COVID-eVax
COVID-eVax
is a DNA-based vaccine candidate against SARS-CoV-2 using electro-gene-transfer (EGT) .
Under development by Takis Biotech S.r.l, in partnership with Rottapharm Biotech S.r.l., IGEA S.p.A., and DPhar S.p.A.
COVID-eVax
COVID-eVax is a vaccine against COVID-19 based on a DNA plasmid encoding a portion of the Spike protein (called RBD), present on SARS-CoV-2 surface and key for viral infectivity. COVID-eVax is a “precision medicine vaccine” approach designed to induce a strong immune response while minimizing potential undesired effects. The vaccine consists of an intramuscular injection followed by the delivery of brief, low voltage, electrical pulses which induces a strong immune response against the antigen. The procedure is called Electro-Gene-Transfer (EGT) and allows efficient DNA transfer through the cell membrane without toxic effect for cells and tissues. Several studies have shown that EGT greatly enhances gene expression and has been already evaluated in Phase I-III clinical trials, showing promising results in terms of safety, tolerability, gene expression levels and immunogenicity.
COVID-eVax EGT system is based on Cliniporator™ technology which is already marketed for use in electrochemotherapy (ECT) in cancer patients. ECT is an EMA approved treatment for cutaneous and subcutaneous tumor nodules. This technique combines the administration of certain anticancer drugs with the application of square or biphasic electric pulses that increase cell membrane permeability. Local application of the electric pulses enhances drug-delivery into cells specifically at the side of the pulse application thus making feasible the uptake of drugs whose transport through the plasma membrane is impaired. The increase of the uptake of such chemodrugs leads to apoptotic cell death of cancer cells thus to a long-lasting local control and overall patient benefit. In Europe 224 medical devices are available in major hospitals. Therefore, COVID-eVax builds on a European advanced platform technology to develop a safe and efficient clinically significant non-viral nucleic acid delivery method using electric pulses. In addition, a gene-gun, portable device is under development and will be tested in the planned trials.
COVID-eVax has been selected out of 5 different candidates and tested in preclinical models. The vaccine has shown a strong immune response, in terms of antibodies against Spike protein and T cell immunity. Importantly, elicited antibodies are able to block SARS-CoV-2 and its variant G614D replication in vitro. A phase I/II will start in February 2021 in three clinical centers in Italy. Results are expected during the first half of 2021. A Contract Manufacturing Organization has been identified to produce the vaccine in large scale and a clinical trial for a Phase III trial has been planned to start end-2021.
Two covidX platform technologies entered clinical validation in Italy this week: COVID-eVax and mAbCo19
our insight of the week - March 4, 2021
Dr. Luigi Aurisicchio, CEO of Takis Srl, photo courtesy company
Amidst worries about a third COVID-19 wave and emerging coronavirus variants, there’s a lot of good news from Italy: 2 clinical trials have started on the same day.
On March 1, Takis and Rottapharm Biotech announced the start of the clinical trial of COVID-eVax, their jointly developed vaccine candidate. "The start of the clinical trials represents an important step in the development of DNA technology against COVID-19 but also for other diseases", says Luigi Aurisicchio, CEO and scientific director of Takis.
But that is not all, AchilleS Vaccines, that was granted financing in June by the EU Malaria Fund, together with Toscana Life Sciences (trial sponsor) and Cross Alliance (a CRO) is managing clinical trial sites on Monday for their monoclonal antibody, mAbCo19. “Within a bit more than six months we’ve been able, with the support of an outstanding team, to transform a patent into a product which is quite an unbelievable outcome”, says Riccardo Baccheschi, CEO and president of AchilleS Vaccines. “The aim is now reached; the product is there.”
Unlike other vaccines already on the market, COVID-eVax is based on DNA. When injected into the muscle the DNA fragment promotes the production of a specific portion of the “spike” protein – the one the coronavirus uses to attach to human cells. Those portions of the “spike” protein produced by human cells then stimulate a strong immune reaction against the virus. In the case of COVID-eVax, the efficiency of the process is increased by “electroporation”, light and short electrical stimuli that facilitate the passage of DNA into the cells. That’s why Takis calls it a “precision medicine vaccine” approach.
A Phase 1 and 2 trial that provides results on safety and immunogenicity has now started in three hospitals: San Gerardo in Monza, Istituto Lazzaro Spallanzani in Rome and Istituto Pascale in Naples. As Luigi Aurisicchio explains in a video call there will be four different cohorts of patients. Three of them will be vaccinated on a prime-boost modality meaning they will get two injections of 0,5 milligram, 1,0 milligram or 2 milligrams of DNA respectively. Since the WHO recommends exploring a vaccine that works with a single administration, the fourth cohort in the COVID-eVax trials will receive only one injection of 2 milligrams of DNA.
Dr. Rino Rappuoli, Chief Scientist of GSK Vaccines, photo courtesy GSK
Just a stone’s throw away in Siena, scientist Rino Rappuoli and his team found the perfect monoclonal antibody candidate. Normally, monoclonal antibodies are administered intravenously. The process can take hours. “Due to the particular need of COVID-19 pandemic, we wanted to produce an intramuscular product and avoid patient hospitalization for treatment purposes. A hospitalization which is necessary with products like those of Regeneron or Lilly’s” says Riccardo Baccheschi. MAbCo19 comes in a vial of 2,5ml that can be given to a patient in a single administration. What the optimal dosage might be the clinical trial will have to tell. It may be given in a low dosage which could significantly reduce costs.
MAbCo19 was administered to the first patient in Verona on Monday. In phase 1, 30 healthy volunteers will participate. Subsequent phases will include a few hundred patients with Covid-19.
Even though the first vaccines and treatments have already been approved, these and other new candidates are still needed.
Covid-eVax has several advantages over the currently approved vaccines. DNA can be produced cheaply and on a large scale. It does not require ultra-cold storage which makes it easily applicable also in regions with weak health infrastructure. It does not induce immunity against the viral vectors used by other vaccines. Above all, its flexibility allows the developers to adapt quickly against new variants of the coronavirus. “We are already testing vaccines against the variants from Great Britain, South Africa and Brazil”, Aurisicchio says. “In a timeframe of two weeks we can generate a new vaccine based on potential new variants that may emerge.” Takis has an algorithm that can predict which variant is probable to emerge over time.
Even when we have vaccines, treatments are still needed as well. The importance of the role monoclonal antibodies will play in the collective efforts to fight COVID-19 depends on several factors. First, the efficacy of the vaccines. Second, their availability – just recently, amidst reports of vaccine production delays Germany has ordered 200.000 doses of antibody treatments. Third: There will be people who cannot or do not want to be vaccinated. For those antibody treatments that come with a high safety profile may be a solution.
After all, mAbCo19 could prove to be more than a treatment. The candidate will be now tested for therapeutic use. However, it is also a candidate for prophylactic use. “At the moment this use is not yet being investigated”, Baccheschi says. “But it could be done soon.”
Both candidates might be instrumental for a long-term solution in the battle against the pandemic. Until then there are still some steps to go.
For Covid-eVax, phase 1/2 trial results are expected around summertime. Plans for a Phase 3 study are yet to be made concrete. A challenging task. Not only because it has to be seen how the pandemic evolves. Circumstances for Phase 3 studies have changed. “Now that many vaccines are available it may be unethical to have a placebo group”, Aurisicchio explains. Takis may have to work with a fewer number of patients and ask for a conditional approval by the EMA. Another option would be a “human challenge trial”, a trial involving the intentional exposure of the test subject. In the UK young volunteers are challenged with SARS-CoV-2 in a controlled environment for research purposes. Once the experimental conditions are established, the human challenge trial could also be a method to test the efficacy of COVID-19 vaccines. But Takis and Rottapharm Biotech are still weighing the options. “It’s too early to have a clear picture”, Aurisicchio says.
The mAbCo19 Phase I clinical trial will be paired with a phase II/III trial a month from now. “With this approach we aim to have the product registered by the end of Spring”, Baccheschi says.
March 4, 2021 by kENUP
COVID-eVax: 35 milliseconds that can make all the difference
our insight of the week - November 14, 2020
Dr. Luigi Aurisicchio, CEO of Takis Srl, photo courtesy company
Back in January 2020, Luigi Aurisicchio, CEO and CSO of Takis Biotech, was working on a cancer vaccine. When Chinese scientists released the sequence of SARS-CoV-2, Aurisicchio and his colleagues said: “We can do something, let’s create a vaccine against this epidemic”, he recalls. When they took that decision on January the 27th, it was still only an epidemic in China.
While more and more cases of Covid-19 all over the world emerged during the next few weeks and the epidemic turned into a pandemic, Takis Biotech started lining up five different vaccine candidates. After a careful selection, they ended up with what they now call COVID-eVax.
COVID-eVax is a genetic vaccine, which means it is working with the genetic information of the virus instead of the virus itself. Genetic vaccines are a fairly new approach. And they might prove to be a particularly convenient model to fight Covid-19. COVID-eVax is based on DNA, which means it uses DNA encoding of a portion of the Spike protein in a “precision medicine vaccine” approach designed to target not the big Spike protein, but only the part that interacts with the receptor which allows the virus to enter the cell. With this precision approach, Takis wants to avoid any possible side effect.
This is closely linked to another innovative aspect at the center of this potential vaccine. The “e” in COVID-eVax stands for electric. More specifically, for a technology called Electro-Gene-Transfer (EGT) with a technique called electroporation, in which an electrical field is applied to the muscle immediately after the vaccine is injected. It only lasts about 35 milliseconds, but it makes all the difference. It allows the DNA in the vaccine to enter the muscle fiber and produce the small fragment of the coronavirus protein through which a strong immunoresponse against the antigen is induced. Without this electroporation, the immunoresponse would be much lower. With it, it can improve by a hundred- to a thousandfold.
Any DNA vaccine has a big advantage compared to other approaches: the DNA is grown in bacteria in big machines called biofermenters, a cheap and widespread technology. Therefore, a large-scale production is easier to establish than in other cases. And this also means that the approach is easily transferable, not just to other viruses but also to potential future mutations of the coronavirus.
COVID-eVAX, first dose, 13-Nov-2020, photo courtesy company
Another advantage of DNA-based vaccines is that – unlike most vaccine approaches which need a cold chain, even at minus 80 degrees Celsius – DNA is stable at room temperature. This might not seem so important, until you take into account the varying realities and limitations of different countries around the world, particularly in remote or poor areas– which is of course a crucial part of fighting a pandemic. “This means that if we want to vaccinate people in Africa or South America, we don’t need a working cold chain”, says Aurisicchio. Because DNA is such a stable molecule, it can even be made into powder and resuspended with sterile water before administering it at the vaccine’s target location.
With all these advantages, there is one hurdle left to tackle on the way to a widespread, cheap and accessible vaccination: the electroporation only works through a specific device, a gene-gun that is connected with a cable to an electroporator, called Cliniporator. It contains the syringe needle for the vaccination and four electrodes, so thin that you don’t even feel them, as Aurisicchio explains. He demonstrates the device on video call from Takis’ offices in Rome. It consists of a reusable outer frame and the disposable, single-use part with the syringe and the electrodes that is applied to the patient’s arm. “We are working on industrializing the disposable part says Aurisicchio. “The final cost in large-scale production should be between two and three dollars.” If everything works out and the device is cheap and can be produced at large scale, the hurdle is met. Aurisicchio hopes to complete this process in the second or third quarter of 2021.
“We already have a business plan and we know that it is doable. Especially with the Italian consortium we have created”, Aurisicchio says. He is talking about Takis Biotech’s collaboration with Rottapharm Biotech, a company with great expertise in clinical trials; IGEA, the manufacturer of the medical gun device for electroporation; and DPhar, a company that will have the capacity to create millions of doses of COVID-eVax by the end of 2021, according to Aurisicchio’s estimate.
“COVID-eVax has the potential to improve the current R&D efforts in the development of new COVID-19 vaccines, thanks to its unique characteristics”, says Lucio Rovati, CEO/CSO of Rottapharm Biotech. “Exploitation of the DNA-based technology may indeed provide increased efficiency and durability of the immunological response and the possibility to be repeated with time, or offer a booster to other COVID-19 vaccines.”
Results from the Phase I and II clinical trials are expected by March and June 2021, respectively, if everything goes according to plan. The Phase III clinical trial is planned for July 2021, but because this stage tests for the efficacy of the vaccine, it needs to be conducted in an area with high numbers of infections. “So, we need to see how the pandemic will behave in the summer of next year”, says Aurisicchio. Right now, that is a question that the whole world would like an answer to.
November 14, 2020 by kENUP