Vaccines and sovereignty (IV)
Cuban vaccine engineering

By Luis A. Montero Cabrera
January 28, 2021
This is the fourth in a series of articles

Translated and edited by Walter Lippmann for CubaNews.

Cuba is rapidly developing four vaccine projects against coronavirus. Photo: Ahora.

It has been news in Cuba for months that we are generating our vaccines from platforms already created. The centers generating such projects work in partnership, exchanging experiences and knowledge, and also competing, as it should be done in a society that works for the good of all. Any group that participates will be happy for the triumph of the other, because what matters is the welfare of the whole society. Obviously they will also be very happy if their own vaccine candidate is successful.

It has been mentioned that our vaccines are all based on a key antigen of the COVID 19 virus: the constituent molecules of the outer spikes of the aggregate that makes up the virus. This molecular complex is referred to as RBD, from the acronym for receptor binding domain. We have also learned that adjuvants are substances that increase the effectiveness of vaccines. Their use is a common practice of this “engineering”, even to achieve vaccines against several diseases simultaneously.

The Finlay Vaccine Institute (IFV) is an institution that has grown from the success in the 80’s of the last century with the world’s first vaccine against meningococcus B. The current management has another very important success under its belt, in this case from the University of Havana (UH), with the world’s first commercial synthetic vaccine. This was put into practice at the beginning of this century against haempphilus influenzae. IFV is now working on at least two vaccine candidates known as SOBERANA 01 and SOBERANA 02. The RBD antigens of both are chemically treated variants of the coronavirus spikes.

The SOBERANA 01 antigen is based on the RBD produced from live mammalian cells into which DNA has been introduced with the codes to make them produce the desired molecules. This is why it is called “recombinant” RBD. The great advantage is that these molecules are identical to those of the virus but have been obtained without the intervention of this harmful entity and in a very efficient and harmless way in our industrial plants for this purpose in the neighboring Center for Molecular Immunology (CIM). The latter has a long experience in these matters and a proverbial willingness to empower itself through collaboration.

The RBD has been transformed with highly advanced laboratory chemical methods to duplicate it in a single structure. This is a so-called “dimeric” form that in preliminary tests proved to be more stimulating to the immune system. In short, it is more immunogenic than the simple “monomeric” form.

SOBERANA 01 also contains proteins that are harmless antigens of the outer membrane of the dreaded meningococcus bacteria in conjunction with aluminum hydroxide as adjuvants. The meningococcal antigen helps to “trigger” the generation of antibodies. Aluminum hydroxide is harmless, but it prolongs the presence of the antigen and gives our defenses more time to react. The interest in the effectiveness of a vaccine lies in the fact that it causes us to generate antibodies (immunogenicity) and that these are the ones that trigger the defense actions against COVID 19 (specific immunogenicity).

The SOBERANA 02 antigen is the same RBD of the COVID 19 virus but in monomeric form. The aim is to provoke the immune response of the organism by conjugating it (molecularly binding it) with another well-known and harmless antigen as adjuvant: the “tetanus toxoid”. This substance is associated with the bacteria that produce tetanus, but is chemically inactivated to render it harmless. It has long been used as their highly effective vaccine. A construction of the RBD with the toxoid creates a complex containing more specific antigens. It can be said that it would be “multimeric”. Thus an interesting engineering of the antigen with an adjuvant ensues.

The Center for Genetic Engineering and Biotechnology (CIGB), one of the most important institutions in Cuban science, has generated the other vaccines. Its track record is transcendental in these matters. It has two candidates also based on the RBD antigen whose coded name is CIGB 669 for nasal application and CIGB 66 for intramuscular application. Their applications have “combat” names such as MAMBISA and ABDALA. The mambisas were the women who joined the forces of the liberating army against the peninsular crown at the end of the 19th century. This denomination was reviled and even pejorative in the Spanish royalist press of the time. They made it equivalent to something like “terrorist” today. However, when the forces of freedom triumphed, it became a symbol of sublime militancy. ABDALA is the name of a play in poetry by José Martí, his first and adolescent literary work. The hero Abdala appears as a young man who is a convinced defender of his homeland, who puts it before all other personal and family interests. Our vaccines are samples of sovereignty, the fight for freedom and love for the homeland.

The nasal formulation of the preparation CIGB 669 takes advantage of the excellent permeability capacity of the intranasal membranes. Most of our skin is shielded against the penetration of molecules of any kind. But nasal membranes are not like that. They encompass a large surface area that is very dense in blood vessels and very permeable, which makes them a very attractive route for medicating. This pathway is also naturally selected to generate some very neutralizing antibodies and in the same location that is the route of virus entry.

Its RBD is accompanied as an adjuvant with another antigen that is used in the proven “HeberNasvac”, the chronic hepatitis B vaccine that is also administered nasally. This is its nucleocapsid, which is what the central molecular complex in a virus particle is called. Viruses are not cells, but they usually have this kind of “nucleus”. HeberNasvac” is the world’s first therapeutic vaccine against a chronic infectious disease. This platform is patented by CIGB for its vaccines. In the world there is only one other nasal vaccine on the market, the FluMist and Fluenz Tetra (according to their applications in the USA and Europe) and it is used against influenza. It has the advantages of being non-invasive and can be applied even in precarious hygienic conditions, as can be the case in many places in this disparate world.

Unlike the Finlay Vaccine Institute vaccines, the adjuvant nucleocapsid in CIGB 669 is recombinant and is produced in a typical culture medium. Its RBD, also recombinant, from CIGB is produced in yeast. MAMBISA is actually a procedure consisting of dose combinations of the two CIGB vaccine candidates. ABDALA is intramuscular only with the CIGB 66 candidate.

The success of a vaccine as a drug needs to be demonstrated before mass application. How is the most indicated and effective one known? How is work being done to test Cuban vaccines in times when a single day’s delay in application can cost a life?

Luis Alberto Cabrera Montero holds a Doctorate Chemical Sciences. He is a Senior Researcher and Full Professor at the University of Havana. He is President of the Scientific Advisory Council of the University of Havana and is a Merit Member and Coordinator of Natural and Exact Sciences of the Academy of Sciences of Cuba. For a full biography, see http://www.academiaciencias.cu/en/node/674