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Five local companies to start trials of Covid drug

In a first of its kind in Indian drug industry, five leading pharmaceutical companies have joined hands to run clinical trials for a Covid-19 drug.

Cipla, Dr Reddy’s Laboratories, Emcure Pharmaceuticals,

Sun Pharmaceutical

and Torrent Pharmaceuticals will collaborate for clinical trial of investigational oral antiviral drug Molnupiravir for the treatment of mild Covid-19 in an outpatient setting in the country, the companies said in a joint statement on Tuesday.

Merck or Merck Sharpe Dohme (MSD), the innovator, has already issued a voluntary licence to these companies to manufacture and supply Molnupiravir to India and over 100 low and middle-income countries (LMICs).

Molnupiravir, which inhibits replication of multiple RNA viruses including SARS-CoV-2, is under phase-3 trial in the US.

The five pharma companies have entered into a collaboration agreement wherein the parties will jointly sponsor, supervise and monitor the clinical trial in India.

As per the directive of subject expert committee (SEC) of the Central Drugs Standard Control Organisation (CDSCO), Dr Reddy’s will conduct the clinical trial using its product, and the other four pharma companies will be required to demonstrate equivalence of their product to the product used by Dr Reddy’s in its clinical trial, the statement said.

The trial is expected to take place between June and September this year across the country with participation of 1,200 patients.

On successful completion of the trial, each company will independently approach regulatory authorities for approval to manufacture and supply Molnupiravir for the treatment of Covid-19 in India.

Merck has tied up with the US government for the supply of Molnupiravir, which is awaiting the emergency use authorisation (EUA) or approval by the US Food and Drug Administration (FDA). The US government has entered into a $1.2-billion deal with Merck for supply of the antiviral.

Sanofi drops plans for messenger RNA vaccine against virus

French drugmaker

Sanofi

said Tuesday it was shelving plans for a COVID-19 vaccine based on messenger RNA despite positive results from early stage testing.

The Paris-based company said it will continue to develop another vaccine candidate that is already undergoing late stage human trials. That vaccine, developed jointly with Britain’s GlaxoSmithKline, is based on the characteristic spike protein of the virus that causes COVID-19.

Messenger RNA vaccines use a different technology that uses genetic information from the virus to trigger an immune response. This technology is already being used in the vaccines produced by Pfizer and Moderna.

“From a public health perspective, mRNA COVID vaccines are widely available today, and starting a placebo-controlled study in countries where vaccines are available would be extremely challenging, so it does not make sense for us to further advance our mRNA Covid vaccine into Phase 3,” Sanofi said in response to questions from The Associated Press.

Sanofi recently expanded trials of its recombinant protein vaccine to test its effectiveness as a booster dose to extend immunity for people inoculated with a variety of other vaccines. Results from that study are expected later this year.

While Sanofi has decided not to pursue a COVID-19 vaccine base on messenger RNA technology, the company said early testing showed “promising results.” As a result, Sanofi said it plans to use the technology to develop a new flu vaccine, with clinical studies expected to start next year.

“Today, we have a promising mRNA platform, which we’re taking to the next level in development, including moving to modified mRNA, and against other diseases, including flu,” Jean-Francois Toussaint, global head of research and development at Sanofi’s vaccine unit, said in a statement.

Researchers develop new, inexpensive COVID-19 test that doesn’t use scarce reagents

WASHINGTON: Scientists have developed a new method of testing for Covid-19 that doesn’t make use of key reagents but still delivers an accurate result, an advance that may lead to an inexpensive diagnosis technique in developing countries where chemical supplies are in short supply.

The method, described in the journal PLOS Biology, omits the step in the widely used reverse transcription polymerase chain reaction (RT-PCR) test where the scarce reagents are needed, but has an accuracy of 92 per cent, missing only the lowest viral loads.

The researchers, including those from the University of Washington in the US, tested the new method using 215 Covid-19 samples that RT-PCR tests had shown were positive, with a range of viral loads, and 30 that were negative.

They said it correctly identified 92 per cent of the positive samples and 100 per cent of the negatives.

While the positive samples the new test failed to catch had very low levels of the virus, the scientists said ultra-sensitive tests that identify inpiduals with even the smallest viral loads may not be needed to slow the spread of the disease.

“It was a very positive result,” said Jason Botten senior author of the study from the University of Vermont in the US.

“You can go for the perfect test, or you can use the one that’s going to pick up the great majority of people and stop transmission,” Botten said.

While standard PCR tests have three steps, the version developed by the researchers has only two, the study noted.

“In step 1 of the RT-PCR test, you take the swab with the nasal sample, clip the end and place it in a vial of liquid, or medium. Any virus on the swab will transfer from the swab into the medium,” Botten said.

“In step 2, you take a small sample of the virus-containing medium and use chemical reagents, the ones that are often in short supply, to extract the viral RNA. In step 3, you use other chemicals to greatly amplify any viral genetic material that might be there. If virus was present, you’ll get a positive signal,” he explained.

In the new method, Botten said, a sample of the medium that held the nasal swab is taken directly to the third, amplification step, removing the need for scarce RNA extraction reagents as well as significantly reducing the time, labour and costs required to extract viral RNA from the medium in step 2.

According to the researchers, the test is ideally suited to screening programs, in both developed and developing countries, since it is “inexpensive, takes much less processing time, and reliably identifies those who are likely to spread the disease.”

Its low cost and efficiency could extend testing capacity to groups not currently being tested, including the asymptomatic, nursing home residents, essential workers and school children, Botten added.

He said the standard RT-PCR test could be reserved for groups, like health care workers, where close to 100 per cent accuracy is essential.

Why are some COVID test results false positives, and how common are they?

Two COVID-19 cases previously linked to Melbourne’s current outbreak have now been reclassified as false positives.

They’re no longer included in Victoria’s official case counts, while a number of exposure sites linked to these cases have been removed.

The main and “gold standard” test for detecting SARS-CoV-2, the virus that causes COVID-19, is the reverse transcriptase polymerase chain reaction (RT-PCR) test.

The RT-PCR test is highly specific. That is, if someone truly doesn’t have the infection, there is a high probability the test will come out negative. The test is also highly sensitive. So, if someone truly is infected with the virus, there is a high probability the test will come back positive.

But even though the test is highly specific, that still leaves a small chance someone who does not have the infection returns a positive test result. This is what’s meant by a “false positive”.

First off, how does the RT-PCR test work?

Although in the age of COVID most people have heard of the PCR test, how it works is understandably a bit of a mystery.

In short, after a swab has been taken from the nose and throat, chemicals are used to extract the RNA (ribunocleic acid, a type of genetic material) from the sample. This comprises a person’s usual RNA and RNA from the SARS-CoV-2 virus, if present.

This RNA is then converted to deoxyribonucleic acid (DNA) – this is what the “reverse transcriptase” bit means. To detect the virus, the tiny segments of the DNA are amplified. With the help of some special fluorescent dye, a sample is identified to be positive or negative based on the brightness of the fluorescence after 35 or more cycles of amplification.

What causes false positive results?

The main reasons for false positive results are laboratory error and off-target reaction (that is, the test cross-reacting with something that’s not SARS-CoV-2).

Laboratory errors include clerical error, testing the wrong sample, cross-contamination from someone else’s positive sample, or problems with the reagents used (such as chemicals, enzymes and dyes). Someone who has had COVID-19 and recovered might also show a false positive result.

How common are false positive results?

To understand how often false positives occur, we look at the false positive rate: the proportion of people tested who do not have the infection but return a positive test.

The authors of a recent preprint (a paper which hasn’t yet been peer-reviewed, or independently verified by other researchers) undertook a review of the evidence on false positive rates for the RT-PCR test used to detect SARS-CoV-2.

They combined the results of multiple studies (some looked at PCR testing for SARS-CoV-2 specifically, and some looked at PCR testing for other RNA viruses). They found false positive rates of 0-16.7 per cent, with 50 per cent of the studies at 0.8-4.0 per cent.

The false positive rates in the systematic review were mainly based on quality assurance testing in laboratories. It’s likely that in real world situations, accuracy is poorer than in the laboratory studies.

A systematic review looking at false negative rates in RT-PCR testing for SARS-CoV-2 found false negative rates were 1.8-58 per cent. However, they point out that many of the studies were poor quality, and these finding are based on low quality evidence.

No test is perfect

Let’s say for example, the real-world false positive rate is 4% for SARS-CoV-2 RT-PCR testing.

For every 100,000 people who test negative and truly don’t have the infection, we would expect to have 4,000 false positives. The problem is that for most of these we never know about them. The person who tested positive is asked to quarantine, and everyone assumes they had asymptomatic disease.

This is also confounded by the fact the false positive rate is dependent upon the underlying prevalence of the disease. With very low prevalence as we see in Australia, the number of false positives can end up being much higher than the actual true number of positives, something known as the false positive paradox.

Because of the nature of Victoria’s current outbreak, authorities are likely being extra vigilant with test results, potentially making it more likely for false positives to be picked up. The Victorian government said:

“Following analysis by an expert review panel, and retesting through the Victorian Infectious Diseases Reference Laboratory, two cases linked to this outbreak have been declared false positives.”

This doesn’t make clear whether the two people were retested, or just the samples were retested.

Either way, it is unlucky to have two false positives. But given the large numbers of people being tested every day in Victoria at present, and the fact we know false positives will occur, it is not unexpected.

The broader implications

For an inpidual who received a false positive test result, they would be forced to go into quarantine when there was no need. Being told you have a potentially lethal disease is very stressful, especially for elderly people or those at risk because of other health conditions. They would also likely be worried about infecting other members of their family, and could lose work while in quarantine.

Particularly given authorities initially pointed to these two cases as examples of transmission of the virus through “fleeting” contact, no doubt many people have wondered whether without these cases, Victoria might not be in lockdown. This is just conjecture and we can’t really know one way or the other.

False negative results are clearly very concerning, as we don’t want infectious people wandering around the community. But false positives can also be problematic.

(This article is syndicated by PTI from The Conversation)