AUGUST 2020: UPDATE OF THE PROGRESS ACHIEVED IN THE INVESTIGATION AGAINST CORONAVIRUS THANKS TO THE INITIATIVE I crown myself
Spain is one of the countries most affected by the SARS-CoV-2 coronavirus pandemic (COVID-19), which continues to cause thousands of deaths worldwide. In July-August 2020, a re-emergence earlier than initially planned, puts the health and economy of our country in critical condition again.
From the Infectious Diseases Service of the Germans Trias i Pujol Hospital in Badalona, the Foundation Fighting AIDS and Infectious Diseases, which carries out its clinical research in this field, and the IrsiCaixa AIDS Research Institute, which focuses its research on the development of vaccines and new treatments for different diseases such as AIDS, Ebola, cancer and now the coronavirus, work tirelessly to fight the pandemic in the short and long term.
We focus on two of the most important pillars of the fight against this pandemic: clinical research and basic research. Regarding the first, we carried out several trials with new drugs to be able to eliminate the virus from the beginning of the infection and prevent progression to inflammatory pulmonary and vascular phases that are the ones that cause the death of the patients. On the other hand, from the basic research, we intend to develop in the laboratory effective vaccines against the current coronavirus and possible new variants that may appear (pancoronavirus vaccine), monoclonal antibodies and others that are bispecific are also developed. Finally, active compounds, already available or under development, are identified to be used quickly in patients.
Specialists from the Infectious Diseases Service of the Germans Trias i Pujol Hospital in Badalona and the Fight Against AIDS and Infectious Diseases Foundation participate in clinical trials. Regarding basic research, a consortium has been created between the Barcelona Supercomputing Center (BSC), IRTA-CReSA (Animal health research center with long experience in the coronavirus), IrsiCaixa (with long experience in the development of vaccines and extensive knowledge of the immune system) and the pharmaceutical company Grifols.
The help that the #YoMeCorono initiative represents is of great importance since it is allowing to accelerate the scientific response that, without these resources, would be much slower.
TEST & TREAT STRATEGY: DEAL AS SOON AS POSSIBLE
On March 18, a team led by Dr. Oriol Mitjà and Dr. Bonaventura Clotet launched, very quickly, a pioneering worldwide study to find out if hydroxychloroquine is useful as an immediate treatment for those infected with COVID- 19 and to prevent contagion between your contacts. This is the first clinical trial approved by the Spanish Medicines Agency at the start of the pandemic and is based on the "Test & Treat" strategy, which consists of starting treatment as soon as possible after diagnosis.
293 people with COVID-19 and 2.300 exposed people participated in the study and it has allowed us to demonstrate that the use of hydroxychloroquine after diagnosis (<5 days) does not contribute to improve symptoms or prevent the progression of the disease to stages of more gravity. Likewise, the study of the contacts of infected patients also demonstrates the ineffectiveness of hydroxychloroquine (OHCQ) to prevent their infection.
It is probable that the absence of OHCQ activity is due to the fact that, although it prevents entry into cells by endocytosis, there is another possible route, which is fusion, thanks to a membrane protease (serine protease) that is not inhibited by OHCQ. This hypothesis, not yet confirmed, was unknown at the beginning of the epidemic in March 2020 and has recently been generated with the "in vitro" studies that we have developed in collaboration with CReSA.
The findings of our studies, therefore, allow us to rule out the use of this drug in patients with COVID-19 and should condition the discontinuation of many studies currently underway around the world and the search for other therapies that may be effective.
Parallel to the development of the clinical trial with OHCQ and thanks to the help represented by the #YoMeCorono project, intensive work has been carried out to identify other compounds active against the virus "in vitro". The objective is clear: to find increasingly effective, safe and economical treatments. Always in the context of "Test & Treat", the trials are carried out with a small number of patients to be able to carry out several at the same time and to test several strategies at the same time.
Thanks to #YoMeCorono we have been able to advance rapidly in many complementary lines of basic research against COVID-19.
This is the chronology of our research:
MARCH / APRIL 2020: GETTING TO KNOW THE VIRUSES
- Isolation and sequencing of the entire virus genome, and its possible mutations.
- Development of an ELISA technique to detect Immunoglobulins (IgM / IgG) with high sensitivity and specificity (> 95%). Publication of the relationship between ELISA test results and the presence of neutralizing antibodies.
- Evaluation of the neutralizing activity of the serum of patients with positive serological tests in cell cultures faced with SARS-CoV-2. We note that it may be that not everyone who has passed COVID-19 generates detectable antibodies. This observation is more frequent in individuals who have been asymptomatic.
- Screening of anti-coronavirus drugs in different cell culture models faced with SARS-CoV-2.
MAY: FIRST VACCINE AND ANTIBODY DESIGNS
- Start of trials in the murine model (mice) of the first designs of the SARS-CoV-2 vaccine.
- Design of first generation therapeutic and preventive bispecific antibodies against coronaviruses (against 2 different regions of protein S). Characterization of its activity and production on a small and medium scale.
JUNE: PRELIMINARY PRODUCTION BEGINS
- Efficient production of pseudoviruses that will speed up the evaluation of neutralizing antibodies and new drugs.
- Isolation of sera very rich in neutralizing antibodies to be able to produce monoclonal antibodies to treat the infection.
- Preliminary results of immunogenicity, neutralization and levels of antibodies and neutralizing capacity of the virus in vaccinated animals.
- Establishment of cohorts to study the immune response to infection according to age, sex, and clinical severity presented (from asymptomatic to patients requiring admission to the ICU). Cohort: KING, CoronaAvis, CIRCUS.
- Study in collaboration with the nephrology service of the Hospital Clínic de Barcelona to evaluate the sensitivity to infection of renal epithelial cells.
- Identification of new highly effective anti SARS-CoV-2 compounds.
JULY: EVALUATION IN ANIMALS OF EXPERIMENTATION
- Evaluation of different animal models of infection in pigs and Golden Hamsters from Syria. Start of experiments to test the activity of bispecific neutralizing antibodies in the Syrian Golden Hamster. We received the first humanized mice for efficacy trials of different therapies and vaccines.
- Preliminary results allow us to be optimistic about the ability of the first vaccine prototype to protect against the virus. We have shown that the vaccine based on protein S and not on the other hand the one based on its subunits (S1 and S2) separately, generates an important immune response with the production of neutralizing antibodies.
- Eight scientific articles pending publication and shared with the scientific community.
- The isolation of neutralizing antibodies from patients with a high titer has been started in order to proceed with the production of monoclonal antibodies.
AUGUST: NEW LABORATORY AND NEW LINES OF INVESTIGATION
- The new laboratory to work with coronaviruses at the Germans Trias i Pujol Hospital, at the Center for Comparative Medicine and Bioimaging (CMCiB) of the Germans Trias i Pujol Research Institute (IGTP) is planned. This new center will make it possible to triple basic research on the coronavirus and therefore speed up the production of the vaccine and the search for effective drugs against the virus. In addition, we will be able to develop new anti-coronavirus drugs more quickly and efficiently and we can test them in cell models that mimic the human lung, which is where the infection takes place in patients with COVID-19.
- It is also essential to develop a cell model that allows evaluating drugs that modulate the inflammation caused by the coronavirus infection. These drugs focus their action on stopping the damage that an exaggerated immune response against the coronavirus causes to the most seriously infected people. These immunomodulatory drugs can be evaluated in immune myeloid cells exposed to the new coronavirus, measuring their response by secreting cytokines such as IL-6, which we know can complicate the progression of the infection. This analysis will identify which treatments can best slow the hyperactivation of the immune response against the coronavirus.
- Both types of drugs, both anti-coronaviruses and immunomodulators, will be tested in animal models to demonstrate their efficacy and safety, and will help us find possible effective treatments that can improve the progression of COVID-19, or even prevent infection. if taken preventively.
- Selection of new vaccine candidates and development of immunogenicity tests in the murine model.
THE PATH OF CELLULAR IMMUNITY
Since the beginning of the COVID-19 epidemic, IrsiCaixa reference groups in T-cell immunology have believed it essential to analyze the role of CD4 + and CD8 + lymphocytes in the response to SARS-CoV2.
The role of the T response in the control of SARS-CoV-2 disease has been confirmed in recent months through different scientific articles that highlight the crucial importance of cellular immunity. At IrsiCaixa, two expert groups in cellular immunology have been working since May on the development of experimental models and laboratory tests to identify and quantify the cellular response to SARS-CoV-2.
The ultimate goal of these studies is to design new prototypes of cell vaccines that effectively protect and that generate long-term immunological memory against the virus, complementing vaccines that favor the production of neutralizing antibodies. Initial analyzes have allowed us to detect the first T responses to CoV-2 protein S in infected individuals.
These are the advances so far:
- Generation of a consensus genome from 1.700 CoV-2 variants worldwide.
- Design of 3.000 protein fragments corresponding to the entire CoV2 consensus genome that allow the detailed evaluation of the T immune response.
- Tuning of experimental protocols to measure the T response by flow cytometry and Elispot techniques.
- Elaboration of a scientific article that describes the CoV-2 peptide library for evaluating the cellular response against the entire genome and that will be available as a reference for the entire scientific community.
- Experimental set-up of the quantification of the cellular response in patients with COVID-19.
- The synthesis of peptides has been completed and the first combinations of the 3000 SARS-CoV-2 protein fragments are being generated to analyze the different role they play in inducing potent cellular immunity.
- First experimental results of the cellular response against Spike and CoV-2 nucleocapside proteins.
We are working against the clock to get results as soon as possible, but we need your help more than ever. Donate now and contribute to the fight against the coronavirus.