Researchers in São Paulo will combine biotechnological techniques to formulate COVID-19 vaccine

Scientists in Butantan Institute’s Special Vaccine Development Laboratory will couple SARS-CoV-2 antigen to bacterial membrane in order to trigger defense against coronavirus.

By Maria Fernanda Ziegler  |  Agência FAPESP – Researchers at Butantan Institute in São Paulo City, Brazil, will combine innovative techniques in biotechnology to formulate a COVID-19 vaccine designed to induce different kinds of immune response more effectively than conventional approaches.

The novel strategy takes inspiration from a mechanism used by certain bacteria to “trick” the immune system. They release tiny spheres made of material from their membranes to act as decoys, allowing the bacteria to evade defense cells and even antibiotics. 

Outer membrane vesicles (OMVs), as the researchers call these spheres, can be used to activate the immune system against the coronavirus. OMVs cultured in the laboratory will be attached to surface proteins from the coronavirus, triggering an immune response that can be deployed from memory in the event of actual infection by SARS-CoV-2. The vaccine will stimulate the production of antibodies and other immune cells such as macrophages and leukocytes. 

“For this approach we’re combining two different strategies used by us in the past to develop vaccines against other diseases. The new technique means the formulation can contain a large amount of one or more antigens of the virus in a strongly adjuvant platform, inducing a more pronounced immune response,” Luciana Cezar Cerqueira Leite, head of Butantan Institute’s Special Vaccine Development Laboratory, told Agência FAPESP.

The study is supported by FAPESP, and is part of a research line involving the development of vaccines against whooping cough (pertussis), pneumonia, tuberculosis and schistosomiasis based on techniques developed for the recombinant BCG vaccine used to prevent severe forms of tuberculosis in children. A new line in the project has recently been started to develop a COVID-19 vaccine.

“Different techniques are being tested all over the world and in Brazil as well,” Cerqueira Leite explained. “Many are based on what was already being developed for other viruses, such as the one that caused the SARS outbreak in 2001. We hope they’ll work, but the truth is that no one knows if they’ll provide real protection. During the current pandemic it’s not a bad idea to try different strategies. Our approach will take longer but if the strategies being tested don’t work out, we already have plans B, C and D.”

Many vaccines consist of solutions containing the dead or attenuated pathogen. Some are cell-based vaccines designed to trigger an immune response in the form of defense cells and specific antibodies. They are considered safe because they do not cause the disease in the vaccinated individual, who retains a long-term “immune memory” of the pathogen in question.

“Cell-based vaccines are simple and often effective, but this approach doesn’t always work, especially against pathogens with significant antigen variability or more complex organisms with sophisticated mechanisms for evading the immune system,” Cerqueira Leite said.

Combining strategies

The Butantan Institute group propose to combine two strategies for the development of a non-cellular vaccine. One will use recombinant surface antigens to trigger the production of specific antibodies against SARS-CoV-2. The other will use OMVs as an antigen scaffold to mimic the virus.

“OMVs can modulate the immune response in general, providing enhanced protection. Many vaccines use aluminum hydroxide as the main adjuvant. In our case we’ll use OMVs to deliver an antigen with strong built-in adjuvant power to ensure a better response,” Cerqueira Leite said.

To this end the group will deploy the multiple antigen presenting system (MAPS), an innovative platform developed by a collaborator at Harvard University in the United States and used in an experimental formulation against pneumococcus.

Basically the molecular complex is assembled by means of a coupling mechanism similar to that used in ELISA (enzyme-linked immunosorbent assay) diagnostic tests. This type of laboratory test detects antibodies against a specific pathogen to diagnose whether a subject has been infected. The process developed at Harvard involves one or several antigens bound to bacterial capsular polysaccharides somewhat like jigsaw puzzle pieces.

“It’s a platform that enables proteins to be non-covalently bound in a highly efficient manner, saturating the surface of the OMVs with viral proteins and making them very immunogenic,” Cerqueira Leite said.

The idea of using OMVs arose from observation of a strategy used by certain gram-negative bacteria to evade the host’s defense system. “When bacteria infect an organism, they produce these vesicles from their own outer membranes. They do so to distract the organism’s immune response. Antibodies and other immune cells try to kill the vesicles instead of attacking the bacteria, which are free to multiply in the organism,” Cerqueira Leite said.

In the novel formulation the OMVs are designed to stimulate an immune response. “They’re highly immunogenic. Recent studies show they have a significant capacity to activate dendritic cells and macrophages,” she said.