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Brazil Resumes CoronaVac Trial After Pause Over 'adverse Event'

CNN — Brazilian trials of the CoronaVac vaccine will resume, after testing was temporarily stopped due to a "serious adverse event" in one of the volunteers.

According to a police report, a volunteer in the study died by suicide, CNN confirmed Tuesday, resulting in an investigation into the cause of death and a pending toxicology report.

Brazil's National Health Surveillance Agency (Anvisa) said on Wednesday that clinical trials of CoronaVac, developed by Chinese drug maker Sinovac, would be allowed to restart.

Phase 3 of the trials have been suspended since Monday, following what Anvisa described as a "serious adverse event" on October 29. A note from Anvisa said the trial had been paused in order to better evaluate the data and assess the risk.

"After evaluating the new data presented by the sponsor after the study was suspended, Anvisa concludes that there are sufficient benefits to allow the vaccination to resume and continues to monitor the investigation of the outcome of the case to define the possible causal relationship between the unexpected adverse event and the vaccine," Anvisa said in a statement on Wednesday.

"It is important to clarify that a suspension does not necessarily mean that the product under investigation is not of quality, safety or efficacy," it said.

Dimas Covas, the director of Brazil's Butantan biomedical institute, said the incident was not linked to the vaccine trial itself. "The serious adverse event observed in a volunteer in the trial has no relation to the vaccine," Covas told reporters Tuesday at a news conference in Sao Paulo. "It was analyzed and determined that there was no relation."

In a statement posted online Tuesday, Sinovac said it was "confident in the safety of the vaccine."

"We have communicated with our Brazilian partner, the Butantan Institute, and the head of the institute believes the incident has nothing to do with the vaccine. Sinovac will continue to communicate with the Brazilian side on this matter. Work related to our clinical research in Brazil will continue to be carried out in strict accordance with GCP (Good Clinical Practice) requirements," the statement said.

Sinovac began Phase 3 clinical trials of its CoronaVac vaccine in collaboration with the Butantan Institute and the state of Sao Paulo in late July, with an aim to recruit 130,000 volunteers.

Phase 3 trials represent the final and most important testing stage before regulatory approval is sought.

Sinovac is also conducting Phase 3 trials in Indonesia and Turkey. Sinovac did not immediately responded to CNN's request for further comment.

Pausing a clinical trial is not unusual. In September, drug giant AstraZeneca paused global trials of its coronavirus vaccine because of an unexplained illness in one of the volunteers.

Out Of The Lab And Into People's Arms: A List Of COVID-19 Vaccines That Are Being Studied In Clinical Trials

The world's leading drug companies, universities and governments are racing to develop a vaccine for COVID-19, the disease that has taken more than 400,000 lives globally. Of the 133 candidates being explored, ten have been approved for human trials, according to the World Health Organization.

Companies and research groups in China, the early epicenter of the coronavirus outbreak, are testing five of those vaccines in human trials.

Meanwhile, U.S.-based companies are involved in the development of four additional vaccines, including one that has NIAID Director Anthony Fauci "cautiously optimistic." The Trump administration established a federal program to make 300 million doses of a successful vaccine available to Americans by January 2021.

Some scientists are testing tried-and-true methods, while others are embracing new technologies like DNA- and RNA-based platforms. The goal is to create a safe, effective vaccine that is easy to replicate -- at record speed.

MORE: In the race for a vaccine, children may be last to be vaccinated

Governments have provided billions in funding to researchers who are accelerating the traditional stepwise approach that includes phases 1, 2 and 3. And many entrants have already partnered with manufacturing companies to start scaling up production before they even know if their vaccine will work.

These accelerated efforts to thwart the pandemic have some officials, including Dr. Fauci, hopeful that a vaccine will be ready by year's end. But if the vaccines currently in human trials fail -- which is possible -- that timeline will be extended.

Here are the companies leading the global race for a coronavirus vaccine. There are no approved vaccines or treatments for COVID-19 to date, and we still need more data to know if any of these vaccines will prove safe and effective.

COVID-19 Vaccines in clincal trials

ABC News/WHO

AZD1222, The University of Oxford and AstraZeneca (Phase 2/3)

Perhaps one of the fastest-moving projects is Oxford's, which is enrolling 10,260 people across the U.K. To begin phase 2/3 human trials. Their AZD1222 vaccine, formerly known as ChAdOx1 nCoV-19, uses a weakened version of a virus derived from chimpanzees. Oxford's partner, AstraZeneca, has already promised enough manufacturing capacity to produce at least 2 billion doses of AZD1222.

mRNA-1273, Moderna Therapeutics and the National Institute of Allergy and Infectious Diseases (NIAID) (Phase 2)

This vaccine uses a new type of technology called messenger RNA, which produces genetic instructions that direct cells to make proteins that prevent disease. Early data from Moderna's first clinical trial show the mRNA vaccine triggered an immune response similar to patients who have recovered from COVID-19. The Massachusetts-based company is quickly moving on to larger human trials as it aims to complete its vaccine trials by year's end.

A scientist checks quality control of vaccine vials for correct volume at the Clinical Biomanufacturing Facility (CBF) in Oxford, Britain, April 2, 2020. The U.K.'s Health Secretary has said the country will be "throwing everything" at finding a coronavirus vaccine.

Courtesy Sean Elias

Ad5-nCoV, CanSino Biological Inc. And the Beijing Institute of Biotechnology (Phase 2)

CanSino Biologics, a Chinese vaccine company, is creating a viral vector vaccine that combines a weakened virus called adenovirus type 5 with genetic material from SARS-CoV-2. Early results from CanSino's phase 1 study, which tests for safety, showed the vaccine produced an immune response against the virus and participants tolerated it well. CanSino is collaborating with Canada's National Research Council to begin research in Canada.

BNT162, Pfizer, Fosun Pharma and BioNTech (Phase 1/2)

Pfizer and BioNTech started dosing the first participants with their vaccine candidate in Berlin in late April. Soon after, the companies began testing four versions of its mRNA-based vaccine at New York University, the University of Maryland, Cincinnati Children's Hospital Medical Center and the University of Rochester, in May. The companies will narrow down the candidates by safety and how well they prevent infection in patients. Pfizer CEO Albert Bourla said the vaccine could be ready by the end of October.

MORE: Vaccine paradox: Will 'flattening the curve' stymie the chances of developing a coronavirus vaccine quickly?

NVX-CoV2373, Novavax (Phase 1/2)

The Department of Defense recently awarded Novavax $60 million for the manufacture of this protein-based vaccine, which uses patented nanoparticle technology to enhance immune response. In animal studies, it stimulated high levels of antibodies that neutralized the virus. Phase 1 trials are taking place in Herston and Melbourne, Australia. Novavax expects preliminary results in July and, if successful, the company will move onto larger clinical trials in multiple countries.

Work on a COVID-19 vaccine is underway at American biotechnology company Moderna in Massachusetts. Moderna plans to start phase II of its vaccine trials soon and phase III in the summer of 2020.

Courtesy Moderna

CoronaVac, Sinovac Biotech (Phase 1/2)

CoronaVac is an inactivated vaccine being tested in China. This type of vaccine uses a killed version of the germ that causes the disease to stimulate an immune response, and has been used to prevent hepatitis A, polio, rabies and the flu. Sinovac published a study in May that showed its vaccine protected monkeys against infection. The company is currently testing 144 people in phase 2 trials.

Unnamed vaccines, Sinopharm (Phase 1/2)

Sinopharm, a state-run Chinese pharmaceutical company, is developing two inactivated vaccines at their subsidiaries, the Wuhan and Beijing Institutes of Biological Products. Both have entered Phase 1/2 testing, according to the WHO.

MORE: Coronavirus vaccine update: Possible by the end of the year?

INO-4800, Inovio Pharmaceuticals (Phase 1)

INO-4800 is a DNA-based vaccine targeting the spike surface protein of SARS-CoV-2 virus that causes COVID-19. Researchers administer the vaccine by skin injection, then follow with Inovio's CELLECTRA smart device. This delivers DNA to cells using a pulse of electricity that temporarily opens pores in the cell membranes. Early data from preclinical studies shows the vaccine produced a strong immune response in mice and guinea pigs. Phase 1 study is taking place at Central Kentucky Research Associates, the Center for Pharmaceutical Research in Kansas City, Missouri, and the University of Pennsylvania.

Unnamed vaccine, Institute of Medical Biology, Chinese Academy of Medical Sciences (Phase 1)

The Institute of Medical Biology at the Chinese Academy of Medical Sciences (IMBCAMS) has previously developed the world's first inactivated vaccines for polio and hand-foot-and-mouth disease, according to the company website. This inactivated vaccine is in phase 1 trials for safety, according to the WHO.

What to know about the coronavirus:

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Phase I/II Trial Findings Support Use Of CoronaVac Vaccine In Older Individuals

Researchers in China have reported phase I/II clinical trial findings showing that the vaccine candidate CoronaVac is well tolerated among older individuals and effectively generates antibody responses against severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) - the agent that causes coronavirus disease 2019 (COVID-19).

CoronaVac is an inactivated SARS-CoV-2 vaccine developed by Chinese pharmaceutical company Sinovac Life Sciences based in Beijing, China.

Writing in The Lancet Infectious Diseases, the team says this is the first report of an inactivated SARS-CoV-2 vaccine tested in older adults (aged 60 years or older). The findings support its use in this older population.

Weidong Yin from Sinovac Biotech and colleagues say all adverse reactions to the vaccine were mild or moderate in severity, with the most common one being pain at the injection site.

Further studies are now needed to test the effectiveness of Coronavac at preventing COVID-19 in older adults, says the team.

The study is ongoing and is registered with ClinicalTrials.Gov (NCT04383574).

Older individuals are at increased risk of severe COVID-19 and death

Research has shown that individuals aged 60 or older are at an increased risk of severe illness and death from COVID-19, particularly if they have underlying health conditions.

A vaccine that protects older individuals against COVID-19 is therefore urgently needed.

However, the response to vaccination is often reduced among older adults due to age-related changes that affect both the innate and adaptive immune systems – a phenomenon called immunosenescence.

More about CoronaVac

"Purified inactivated viruses have traditionally been used for vaccine development, and currently eight inactivated COVID-19 candidate vaccines are in clinical evaluation," says Yin and the team.

Although efficacy results are not yet available, studies have demonstrated that these vaccines induce neutralizing antibody responses against SARS-CoV-2 and have good safety profiles.

The researchers previously reported the results of a phase I/II clinical trial of CoronaVac in participants aged 18–59 years.

The results showed that CoronaVac was well tolerated and induced humoral responses against SARS-CoV-2. Seroconversion rates ranged from 92% to 100% after two doses of CoronaVac (3 µg and 6 µg) administered 2 or 4 weeks apart.

What did the current study involve?

Now, the team has conducted a randomized, double-blind, placebo-controlled, phase I/II clinical trial to assess the safety, tolerability, and immunogenicity of CoronaVac in adults aged 60 years and older.

"This is the first report of an inactivated SARS-CoV-2 vaccine, CoronaVac, tested in older adults (aged 60 years or older)," writes Yin and colleagues.

Phase I involved 72 participants, aged a mean of 65·8 years, who were enrolled between May 22nd and June 1st, 2020. Phase II involved 350 participants, aged a mean of 66·6 years, enrolled between June 12th and June 15th, 2020.

For phase 1, a dose-escalation study was performed with participants randomly assigned to receive 3 µg or 6 µg doses of either CoronaVac or placebo 28 days apart.

For phase 2, participants were randomly assigned to receive 1·5μg, 3µg, or 6µg doses of CoronaVac or placebo 28 days apart.

The primary safety endpoint was adverse reactions within the 28 days following each injection. The primary immunogenicity endpoint was seroconversion rate 28 days following the second injection.

Seroconversion was defined as a change from seronegativity at baseline to seropositivity for neutralizing antibodies against live SARS-CoV-2. For those who were seropositive at baseline, seroconversion was defined as a four-fold increase in anti-SARS-CoV-2 neutralizing antibody titer.

What were the findings?

The researchers found that two shots of CoronaVac were safe and well-tolerated at doses of 1·5μg, 3μg, and 6μg among adults aged 60 years and older.

"The results were similar to our study of adults aged 18–59 years," says the team.

Across both phases, adverse reactions within 28 days of injection occurred at a rate of 20% in the 1·5μg group, 20% in the 3μg group, 22% in the 6μg group, and 21% in the placebo group.

"The incidence of adverse reactions in different dose groups was similar, indicating that there was no dose-related aggravation concern with regard to safety," writes Yin and colleagues.

Moreover, all adverse reactions were mild or moderate in severity and pain at the injection site was the most commonly reported (9%) event.

The researchers say, "CoronaVac is safe and well-tolerated in older adults."

What about immunogenicity?

In phase I, seroconversion was observed in 24 of 24 (100%) participants in the 3μg group and in 22 of 23 (95·7%) participants in the 6μg group.

In phase 2, seroconversion was observed in 88 of 97 (90.7%) participants in the 1·5μg group, 96 of 98 (98.0%) in the 3μg group, and 97 of 98 (99·0%) participants in the 6μg group.

"Among the three doses evaluated, the neutralizing antibody titers induced by the 3μg dose were similar to those of the 6μg dose and higher than those of the 1·5μg dose," writes Yin and colleagues.

"Combined with the safety and production capacity, the 3μg dose of CoronaVac with a two-dose immunization schedule is being used in the ongoing phase 3 trials to assess protection against COVID-19," says the team.

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