Few people are living in this world today who remember a pandemic of a similar extent as COVID 19. Despite all the progress and knowledge that humanity has gained since the Spanish influenza pandemic more than 100 years ago, COVID 19 has hit us largely unprepared and sadly many underestimated the strength of the current pandemic. Wearing protective masks, social distancing, and gathering restrictions were controversial measures 100 years ago, yet they proved to be the most effective at the time. Today, many countries have decided to take these measures only under the pressure of fatal circumstances. Those who do not learn from past mistakes are forced to repeat them again, unfortunately.
Thankfully, we already know much more about viruses and virus replication today than we did a century ago. We know the genome of the SARS-CoV-2 the virus causing COVID-19 and thus we can identify structures within its constitution which we can use against this virus as therapeutic targets. Knowledge of the immune system and advances in biotechnology and genetics have enabled the spread of vaccination against a wide range of life-threatening and debilitating diseases worldwide. We also recognize unusual nuances of the immune response to SARS-CoV-2, which are probably also responsible for the severe course of the disease in some patients.
Those skilled in the art know that drug development takes time, a lot of time, and therefore our efforts initially focused on existing drugs that could potentially affect replication of the SARS-CoV-2 virus. Here, the knowledge gained during the first SARS and MERS epidemics helped us, as genetic similarity suggested that molecules that were shown to be effective in these infections might also function in COVID-19. Several classes of drugs have been identified as potentially effective in vitro – antimalarials, antiretrovirals, RNA polymerase inhibitors, anti-IL-6 agents, etc. which led physicians in China, where this all started, and later around the world to use them experimentally, especially in patients with severe disease.
Gradually, clinical studies were launched with better and worse design, sponsored by the pharmaceutical industry and scientific institutions. At the same time, many companies have utilized their vaccine platforms and started working on the development of SARS-CoV-2 vaccines, the ultimate tool to get the contagion under control. However, this would not be possible without the unprecedented initiative of WHO and leaders of many countries worldwide who provided the necessary resources to carry out this research effort.
Both medicines belong to antimalarials but in geographies where Plasmodium species is not present is hydroxychloroquine mainly used off label for the treatment of some autoimmune diseases such as rheumatoid arthritis. It was proposed that these molecules interact with endocytosis, which is one of the steps when the virus enters the host cell. Preliminary reports were positive about hydroxychloroquine and chloroquine use in COVID-19 patients, but these reports were based on studies with poor design, retrospective cohorts usually without a control arm. The story of hydroxychloroquine in COVID-19 is a great example, why strong scientific evidence is so important in medicine. Later when data from controlled studies emerged more physicians expressed their doubts in using these drugs for their patients. Nevertheless, this didn’t stop some influential person without medical background in giving it a “gamechanger” tag what also contributed to worldwide hype around Hydroxychloroquine/ Chloroquine and their use as prophylactic treatment. Consult your physician or pharmacist before taking your medicine as it is written in the patient information leaflet. There’s no mention about consulting your favorite social media influencer indeed. Not only these drugs have no effect, but they have been shown to cause harm to patients as it is reported in the latest Lancet paper. More than 96 000 patients were included in this analysis almost 15 000 were treated with Hydroxychloroquine or Chloroquine in monotherapy or in combination with macrolide antibiotics and the rest of the patients were in the control group. The mortality rate in the control group was 9,3% but a more terrifying mortality rate was reported in the Chloroquine group (16,4%), Hydroxychloroquine (18%), Chloroquine and macrolide combo (22,2%) and lately Hydroxychloroquine macrolide combo (23,8%). Ventricular arrhythmias were important contributing factors as these were more frequently reported in Hydoxychloroquine/ Chloroquine arm comparing to the control group. After these results were published WHO decided to temporarily stop recruitment in hydroxychloroquine arm of large international SOLIDARITY trial that evaluates several possible treatments against COVID-19.
Update:Following the controversy over the credibility of the data provided by Surgisphere the study on the harmful effects of hydroxychloroquine was retracted by Lancet and WHO recommended to the continuation of all arms of the Solidarity Trial, including hydroxychloroquine. Nevertheless, the positive effect of Hydroxychloroquine on outcome in COVID-19 patients was not confirmed either as a therapeutic approach nor as a preventive measure.
Lopinavir an HIV protease inhibitor used in combination with ritonavir that boosts its activity was shown to act against MERS-CoV in vitro studies. This knowledge led to the early use of Lopinavir/ritonavir combo in COVID-19 patients and the inclusion of this combination in the before-mentioned SOLIDARITY trial. Most probably this also inspired some researchers to try other HIV protease targeted drugs like darunavir and atazanavir. Apart from blocking HIV protease is was thought that they block SARS-CoV-2 main protease – Mpro, another enzyme playing an important role in virus replication. Unfortunately, later it has been proved that neither of these drugs has activity against SARS-CoV-2 either in clinical settings or preclinical models.
Just as one antibiotic can work against several bacteria species, one antiviral can work against several types of viruses. Remdesivir was initially developed against RSV and hepatitis C but candidates with better efficacy were selected for further development. Then it got a second chance during the Ebola outbreak in West Africa, but it was less effective than other treatments tested at the time. Nevertheless, ebola clinical trials helped establish its safety profile. Remdesivir inhibits viral RNA dependent RNA polymerase – RdRp by its incorporation into viral RNA what causes RNA chain termination. It also evades viral Exonuclease proofreading activity and these two mechanisms result in blocking the replication of viral genetic information. The activity of Remdesivir was later confirmed in vitro against several RNA viruses including filoviruses, pneumoviruses, paramyxoviruses, and coronaviruses. As a consequence of this several clinical trials with Remdesivir were rolled out in COVID-19. In early February 2020, two randomized studies in moderate and severe COVID-19 patients started in China, however, once the pandemic came under control in Wuhan, both studies were terminated prematurely due to the lack of suitable patients meeting the entry criteria and adverse events. The results were published in Lancet showing no effect in reducing the time for improvement from COVID‑19 or deaths due to underpowering.
Fortunately, a few days later, NIAID announced the preliminary results of a large randomized placebo-controlled study in patients with COVID-19 involving 1,063 patients from 73 centers around the world. Data indicate that those who received a 10-day course of Remdesivir had a significantly better median recovery time of 11 days, as compared with 15 days in those who received a placebo. The benefit was most apparent in patients requiring oxygen, a finding most likely due to the larger sample size in this category. Results for patients not receiving oxygen, receiving high-flow oxygen, or receiving ECMO or mechanical ventilation were inconclusive.
Mortality estimates by 14 days were 7.1% with Remdesivir and 11.9% with placebo, but these data also lack statistical significance at the time of this analysis. We have to wait for the full analysis of this trial to get a better understanding of Remdesivir use in patients with different stages of COVID-19.
These preliminary findings support the use of Remdesivir for patients who are hospitalized with COVID-19 and require supplemental oxygen therapy but as authors of this study said Remdesivir treatment alone is probably not sufficient and combinations with other antivirals or different treatment strategies will be needed.
Now we put our hopes in a recently announced study combining tocilizumab, an anti-IL-6 antibody, and Remdesivir, in hospitalized patients with severe COVID-19 pneumonia. Another recently announced study is looking into prospects of combining Remdesivir with JAK1/2 inhibitor baricitinib.
There are repurposing attempts with other antivirals as well. We see encouraging in silico data with HCV and HBV antivirals like ribavirin, sofosbuvir, tenofovir, setrobuvir targeting RdRp. Some already abandoned HCV protease inhibitor seems to bind well on viral Mpro as boceprevir does and it might be a candidate in combination with Remdesivir. Of course, we have to wait for the results from well designed controlled studies to draw a conclusion about their use in the clinic.
Some early observation during the COVID-19 pandemic suggested that at least in some patients disproportionately strong immune response might be responsible for a severe course of the disease. The link between high expression of interleukin 6 (IL-6) was described to be somehow related to worse outcomes in patients. This was further elaborated by other research teams with interesting findings of the unusual immune response to SARS-CoV-2 infection comparing to what we usually see in other viral infections. SARS-Cov-2 leads to low interferon levels (that’s the unusual thing during viral infections) and high pro-inflammatory cytokine production with IL-6 among them.
This led to the exploration of anti-IL-6 therapeutics. Tocilizumab which is used in the treatment of rheumatoid arthritis and cytokine release syndrome related to CAR-T cell therapy showed promising results in reducing the risk of the need for ventilation or death in patients suffering from Covid-19. Surprisingly another anti-IL-6 antibody sarilumab has failed in showing any promise. When two do the same thing, it might not always be the very same thing.
RNA viruses are known for their higher mutation rate which causes some concerns at the beginning of COVID-19 vaccine development. A lot of efforts were put into the development of HCV or HIV vaccines and we still do not have an effective vaccine for these diseases even after years of trying. Luckily, the SARS-CoV-2 genome seems to be quite stable especially at location encoding viral spike protein that is the target of choice for vaccine development.
There are 10 COVID-19 vaccine programs in clinical development and over 100 in pre-clinical at the time writing this article. The list is regularly updated on the WHO website.
Some companies already proceeded to phase II of clinical development and have been heard that they plan to have a vaccine ready for use in 12-18 months’ timeframe. That’s a very ambitious plan and a lot of experts doubt it is possible as the usual timeframe for a new drug and vaccine development lasts around 10 years of making. Public debate regarding COVID -19 vaccine development will certainly benefit from discussion related to a vaccine safety in parallel to the speed of development, especially as some shortcuts in development will be necessary to speed the process fast enough. And we see first signs of this, MODERNA has proceeded to the first time in human testing before animal testing of their vaccine candidate was finalized. Importance of safety debate is highlighted by fact that a lot of companies are using technologies, like viral vector vaccines and RNA and DNA vaccines, that haven’t been used so far in humans or their use and understanding are very limited.
At the end of the day if the debate around COVID vaccine safety won’t be handled carefully we can put ourselves on a bigger problem than we have today. Public trust to COVID vaccination is still very low and we don’t need to discuss how this might be misused by all those anti-vax groups around the world.
First results from vaccine studies are already available with promising efficacy and of course, we see some safety signals but that is nothing unusual at this stage of development. The chances of having a working vaccine are thus high the question remains when it will be available.
There are a lot of other preventive and therapeutic approaches to COVID-19 in development that didn’t fit in this article like, Interferon-alpha nasal installation as prevention of infection, the monoclonal antibody’s targeting spike protein blocking virus cell entry, etc. It will take years until some of them will translate into something usable in the clinic, so until that time our treatment options for COVID-19 are still suboptimal and in many cases, we have to rely mainly on those preventive measures available hundred years ago, but the prospects are positive.
And even in the case of the most optimistic scenario when the contagion disappears sooner, all this effort will not be in vain because it will certainly help us to be better prepared for the next pandemics to come.