Combining different vaccines could extend protection against COVID-19, scientists believe

Testing has begun in Brazilian volunteers of two candidate vaccines at an advanced stage of development. In an online seminar co-organized by Agência FAPESP, researchers involved in Phase 3 clinical trials said the more vaccines are approved, the better mankind’s chances of controlling COVID-19.

By Karina Toledo  |  Agência FAPESP – Even before the World Health Organization (WHO) announced that COVID-19 was a public health emergency of international concern, in March 2020, the search for a vaccine had begun in various parts of the world. Some projects have progressed faster than ever before in the history of vaccines. Only seven months after the start of the first COVID-19 outbreak, 18 of the more than 140 formulations developed by different methodologies are being tested in human subjects.

Two candidate vaccines are already in Phase 3 clinical trials, which aim to confirm that the vaccine is safe, beneficial, and effective by giving it to a large group of volunteers, some of them in Brazil. The first, known as ChAdOx1 nCoV-19, was developed at the University of Oxford in the UK and licensed to AstraZeneca. The second, known as Coronavac, was developed in China by a company called Sinovac Biotech, which is partnering with Butantan Institute in São Paulo to conduct clinical trials.

Brazil is one of the countries in which the virus is spreading particularly quickly and where tens of thousands of cases of COVID-19 are confirmed every day, so it offers an ideal opportunity for vaccine trials, and other candidates will be tested there soon. For the researchers involved in the trials, however, this is not a race to discover which candidate is the best or which will be the first to win regulatory approval. The more vaccines prove capable of protecting at least a substantial proportion of those susceptible, the better will be mankind’s chances of ensuring that COVID-19 is a controllable disease, like flu.

These are some of the views expressed by the participants in an online seminar entitled “The COVID-19 vaccines being tested in Brazil”. The webinar was held on July 2 by Butantan Institute in partnership with Agência FAPESP.

“Having several COVID-19 vaccines approved could be useful, as it’s possible that the best strategy to induce a protective immune response is to combine various formulations. In addition, all the ongoing studies let us learn more about the immune response to SARS-CoV-2. An understanding of how these vaccines work can give us a clearer picture of the markers of protection against the disease, and this, in turn, should speed up future studies,” said Esper Kallás, a professor in the University of São Paulo’s Medical School (FM-USP) who is leading the Phase 3 trial of Coronavac in Brazil. The trial involves some 9,000 volunteers in different parts of Brazil and is sponsored by Butantan Institute.

Based on a viral strain isolated from a patient in January and chemically inactivated in the laboratory, Coronavac has made speedy progress thanks to the knowledge gleaned from efforts to develop a vaccine against SARS-CoV-1, the coronavirus that caused the 2002-03 outbreak of severe acute respiratory syndrome (SARS) in China and several other countries, according to Ricardo Palacios, head of clinical research at Butantan Institute.

“The SARS vaccine advanced to Phase 1 clinical trials but at that point the epidemic was contained and the project was shut down,” Palacios said. “The company obtained plenty of knowledge about how to develop vaccines against a coronavirus and this is now proving extremely useful. The conventional R&D and testing process has been followed in a very short time span. Preclinical and clinical trials are usually performed in succession, but in this case, several phases are being performed concurrently.”

The safety of Coronavac and its capacity to induce an immune response have been tested in different animal species. It has been found to reduce viral load to a significant extent in the nasal mucus of infected animals and to protect their lungs against infection by the virus.

Phase 1 and 2 clinical trials have shown the vaccine to be safe and to have immunogenic potential when two doses are administered in different amounts and at different intervals. So far some 90% of the volunteers given two doses of the vaccine have developed antibodies that protect them from infection by SARS-CoV-2.

Phase 3 clinical trials should show how long these antibodies remain in the organism and whether they assure complete protection against the disease, or at least against the development of severe symptoms, according to the researchers who took part in the webinar.

“Producing protective antibodies is the main way most vaccines work, but to perform well against some diseases they also have to be able to teach defense cells to act against the pathogen. A case in point is the novel shingles vaccine used in people aged 50 or more,” Kallás said.

According to the webinar participants, both Coronavac and ChAdOx1 nCoV-19 appear to be capable of inducing the production of neutralizing antibodies as well as creating cellular immunity, in which T lymphocytes are “taught” to recognize and attack cells infected by the virus.

The vaccine developed by the University of Oxford uses a weakened version of a common cold virus (adenovirus) that infects chimpanzees. It has been genetically changed so that it cannot replicate, but it will induce production of the SARS-CoV-2 spike protein in the human organism.

The spike protein is found on the surface of the virus, which uses it to bind to receptors on human cell membranes to gain entry to the cells and cause an infection. The vaccine is designed to make the body recognize and develop an immune response to the spike protein that will stop the virus from entering and replicating inside an infected person’s cells.

The same strategy has been used by the University of Oxford’s Jenner Institute for some years to develop investigational vaccines against several pathogens, including MERS-Cov, a closely related coronavirus that causes Middle East respiratory syndrome (MERS). The scientists quickly adapted the platform to SARS-CoV-2 when the first cases of COVID-19 emerged. This enabled the group to advance rapidly to clinical trials of ChAdOx1 nCoV-19, according to Pedro Folegatti, a Brazilian-born physician and researcher at the Jenner Institute, which is named after Edward Jenner, the inventor of vaccination. 

“The advantage of this technology is that the vector [the adenovirus] can be adapted for use against other diseases and is considered a good humoral [antibody] and cellular response inducer,” Folegatti said. “Other groups are testing a similar methodology for influenza, tuberculosis, Rift Valley fever, chikungunya and zika vaccines. All these studies are showing a consistent single-dose safety and immunogenicity profile.”

The preclinical trials of ChAdOx1 nCoV-19 proved the vaccine’s effectiveness to protect the lower respiratory tract, which comprises the trachea and the bronchi, bronchioles and alveoli in the lungs. However, it did not significantly reduce nasal mucus viral load in the animals.

The Phase 1 clinical trial began on April 23 with 330 volunteers. Phase 2 and 3 trials began about a month later. The Phase 3 trial will involve some 50,000 volunteers in several countries, 5,000 of them in Brazil.

“Negotiations to bring the Phase 3 trial to Brazil began in May. The infection curve was rising in Brazil and the city of São Paulo was the epicenter of the epidemic. Rio came a close second,” said Lily Weckx, a professor in the Federal University of São Paulo (UNIFESP) and leader of the São Paulo arm of the trial. Volunteers residing in the state of Bahia, northeast Brazil, will also participate, she added.

The agreement signed by AstraZeneca and Oswaldo Cruz Foundation (Fiocruz, a Rio-based public health research institution subordinated to the Brazilian Ministry of Health), calls for technology transfer to Brazil and a license to produce the vaccine here if it wins regulatory approval.

“Brazil has large groups involved in various studies aiming at the production of COVID-19 vaccines, and in my view this is strategic for the country,” Kallás said. “Our epidemiological situation has unfortunately made us the ideal site for Phase 3 trials and this ought at least to facilitate negotiations with the companies that are developing the vaccines, so that if one or more vaccines are approved they will be made available to the entire Brazilian population, including the most disadvantaged citizens.”

When will the vaccine be ready?

Volunteers in the ongoing clinical trials must be monitored for up to 12 months, but according to Palacios, a preliminary result may be announced sooner. “If the number of cases among the subjects given the vaccine reaches a level deemed satisfactory, an independent group of scientists will be asked to make an assessment. If they conclude that the preliminary efficacy results are statistically significant, a public announcement may be made,” he said.

It is not clear what proportion of those vaccinated need to be protected for a vaccine to be considered effective, however. The WHO recommends between 50% and 70%. Guidelines recently issued by the United States Food and Drug Administration (FDA) require vaccines to protect at least one in every two people vaccinated in order to win approval in the US. For Palacios, this level of efficacy would be sufficient.

“Even if one or more vaccines are approved, we won’t eradicate this coronavirus,” he said. “It’s here to stay and will be with us for the rest of our lives. Vaccines protect against disease, not infection. If we can achieve at least 50% protection, we’ll avert the main problem, which is the overwhelming of health services and excessive demand for intensive care, and COVID-19 will become controllable.”