[An international consortium is racing to test three possible
antiviral treatments for Covid-19 and 10 different vaccines. No one of
these experiments is guaranteed to succeed, but the chances of finding
one that will are high.] [[link removed]]

COVID-19: THE PATH TO TREATMENT AND PREVENTION  
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Ignacio López-Goñi
March 26, 2020
The Conversation
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_ An international consortium is racing to test three possible
antiviral treatments for Covid-19 and 10 different vaccines. No one of
these experiments is guaranteed to succeed, but the chances of finding
one that will are high. _

Scientific research on the novel coronavirus has progressed at
unprecedented speed, Mongkolchon Akesin / Shutterstock

 

Just three months after China first notified the World Health
Organization about a deadly new coronavirus
[[link removed]],
studies of numerous antiviral treatments and potential vaccines are
already underway. Never has science advanced so much in such a short
period of time to combat an epidemic.

Many of the proposals now under study come from research groups that
have spent years working to combat similar coronaviruses, particularly
SARS
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and MERS. All that accumulated knowledge
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has allowed scientists to advance at unprecedented speed.

We know, for example, that the genome of the novel coronavirus, called
SARS-CoV-2, is 79% like that of SARS. We know the “key” used by
the virus to get into human lung cells is protein S and that the
“lock” in the cell is the ACE2 receptor. We also know that the
entry of the virus is facilitated by a protease, or an enzyme that
breaks down proteins, from the cell itself, called TMPRSS211.

Other SARS-CoV-2 genes get to work once the virus is inside the lung
cell: the genes for RNA polymerase (RdRp), an enzyme that replicates
the virus genome, and for C3CLpro and PLpro proteases, which are
involved in the processing of viral proteins. These genes are likewise
very similar to those of SARS
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These details are important. Understanding the biology of SARS-CoV-2
– and how it resembles or differs from other deadly viruses –
facilitates the design of antiviral drugs to treat the disease and
vaccines to prevent it.

Genome, structure and replication of the SARS and MERS coronaviruses.
Nature [[link removed]]

Antiviral treatments

Antivirals
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are drugs that interfere with the replication of harmful viruses
without also harming the host cells. They can work by blocking the
entry of the virus into the host cell, or by inhibiting the
replication of the virus.

CHLOROQUINE, HYDROCHLOROQUINE AND OTHER VIRUS BLOCKERS

Chloroquine has been used for years against malaria
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This cheap and widely available drug is also a powerful antiviral,
meaning it blocks a virus from entering human cells. Several research
groups, including one at the University of Minnesota
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are now studying whether it is effective in reducing the viral load in
patients with SARS-CoV-2.

Some enveloped viruses, such as SARS-CoV-2, enter the cell by
endocytosis – a cellular process in which substances are brought
into the cell – forming a small vesicle. Once inside, a drop in pH
promotes the fusion of the virus envelope with the membrane of the
vesicle that contains it, in order to be released into the cytoplasm.

Chloroquine prevents this drop in pH, inhibiting the fusion of the
membranes and thus prevent the passage of the virus to the cell
cytoplasm. Hydroxychloroquine, a less toxic derivative of chloroquine,
has already been found to inhibit the replication of SARS-CoV-2 in
vitro in cell culture.

Researchers are also testing Barcitinib, an anti-inflammatory drug
approved to treat rheumatoid arthritis, which may also inhibit
endocytosis of the virus
[[link removed](20)30304-4/fulltext].
Another drug they are testing is camostat mesylate, a drug approved in
Japan for use in treating inflammation of the pancreas, which has been
shown to block the entry of the SARS-CoV-2 virus into lung cells
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REMDESIVIR AND OTHER VIRAL ANALOGUES

One of the most promising antiviral treatments for SARS-CoV-2 is
called remdesivir
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which has been used successfully against SARS, MERS and Ebola.
Remdesivir is nucleotide analogue, a major class of anti-cancer and
antiviral drugs that prevents the virus from multiplying within the
cell. At least 13 clinical trials are already underway in China and
the United States [[link removed]]
to see if remdesivir may stop SARS-CoV-2.

Another wide-spectrum viral RNA polymerase inhibitor that has already
started clinical trials is called favipiravir
[[link removed]?], already an
approved flu treatment. The first results with 340 Chinese patients
have been satisfactory
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reducing the number of days coronavirus patients were sick.

PROTEASE INHIBITORS

Some scientists have suggested
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that a combination of the drugs ritonavir and lopinavir – compounds
used to treat HIV – may also inhibit SARS-CoV-2 proteases, or
enzymes that break down proteins. Lopinavir is a virus protease
inhibitor that breaks down easily in the patient’s blood. Ritonavir
is administered with lopinavir to protect it from breaking down.

A recently published article detailing the results of a study of 199
patients
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shows that the ritonavir/lopinavir treatment is not effective against
coronavirus.

At least 27 other clinical trials
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combinations of different antiviral treatments – such as interferon
alfa-2b, ribavirin, methylprednisolone and azvudine – are now
underway.

Coronavirus vaccines

The World Health Organization highlights at least 41 proposed vaccines
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for testing against coronavirus. Vaccines are a prevention strategy.
If they are developed now, they can give people immunity from future
outbreaks.

One of the most advanced efforts is happening in China with a
recombinant adenovirus vector-based vaccine based on the SARS-CoV-2 S
gene. When tested in monkeys, this vaccine candidate produced
antibodies, which help fight the virus. A phase I clinical trial
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will soon begin in Wuhan with 108 healthy volunteers between 18 and 60
years old, in which three different doses will be tested.

The goal of a phase I trial is to check the safety of the vaccine at
different doses, evaluating any side effects. If a drug is proven to
be safe, it may then be moved into a phase II trial, in which the drug
is administered to people to see if it works.

Other proposals are being promoted by CEPI [[link removed]], an
international association in which public, private, civil and
philanthropic organizations collaborate to develop vaccines against
future epidemics. It is currently funding eight coronavirus vaccine
projects that include recombinant, protein, and nucleic acid vaccines
(all are in the preclinical phase unless otherwise noted):

RECOMBINANT MEASLES VIRUS VACCINE (PASTEUR INSTITUTE, THEMIS
BIOSCIENCE AND UNIVERSITY OF PITTSBURG) - Adds a SARS-CoV-2 gene to a
non-virulent measles virus to induce a protective response.

RECOMBINANT INFLUENZA VIRUS VACCINE (UNIVERSITY OF HONG KONG) - Adds a
SARS-CoV-2 gene to a non-virulent strain of the flu, which could be
administered intranasally and work dually as a flu vaccine.

RECOMBINANT VACCINE USING THE OXFORD CHIMPANZEE ADENOVIRUS, CHADOX1
(JENNER INSTITUTE, UNIVERSITY OF OXFORD) - Models of this vaccine type
have been tested against MERS, influenza, chikungunya and other
pathogens such as malaria and tuberculosis, and can be manufactured in
large scale in bird embryo cell lines.

RECOMBINANT PROTEIN VACCINE (NOVAVAX) - This vaccine relies on
nanoparticle technology, a proprietary technology that Novavax has
already employed to manufacture several well-tolerated vaccines that
stimulate a powerful and long-lasting non-specific immune response
that prevents respiratory infections like adult flu, SARS and MERS.

[[link removed]]

A computer model showing the protein structure of a potential COVID-19
vaccine at Novavax labs in Rockville, Maryland, March 20, 2020. ANDREW
CABALLERO-REYNOLDS/AFP via Getty Images
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RECOMBINANT PROTEIN VACCINE (UNIVERSITY OF QUEENSLAND) - This vaccine
relies on the creation of chimeric molecules capable of maintaining
the original three-dimensional structure of the viral antigen. They
use the technique called “molecular clamp,” which allows vaccines
to be produced using the virus genome in record time. It is in the
preclinical phase.

VACCINE MRNA-1273 (MODERNA) made up of a small fragment of messenger
RNA with the instructions to synthesize part of the SARS-Co-V protein
S. The idea is that once introduced into our cells, they would make
this protein, which would then act as an antigen and stimulate the
production of antibodies. It is already in the clinical phase and it
has begun to be tested in healthy volunteers.

MESSENGER RNA VACCINE (CUREVAC) - This is similar to the Moderna
proposal, with recombinant messenger RNA molecules that are easily
recognized by the cellular machinery and produce large amounts of
antigen. They are packaged in lipid nanoparticles or other vectors.

DNA INO-4800 VACCINE (INOVIO PHARMACEUTICALS) - Inovio manufactures
synthetic vaccines using DNA of the S gene that is present in the
surface of the coronavirus. Clinical tests of a similar prototype
vaccine against MERS, called the INO-4700 vaccine, found that the drug
was well tolerated and produced a good immune response (high antibody
levels and good T-cell response, maintained for at least 60 weeks
after vaccination).

Finally, two Spanish researchers, Luis Enjuanes and Isabel Sola, have
just received express funding from the Spanish government to develop a
LIVE ATTENUATED CORONAVIRUS VACCINE
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that would create an altered copy of the virus that is incapable of
producing the disease but that serves to activate our defenses.

The takeaway

There is still no approved antiviral or specific SARS-CoV-2 vaccine.
All of these antiviral and vaccine proposals are in the experimental
phase. Some will not work, but the chances of finding one that will
are high
[[link removed]].

The WHO’s new international consortium, called Solidarity, seeks
effective treatment for COVID-19. At the moment, Argentina, Bahrain,
Canada, France, Iran, Norway, South Africa, Spain, Switzerland and
Thailand are participating, and it is expected that ever more nations
will join in this great global clinical trial project
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[_You’re smart and curious about the world. So are The
Conversation’s authors and editors._ You can get our highlights each
weekend
[[link removed]].][The
Conversation]

Ignacio López-Goñi
[[link removed]],
Catedrático de Microbiología, _Universidad de Navarra
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This article is republished from The Conversation
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the original article
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