Combination drug treatments for COVID-19 show promise in cell culture
tests
Clinical testing should be an urgent next step, researchers say

Date:
June 15, 2020
Source:
Norwegian University of Science and Technology
Summary:
Researchers have established a cell culture that allows them to
test antibody-laden plasma, drugs and drug combinations in the
laboratory. A screen of 136 safe-in-human antiviral drugs and
identified six promising candidates. One combination of two drugs
was so effective that researchers hope others can begin clinical
trials on the drugs now.



FULL STORY ==========================================================================
Six months into the COVID-19 pandemic, more than 7.4 million people
have been infected, and more than 410 000 have died. As yet, there is
no treatment or vaccine for the disease.


==========================================================================
Now, a team of researchers from Norway and Estonia have looked at
different possible treatment options -- and found both good and bad news.

The good news is that the team identified six existing safe-in-humans
broad- spectrum antivirals that worked against the disease in laboratory
tests. Two of the six, when combined, showed an even stronger effect in infected cell cultures.

"This is exciting new data from the work we did," said Magnar Bjo/raas,
a professor in the Norwegian University of Science and Technology's
(NTNU) Department of Clinical and Molecular Medicine, and one of the
paper's co- authors.

The bad news is that another, non-drug treatment -- the use of
antibody-laden plasma from recovered patients to treat the severely ill --
may only work if the donor has recently recovered from COVID-19.

"This means if you collect blood from patients who have recovered from
COVID-19 after 2 months from diagnosis of the disease, and transfuse their plasma/serum to severely sick patients, it may not help," said Svein Arne Nordbo/, an associate professor at the university's Department of Clinical
and Molecular Medicine and an MD at Department of Medical Microbiology
at St. Olavs Hospital in Trondheim, and another of the paper's authors.



==========================================================================
The study has been published in the journal Viruses.

The research team developed a cell culture that they could use to grow
SARS- CoV-2, the name of the coronavirus that causes COVID-19. The
culture allowed them to actually test the efficacy of the different
drugs in the laboratory.

They determined that a cell type called Vero-E6 was best suited to
propagate the coronavirus, and were able to screen 136 drugs using the
cell culture.

The screening identified six existing drugs that had some effect, and
several combinations of drugs that acted synergistically, the researchers
said. The six drugs were nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine, said Denis Kainov, an associate professor
at the university's Department of Clinical and Molecular Medicine,
and senior author of the article.

A combination of nelfinar and amodiaquine "exhibited the highest synergy,"
he said.



==========================================================================
This last finding was encouraging enough that the researchers hope that
others will follow up and start testing the drug combinations in patients.

"This orally available drug combination -- nelfinavir -amodiaquine --
inhibits the virus infection in cell cultures," Kainov said. "It should
be tested further in pre-clinical studies and clinical trials now."
The researchers also wanted to look more closely at the efficacy of
using blood plasma from recovered patients to treat people with COVID-19.

The Vero-E6 cell line enabled them to develop a "neutralizing antibody"
test, which they could use to determine the strength of antibodies from
the blood of recovered patients.

The neutralizing antibody test works much like its name suggests.

The researchers took blood plasma from recovered patients and added it
to the cell cultures containing the live virus. That allowed them to see
how effectively the antibodies in the plasma neutralized or killed the
virus that was growing in the cell culture. Researchers call the plasma
from recovered patients "convalescent serum." "Convalescent serum
from patients containing antibodies against the virus has been used
for treatment of different viral diseases over the last decades with
some success, when vaccines or antivirals are not available," Nordbo/
said. "If used for treatment, it is essential that the convalescent
serum contains enough antibodies that are capable of inactivating or
killing the virus." But Nordbo/ points out that the only way to know
if the convalescent serum is strong enough is by adding dilutions of it
to a live virus strain and testing the mixtures on cell lines that can propagate the virus, as the researchers did.

Ordinary antibody tests may not reflect the ability of the convalescent
serum to actually kill or neutralize the virus, he said. That means the neutralization tests are still the most specific.

The neutralizing antibody tests allowed the researchers to test
convalescent sera from a number of recovered patients. They were able
to see that some recovered patients didn't produce lots of antibodies
at all, a finding that has been confirmed by other research.

They also were able to see that the more recent the recovery from
COVID-19, the more effective was the serum. Two months after a patient
had been diagnosed, their serum didn't have enough antibodies to combat
the virus in the cell culture.

"The conclusion so far is that clinicians need to collect plasma for
treatment purposes as soon as patients recover from COVID-19," Nordbo/
said, because the amounts of antibodies decline with time.

However, this finding is not contrary to the notion of lasting
immunity. If the patient was exposed the virus a second time, the cells of
the immune system would most likely be prepared to increase the production
of antibodies again, said Mona Ho/ysaeter Fenstad, a researcher at the Department of Immunology and Transfusion Medicine at St. Olavs Hospital,
and another co-author.

The fact that the researchers had been able to diagnose and isolate the
virus from Tro/ndelag patients gave them the chance to identify the origin
and evolution of the viral strains. This was achieved with the help
of a new nanotechnology-based test for COVID-19 that was spearheaded
by Bjo/raas and adopted by the Norwegian government and that could
potentially be exported for use in other countries.

By determining the genetic make-up of the strains, the researchers were
able to compare the strains to those registered in an online resource
and figure out where the different strains originated.

"We determined that the SARS-CoV-2 strains isolated in Trondheim had
originated from China, Denmark, the USA and Canada," said Aleksandr
Ianevski, the first author of the paper and a PhD candidate in the
university's Department of Clinical and Molecular Medicine.

That raises the question of whether or not Norway's travel restrictions, enacted on March 12, should perhaps have been introduced earlier to
prevent the import of the virus to the country, the researchers said.

But seeing how strains are moving across the globe offers potential
helpful insights into the virus and its transmission, Ianevski said.

"Monitoring pathogen epidemiology and the evolution of the virus helps
with our epidemiological understanding of the disease and may improve
outbreak response," he said.

Kainov and Ianevski had previously gone through the academic literature
to identify what are called "safe-in-man" broad spectrum antivirals (abbreviated BSAAs). These are drugs that are known to inhibit human
viruses that belong to two or more viral families, and have passed the
first phase of clinical trials.

That database of the drugs was published in the International Journal of Infectious Diseases and is accessible at https://drugvirus.info/. The
authors also identified 46 BSAAs that could potentially act against
the SARS-CoV- 2 virus including remdesivir and favipiravir, which are
currently being studied in different clinical trials across the globe.

The advantage of these drugs is that if they are shown to be able to
inhibit the coronavirus in the lab, they can be given to patients without having to first test the drugs for safety.

They would still require clinical trials to see how well they actually
work in the human body and what kind of doses are needed for them to
control or kill the virus.

Ianevski and his colleagues have created a second website that presents
up-to- date information on this and other COVID-19 research, with some
sections in as many as eight languages. The website can be found at https://sars-coronavirus- 2.info/

========================================================================== Story Source: Materials provided by Norwegian_University_of_Science_and_Technology. Original written by
Nancy Bazilchuk. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Aleksandr Ianevski, Rouan Yao, Mona Ho/ysaeter Fenstad, Svetlana
Biza,
Eva Zusinaite, Tuuli Reisberg, Hilde Lysvand, Kirsti Lo/seth,
Veslemo/ y Malm Landsem, Janne Fossum Malmring, Valentyn
Oksenych, Sten Even Erlandsen, Per Arne Aas, Lars Hagen, Caroline
H. Pettersen, Tanel Tenson, Jan Egil Afset, Svein Arne Nordbo/,
Magnar Bjo/raas, Denis E. Kainov.

Potential Antiviral Options against SARS-CoV-2 Infection. Viruses,
2020; 12 (6): 642 DOI: 10.3390/v12060642 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/06/200615140845.htm

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