The devastating effects of the new coronavirus (SARS-CoV-2) pandemic have sparked a global race for a vaccine against Covid-19. Research is already underway to find a way to immunize people against the virus, but that goal has not yet been achieved. No country has produced a vaccine so far, and the most optimistic forecasts indicate that this should not happen until 2021.
U.S and China took the lead by announcing the start of human trials on March 16 and 17, respectively. Many people took this as a sign that the two countries had already found a solution to face the disease. But this is not true.
Vaccines are products that protect people from being contaminated by a particular disease. They usually contain the virus or bacteria that cause the disease in attenuated or inactive form – that is, harmless to health. More current technologies also allow to include only parts of these microorganisms, such as proteins, and other types of molecules. After the dose is injected, the antigens cause the body to produce antibodies to fight these invaders. Thus, when the immunized person is actually infected by the virus or bacteria, he will hardly have the disease or will develop it in a much milder form.
The fact that laboratories in China and the United States have started testing with humans does not mean that vaccines against Covid-19 are practically ready, or that their development is nearing an end. In fact, these are prototypes. Its efficiency will only be proven after clinical tests, divided into three phases.
This is the most time-consuming and important step in finding an immunization. These tests will verify the safety of applying the product, which can cause adverse reactions, and its ability to protect against the virus. Rushing this phase would put the population at risk. “The vaccine would be the best tool [contra o novo coronavírus], because it is a prevention tool, but it is the most difficult to be reached ”, says Marco Aurélio Krieger, vice president of Health Production and Innovation at the Oswaldo Cruz Foundation (Fiocruz).
Traditionally, creating a vaccine can take more than a decade. Initiatives against SARS-CoV-2 are at a much faster pace because they are betting on new development technologies, capable of shortening the time required in some stages of the process. The pandemic emergency has also prompted regulatory agencies to accept shorter testing periods. Even so, experts forecast that immunization against the new coronavirus will take at least 12 to 18 months, which would be considered a record. That deadline will only be met if any of the vaccine prototypes are really effective against the virus. Otherwise, the job will take more time. There are now more than 30 initiatives trying to find a way to prevent Covid-19.
Clinical trials of vaccine prototypes – that is, their experimental use in humans – are divided into three phases. Phase 1, initiated by laboratories in the United States and China, consists of applying the product to a small number of people. In the USA, the National Institutes of Health (NIH) and the modern biotechnology company expect to have 45 volunteers aged 18 to 55, who will receive two injections in an interval of 28 days – the first patient, Jennifer Haller, received the initial dose on March 16. The company promised to deliver an emergency version of the vaccine, aimed only at health professionals at the end of 2020. But that depends on the results of the analyzes and also on a special authorization from regulatory agencies. In China, 108 individuals will be tested. The company CanSinoBIO, that develops the product with the Beijing Biotechnology Institute, and the Military Academy of Medical Sciences will conduct the tests.
After application, patients will be examined carefully to see if they have had a reaction, such as an allergy or an even more serious problem, and if there has been an immune response from the body. In the case of initiatives against SARS-CoV-2, this can take about six months. If all goes well, a few hundred people are selected for phase 2, which will analyze whether the prototype can really create immunity against the new coronavirus.
At this stage, the researchers verify the response of individuals with different characteristics. This will show if the product behaves the same for all of them. “In addition to safety, the effectiveness, the capacity that this vaccine has to produce, for example, neutralizing antibodies, is also evaluated”, explains Krieger, from Fiocruz. As the number of volunteers is greater, the time needed to analyze the results also increases and can exceed six months.
The last step, phase 3, is the most complex and consists of carrying out tests on a large scale, with thousands of people, to confirm the efficiency and safety previously identified. Again, the entire process can take a long time, and can take up to a year or more. “Often, the adverse effects of a vaccine do not happen to everyone in the same way,” explains Krieger. By applying doses to thousands of volunteers, it becomes easier to identify the increased occurrence of any adverse effects. In other words, everything needs to be successful throughout these three phases for the prototype to be considered as a vaccine.
After that, production begins. It would still take a few months to make millions of doses. Even when ready, the vaccine continues to be monitored in a pharmacovigilance phase 4. “We continue to monitor performance, assessing adverse reactions and efficiency even with the product on the market,” says Krieger.
Allergies are just one of the problems that can occur as a reaction to a vaccine prototype. Other risks, such as developing an autoimmune response (when the immune system attacks cells in our own body), also need to be assessed. But one of the scientists’ main fears about SARS-CoV-2 is that the vaccine will cause a more acute Covid-19 for those who take it and become infected later.
The fear stems from studies of other types of coronavirus. “Research groups immunized with a part of the virus. That didn’t protect right, and when the animal [utilizado como cobaia nos testes pré-clínicos] was infected with the active virus, had an illness worse than those who were not vaccinated. This is a phenomenon that happens a lot when you do not have a neutralizing immune response from the virus ”, says Renato Astray, scientific researcher at the Butantan Institute’s Multi-Purpose Laboratory.
The phenomenon is known as reinforcement of the disease by antibodies (antibody disease enhancement, in English). A common situation in which this occurs is when someone catches more than one different type of dengue throughout their lives. If in the first one, for example, the person contracts type 2, develops antibodies against this virus serotype and is cured. But, the second time, when taking any of the existing types (1 or 4), the antibodies developed against type 2 recognize the dengue virus, bind to it, but are not effective in neutralizing it – with that, its infection power ends up increasing. “The same thing happened to [outros] coronavirus. That is why it is not such a simple vaccine to develop, ”says Astray. To obtain approval from regulatory agencies, research teams need to demonstrate that the problem will not occur when someone contracts SARS-CoV-2 after being immunized.
This difficulty explains why the classic vaccine production process, with inactivation and injection of the virus, would probably not work against Covid-19. The bet of the researchers to work around this problem is in the adoption of other types of technology. The prototype developed by Moderna, for example, uses messenger RNA (mRNA), a molecule that guides protein synthesis inside cells – in that case, to produce proteins against which the body will create an immune response. It is a vaccine creation platform, that is, a solution that has already been tested and approved in the preclinical, research phase, with other viruses. Just replace one mRNA with another to get immunization against a different disease.
The CanSinoBIO prototype adopts another platform, based on human adenovirus type 5 (which causes mainly respiratory infections and pneumonia), to create an immune response against Covid-19. The ease of adapting one solution to another allowed Moderna and CanSinoBIO to enter phase 1 of clinical trials less than three months after the emergence of Covid-19. There are also vaccines based on DNA platforms and synthetic peptides, among others. According to Astray, from Butantan, although these technologies are promising, until today only one of them has managed to originate a product available on the market. It is a flu vaccine, Flublok, created with recombinant technology, which synthesizes the antigen in the laboratory.
Another obstacle is the lack of knowledge about how immunization against the new coronavirus occurs in people who have taken Covid-19 and healed. “We know that there is an antibody response. And we know that there is a cell-type immune response involved. Now, what characteristics are necessary for these two responses to be sufficient to immunize the person, is still unknown. This is being studied ”, says Astray, from Butantan. The development of vaccine prototypes is taking place at the same time as it seeks to better understand how the human body’s immunization process for SARS-CoV-2 works. This rush of parallel research has also recently occurred in the case of the Zika virus.
Clinical tests for vaccine development are very expensive and time-consuming procedures. Therefore, the discovery of immunization against Covid-19 will be directly related to the duration of the pandemic. If the spread of the disease does not spread too far, there is a risk that most initiatives will be stopped. This was the case with efforts to create a vaccine against SARS, the severe acute respiratory syndrome, also caused by a type of coronavirus. The studies were terminated at the end of phase 1 because the disease had already been eradicated.
Until the vaccine arrives, it is possible – and desirable – that the treatment of the disease with existing drugs will help to alleviate, or in an ideal scenario, curb the epidemic. Several existing drugs, including hydroxychloroquine it’s the tocilizumab, have been tested in the treatment of the disease, but it is too early to know its effectiveness.
The discovery of a vaccine against SARS-CoV-2 may be the chance for new platforms for the development of these antidotes to show their effectiveness against a threat that has just appeared. If they prove that they are capable of providing an answer, they can serve as a solution to other future epidemics. Still, the security requirements, costs and risks involved show that the process is not simple. As fast as any laboratory can be, a vaccine against Covid-19 will still take time to reach the market.
Since the beginning of the pandemic, The Magnifying glass is checking for fake news about Covid-19 circulating on social media. THE Magnifying glass it is also part of the CoronaVirusFacts alliance, which brings together more than 100 checkers from almost 50 countries that check information circulating about the disease. This work is being coordinated by IFCN.
Edited by: Chico Marés and Natália Leal