professor of medicine at Johns Hopkins School Medicine. “Studies like this are also relatively easy to do, so we think they have the potential to be useful tools for identification of places or population subgroups with higher vulnerability.”

The novel coronavirus SARS-CoV-2 has infected nearly 27 million people around the world, of whom some 900,000 have died, according to the World Health Organization. In the absence of a vaccine, public health authorities have emphasized practices such as staying at home, and wearing masks and maintaining social distancing while in public. Yet there hasn’t been a good way to monitor whether—and among which groups—such practices are being followed.

Solomon and colleagues, including first author Steven Clipman, a PhD candidate in the Bloomberg School’s Department of International Health, quickly accessed willing survey participants via a company that maintains a large nationwide pool of potential participants as a commercial service for market research. The 1,030 people included in the study were all living in Maryland, which has logged more than 113,000 SARS-CoV-2 confirmed cases and nearly 3,700 confirmed deaths, according to the Maryland Department of Health.

The researchers asked the survey participants questions about recent travel outside the home, their use of masks, social distancing and related practices, and any confirmed infection with SARS-CoV-2 either recently or at all.

The results indicated that 55 (5.3 percent) of the 1,030 participants had tested positive for SARS-CoV-2 infection at any time, while 18 (1.7 percent) reported testing positive in the two weeks before they were surveyed.

The researchers found that when considering all the variables they could evaluate, spending more time in public places was strongly associated with having a history of SARS-CoV-2 infection. For example, an infection history was about 4.3 times more common among participants who stated that they had used public transportation more than three times in the prior two weeks, compared to participants who stated they had never used public transportation in the two-week period.

An infection history also was 16 times more common among those who reported having visited a place of worship three or more times in the prior two weeks, compared to those who reported visiting no place of worship during the period. The survey did not distinguish between visiting a place of worship for a religious service or other purposes, such as a meeting, summer camp or meal.

Conversely, those who reported practicing social distancing outdoors “always” were only 10 percent as likely to have a SARS-CoV-2 history, compared to those who reported “never” practicing social distancing.

An initial, relatively simple analysis linked many other variables to SARS-CoV-2 infection history, including being Black or Hispanic. But a more sophisticated, “multivariable” analysis suggested that many of these apparent links were largely due to differences in movement and social distancing.

“When we adjusted for other variables such as social distancing practices, a lot of those simple associations went away, which provides evidence that social distancing is an effective measure for reducing SARS-CoV-2 transmission,” Clipman says.

The data indicated a greater adoption of social distancing practices among some groups who are especially vulnerable to serious COVID-19 illness, suggesting that they were relatively aware of their vulnerability. For example, 81 percent of over-65 participants reported always practicing social distancing at outdoor activities, while only 58 percent of 18-24 year olds did so.

The results are consistent with the general public health message that mask-wearing, social distancing, and limiting travel whenever possible reduce SARS-CoV-2 transmission. The researchers suggest, though, that studies such as these, employing similarly rapid surveys of targeted groups, could also become useful tools for predicting where and among which groups infectious diseases will spread most quickly.

“We did this study in Maryland in June, and it showed among other things that younger people in the state were less likely to reduce their infection risk with social distancing—and a month later a large proportion of the SARS-CoV-2 infections detected in Maryland was among younger people,” says Solomon. “So, it points to the possibility of using these quick, inexpensive surveys to predict where outbreaks are going to happen based on behaviors, and then mobilizing public health resources accordingly.”

Solomon and his team are now conducting similar surveys in other states and are studying the surveys’ potential as predictive epidemiological tools.

“Rapid real-time tracking of non-pharmaceutical interventions and their association with SARS-CoV-2 positivity: The COVID-19 Pandemic Pulse Study” was written by Steven Clipman, Amy Wesolowski, Dustin Gibson, Smisha Agarwal, Anastasia Lambrou, Gregory Kirk, Alain Labrique, Shruti H. Mehta, and Sunil Solomon.

Support for the research and for some of the individual researchers came from the Johns Hopkins COVID-19 Research Response Program, the Burroughs Wellcome Fund, and the National Institutes of Health (DP2LM013102, DP2DA040244).

https://www.jhsph.edu/news/news-releases/2020/covid-19-study-links-strict-social-distancing-to-much-lower-chance-of-infection.html

Beyond Six Feet: A Guideline to Limit Indoor Airborne Transmission of COVID-19

View ORCID ProfileMartin Z. Bazant, View ORCID ProfileJohn W. M. Bush

doi: https://doi.org/10.1101/2020.08.26.20182824

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

PDF: https://www.medrxiv.org/content/10.1101/2020.08.26.20182824v1.full.pdf

Abstract

The revival of the global economy is being predicated on the Six-Foot Rule, a guideline that offers little protection from pathogen-bearing droplets sufficiently small to be continuously mixed through an indoor space. The importance of indoor, airborne transmission of COVID-19 is now widely recognized; nevertheless, no quantitative measures have been proposed to protect against it. In this article, we build upon models of airborne disease transmission in order to derive a safety guideline that would impose a precise upper bound on the cumulative exposure time, the product of the number of occupants and their time in an enclosed space. We demonstrate the manner in which this bound depends on the ventilation rate and dimensions of the room; the breathing rate, respiratory activity and face-mask use of its occupants; and the infectiousness of the respiratory aerosols, a disease-specific parameter that we estimate from available data. Case studies are presented, implications for contact tracing considered, and appropriate caveats enumerated.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

No external funding was received.

https://www.medrxiv.org/content/10.1101/2020.08.26.20182824v1

University of Oxford resumes Covid vaccine trial

The ongoing randomised controlled clinical trials of the Oxford coronavirus vaccine ChAdOx1 nCoV-19 will resume across all UK clinical trial sites.

Globally some 18,000 individuals have received study vaccines as part of the trial. In large trials such as this, it is expected that some participants will become unwell and every case must be carefully evaluated to ensure careful assessment of safety. 

On Sunday [06/09/2020] our standard review process triggered a study pause to vaccination across all of our global trials to allow the review of safety data by an independent safety review committee, and the national regulators. All routine follow-up appointments continued as normal during this period. 

The independent review process has concluded and following the recommendations of both the independent safety review committee and the UK regulator, the MHRA, the trials will recommence in the UK.

We cannot disclose medical information about the illness for reasons of participant confidentiality.

We are committed to the safety of our participants and the highest standards of conduct in our studies and will continue to monitor safety closely.

https://covid19vaccinetrial.co.uk/trial-resumes

Efficient high-throughput SARS-CoV-2 testing to detect asymptomatic carriers

1. Noam Shental¹,*,†,
2. Shlomia Levy²,³,‡,
3. Vered Wuvshet²,³,‡,
4. Shosh Skorniakov²,³,‡,
5. Bar Shalem⁴,
6. View ORCID ProfileAner Ottolenghi²,³

DOI: 10.1126/sciadv.abc5961

PDF: https://advances.sciencemag.org/content/6/37/eabc5961/tab-pdf

Abstract

Recent reports suggest that 10 to 30% of severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infected patients are asymptomatic and that viral shedding may occur before symptom onset. Therefore, there is an urgent need to increase diagnostic testing capabilities to prevent disease spread. We developed P-BEST, a method for Pooling-Based Efficient SARS-CoV-2 Testing, which identifies all positive subjects within a set of samples using a single round of testing. Each sample is assigned into multiple pools using a combinatorial pooling strategy based on compressed sensing. We pooled sets of 384 samples into 48 pools, providing both an eightfold increase in testing efficiency and an eightfold reduction in test costs, while identifying up to five positive carriers. We then used P-BEST to screen 1115 health care workers using 144 tests. P- BEST provides an efficient and easy-to-implement solution for increasing testing capacity that can be easily integrated into diagnostic laboratories.

Funding: Funding for this study was provided by a donation to BGU from the Rosetrees Trust. A.P. was supported by an Israeli Science Foundation grant ISF-2484/19 (10/2019-9/2023). T.H. was supported by an Israeli Science Foundation grant ISF-882/17 (10/2017-9/2021).

Competing interests: N.S., T.H., and A.P. are authors on a pending patent application related to this work filed by the National Institute of Biotechnology of the Negev and the Open University of Israel (no. 06953-P0029A, filed 13 April 2020). The other authors declare that they have no competing interests.

https://advances.sciencemag.org/content/6/37/eabc5961

Drug Repurposing: How Often Does It Work?

By Derek Lowe

Here’s an article that will not be popular among some constituencies. It’s in a special issue of the Journal of Chemical Information and Modeling, devoted to how these disciplines have responded to the coronavirus pandemic. And in it, Aled Edwards of the Structural Genomics Consortium surveys past attempts at drug repurposing and arrives at a conclusion that others in the field have as well: it rarely works the way you’d hope.

Indeed this paper says that it has been “unable to document a single instance of a drug approved for clinical use where the idea for the clinical trial derived first from a virtual or lab-based screen of old drugs“. And the other linked paper above noted that despite all the press, there have been “impressively few data on success rates” for the approach (which it goes on to try to provide). And as is always the case, success depends on how you define it. I agree with Edwards that using the stringent definition given above, that the success rate is likely zero. Unfortunately, that definition is what popular press stories about drug repurposing tend to play up.

The successes that have come along are more modest. Look at remdesivir, for example. Although its real utility in the pandemic is still being defined, I’m willing to stipulate that it’s a useful drug (although, sadly, not the “game changer” that everyone has been looking for). But trying it against the coronavirus did not require a random screen – remdesivir is expected to have some level of activity against basically every RNA virus that comes up, due to its mechanism targeting viral-RNA-dependent RNA polymerase. The same goes for the Emory/Ridgeback/Merck compound (MK-4482) that’s going into trials now – it’s shown strong activity against a whole range of RNA viruses, because it causes an “error catastrophe” in the same viral RNA replication step.

Compounds like this are great to have on the shelf, because of that broad-spectrum activity. At the same time, there’s a definite “jack of all trade, master of none” problem with broad-spectrum antiviral drugs. When you look at the field, the only time we’ve ever really been able to control or cure any viral infections with small molecules, it’s been with a cocktail of drugs that hit several mechanisms at once (HIV, HepC). Which makes perfect sense, given viral mutation rates. I don’t see how a single small molecule drug is ever going to be an effective antiviral by itself, at least not if it’s working by the mechanisms we know now. And in the case of remedesivir, or ribavirin, or AZT or any other broad-spectrum-ish antiviral you can name, the chances of a single agent hitting a knockout blow are basically zero. They’ll do some good, and they’ll do even more good if they can be combined with a drug with a completely different mechanism such as a viral protease inhibitor. (Note also that broad-spectrum viral protease inhibitors are a lot thinner on the ground, at least ones that aren’t cytotoxic at the same time!) All that is to say that calling remdesivir a “repurposed” drug isn’t quite accurate. It’s being used for its intended purpose: to mess up viral RNA replication. Next RNA virus that causes trouble, we’ll try it on that one, too.

And not just with antivirals – if we have some mechanistic understanding of a drug’s actions, it makes perfect sense to keep an eye out for similar applications that might turn out (you see this a lot in oncology, for example). Likewise, if a known drug has unexpected side effects and unusual activities when dosed in human patients, it makes perfect sense to try to figure out what’s causing these and add that information to the mechanistic understanding pile. That’s exactly what happened with thalidomide and led to its use as an anticancer drug – for that matter, intensive study of why thalidomide caused the disaster it did in human usage is what’s led to the modern field of targeted protein degradation, opening up a whole new area of medicinal chemistry and chemical biology. So one could call this repurposing as well, but it’s still very different from deliberately screening a collection of known drugs, hypothesis-free, and hoping for something interesting to happen. Because it rarely (if ever) does.

But mechanistic understanding is a sliding scale, too. All too often, we don’t understand the diseases understudy well enough to be sure about what we’re seeing. This example from today’s new paper is (sadly) very instructive:

In the early 2000s, the NIH’s Neurodegenerative Drug Screening Consortium launched what was among the first systematic repositioning initiatives.(9) Ahead of their time, they assembled approximately 1000 FDA-approved compounds, including many antibiotics, with the idea of identifying new uses for old drugs, and described the effort in a set of influential papers.(10)

The experiments were designed well; compounds were sent to many investigators blinded for testing in their various models. When the assay results were unblinded, several antibiotics, including minocycline, an antibiotic that had previously shown activity in other models of neurological diseases, and ceftriaxone, a cephalosporin antibiotic, showed great promise in a number of assays for amyotrophic lateral sclerosis (ALS). It was a brilliant concept, a beautiful experiment, and a beautiful result. . .

. . .Fast forward to 2014, when the results from the clinical testing of ceftriaxone in ALS patients were published,(11) and that story did not end well. Not only was ceftriaxone ineffective in ALS, but it actually caused serious adverse events. The clinical testing of minocycline in ALS also failed to show efficacy in patients.(12) However, this lesser known part of the story had little impact on the repositioning horse, which had long since left the stable.

Repurposing is hard because drug discovery is hard, because understanding human biology and human disease is hard. There are no shortcuts.

https://blogs.sciencemag.org/pipeline/archives/2020/09/11/drug-repurposing-how-often-does-it-work