Ever since the COVID-19 disease exploded in China in January of this year and spread to the rest of the world, research into sequencing the gene of the virus and development of vaccines and treatments has been progressing at an unprecedented speed, aided by modern technology and worldwide collaboration. In diary “Coronovirus Vaccines and Treatments under Development”, we took a broad look at the various research efforts taking place.
In this diary, we focus on a few novel treatment options that are making news recently and in particular the approach called convalescent serum or plasma therapy. Do keep in mind that all the efforts will require months of testing to prove efficacy and safety.
Vaccines: We know that vaccines take years to develop and test, but in this case, researchers predict they will be able to develop one in 12-18 months. There is one vaccine from Moderna that is already in phase 1 trials in the USA, but even that will take 12-18 months to finish testing and be available in sufficient quantities for widespread use. The diary mentioned above lists 21 different efforts to develop SARS-CoV-2 vaccines.
Treatments: Next, we have treatments, that can kill or stop the virus in infected patients. Many anti-virals have been developed for treating HIV, Ebola, Hepatitis, cancer and SARS and many of them are being tried in China (and S. Korea and Italy) on an experimental basis. Some of the anti-virals are being modified based on an understanding of the genetic and protein structure of the new virus. Even the malaria drug Hydroxychloroquine is proving effective is some cases. The diary mentioned above lists 24 different efforts to develop SARS-CoV-2 treatments.
Antibodies: In between these two approaches lies a method that has been used since the 1890s to treat various diseases — the injection of virus antibodies into the bodies of patients or healthy individuals. In other words, unlike vaccines where the immune system generates antibodies to fight the virus, we can develop or harvest anti-bodies and inject them into patients and healthy individuals. Unlike vaccines, the period during which the antibodies will be effective is shorter (weeks to months), but these antibodies can be developed in a much shorter time than vaccines and can save lives until a vaccine is available.
There are two different approaches to developing antibodies — one is to develop them based on knowledge of the SARS-CoV-2 virus structure and to grow them in lab animals; the other approach is to “harvest” antibodies from recovered Coronavirus patients. The 2nd approach is also known as plasma therapy, convalescent serum treatment and passive antibody therapy .
Plasma or Convalescent Sera Treatment
Here is an article published more than a week ago that provides some background on plasma treatment for COVID-19.
Patients who have recovered from a disease have antibodies generated by their immune system floating in their blood system. These antibodies are harvested from patient blood, tested for safety, and purified. When injected into a new patient, the “plasma-derived therapy” provides “passive immunity” until the patient’s own immune system can generate antibodies.
Transfusions of blood products from recovered patients was used during the Spanish flu pandemic of 1918, during a measles outbreak in PA in 1934, and more recently in Ebola and avian flu cases.
Dr. Arturo Casadevall, chair of the molecular microbiology and immunology department at the Johns Hopkins Bloomberg School of Public Health, along with Liise-anne Pirofski of the Albert Einstein College of Medicine, recently published a paper advocating this approach of using convalescent serum for containing COVID-19. Although the treatment is not a cure, Casadevall says it might be an important stopgap.
Here are some snippets from the paper -
With the right pieces in place, the treatment could be set up at Johns Hopkins University in Baltimore within a matter of weeks.
The procedure for isolating serum or plasma is a long-established technology that can be performed using equipment normally found in hospitals and blood-banking facilities, and recent advances make it as safe as a blood transfusion.
The authors point out that passive antibody therapy is more effective when used for prophylaxis (prevention) than for treatment of disease. When used for therapy, antibody is most effective when administered shortly after the onset of symptoms.
Casadevall argues that convalescent serum could also be given to front-line health care workers to help protect them from becoming ill.
To implement his plan, academic hospitals would need to work collaboratively with blood banks to set up research protocols and treatment guidelines. Doctors at Johns Hopkins started that work weeks ago, Casadevall said, and they have begun drafting guidelines that can be copied by hospitals across the country.
The tweet below has a link to the paper and also includes a diagram illustrating the convalescent sera approach.
And they are off and running -
There are risks associated with convalescent sera therapy —
- Transfer of harmful blood substances, such as another infectious disease agent and reactions to serum constituents, including immunological reactions such as serum sickness. With modern blood banking techniques that screen for blood-borne pathogens and match the blood type of donors and recipients, the risks of inadvertently transferring known infectious agents or triggering transfusion reactions are low.
- Negative effects on organs such as the liver and lungs.
- Antibodies to one type of coronavirus could theoretically enhance infection to another viral strain
- Another theoretical risk is that antibody administration to infected patients may attenuate the immune response, leaving such individuals vulnerable to subsequent reinfection.
Trials and Experiments
Here is an article reporting on some plasma treatments performed in Wuhan with some positive results. According to Zhang Dingyu, director of Jinyintan Hospital in Wuhan, more than 10 infected patients with severe symptoms saw their inflammatory markers go down and lymphocytes rise within 12-24 hours after receiving plasma transfusions, since Feb. 8.
The results also confirm the presence of immune antibodies in recovered patients.
The following article also reports on this same experimental treatment -
In the article, virologist Dr. Jacob John reemphasize some caveats on the efficacy of this treatment.
Best time to give convalescent plasma containing antibodies is before disease develops. In the case of COVID-19, by the time pneumonia is diagnosed it is too late. That is the reason why therapy using convalescent plasma is not popular for other viral diseases.
As the disease develops, the body has already begun developing antibodies against the virus. Infusing convalescent plasma is essentially like topping with more antibodies hoping that increased amount of antibodies will dampen the disease progression.
Antibodies in the plasma bind to the virus and prevent them from entering the cells. But by the time it is given, many cells have already been infected. Hence, convalescent plasma therapy is not very effective in such cases.
Plasma Therapies in the making
Independent of the Johns Hopkins work, Japanese drugmaker Takeda Pharmaceutical Co. is developing an intravenous coronavirus drug based on blood taken from recovered COVID-19 patients. They have similar products for other diseases. Takeda states that it might require blood from more than one recovered patient to treat one infected patient, so they expect sufficient quantities to be available to just treat severely ill patients. There is still lot of work left to be done and they do not expect it to be available before 9 months.
Antibody Generation
Regeneron and Vir Biotechnology are pursuing a different approach to develop what are known as monoclonal antibodies (mAbs, which are single antibodies, not a mix), which can be grown in genetically engineered animals, and can scale up better.
Plant Based Vaccines
This is an interesting announcement by Canadian company Medicago, which uses plants instead of eggs to produce vaccines. They insert a genetic sequence into agrobacterium, a soil bacteria, which is taken up by plants — in this case, a close cousin of tobacco. The plant begins to produce the protein that can then be extracted and used as a vaccine. The process does not require a live virus, just the genetic sequence for the virus. The company announced this week that it has successfully produced a Virus-Like Particle (VLP) of the Coronavirus in just 20 days of development. The company is also working on developing antibodies for Coronavirus treatment using a similar process.
This is a relatively new field described in www.ncbi.nlm.nih.gov/… and www.sciencedirect.com/...
There is not much other technical info. available on the discovery. This is a 21-year-old company, headquartered in Quebec City with over 450 employees and a a biomanufacturing facility in Durham, NC. In 2012, Medicago manufactured 10 million doses of a monovalent influenza vaccine within one month for DARPA. But it will still be a 12-18 month arduous path to widespread availability, even if the vaccine proves out to be effective.
There is some more info about the Medicago announcement at www.ncbiotech.org/… and media.medicago.com/...
Other News about Coronavirus Treatments
Monoclonal antibody development: This paper from a team of researchers from the Erasmus Medical Center in Rotterdam and Utrecht University describes the development of a human monoclonal antibody (using transgenic mice) that neutralizes SARS-CoV-2 by targeting certain proteins on its surface. The researchers claims that the antibody offers the potential to prevent and/or treat COVID-19. The group plans to team up with pharmaceutical companies for production and soon initiate testing and clinical trials.
Interferon Alpha 2b: The anti-viral drug Interferon Alpha 2b was tried out in China recently against the COVID-19 virus. The drug was developed in Cuba to arrest a deadly outbreak of the dengue virus in 1981 and has an interesting history.
Remdesivir: The anti-viral drug developed for Ebola Remdesivir developed by Gilead Sciences has been making waves since it has been tried out in China, South Korea, Italy and in the U.S. for critically ill patients and has shown positive results.
Top candidate drugs -
From Italy: In yesterday’s diary “Coronavirus - A Sobering Letter from Italy”, Angie P, a doctor (anesthesiologist/Intensivist) in Milan, who is extremely knowledgeable in these matters and who is working on the front lines of this battle wrote eloquently about treatments in Italy -
We have several trials running with off-label and compassionate use drugs. We’re trying some HIV (Lopinavir/Ritonavir) and EBOLA (Remdisivir) drugs with mixed result, we had also some positive results with an old antimalaria drugs (Clorochinina) which had good results during the SARS epidemy. An oncological hospital (of all places) in Naples is showing good results with a monoclonal antibody (Tocilizumab) usually used for RA patients. We also started a trial by transfusing patients with blood from recovered patients.
Check out that diary for more insights from Angie P.
Epilogue
I do not want to leave readers with the impression that these treatments are just around the corner. They will all require testing and clinical trials. Vaccines will take longer to get tested and to scale up. But we can see that a lot of R&D is being done at breakneck speed by many different organizations and dedicated teams of scientists and health professionals. We can hope that one or more of these treatments will become viable and widely available within a few months. And let’s not forget those on the front lines who are working in extremely stressful conditions, taking care of patients, trying out new unproven drugs and treatments and providing vital information to guide research.
Meanwhile, let’s take all the precautionary measures that have been recommended many times — practice social distancing, work from home, wash hands, avoid touching our faces, avoid infecting others, avoid large gatherings. All this needs to be done by everyone, not a random few. We need to shut down all public gatherings for a few weeks to slow down the spread of the virus enough to allow hospitals and healthcare workers to handle the case load that will emerge. All this should have been done 8 weeks ago, when the epidemic in Wuhan was peaking; instead the world (and the USA in particular) dropped the ball on this one and everyone will pay the price.
Stay calm and stay strong.
Further Reading
- Coronovirus Vaccines and Treatments under Development — www.dailykos.com/…
- A simple guide to the vaccines and drugs that could fight coronavirus — www.vox.com/…
- Coronavirus Drug Update: The Latest Info On Pharmaceutical Treatments And Vaccines — www.forbes.com/...
- The convalescent sera option for containing COVID-19 — www.jci.org/...
- Medicago announces production of a viable vaccine candidate for COVID-19 — media.medicago.com/...
- Innovation in plant-based transient protein expression for infectious disease prevention and preparedness — www.sciencedirect.com/…
- Plant-derived virus-like particles as vaccines — www.ncbi.nlm.nih.gov/...
P.S.
I am not a doctor or a biologist; please feel free to correct any mistakes or inaccuracies I may have introduced in the diary and add your own insights.