Following the use of the Cuban recombinant human interferon alfa-2B as one of the 30 medicines chosen in China to counter the epidemic (COVID-19) caused by Coronavirus (SARS-CoV-2), many have heard the word interferon for the first time.
But what is interferon (IFN) and how to understand its possible role in dealing with this virus?
Biology is very complex, cellular and molecular processes need many years of study for a “medium understanding,” in this article I will try to explain the basic information in the simplest possible way.
Some basic concepts
Viruses: They are microscopic entities, made up of genetic material (can be DNA or RNA) and other molecules. Viruses cause different diseases when they enter the body. In other words, viruses cannot live independently, they need a cell from a host to replicate, they enter it and put the entire mechanism of that cell in function of its replication.
Pathogen: It is a biological entity capable of causing damage or disease to a plant or animal, including humans, that is susceptible to it. The SARS-CoV-2 virus, for example, is a pathogen for humans.
Immune system: The immune system is like the protective army. It is the system that fights everything the body recognizes as “harmful” and has a very sophisticated apparatus, made up of diverse cells that perform different functions.
Innate immunity: We are all born with a defensive load that works for different types of threats, let’s say it is the first line of defense. This is called innate immunity (we are already born with it), and it has the ability to work fast, but the problem is that it isn’t specific, and therefore, some pathogens manage to pass that barrier.
Acquired immunity: It is a mechanism of action that activates the body against a specific pathogen. That second barrier is more efficient, but when it has to produce itself, it takes longer to start working.
Interferons
Interferons are a group of proteins produced naturally by cells of the immune system, in response to infection by different pathogens.
Interferon was first described in 1957 by Isaacs and Lindenmann of London’s National Institute for Medical Research. It owes its name to the discovery that they were capable of “interfering” in viral replication. [1]
Interferons produced by human cells have been divided into three groups: alpha, beta and gamma.
They have these main functions: on the one hand, they prevent viruses from replicating (since they activate the production of molecules that inhibit viral replication), and, on the other, they activate the action of other immune cells whose function is to eliminate “bad” cells (such as virus-infected cells, bacterial cells, or tumoral cells).
In an interview carried out by the Cubavisión Internacional Channel with Dr. Gerardo Guillén, director of biomedical research at the Center for Genetic Engineering and Biotechnology (CIGB), the Cuban scientist said: “Interferon participates in the regulation of the immune system, both in what is part of innate and acquired immunity,” that is, it is part of that first, more general immunity, as well as the most specific in some cases.
Cuban Interferon alfa-2B (marketed as Heberon® Alfa R)
In 1981 then Cuban President Fidel Castro, who had promoted the emergence of medical research institutes in Cuba, met in Havana with American doctor Randolph Lee Clark. On that occasion the doctor told him about a new treatment (with interferon) that was being developed in the hospital that he was running in Texas as a new cancer therapy. That meeting generated the training of Cuban scientists, first with Dr. Lee Clark in Texas and, later, with Professor Kari Kantel in Helsinki, where the interferon that the American doctor was using was being produced.
Upon their return to Cuba, in a very short time, in a house that was set up as a small laboratory, on May 28, 1981, the island’s scientists produced the first Cuban Interferon. This INF was leukocyte, that is, it was produced from leukocytes (the so-called white blood cells) that were obtained through blood donations.
This Cuban leukocyte IFN was successfully used in the hemorrhagic dengue epidemic that occurred in Cuba in 1981 that Cuban scientists allege was introduced to the island, and in the epidemic of hemorrhagic conjunctivitis.
However, this novel medicine had the drawback that it was not possible to produce it on larger scales. Research was then carried out that allowed the recombinant human interferon alfa-2B to be produced in Cuba for the first time in 1986.
Dr. Luis Herrera Martínez, one of the creators of the Cuban recombinant interferon, said:
“We cloned the interferon based on bacteria, in a fermenter, and we obtained a homogeneous product, more than 99% pure, with the satisfaction of having managed to produce the interferon that is most used in treatments. The leukocyte was a minority in the long run, because the amount that can be produced depends a lot on the cells―which do not produce as much interferon―and blood donations. However, the one produced in bacteria is obtained unlimitedly.”
The efficacy of Cuban recombinant human interferon alfa-2B has been demonstrated in a wide range of diseases. Mainly for the infection caused by the hepatitis B and C viruses, followed by different manifestations of the human papillomavirus and the herpes simplex virus.
Also in oncological-hematological diseases, as well as skin, bladder and kidney carcinomas. Likewise, its effectiveness is recognized in the treatment of hemangiomas in children, as well as in solid tumors such as melanoma and ovarian tumor. [2]
The antiviral effect of interferon alfa has been scientifically proven, as part of the first line of antiviral defense, activating both the innate immune response against the virus and the mechanism of inhibition of viral replication. [3]
Cuban interferon alfa-2B and the Coronavirus
Little is known about the effect of IFN specifically against the coronavirus, although it is common for its known mechanism of action to be used against viral infections for which therapies are not available.
It has been reported that far from naturally increasing the production of interferon in the body against infection (as it does against other pathogens), SARS-CoV reduces it. Producing less interferon favors the rapid spread of the infection and limits the effectiveness of the immune system to fight the virus.
Interferon is known to stimulate genes that produce viral RNA enzymes, which are responsible for destroying the RNA of some viruses. SARS-CoV-2 is an RNA virus. Therefore, supplying interferon seems logical to combat this virus.
Recent articles have also shown that early administration of INF favors the rapid induction of the neutralizing antibody response. [4]
What is known about IFN alfa-2B produced by the Cuban-Chinese joint venture Changheber in the current Coronavirus epidemic is that it has been used nebulized and combined with other antivirals.
Scientists, however, recommend caution in the use of IFN as the results of clinical studies show that it may cause adverse reactions in some patients. [5]
These evidences and previous studies suggest the possible utility of interferon alfa-2B in a preventive way and in very early stages of infection. Everything seems to indicate that if it is administered at the beginning of the infection or as a prevention medication, it has positive results, the results of using it with the most advanced infection are still inconclusive.
Cuba is not the only producer in the world of interferons. Cuban recombinant human Interferon alfa-2B has been proven effective against other viral infections. The administration of IFN drugs is usually injectable, and nowadays most companies produce them combined with other molecules that increase their life span in blood. However, this Cuban Interferon is specifically not combined, so it can also be used through the respiratory tract by nebulization as it has been used in China “because it is a fast means of getting to the lungs and acts in the early stage of the infection,” said Dr. Eduardo Martínez Díaz, president of the Biotechnological and Pharmaceutical Industries Group (BioCubaFarma).
Dr. Gerardo Guillén announced that other viral replication inhibiting products developed on the island are under development and that a vaccine is also being worked on. “The CIGB 210 is a project in development several years ago against the AIDS virus. Now we are experimenting with a coronavirus of bovine origin to evaluate its inhibition capacity before using it for COVID-19. The CIGB 300 is being studied for different types of cancer, and its antiviral capacity has already been assessed, for example, against the AIDS virus and hepatitis C. The vaccine on which Cuban scientists are working is based on nasal immunization platforms developed in the CIGB from virus-like particles, and direct communication with China based on this research can yield satisfactory results.”
In the face of a pandemic caused by a virus whose mechanisms of action are not yet fully known, the scientific community shares information, results, tests with possible drugs that could counteract the damage, training. Cuban recombinant interferon is not the cure for coronavirus, but according to known studies, it could be effective in the treatment of the disease in its early stages and, above all, in prevention.
Many American readers have asked us if the interferon produced by Cuba could be exported to the United States. Yes, it could. In the early 1960s, the U.S. government imposed a trade embargo on Cuba that prohibits Cuban productions from being exported to the United States and that Cuba, in turn, import those produced in the United States. However, as part of the measures taken by the Obama administration to relax said embargo and move towards normalization of relations between the two countries, in October 2016 the Treasury Department’s Office of Foreign Assets Control (OFAC) approved regulations to authorize scientific collaboration in the medical field between Americans and Cubans, as well as the possibility that drugs produced in Cuba could obtain the approval of the Food and Drug Administration (FDA) and be marketed in the United States.
Despite the fact that most of the measures taken by the Obama administration in relation to Cuba have been repealed by the Donald Trump government, and also the scientific collaboration has deteriorated, this measure approved by Obama has survived. So if necessary and obtaining the FDA license, the interferon produced in Cuba could benefit thousands of Americans.
Information on the treatments used in practice in China to deal with COVID-19 where they include the Cuban Interferon
Report on the course of treatment for COVID-19 by the Chinese authorities “Novel Coronavirus Pneumonia Diagnosis and Treatment Plan (Provisional 6th Edition)” February 19, 2020. (Excerpt)
Regular treatment:
- Treatment for mild cases includes bed rest, support treatments, and maintenance of caloric intake. Attention to the balance of liquids and electrolytes and maintenance of homeostasis. Close monitoring of the patient’s vital signs and oxygen saturation.
- Hematology panel monitoring, routine urinalysis, PCR, biochemistry (liver enzymes, cardiac enzymes, kidney function), coagulation, arterial blood gas analysis, chest x-ray, etc. Cytokine analysis if possible.
- Administration of effective oxygenation measures immediately, including nasal catheter, oxygen mask, and high-flow nasal cannula.
- Antiviral therapies: Interferon alfa (adult: 5 million units or equivalent to 2 ml of sterile water can be added for injection and administered with a nebulizer twice a day), lopinavir / ritonavir (adult: 200 mg / 50 mg / tablet, 2 tablets twice a day; the duration of treatment should not exceed 10 days), ribavirin (recommended in combination with interferon or lopinavir / ritonavir, adult: 500 mg two or three times a day by IV, the duration of treatment should not exceed 10 days), chloroquine phosphate (adult: 500 mg twice a day; the duration of treatment should not exceed 10 days), umifenovir (adult: 200 mg three times a day; the duration of treatment should not exceed 10 days). Pay attention to the adverse effects associated with lopinavir / ritonavir, such as diarrhea, nausea, vomiting and liver dysfunction, as well as interactions with other medications. The efficacy of current medications in use will be evaluated in the clinical application. The use of 3 or more antiviral drugs is not recommended. The corresponding medication should be discontinued if intolerance side effects occur.
- Antibiotic Therapies: Avoid unwarranted or inappropriate use of antibiotics, especially the combined use of broad-spectrum antibiotics.
Notes:
[1] Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci.. 1957;147(927):258-67.
[2] Cuban interferon alfa-2B. Thirty years as an effective and safe drug. Hugo Nodarse-Cuní, Pedro A. López-Saura. Biotecnología Aplicada 2017;34:1211-1217
[3] W.M. Schneider, et al. Annual Review of Immunology. 2014; 32:513-545
[4] Marco de Giovani, et al. Nature Immunology, 2020.
[5] See S. Shalhoud et al. J Antimicrob Chemother 2015; 70: 2129 –2132 and Al-Tawfig et al. IJID 2014; 20:42-46 and A.S. Onrani, et al. Lancet Infect Dis 2014; 14: 1090–9517
