Covid vaccine and drugs: daunting challenges

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Some bosses in the pharmaceutical industry are hoping for a vaccine before the end of 2020. However, doubts about production capacities remain.

[Mis à jour le 29 mai 2020 à 17h35] A vaccine before the end of the year is what the bosses of the pharmaceutical industry are hoping for. “The hope of many people is that we will have a vaccine, perhaps several, by the end of the year,” said Pascal Soriot, general manager of AstraZeneca. Albert Bourla, boss of Pfizer, carries the same hopes. “If things go well, the stars are aligned, we will have enough evidence of safety and efficiency to be able to […] have a vaccine by the end of October, “he said. However, the International Federation of the Medicines Industry (IFPMA) has tempered some hopes. According to their estimates, 15 billion doses will be necessary to vaccinate the world population In fact, the production and distribution of the vaccine face “colossal” challenges. All the more so, since clinical trials are stagnating due to the decrease in transmission rates of the virus. If the decreases continue, experiments will not can no longer take place in a natural setting.

  • Chloroquine Chloroquine (CQ) is a common antimalarial. In the sketches of the epidemic, this treatment was praised by Professor Didier Raoult, director of the IHU in Marseille. The infectiologist successively carried out three studies which demonstrated a certain efficacy of hydroxychloroquine (HCQ). However, these promising results have been widely questioned by a study published on Friday, May 22, 2020 in the journal The Lancet. The authors analyzed, a posteriori, the records of 96,000 Covid + patients admitted to 671 hospitals between December 20, 2019 and April 14, 2020. 14,888 of these patients received four different combinations of CQ and HCQ: the treatments were either administered alone or combined with an antibiotic from the macrolide family. In order to compare these clinical results, the “control group” consisted of 81,000 patients. After examining the statistical data, the mortality rate in the “drug groups” was 34% to 45% higher than in the “control group”. In addition, the risk of arrhythmia is increased with the intake of the two molecules (five times higher). The research team concluded: “We have not been able to confirm the benefits of hydroxychloroquine or chloroquine, when used alone or with a macrolide.” Consequently, the National Agency for Drug Safety has announced its intention to suspend clinical trials with the HCQ in France “as a precaution”. The High Council of Public Health (HCSP) advised “not to use hydroxychloroquine” outside of therapeutic trials. Also, the CQ forms for the Discovery (Inserm) and Solidarity (OMS) clinical trials are suspended. However, despite the controversies, Professor Raoult has published a new study which refutes the above-mentioned thesis. “We retrospectively report the clinical management of 3,737 patients, of whom 3,054 (81.7%) treated with hydroxychloroquine-Azithromycin for at least three days and 683 (18.3%) patients treated with other methods”, is it described in the study available on the IHU Marseille website. The mortality rate was 0.9%. No cardiovascular side effects have been reported. “Early diagnosis, early isolation and early treatment with at least three days of hydroxychloroquine-Azithromycin results in significantly better clinical outcome and contagiousness in patients with Covid-19 than other treatments,” concluded the research team.
  • Azithromycin Pr Raoult’s protocol is based on the administration of hydroxychloroquine coupled with the antibiotic azithromycin. To stop the coronavirus, three general practitioners have combined this antibiotic with zinc. Doctor Gastaldi, one of the practitioners, explained to the Parisian: “We thought about what could increase the effect of this drug. Zinc is very effective for this. We add two capsules of Effizinc in the protocol. Still empirically, we added Singulair, used in people with asthma, for its role of anti-inflammatory on the interstitial lung tissues. In severe forms, heparin is added at low doses, to prevent thrombosis , phlebitis and pulmonary embolism, common with coronavirus. ” Taken early, the results of these associations seem encouraging. “For the past few weeks, the three of us have prescribed this treatment to all of our coronavirus patients. For my part, this represents more than 200 patients. I have had only two serious cases requiring hospitalization and who have since been discharged. […] If we rely on known data on the disease, on at least 200 cases, we should have had at least two deaths and forty hospitalizations. “One of the advantages of azithromycin is its limited toxicity. This drug” is widely prescribed every winter in children and adults, with no side effects. There is no reason to deprive yourself of it at the first symptom. It would be great to save lives! “, Developed Dr. Gastaldi. However, these results remain fragile. Indeed, this is not a multicenter and randomized study. In addition, the patients treated did not not tested positive for Covid-19.
  • Tocilizumab. One of the last tracks mentioned is that of tocilizumb. Some patients severely affected by the new coronavirus have cytokine storm syndrome. This pathology is an excessive inflammatory reaction notably linked to an excess of interleukin-6 (a protein secreted by the lymphocytes which activate the immune reaction). To avoid an excessive immune response, interleukin-6 inhibitor molecules could be administered. The preferred treatment would be tocilizumab, marketed by the Roche laboratory under the name of Actemra. A Chinese study reports this protocol. “A single dose of tocilizumab was used in 21 patients in China with severe respiratory syndrome during CoviD-19 infection, at a dose of 400 mg intravenously, in addition to routine treatment In a few days, 90% of the patients recovered and the pulmonary opacities disappeared “, explained in Le Figaro Julien Lion, postdoctoral fellow within an Inserm research unit of the Hôpital Saint-Louis, in Paris. In addition, the Necker hospital will begin an experiment with another IL-6 inhibitor, sarilumab.
  • EIDD-2801 – an antiviral tested on human airway cell cultures – inhibited viral replication of SARS-CoV-2, MERS-CoV and SARS-CoV-1 without causing toxicity. This treatment has not yet been tested in mice for Covid-19, but its efficacy in animals has been demonstrated for MERS and SARS. In the journal Science Translational Medicine, the research team estimated that “if another SARS or MERS type virus were to spread in the future, [l’EIDD-2801] would probably be sensitive to the antiviral activity of this treatment. “In a press release, Timothy Sheahan, first author of the study, explained:” This antiviral could be evaluated in the context of compassionate use and clinical trials in the man. The goal is to directly attack the virus, alleviate symptoms, decrease pathogenesis and save lives. “
  • Remdesivir, Kaletra … Since March 20, the Discovery project has been carried out on a European scale. This study aims to test 3,200 European patients hospitalized for severe forms of Covid-19 treatments. Pislanded by the Thematic Institute of Immunology, Inflammation, Infectiology and Microbiology in France, this clinical trial, coordinated by Inserm, covers 800 French patients hospitalized in five establishments (in Paris, Lille, Lyon, Nantes, Strasbourg). Each quarter of the patients will receive a different treatment: either symptomatic (which treat the symptoms, but not the disease itself), or Remdesivir (this antiviral prevents the virus from adapting its genetic code to the patient), or Kaletra (used for HIV positive patients) or Kaletra in combination with beta interferon. Another will focus on the plasma of recovered people reinjected into the sick. The trial with chloroquine, on a large sample of patients, has been suspended. (Discover the latest information on our article on Remdesivir and Kaletra.)
  • Plasma. In continuation of the Discovery program, a clinical trial using plasma began in early April. “This clinical trial involves the transfusion of plasma from recovered Covid-19 patients, containing antibodies against the virus, and which could transfer this immunity to a patient suffering from Covid-19”, explained in a press release the Assistance public-Hospitals of Paris, the French Blood Establishment and the National Institute of Health and Medical Research. This experiment, called Coviplasm, gives rise to samples in the Grand-Est and in Bourgogne-Franche-Comté from around 200 patients who have been cured for at least 14 days. “An initial assessment can be made two to three weeks after the start of the clinical trial,” they said. Similar tests are underway in China and the United States.
  • Ivermectin, an anti-parasite, has shown promising effects on Covid-19. According to a pre-published American study, taking the drug in Covid + patients allows a significant reduction in mortality and a shorter hospital stay. Research teams from the American universities of Utah and Harvard conducted a study and analyzed and compared the course of the disease in 1,400 patients. The first half was treated with ivermectin, the other half with usual treatment. It appeared that among the patients on respirators 7% died in the ivermectin group, against 21% in the “control group”. The overall mortality rate is 1% in the first group against 8% in the second. However, “despite a large number of patients included and the presence of a control group which allows a comparison, the study does not meet the criteria of the randomized double-blind clinical trial”, estimated, in Le Figaro, Pr François Chast, pharmacist. Étienne Decroly, CNRS researcher, abounded: “We still don’t know the molecular mechanism by which ivermectin slows down the replication of the coronavirus. However, it is not enough to observe an effect, we must understand the mechanisms at work . “
  • Avigan – the trade name for favipiravir – offers hope in seeking treatment for Covid-19. This antiviral, approved in 2017 in Japan, is usually used to fight against Ebola and influenza epidemics. Favipiravir prevents viral replication, that is, it blocks the duplication of the virus inside a cell. Animal experiments have shown that this drug affects the development of the fetus. As a result, it is not administered to pregnant women. In addition, it is not recommended for children and adolescents. Despite these supposed side effects, some doctors have started using Avigan for coronavirus. Initial feedback indicates that this treatment may help shorten the healing time for patients. AFP reported that in China, the Ministry of Science and Technology spoke of “very good clinical results”. Five trials – with control groups – are underway in the United States, Italy and Japan. Fujifilm, the producing company, announced that it would verify the effectiveness of the remedy on 100 patients until the end of June.
  • Tocilizumab is a serious avenue against Covid-19. A randomized study, carried out by the Paris Hospitals – Public Assistance, demonstrated that this drug “significantly improves the prognosis of patients with moderate or severe covid pneumonia”. This immunosuppressant could prevent the formation of “cytokine storms” (serious conditions of the lungs linked to a disproportionate immune response). The study was carried out on 129 patients: 65 received tocilizumab, the others a usual treatment. These promising results must, however, be confirmed by “additional trials.”
  • Interferon alpha-2b (IFN-α2b) could be a new avenue of treatment for Covid-19. This antiviral, usually prescribed to treat hepatitis C, has shown promising effects against the new coronavirus. A Chinese research team tested this drug on 77 adults Covid + hospitalized. The patients were divided into three distinct groups: the first received IFN-α2b; a second of arbidol (an antiviral against influenza); a third the combination of IFN-α2b and arbidol. In an experience report, published in the scientific journal Frontiers in Immunology, the scientists pointed out that IFN-α2b “significantly reduced” the presence of the virus “in the upper respiratory tract” of the subjects. At the same time, the researchers noted a reduction in the “inflammatory markers IL-6 and CRP” responsible for “cytokine storms”. It is specified that no patient “has developed respiratory distress requiring supplementation with oxygen.” According to the authors, “these results suggest that IFN-α2b should be further studied” as a therapy in cases of COVID-19.
  • RNA vaccine. At the moment there is no vaccine against Covid-19, but a hundred projects are under development. Some laboratories – like Moderna which hopes to be marketed in early 2021 – are applying a new vaccine strategy. “It consists in directly injecting an RNA [Ndlr : un morceau de patrimoine génétique] synthetic in humans, which will allow the body to directly produce one of the proteins of the coronavirus. The objective is that the patient develops specific resistance to the virus, by producing neutralizing antibodies against this protein “, explained to Figaro Olivier Schwartz, director of the virus and immunity unit at the Pasteur Institute.
  • Weak mutation. The good news, in the race to develop a vaccine, is that the virus would evolve slowly. Andrew Rambaut, a molecular evolutionary biologist at the University of Edinburgh, said in Science magazine that the new coronavirus undergoes two monthly mutations: “It’s about two to four times slower than the flu,” said he commented. In addition, Peter Thielen, molecular geneticist at Johns Hopkins University explained in the Washington Post: “At this point, the mutation rate of the virus suggests that the vaccine developed for SARS-CoV-2 would be a unique vaccine, rather than a new vaccine every year like the flu shot. “
  • Institut Pasteur, Germany, Japan … Several notable works are to be notified. The Institut Pasteur, a French foundation, has started developing a vaccine based on the attenuated measles virus. In early May, Nantes biotech laboratory Ose Immunotherapeutics announced that it was currently working on the development of a prophylactic vaccine against Covid-19. The process established by the company aims to stimulate T lymphocytes, that is to say the cells responsible for immune defense in the long term. The German company, CureVac, hopes to launch its first tests by July and to market a stand-alone vaccine. The American company Johnson & Johnson has selected a vaccine candidate, it will be tested on humans by September, the marketing is scheduled for early 2021. Finally, the serum developed by the University of Oxford has entered during the human experimentation phase, the research team evaluated the chances of project success at 80%.
  • ACT-A, a global project. This vaccine project, under the aegis of the WHO, is co-financed by private and public donors. After a fundraiser, 7.4 billion euros were raised. France has contributed 500 million euros. Emmanuel Macron stressed that the future serum should be “a global public good”.

BCG, a tuberculosis vaccine, is a potential avenue in the fight against Covid-19. In a press release, Inserm explained that “epidemiological studies have interestingly shown a correlation between BCG vaccination rate and morbidity and mortality rate against Covid-19.” While remaining cautious, the institute has mentioned that the serum “could reduce the importance of infection with the SARS-CoV-2 virus by stimulating the memory of innate immunity.”

In the absence of medication, symptomatic treatment is applied to mild cases. This is to limit unwanted effects – headache, sore throat, body aches. For this, patients can take paracetamol (Doliprane, Dafalgan, Efferalgan) up to 3g / day. Saturday March 14, 2020, the Ministry of Health strongly advised against taking anti-inflammatory drugs such as Ibuprofen, aspirin or cortisone. The most serious cases are admitted to dedicated units in the intensive care unit. Patients are immersed in an artificial coma, they are on respiratory assistance and often follow antibiotic treatments. They are also placed on the stomach sixteen hours a day. This position is a way of relieving them. This support lasts several weeks.

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