Oxford vaccine enters final phase of COVID-19 trials. Here's what happens now.
"It is my duty as a citizen," one volunteer says of the rigorous experience as the phase three trial kicks off in Brazil.
Rio de Janeiro, BrazilAndréa Barbosa was thrilled to be jabbed in the arm. The 46-year-old ophthalmologist is one of the 5,000 volunteers in the clinical trial in Brazil of a COVID-19 vaccine candidate, ChAdOx1. The vaccine is being developed by the University of Oxford in the United Kingdom in collaboration with the biopharmaceutical company AstraZeneca.
In May, Soumya Swaminathan, the head scientist of the World Health Organization, called ChAdOx1 the most advanced COVID-19 vaccine candidate.
Phases one and two of the clinical trial took place simultaneously in April in southern England, when safety and immune responses were checked in more than a thousand healthy volunteers ages 18 to 55. The vaccine is now in the third and final development phase: testing volunteers in Brazil at the Federal University of São Paulo’s Reference Center for Special Immunobiologicals, as well as at two locations run by the D'Or Institute for Research and Education.
That makes Brazil an important proving ground as this vaccine candidate continues its rapid march toward approval by the U.K.’s Medicines and Healthcare products Regulatory Agency (MHRA). Eventually, the ChAdOx1 clinical study will also take place in the United Kingdom, the United States, and South Africa, aiming to recruit up to 50,000 volunteers. Preliminary results from all these trials will be collected through November, and if they confirm that the vaccine is effective, the Oxford team will submit it for an initial registration with MHRA by the end of the year.
In the U.S., another vaccine candidate from biotech firm Moderna started its phase three clinical trial this week. This trial is recruiting 30,000 volunteers from 89 sites around the country to test the effectiveness of the mRNA vaccine, which would be a first of its kind if approved by the National Institutes of Health.
Participating in a vaccine trial is a rigorous and time-consuming process. Volunteers must be carefully vetted and monitored for months, and they face some risks from potentially damaging side effects. But, Barbosa says, there’s no question that the effort is worth it. “This is my duty as a citizen. It is a humanitarian cause. Without a vaccine, we don’t know when this situation will be over.” (Here's how we'll know when a COVID-19 vaccine is ready.)
Barbosa has been the head of the ophthalmology department at Rede D'Or São Luiz, a system of hospitals operating across Brazil, since 2007. The number of patients visiting her clinics fell from a hundred a day to about a dozen between the end of March and June—mostly people requiring continued treatment for severe conditions such as glaucoma and diabetic retinopathy.
Amid the growing COVID-19 public health emergency, Barbosa wanted to join the fight against the virus, so she asked the board of Rede D'Or São Luiz for permission to work on the front lines with other health care professionals. Her request was denied—she was told she had not worked long enough in an emergency care unit. “I was really frustrated about not being able to treat COVID-19 patients,” Barbosa says.
So when the Brazilian Health Regulatory Agency approved the clinical trial of ChAdOx1, she leaped at the opportunity to participate. “Now I will somehow be part of it,” she says.
The candidate is born
Oxford University was already using what’s known as viral vector technology to develop a vaccine for another type of coronavirus, MERS, when the current pandemic hit. Since it emerged in September 2012 in Saudi Arabia, MERS has been reported in 27 countries, with 2,494 reported cases and 858 deaths to date.
The research had reached an advanced stage when SARS-CoV-2, the novel coronavirus, was first reported in December 2019, so the scientists used their MERS technology and knowledge as the starting point for a vaccine. They inserted the SARS-CoV-2 spike protein, the studs on the COVID-19 virus that help it invade cells, into an adenovirus that causes the common cold. Weakened via genetic tweaks and unable to replicate in human cells, the adenovirus acts as the so-called viral vector.
A viral vector vaccine works “as a Trojan horse,” according to physician Sue Ann Costa Clemens, coordinator of the study in Brazil. “The adenovirus carries a part of SARS-CoV-2, the spike protein, hidden in it. This spike will trigger the immune response when injected in humans.”
Preliminary results from the first two phases of clinical trials were published by The Lancet on July 20. Participants had minor side effects, such as fatigue and headache, and none had serious adverse reactions. Researchers also identified that the Oxford vaccine had triggered a strong immune response in the two main defenses responsible for detecting and attacking pathogens—antibodies and T-cells.
Clemens was responsible for Brazil’s selection for the third phase of the ChAdOx1 trial. The 52-year-old physician from Rio de Janeiro has lived in Italy for about two decades. A professor of pediatric infectious diseases at the University of Siena, where she founded the first global vaccinology course, she’s also a coordinator of the university’s Institute for Global Health and director of the master’s program in vaccinology, and she’s the head of the scientific committee at the Bill and Melinda Gates Foundation.
On May 5, Andrew Pollard, who’s the coordinator of the Oxford coronavirus vaccine group and also teaches part of the vaccinology course in Siena, invited Clemens to work on the ChAdOx1 clinical trial. She accepted immediately. Throughout her career, Clemens has guided similar clinical trials requiring extensive recruitment of test takers. In 2005, she worked on a rotavirus vaccine study in Latin America that involved finding 60,000 volunteers over a period of six months.
This time, Clemens’ initial goal was to select research centers to carry out the clinical trials. She was looking for places with good medical professionals and a setting with large numbers of people exposed to COVID-19. The Federal University of São Paulo, where she had obtained her Ph.D. degree and is also currently a researcher, met these requirements, and they agreed to participate.
“At a phase three trial, the goal is to prove that the vaccine offers protection against the disease,” Clemens says. “How can we work fast to prove it and offer the vaccine to the population in a short period of time?”
The trial in Brazil started on June 28 in the three centers, coordinated by Clemens. In total, 5,000 volunteers, divided into two groups, are being vaccinated. One group is receiving the vaccine candidate ChAdOx1; the other gets a control vaccine. This is a randomized, double-blind trial, which means that volunteers are randomly assigned to one of the groups, and neither the vaccinated person nor the researcher knows which vaccine was given to each person until the end of the trial.
The researchers chose the quadrivalent meningitis ACWY vaccine as the control. The dosage is similar to that for ChAdOx1, which means volunteers will get similar amounts of the vaccine ingredients. In addition, researchers already know its side effects, including redness or pain at the injection sit and mild flu-like symptoms. The team decided against a placebo vaccine—a substance without an active effect—so that the volunteers could derive some benefit from the study. (This meningitis vaccine generally isn’t widely distributed in Brazil, Clemens says, because it is more expensive.)
Becoming a human subject
Andréa Barbosa, the ophthalmologist, met the basic requirements for participation in the vaccine trial: As a health professional, she has significant exposure to the coronavirus in daily life, and she’s between 18 and 55 years old.
She had her first visit to the Idor clinic in Botafogo on July 4. A nursing team checked her vital signs, height, and weight. Then she was interviewed to assure that she met all the trial criteria. People with manageable conditions, such as asthma, were accepted, but those with chronic diseases or an immunosuppressive condition were precluded.
“My case was a little more complicated because I have episodes of contact allergy, but they went over it, and my type was not an exclusion criterion,” she says. By contact allergy, she means she has mild allergic reactions when certain substances touch her skin.
Barbosa signed an informed consent form, confirming her agreement not to participate in other vaccine tests or to get pregnant in the next 12 months and to be available to attend regular checkups. The 15-page form explains the study, the vaccine, and the context of the epidemic and describes the risks involved for participants in the study. It also points out that until the vaccine’s effectiveness has been proven, subjects cannot assume that they’re protected against COVID-19. Volunteers can withdraw from the study at any time.
Right after her appointment, she returned to the nursing ward to have a nasal swab sample collected to determine if she was infected with COVID-19. She had a pregnancy test, and nurses collected a blood sample for serology testing to find out if she had antibodies to COVID-19, indicating previous infection. Researchers estimate that 10 percent of volunteers have positive results, making them ineligible to participate.
Back in the clinic on July 9, Barbosa was told that all her tests were negative. She was asked again about her health status, then she took another pregnancy test and gave another blood sample. After that, she was finally vaccinated.
She was kept under observation for about 30 minutes to monitor her for any immediate adverse effects. Before leaving, she was given pain-relief medication for that day and was asked to fill out a daily online questionnaire.
“They ask me if I had nausea or fever. I check my body temperature with the thermometer they provided. I have to record all symptoms and signs observed in the injection site, whether it’s red, stiff, or swollen—they gave me a ruler to measure it,” Barbosa says.
Barbosa’s next appointment is on August 1. Until then, she’s leading a normal life working in hospitals and clinics, but always attentive to any potential symptom or reaction she should report in the questionnaire. “I'm watching for any symptoms, but I’m fine—I haven’t felt anything different. I didn’t have any reaction at the injection site. Nothing at all.”
If the trial participants show any likely symptoms of COVID-19, they must return to the clinic and be tested. Adverse reactions are assessed regularly, and researchers also check whether subjects have produced antibodies.
The body starts developing an immune response between eight and 10 days after the vaccine is given, but full protection isn’t guaranteed during this period. Researchers therefore collect blood samples about 28 days after vaccination, a period long enough to allow the body to produce recognizable defense cells.
“Unblinding” the study involves determining whether people assigned to the control group or those who received the trial vaccine were diagnosed with COVID-19. This is how vaccine efficacy is tested. Volunteers will be assessed for one year, but the team will use early data from the trial in Brazil, as well as the expanded trials in the U.S., the U.K., and elsewhere, to move ahead quickly with development.
“Partial results from the combination of all of these studies should be ready by November,” Clemens says. “The idea is to combine a registration dossier to be submitted in the United Kingdom, and if vaccine efficacy is proven, it can be licensed there this year.” Vaccine deployment would start right after that in the U.K. and other countries, including Brazil.
In April, the University of Oxford and AstraZeneca announced an agreement to produce a billion doses of the vaccine. They agreed to sell the vaccine at cost, to make it as widely available as possible.