Vaccine Takis / Rottapharm: how does it work and why is it different from others?

Vaccine Takis / Rottapharm: how does it work and why is it different from others?

The clinical trial for the second Italian vaccine, developed by the Roman company Takis in collaboration with Rottapharm biotech, has started last week. The first volunteer vaccinated with COVID-eVax  is Luca Rivolti, a 21 year old man from Monza. COVID-eVax, is a DNA-based vaccine, different from all the others already authorized,. It is the very first vaccine of this type to reach clinical stage in Europe. Eighty volunteers will participate in the first phase of the experimentation between the San Gerardo hospital in Monza and the Pascale hospital in Naples. The aim is to test the safety of the vaccine and establish the dose and number of administrations.

Genetic vaccines against the pandemic

Takis was one of the first companies to understand the danger of the new coronavirus and to start the search for a vaccine. The company, specialized in the research of anticancer vaccines, immediately made available its skills and a technology – that of DNA-based genetic vaccines – with the potential to respond quickly to an epidemic that would soon become a worldwide emergency.

Genetic vaccines were the first to reach testing and then authorization from regulatory authorities, as they are the fastest to produce. Thanks to modern technologies, synthesis of genetic material in the laboratory takes little time and is also relatively inexpensive. The genetic sequence of the virus was disclosed in January 2020, a few weeks after the news of the first case of COVID-19. It was therefore possible to produce a synthetic version of it in the laboratory in record time. This is the starting point for a genetic vaccine, which does not need the whole virus.

The DNA vaccine

The Takis vaccine is therefore similar, but at the same time different, compared to the others already authorized. Let's start with the similarities: all vaccines have a common target: the Spike protein, which the coronavirus uses to infect human cells. These are, in fact, genetic vaccines: they do not contain the whole virus, but only a portion of its genetic material, which can be in the form of messenger RNA, encapsulated in fat particles (Pzifer, Moderna) or inside a viral vector harmless to the organism (Astra Zeneca, Reithera, Jhonson & Jhonson). Or, in Takis case, it can be based on DNA.

The COVID-eVax vaccine contains only a fragment of Sars-Cov-2 DNA that encodes a portion of the Spike protein responsible for binding to the ACE-2 receptor on human cells. The purpose of the vaccine, therefore, is to stimulate the production of antibodies that block the entry of the virus into cells, and of lymphocytes that destroy infected cells.

Why is it different from the others?

DNA is more stable than RNA: it can be stored at the normal temperature of a refrigerator or freezer, and in freeze-dried form even at room temperature, and can be transported without the need for maintaining  the cold chain. However, it is a larger molecule:  unlike RNA, which is made up of a single strand, DNA has two strands and the classic double helix structure. In other words, to enter cells it needs a procedure called "electroporation", which consists of administering a tiny electric shock that temporarily opens pores on the cell membrane, allowing DNA to enter.

The vaccine with the gun

Takis vaccine is not administered with the classic syringe, but with a tool similar to a gun. The gun contains the needle to inject the DNA, but also needles with the function of electrodes that transmit an electrical impulse of a few volts - comparable to those of a light bulb - at the injection site. The procedure takes a total of 35 milliseconds and is not painful for the patient, who typically only feels pressure on the arm and a small involuntary contraction of the muscle. It has no permanent effects: its function is only to open transient pores on the cell membrane, which close immediately after the cell's DNA enters. Side effects are likely similar to those of other vaccines, or perhaps even milder, since this type of vaccine does not contain an inactivated virus or excipients that can cause allergic reactions. However, there may be a small bruise at the injection site and pain in the arm.

The vaccine does not modify the human genome

The vaccine instructs the cell to synthesize a portion of the Spike protein, but does not modify the DNA of human cells. The fragment, in fact, is contained in a larger and circular DNA molecule, a plasmid. The plasmid is what in biology is called expression vector: it contains sequences that signal the beginning and the end of the gene to be expressed. The cellular enzymes responsible for reading the DNA recognize these sequences and start producing the corresponding protein. The plasmid, therefore, always remains separate from the human genome.

The theoretical possibility of integration exists, but it has a negligible frequency: in fact it has never been observed in preclinical and clinical evaluations of DNA-based products. Furthermore, plasmid DNA does not remain forever inside the cell, but is lost after a certain number of cell divisions. The probability that a DNA vaccine will integrate into the human genome, in short, is many orders of magnitude lower than the frequency of spontaneous mutations, which can emerge randomly, at any time in the human genome.

The mechanism of the vaccine

The muscle cells and immune cells residing at the injection site then begin to produce the Spike protein and present it on the surface, mimicking what would happen if there was really an infection in progress. But the vaccinated person is not infected and cannot infect anyone: the vaccine, in fact, cannot generate the whole virus. The Spike protein, on the other hand, is like a fingerprint, which teaches the immune system to recognize infected cells and above all stimulates it to produce antibodies capable of neutralizing Sars-Cov-2 infection.

The preclinical results

The preclinical data of the Takis vaccine were promising: the drug stimulated a good production of antibodies in animal models, which remain in blood circulation for months even after a single injection. Furthermore, the antibodies were able to neutralize the virus in vitro, which means that they prevent the infection of human cells. Some experiments have confirmed that the vaccine prevents the symptoms of the disease in animals that express the ACE-2 receptor, which allows the coronavirus to enter human cells.

The future of the fight against the pandemic

If the data is confirmed in humans in the phase I / II trial, first on 80 and then on 240 patients, the company will prepare for phase III, which could start in the autumn. It will also be crucial to monitor coronavirus variants that continue to emerge. Experiments are already underway to test the effectiveness of the vaccine on the main variants isolated to date: the English, South African and Brazilian ones. The Takis vaccine has one major advantage, however: it can be quickly updated based on emerging virus mutations by replacing only a few letters in its sequence,  a process that takes a few weeks at most.

The COVID-19 pandemic has accelerated the development of genetic vaccines and provided important proof of concept that this type of approach works. In fact, they represent effective tools for responding quickly to pandemics that could affect us in the future and for viruses with a high mutation rate.

Erika Salvatori

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16 March 2021 – Stasera Italia, the Italian way to the COVID-19 vaccine

16 March 2021 – Stasera Italia, the Italian way to the COVID-19 vaccine

COVID-eVax is the second Italian vaccine to enter clinical trials and the first of its kind to reach that stage in Europe. On Stasera Italia, Luigi Aurisicchio - CEO of Takis - and Lucio Rovati - CEO of Rottapharm - answered key questions about the main features of COVID-eVax, the ongoing clinical trial and the Italian consortium we have put together to produce our vaccine in Italy.

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14 March 2021 – TGR Officina Italia, Italy is going to produce COVID-19 vaccines

14 March 2021 – TGR Officina Italia, Italy is going to produce COVID-19 vaccines

Italy can make a fundamental contribution to the fight against the pandemic by participating in the European and global network for the production of vaccines using bioreactors.

We are planning to produce COVID-eVax in Italy, thanks to a consortium made up entirely of Italian companies. We have always had faith in the potential of our country for scientific research and development.

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9 March 2021 – Agorà, a new vaccine entirely made in Italy

9 March 2021 – Agorà, a new vaccine entirely made in Italy

Emanuele Marra – Director of Infectious Disease Area – and Giuseppe Roscilli – Director of Antibody Development Area – take stock of the development of our vaccine and its potential to fight the new emerging variants for coronavirus. 

Luigi Aurisicchio – CEO of Takis – mentioned our collaboration with a company based in Anagni to produce our vaccine in bioreactors.

As we complete all these steps and move forward with the clinical trial, we hope COVID-eVax will be on the market by 2022.

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4 March 2021 – The first volunteer tested Takis vaccine COVID-eVax

4 March 2021 – The first volunteer tested Takis vaccine COVID-eVax

Luca Rivolti, 21, is the first volunteer who tested the vaccine against COVID-19 developed by Takis and Rottapharm biotech. The clinical trial has just started at the San Gerardo hospital in Monza and Luca was the first of 80 healthy volunteers who will be vaccinated in the coming weeks / months. He has had no significant side effects so far and will receive the second dose of the vaccine by the end of March.

We thank him and all the volunteers for their valuable contribution to the Italian fight against the pandemic.

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1 March 2021 - The phase I/II Clinical Study of the first European DNA Vaccine against Covid-19 has started today in Italy

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March 1, 2021 - The first healthy volunteers received the initial dose of the DNA vaccine against COVID-19 (COVID-eVax) designed by Takis and developed in collaboration with Rottapharm Biotech in Italy: it is the first DNA vaccine to reach the clinical stage in Europe.

Phase 1 will involve 80 healthy volunteers divided into 4 groups with different doses administered with or without booster, while Phase 2 will reach up to 240 subjects on the most promising doses.

The phase I/II clinical study of the first european DNA vaccine against Covid-19 has started today in Italy

The DNA vaccine represents an innovation compared to other technological platforms already available, such as those with messenger RNA or viral vectors. "DNA allows us to avoid the cold chain in storage and transport," said Luigi Aurisicchio, CEO and Scientific Director of Takis. "Due to its characteristics, the production of the antigen is prolonged over time and the vaccine could work well already in the first cycle. Furthermore, if necessary, the administration can be repeated several times for a more solid immune response, also thanks to the use of the electroporation technique developed by another Italian company, IGEA, which facilitates the entry of DNA into muscle cells and it also acts as an adjuvant, thus stimulating immunological processes ".

A vaccine therefore developed entirely in Italy and which also makes use of a prestigious consortium of Italian clinical centers for Phase 1 and Phase 2 of the clinical trial. In fact, the National Cancer Institute IRCCS Pascale Foundation in Naples, the National Institute of Infectious Diseases Lazzaro Spallanzani in Rome and the San Gerardo Hospital in Monza in collaboration with the University of Milan-Bicocca are participating in the study. The three clinical centers are involved in all study activities, but each has greater responsibility for one of the three main aspects of the trial.

The San Gerardo Hospital in Monza is responsible for the treatment of the first subjects in each dose and therefore for the verification of the preliminary results: the first administration took place today in the Phase 1 Research Center directed by Prof. Marina Cazzaniga, medical oncology scientist at the University of Milan-Bicocca. "The vaccine promotes the production of a very specific portion of the "Spike" protein, which the virus uses to bind to human cells" underlines Prof. Paolo Bonfanti, Director of the Infectious Diseases Unit of ASST Monza and associate professor of Infectious Diseases at the University of Milano-Bicocca “and against which, therefore, the body will trigger the immune response”.

Pascale Institute in Naples plays a decisive role in expanding the number of subjects for each dose, in order to consolidate the results. "Among other things" explains Prof. Paolo Ascierto, Director of the Unit of Melanoma, Oncological Immunotherapy and Innovative Therapies of the Pascale Institute in Naples, "the DNA vaccine can be easily and quickly modified to take into account the variants of the virus that are becoming prevalent or that may appear in the future ”.

Finally, the Spallanzani Institute in Rome is responsible for all laboratory tests that document the immune response and therefore the potential efficacy. In fact, the vaccine performed very well in laboratory tests, evoking a strong humoral and cellular immune response, which will now be confirmed in humans.

"With COVID-eVax we are demonstrating the ability of Italian Research in generating innovative solutions against the pandemic and we have asked for the collaboration of important Italian development centers" concludes Aurisicchio "We have found in Rottapharm Biotech a partner for the initial investment and support in clinical development, but financial intervention by Italian and European institutions is now required on a technology that could prove useful not only against COVID-19, but also on a series of other therapeutic indications, starting with cancer vaccines " .

For more information:

Takis

Dr Luigi Aurisicchio (CEO/CSO)

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Rottapharm Biotech

Dr. Federica Girolami (Business Development, Scientific Liaison and Drug Safety Director)

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Takis

Takis is a biotechnology company created by a group of scientists formerly from Merck Research Laboratories (MRL) and it is located in Rome (Italy). The group has more than 15 years of experience and proven expertise in drug discovery in Oncology and is recognized for the design and implementation of a number of innovative technologies, including that of DNA gene therapy. One of Takis’s core assets is its experience with electroporation, a technology that can be used for a variety of clinically useful applications, from vaccine development to somatic gene therapy. Takis' pipeline includes four cancer vaccine candidates based on this technology. Takis is also actively involved in the generation of humanized monoclonal antibodies for use in oncology and infectious diseases, including COVID-19.

For more information on the company, visit www.takisbiotech.it

Rottapharm Biotech

Rottapharm Biotech is a research company dedicated to the discovery and development of innovative drugs. It is located in Monza (Italy) The company expertise in research and development includes medicinal / computational chemistry for small molecules, a proprietary platform for the generation and selection of new monoclonal antibodies and the development of other biological drugs and advanced therapies, the validation of new molecular targets, the pharmacological, pharmacokinetic, toxicological and pharmaceutical characterization of new drug candidates; the design and conduct of innovative clinical trials. The company strategy is to develop its own pipeline independently and then seek partnerships with pharmaceutical companies, as well as investing in alliances on innovative projects of other biotech companies or university spin-offs.

For more information on the company, visit www.rottapharmbiotech.com