Soberana 02 in phase III clinical trials. What does it mean?

On March 3, the Center for the State Control of Medicines, Equipment and Medical Devices (CECMED) gave authorization for one of the Cuban vaccine candidates that are being developed to begin phase III of clinical trials in humans. Several of the main world media: The New York Times, CNN, BBC, El País reported the news. And the thing is that Cuba is included in a small list of countries—almost all of the first world—that have been able to develop vaccine candidates against SARS-CoV-2, and the first country in Latin America to reach this advanced phase of trials.

In order to be approved, vaccines must follow a strict protocol that includes the exploration stage, the pre-clinical trials and the clinical trials in humans, the latter, in turn, consisting of three phases.

Final approval for the use of vaccines in humans is granted by regulatory bodies in each country. These must have the status of Competent Authority for the vaccine regulatory system granted by the World Health Organization (WHO).

What has happened to the COVID-19 vaccines and what is an approval for emergency use?

The scientific community—public and private entities, research centers, universities, pharmaceutical companies, enterprises and NGOs—has collaborated as never before in the history of science and health to achieve a cure for a pandemic crisis. More than 100,000 scientific articles have been published on this subject. More than 4,800 ongoing studies on treatments and vaccines are registered. We know more about SARS-CoV-2 and COVID-19 than about other diseases that the scientific community has been studying for decades.

According to the WHO, until March 5 against were 79 COVID-19 vaccine candidates in clinical trials and 182 in pre-clinical trials. Several of these have been approved by the regulatory bodies of some countries and two vaccines (Pfizer and AstraZeneca/Oxford) are approved for emergency use by the WHO.

The development and approval of a vaccine is usually a long process that can take between 5 and 15 years, so many are surprised that just over a year after the start of what became the COVID-19 pandemic, there already are vaccines against the disease.

Several factors have influenced this: the priority given to it, the collaboration among the international scientific community, the achievement of rapid funding, the response of the regulatory bodies to redesign protocols that allow the overlap of some phases, and the development achieved by biotechnology in the world.

The regulatory bodies of each country and the WHO have designed and approved accelerated protocols for these vaccines that have allowed the phases to overlap, that is, with partial positive results, they have been able to advance to the next phase without having fully concluded the previous one. On the other hand, the pauses between each development step, which generally need to be carried out in order to obtain more funding, have been shortened or eliminated. As with all vaccines, those developed against COVID-19 must go through a rigorous process with several phases that include, for example, large phase III trials with tens of thousands of people. The WHO has confirmed that the most demanding criteria and required controls have been respected.

The manufacturers of COVID-19 vaccines signed a joint commitment not to apply to governments for the authorization of their vaccines until their safety and efficacy are proven, as reported by the WHO.

Emergency use

Regulatory entities can, and have done in this case, approve drugs and vaccines for use during medical emergencies without following the usual protocol that is more time consuming, but this does not mean that they can skip necessary steps, an approval of this type requires a protocol—faster—but extremely rigorous. Both the WHO and the regulatory bodies of each country establish their protocol for this and approve the candidates that comply with it.

CUBAN VACCINE CANDIDATES

Of the 79 vaccine candidates in clinical trials registered by the WHO until March 5, four are Cuban: two developed by the Finlay Vaccine Institute (IFV) and another two by the Center for Genetic Engineering and Biotechnology (CIGB), one of them (Soberana 02) is among the 23 that have reached phase III.

The five Cuban vaccine candidates are of the subunit1 type of vaccine, in all cases the receptor binding domain (RBD)2 is used as an antigen to elicit the specific immune response against the virus that causes COVID-19.

One of the advantages of the Cuban vaccine candidates is that they require refrigeration between 8° C and 2° C—unlike DNA/RNA vaccines that must be stored at much lower temperatures, which complicates transportation.

The vaccine candidates developed by the Finlay Institute use the RBD antigen expressed in higher mammalian cells; while Mambisa and Abdala, developed by the CIGB, use the antigen expressed in pichia pastoris yeast. Both platforms are used by other Cuban vaccines of wide distribution and proven effectiveness. Mambisa, for its part, has the peculiarity of being a nasal spray.

SOBERANA 02

The Soberana 02 vaccine candidate (FINLAY-FR-2) is a conjugate vaccine (an antigen is fused with a carrier molecule to enhance its stability and efficacy) in which the RBD (antigen) chemically binds to the tetanus toxin (molecule carrier).

Some results:

The safety and immunogenicity of the vaccine candidate is evaluated in phases I and II of clinical trials. Safety has to do with the adverse effects that the vaccinated person may develop and immunogenicity with the ability of the vaccine to generate an immune response (emphasizing antibodies) in the inoculated person that manages to protect it against the disease.

Safety:

Phase I: Of the 40 vaccinated subjects, 23 adverse events were detected (none serious)

Phase II: Of the 910 vaccinated subjects, 39.4% reported some adverse effect, of these 40% was pain at the vaccination site, which is an expected effect.

Immunogenicity:

In phase I it was found that, after the second dose, 84% of the individuals were responders (presence in the serum of antibodies against COVID-19).

The researchers decided to add a third dose, half of the individuals were vaccinated with a third dose of Soberana 02 and the other half with a new formulation: Soberana Plus.

It was detected that after the third dose, 100% of the individuals were responders, and in 90% they managed to produce a neutralizing antibody response. This means that not only levels of antibodies against SARS-CoV-2 were detected, but the antibodies of 90% of the individuals were able to neutralize the entry of the virus into the cell in vitro. This is the answer that is most sought after in this phase.

Between 60-75% of the individuals developed a significant T cell response, which reinforces the immune system response elicited by the vaccine.

In phase II, 81% of the individuals were responders after the second dose (76% with neutralizing antibodies) and 96% were responders after the third dose.

These results are really encouraging. The researchers compared the serum of those vaccinated with sera from people who had suffered the disease and had recovered and the antibody response was very similar after the second dose (a result that is what is sought, that the vaccine manages to activate the immune system as it occurs naturally to overcome the disease), but after the third dose, the response of the vaccinated subjects was significantly higher (relevant result).

Phase III

With these excellent results, the Cuban vaccine candidate passes to phase III of clinical trials, according to Dr. Dagmar García Rivero, Director of Research at the Finlay Vaccine Institute, this will be the most complex clinical trial that Cuban science will have to face due to the size of the sample, its methodological and operational complexity, and because it takes place in the midst of the epidemic. As confirmed by the scientist, Cuba already has two batches of Soberana 02 produced on a large scale that represent a total of 320,000 doses.

This is a phase III multicenter, adaptive, parallel-group, randomized, placebo-controlled, double-blind trial in volunteers between the ages of 19 and 80 years, with no known history of SARS-CoV-2 infection.

What does it mean that it is a placebo-controlled trial?

It means that a percentage of the sample will be the control group with which the results of the people to whom the vaccine candidate will be inoculated will be compared. In this case, the same vaccine candidate preparation will be used as placebo without the RBD subunit (the portion of the vaccine that stimulates the specific response against SARS-CoV-2).

What does it mean that it will be double-blind?

It means that neither those who receive the inoculation, nor those who administer it, nor those who evaluate the response of each person, will know to whom the placebo was inoculated and to whom the vaccine candidate. Only the researchers who will analyze the results will know the composition of the groups.

What will happen to the placebo group?

According to Dr. María Eugenia Toledo Romaní, from the Pedro Kourí Institute of Tropical Medicine (IPK) and principal investigator of the Soberana 02 clinical trial, once the follow-up period has elapsed, the group of people who have been included in the placebo group will receive what has turned out to be the best formulation of the vaccine.

Two vaccination schemes:

Two treatment schemes will be evaluated:

1. Two doses of Soberana 02 vaccine at an interval of 28 days.
2. Three doses (two of Soberana 02 and a third of Soberana Plus at 28-day intervals)

Both schemes will be followed up for three months after 14 days have elapsed since the last immunization.

The objectives of this phase will be to evaluate:

1. Safety and immunogenicity
2. If the vaccine succeeds in preventing symptomatic disease
3. If the vaccine succeeds in preventing severe forms of the disease from developing and death
4. Duration of illness
5. If the vaccine succeeds in preventing infection

What is Soberana Plus?

The Soberana 01 vaccine candidate is a conjugate formulation that has RBD as antigen and as adjuvant the outer membrane vesicle system of meningococcus and alumina (the basis of VA-MENGOC, meningococcal BC vaccine). Soberana Plus is a variant of this formulation without the meningococcal outer membrane vesicle, using alumina as an adjuvant.

How long will this phase last?

As has been done in the rest of the vaccine candidates that have reached phase III and following the recommendation of the WHO, during this trial, interim tests will be carried out, said Yury Valdés Balbín, deputy director of the IFV. “The partial results of these trials can be used to advance in other categories such as emergency use authorization. That is what everyone has done, and what we have conceived in our study.”

It is important to note that the different tests to measure the responses of the participating individuals are not carried out by the Finlay Institute itself, but by the Civil Defense Laboratory and the Molecular Immunology Center (CIM), which is another strength when it comes to being audited by international organizations and by the CECMED itself with a view to the approval of the vaccine candidate.

Regardless of the results that are obtained in the partial tests, phase III must be carried out completely and lasts approximately three months, starting from the last dose of the third group.

What are the cutting moments?

In phase III of the vaccine, the most important indicator to measure is efficacy, that is, the ability of the vaccine to prevent vaccinated people from getting sick (developing symptoms).

When the race to obtain preventive COVID-19 vaccines began, the scientific community valued that obtaining vaccines with 50% efficacy would be an achievement. Most flu vaccines, for example, are around 40% effective and still prevent many deaths annually.

In order to carry out a phase III clinical trial in a specific place, several factors must be taken into account, including the incidence rate of the disease in that place. According to Cuban scientists, this indicator in Havana makes it possible to carry out the trial in this province at this time.

According to Dr. Vicente Vérez Bencomo, general director of the Finlay Vaccine Institute, the Cuban trial has designed three cuts that will depend on the number of sick that appear among the participants: the cuts are expected to be 53, 106, and 159 cases.

“The total sample is 159 cases at the end of the trial. When the first 53 appear, a cut is made and evaluated. If your vaccine is very good and all 53 appear on the placebo, right there you can stop the trial and say that the vaccine is 100% effective,” he explained.

“If in that first cut there is a placebo versus vaccine relationship with which 53 is not enough, you have to continue, until 106 appear, and there a second cut is made. And then until 159 shows up. Those are the three defining moments of the study. We are designing other efficacy studies and there are other ways to evaluate the efficacy and effectiveness of a vaccine. We now prefer to focus on conventional phase III and when we move a little further towards authorizing these other trials, we will explain what it is about. What we are talking about is that in no case are we going to start using the vaccine without demonstrating its real efficacy,” he said.

Therefore, the time that may elapse to advance to other stages, such as the request for approval for emergency use, will depend on the results that are obtained as the trial progresses. It is a long vaccination scheme, that of the three doses requires approximately 3 months to complete and efficacy evaluations begin 14 days after the last inoculation. Considering this, the results will appear towards the third quarter of the year.

Efficacy and effectiveness in vaccines

The United States Center for Disease Control (CDC) refers that “the efficacy and effectiveness of a vaccine measure the proportional reduction of cases among vaccinated people.” The term efficacy is used when it refers to “a study that is carried out under ideal conditions, for example, during a clinical trial.” The term effectiveness is the one used in “a study that is carried out under typical environmental conditions, that is, less controlled.”

For this reason, as the main researcher of the Soberana 02 clinical trial, Dr. María Eugenia Toledo, has reiterated, it is very important that phase III has a design that tries to resemble reality as much as possible, in terms of sample composition and conditions in which it is carried out.

When we say that a vaccine candidate demonstrated 96% efficacy in phase III, for example, we mean that, when a significant number of trial participants became ill, only 4% belonged to the vaccinated group.

In COVID-19 vaccines, the last known figure was the 92% efficacy that an article published in the scientific journal The Lancet attributes to the Russian Sputnik-V vaccine, which is in addition to the 95% reported by the one developed by Pfizer-BioNtech, 94.1% from Moderna and 70% from Oxford University and AstraZeneca.

Production capacity for Sovereign 02

Regarding the production capacity associated with the process, Eduardo Ojito Magaz, general director of the Center for Molecular Immunology (CIM) specified that “all the necessary product associated with phase III of this trial has already been produced and released.”

The scientist pointed out that the CIM and the Finlay Institute are preparing to produce at higher scales between one million and two million doses per month and “that should allow us to be vaccinating the country within approximately six months.”

According to the Our World in Data website, until March 6, 211.73 million doses of COVID-19 vaccines had been administered in the world, mainly in developed countries. It must be taken into account that most of the vaccines approved so far require two doses of administration, so that number does not correspond to the number of immunized people.

Until March 7, 117,279,487 coronavirus positive cases had been reported in the world and 2,602,555 people have died from this cause. Some scientists claim that 75% of the world’s population will need to be vaccinated to achieve immunity, the percentage that has been immunized so far is minimal, so many millions more doses would be missing to achieve it.

The Cuban strategy of developing several vaccine candidates is the most effective, but it is available to very few countries in the world. The Abdala vaccine candidate, also a subunit vaccine that contains RBD expressed in yeast (a platform used by the Cuban recombinant vaccine against hepatitis B that belongs to the national vaccination scheme) has also shown very positive results in phases I and II and on March 3 its application file was submitted to CECMED to begin phase III, which, if approved, will take place in Santiago de Cuba and Guantánamo. As reported by Dr. Verena Muzio González, director of Clinical Research at the Center for Genetic Engineering and Biotechnology (CIGB), the participation of 42,000 subjects is expected for phase III of this candidate and vaccination schemes shorter than those used in Soberana 02 will be evaluated. Two schemes of three doses each (0-14-28 days) and (0-28-56 days) will be tested. This means that, if the trial is approved soon, the results of Abdala could appear even before those of Soberana 02.

Without a doubt, Cuba’s science and health system are close to achieving one of their most commendable results. In the midst of a serious economic crisis and the well-known U.S. embargo/blockade on the island, which, far from being made more flexible has strengthened during the pandemic, Cuba could become one of the first countries in the world to fully vaccinate its population—with its own vaccine—and Cuban biotechnology is preparing the conditions for the large scale production of vaccines that could save the lives of millions of people in the world.

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Notes:

1 Among the types of vaccines that are being developed against COVID-19, the following types stand out: inactivated virus, those that use a viral vector, those that use viral DNA or RNA and those of subunit. The latter use innocuous fragments of proteins or protein structures of the virus that causes COVID-19 in order to generate an immune response.

2 The SARS-CoV-2 virus, which causes COVID-19, has a protein in its envelope (the famous Spike protein-S protein) that “binds” to a receptor on human respiratory and digestive cells. Apparently the union between the virus and the cell is determined by a subunit of the S protein known as the receptor binding domain (RBD), that would be the famous “key” that opens the cell for the virus to enter and multiply and it has a great relevance in the viral multiplication capacity. The idea of ​​Cuban vaccines then is to generate antibodies that inhibit the entry of the virus into cells.

Authors

Tahimi Arboleya, tahimi-arboleya