Step By Step Anti-SARS-CoV-2 Serum: learn more about Butantan’s multidisciplinary research that resulted in the product
by Butantan Team
Published: October 18, 2021
Since the beginning of the Covid-19 pandemic, the Butantan Institute has dedicated efforts on all its fronts to develop strategies to combat SARS-CoV-2 through the production of vaccines, diagnostic tests, genomic sequencing of virus variants and research of new treatments for the disease. One of the main initiatives in this context is the research of anti-SARS-CoV-2 serum – a product that relies on the institute’s 120 years of expertise in the production of hyperimmune serums (which contain a large amount of antibodies against poisons and bacterial toxins or virus), is the result of a multidisciplinary work, which involves several areas of the Butantan, and will soon begin to be tested in humans.
Unlike the vaccine, anti-SARS-CoV-2 serum is a form of treatment, not prevention. Therefore, its objective is to reduce the severity of Covid-19 cases and prevent deaths, especially in patients from risk groups.
“The expectation is that this serum, once administered early in patients who may develop complications, neutralize the virus and reduce the risk of the person presenting severe symptoms”, points out the production manager of the Serum Production Nucleus of Butantan, Fan Hui Wen.
But what was the process that led to the development of the anti-SARS-CoV-2 serum?
Step 1: Virus cultivation, purification and inactivation
To investigate the production of anti SARS-CoV-2 serum, first of all, a sample from an infected patient was collected at the Institute of Biomedical Sciences of the University of São Paulo. The virus, which needs a cell to spread and infect, was grown in a laboratory. The work had the contribution of researchers from the Development and Innovation Center and the Butantan Bioindustrial Center.
“We cultivated the virus, using techniques that we have already established, purified and inactivated the virus, and then obtained the plasma and produced the serum”, summarizes the director of production at Butantan, Ricardo Oliveira.
The pathological agent was multiplied to preserve the genetic material – if only one virus was used in several cells, some genetic material could be lost and change the composition of SARS-CoV-2. After that, purification was carried out, which is carried out every time a viral antigen is prepared.
“As the virus infects the cell, it destroys it, and we are left with protein residues that need to be eliminated in order to remove as much of the reaction as possible due to the host cell where the virus grew”, explains the technical director of the Laboratory of Virology at Butantan, Viviane Botosso.
For purification, a high-speed ultracentrifuge is used, in which it is possible to isolate only the virus, containing as little host cell contaminant as possible.
The virus was then inactivated through radiation. In experiments, scientists found that antibodies generated by SARS-CoV-2 were able to induce an immune response, fighting the effect of the infection.
“If I have a neutralizing antibody, it’s because the virus was neutralized. If it was neutralized, it won’t be able to infect the cell, so this cell is intact”, completes Viviane.
Step 2: the production of anti-SARS-CoV-2 serum
There is a very important agent in the production of any hyperimmune serum: the horse. It is through the application of the antigen in this animal that it is possible to obtain a serum rich in antibodies and capable of fighting the disease. As one of the largest serum producers in Latin America, Butantan has a space dedicated to the maintenance of horses, Fazenda São Joaquim, in Araçariguama, São Paulo. The site houses about 900 horses that work in the production of 13 types of serum, including anti-venom (against snake venom), anti-scorpion (scorpion), anti-arachnidic (spiders and scorpion), antilonomic (caterpillar), antidiphtheria (diphtheria), anti-tetanus ( tetanus), anti-botulinum (botulism) and anti-rabies (rabies), in addition to combined versions.
When studies in laboratory animals proved feasible, a group of ten horses was selected to assist in the research.
“From the moment we got a sufficient amount of antigen for us to be able to immunize the horses, we started the work”, says Fan.
The immunization scheme followed a protocol where the inactivated virus (infectious, but not causing the disease) is inoculated into horses, which respond by producing antibodies. The animal’s plasma, rich in antibodies, is collected by an automated system, and goes through several stages within the industrial unit certified with Good Manufacturing Practices. Through physical chemical processes, the antibodies are separated, fragmented (when the immunoglobulin molecule, which is the antibody, is broken) and purified, so that it results in serum vials to be applied to infected people
The pathogen does not harm the animals and, as it has been neutralized, it cannot multiply in their organism.
“We carry out all the control tests to make sure that this virus is inactive, so there is no risk for the animals, neither for the operators nor for the population that may need this serum”, says Ricardo.
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