Searching for the drug against Covid-19

Chinese virus experts ‘unanimously’ agree that chloroquine, an old anti-malaria drug, should be included in the treatment of Covid-19, the serious infectious disease caused by the new corona virus SARS-CoV2. Sun Yanrong, an expert from the China National Center for Biotechnology Development, reported at a press conference in Beijing last week. She referred to clinical studies in progress in China in which the drug has since been tried in more than 100 patients; after a week they would have a lower fever, develop a less severe pneumonia and be virus-free faster than patients who had not received the medicine. But the results of the investigation have not yet been published.

A large number of trials with experimental treatments against Covid-19 have started in China. In addition to chloroquine, flu inhibitors, HIV inhibitors, interferons (certain proteins that play a role in the immune system) and herbal preparations from traditional Chinese medicine are also being tested, according to the Chinese register of clinical drug trials. The number of registered studies is already approaching two hundred and new ones are being added every day. Dozens of studies test the effect of chloroquine in Covid-19 patients, whether or not in comparison with other experimental treatments or in combination with other therapies.

Deadly epidemic

In 2004, Belgian virologist Marc van Ranst from KU Leuven discovered that chloroquine in human cells can inhibit the growth of the SARS virus, another type of corona virus that caused a deadly epidemic in 2003. At that time it was no longer possible to study whether the drug would indeed do something about the disease in patients, since the SARS epidemic was already over.

Read more about the corona virus: all questions and answers about the epidemic

The way in which the antiviral effect of chloroquine works is not yet fully explained. The substance increases the acidity in parts of the host cell, making it more difficult for the virus to multiply, and possibly places other sugar molecules on the receptor through which the virus penetrates the host cell, making it more difficult. In addition, chloroquine dampens the exaggerated immune response that can endanger the lives of patients.

Researchers from the Wuhan Institute of Virology picked this up. At the end of January they published a short article Cell Research in which they showed that chloroquine in cell cultures can also inhibit the growth of SARS-CoV2. And that at concentrations that are not toxic to humans. “Chloroquine is a safe and inexpensive medicine that has been used for more than seventy years,” they write. “It is potential to be used clinically against the new corona virus.” Less than five days after that publication, the Sun Yat Sen Memorial Hospital in Guangdong began the first drug study in Covid-19 patients. Dozens of others followed and various Chinese pharmaceutical companies announced that they would significantly increase the dormant production of chloroquine.

But chloroquine is “no panacea” against Covid-19, warned Zhong Nanshan, a leading virologist who directs Chinese efforts to fight the epidemic. Zhong stated that he himself saw more in the treatment of patients with germ-free blood plasma from people who have already recovered. That is because it contains antibodies that kill the virus. That treatment has been tried more often with, for example, Ebola and deadly flu viruses, but there is still no solid evidence that this works well. The fact that the outcome is uncertain is also apparent from the fact that only a handful of clinical studies have been reported in which the beneficial effect of blood plasma against Covid-19 is being investigated.

Existing virus inhibitors

It seems much more promising for the short term to use virus inhibitors that are already on the market for other virus diseases. The advantage of this repurposed medicines is that its safety has already been investigated and that the studies can therefore focus on the effectiveness of the medicine. This concerns so-called protease inhibitors and nucleotide analogues. The first category blocks the enzymes that the virus needs to make its protein coat. The second category blocks the ability of the virus to copy its genetic material. These agents have already been tested at SARS and MERS. For example, the combination of the HIV inhibitors lopinavir and ritonavir (both protease inhibitors) in 2003 in SARS patients appeared to reduce the severity of the disease and the risk of death. A dozen studies in China have included this combination in their protocol, and Japan is also planning to test these drugs against Covid-19. Outside of a study context, Covid-19 patients were treated with this combination in Germany and South Korea (where lopinavir and ritonavir had been used against MERS before).

Much time is spent on research into the safety and effectiveness of a vaccine

A large study has also started in China with the experimental virus inhibitor remdesivir, made available by the American company Gilead. It had originally developed that as an anti-Ebola drug, but it didn’t work well against it. The hope is that it can tackle SARS-CoV2, as was shown by the cell tests carried out by Wuhan virologists at the same time as their chloroquine research. A case study of the first coronavirus patient in the US who was treated and repaired with remdesivir, published in The New England Journal of Medicine, sparked further interest. The intention is that efficacy against Covid-19 will now be further investigated in a study blinded by physicians and patients with 761 patients in Wuhan. Because the situation is so dire, two thirds of the participants will receive remdesivir, while the rest will receive standard treatment. Only after the trial, at the end of April, will it become clear whether the medicine helps.

Instead of treating people who are sick, you would naturally prefer to prevent people from becoming sick. This is possible with a vaccine that ensures that people already have antibodies against the virus before they come into contact with it.

Vaccine development takes a long time

But the development of a vaccine will take a long time. “Expect at least a year and a half,” said Tedros Adhanom Ghebreyesus, Director General of the World Health Organization WHO earlier this month. “Actually, vaccine development takes far too long to properly anticipate this kind of unexpected and rapidly spreading outbreaks,” says virologist Berend-Jan Bosch of Utrecht University. “We saw that in 2003 with SARS, which was also a hasty attempt to develop vaccines. When the first vaccines were well done, the epidemic was already over. That is why we have never been able to test whether these vaccines actually protect people against SARS. ”

The question is whether we can benefit from those old SARS vaccines. After all: SARS-CoV2 is very similar to the SARS virus. The WHO made an inventory of the previous research on corona vaccines. That yielded 33 candidate vaccines against SARS and even 51 candidate vaccines against MERS. That seems like a rich harvest, but none of those vaccines is yet on the market. Moreover, ripe and green are mixed together. Some have only been tested on cell cultures, others have already been tested in animal models. It would be worth trying to test whether the antibodies they generate also provide protection against the new corona virus.

Handful of candidate vaccines

But could you not immediately make a new, targeted vaccine against the new corona virus? That is not the work, because with the genetic code of the virus a new vaccine candidate can be made within a few weeks to a month. In fact, research laboratories and pharmaceutical companies worldwide have already started this. In a few months, a handful of candidate vaccines are expected to be available, specifically against the new corona virus. But then it only starts, because most of the time for developing a vaccine is spent on research into its safety and effectiveness. Moreover, that is also very expensive research, with a large risk of damage. The World Health Organization wants to coordinate research to accelerate development and increase the chances of success. The Coalition for Epidemic Prepraredness Innovations (CEPI) in Oslo also plays a leading role in this. CEPI brings pharmaceutical companies and clinical study providers together and finances the research.

The best solution would be if we succeed in developing a platform technology for vaccines, says Utrecht virologist Berend-Jan Bosch. “You also make a standard carrier vaccine that you extensively test for safety. When a new infectious disease reappears, all you have to do is add a characteristic piece of the new virus. The number of tests that are needed to see if the vaccine is safe can be greatly reduced. That way you can drastically shorten the development time of new vaccines. “

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