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Innovation

The 5 Stages of COVID-19 Vaccine Development: What You Need to Know About How a Clinical Trial Works

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Johnson & Johnson just announced the launch of a Phase 3 clinical trial for its COVID-19 vaccine candidate. But what does this step in the process really mean? We asked two experts whose job it is to test vaccines to help demystify the clinical trial process—step by step.

ohnson & Johnson is known for its longstanding commitment to fighting emerging epidemics around the world.

In July, the company's Ebola vaccine was granted Marketing Authorization by the European Commission. Company scientists are also actively researching vaccine candidates for HIV and RSV.

So it should come as no surprise that since the early days of the COVID-19 pandemic, the company has been working closely with industry partners, governments, universities and health authorities to develop a preventive vaccine against SARS-CoV-2, the virus that causes COVID-19.

It can take up to a decade to go from vaccine discovery and development to approval, but scientists at the Janssen Pharmaceutical Companies of Johnson & Johnson are aiming to get it done in a much shorter time frame. The ultimate goal: supply a safe, effective vaccine in 2021.

“Every day that we’re able to accelerate the process could mean potentially hundreds, even thousands, of lives saved down the road,” says Macaya Douoguih, M.D., MPH Macaya Douoguih, M.D., MPH, Head of Clinical Development & Medical Affairs, Janssen Vaccines, Head of Clinical Development & Medical Affairs, Janssen Vaccines.

At the same time, vaccines have to go through rigorous testing and scrutiny to ensure safety, because they’re given to healthy people to prevent them from getting sick. This holds true even with the urgency to develop a potential vaccine for COVID-19.

“We’re committed to not cutting corners in any way when it comes to developing a safe and effective vaccine,” says Dirk Redlich, Ph.D., Dirk Redlich, Ph.D., Head, Chemistry, Manufacturing and Controls (CMC) Development and Clinical Trial Material (CTM) Manufacturing, Janssen Vaccines Head, Chemistry, Manufacturing and Controls (CMC) Development and Clinical Trial Material (CTM) Manufacturing, Janssen Vaccines. At each step, Janssen works closely with regulatory authorities to make sure it’s meeting all requirements.

So what exactly does it take to create a vaccine?

Throughout this pandemic, you've likely heard terms like Phase 1-2a trial and FDA approval, but what do these really mean—and at what point do they happen?

We asked Dr. Douoguih and Dr. Redlich to help break down the process for us—just as the company is launching the Phase 3 trial of its COVID-19 vaccine candidate, enrolling up to 60,000 volunteers across three continents.

1.

Preclinical Stage: How will this vaccine work?

This research-intensive stage is designed to find natural or synthetic antigens—foreign substances that induce an immune reaction in your body—that trigger the same reaction an actual virus or bacteria would. Identifying the right antigen or antigens can often take up to four years.

Janssen has been investigating candidates for a potential SARS-CoV-2 vaccine since January 2020. By March 30, the company was able to announce that a lead vaccine candidate had been identified.

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“Usually, you look at several different vaccine candidates and ultimately choose the one that has the best immune response and evidence of protection,” Dr. Douoguih says. This stage of preclinical work generally lasts one to two years.

Janssen has been investigating candidates for a potential SARS-CoV-2 vaccine since January 2020. By March 30, the company was able to announce that a lead vaccine candidate had been identified, with two backups.

How was this accomplished in a matter of months, rather than years?

Janssen already has a tested vaccine technology platform, called AdVac®, that’s been used in its Ebola vaccine, as well as investigational vaccines for HIV and RSV. The AdVac “viral vector”—a version of adenovirus 26 (Ad26), which normally causes common colds, but that’s been disabled so it can’t make you sick—transports part of a pathogen's genetic code into the body. This stimulates the immune system to fight the disease caused by the virus so that you develop immunity to that disease without actually developing the disease itself.

“Our investigational vaccine produces an antigen, or protein, which should cause the body’s immune system to react and get rid of the novel coronavirus,” Dr. Redlich explains.

2.

Phases 1/2a and 2b: Is it safe, and what's the right dose?

Phase 1 testing marks the first time the vaccine is tested in a small group of adults, usually between 20 to 80 people, to evaluate its safety and measure the immune response it generates. Phase 2a studies aim to determine the most effective dose, and expand the safety experience with the vaccine.

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Janssen’s investigational vaccine candidate ready for Phase 3 trials

Researchers look for expected reactions to the vaccine—which could include anticipated adverse events, like headache, muscle pain, redness and swelling at the injection site or low-grade fevers—as well as serious adverse events, which are expected to be rare, over the entire duration of the study.

“We want to make sure that when it comes to safety, we’re taking precautions,” Dr. Douoguih says.

Phase 1 and 2a clinical trials normally last several months to even a year before proceeding to Phase 2b or Phase 3 trials, in which the pool of people receiving the vaccine increases.

Janssen combined Phase 1 and Phase 2 trials for its investigational SARS-CoV-2 vaccine into one phase, known as Phase 1/2a—a step it often takes with its vaccine platform in order to answer many questions in one study, at one time.

“Our discovery and manufacturing teams have a process that they both go through and most of the steps are sequential. They managed to do some of those sequential steps in parallel, without compromising the integrity of the vaccine candidate,” Dr. Douoguih explains. “This is what really enables us to move that timeline up so substantially, from a year or more to just months, to get to 1/2a.”

In July, the company began testing its investigational vaccine in over 1,000 healthy adults between the ages of 18 and 55 in the United States and Belgium, home to a large Janssen site, as part of that 1/2a phase. People ages 65 and over were then recruited as well.

“During this phase, we really zero in on establishing safety and finding the correct dose,” Dr. Douoguih says. “We observe people’s symptoms for seven days after each vaccination, as well as reassess them within a month. The good news here is, because we have a lot of experience with Ad26, we have a strong sense of the best doses to use.”

Johnson & Johnson has identified clinical study sites in cities that have underserved and underrepresented populations, and has partnered with organizations to proactively identify and target diverse patient populations.

3.

Phase 3: How effective is the vaccine?

In this stage of the clinical trial, even more volunteers receive the vaccine to study whether it's effective.

In September, Janssen scientists plan to administer the investigational SARS-CoV-2 vaccine to tens of thousands of healthy people, as well as those particularly vulnerable to COVID-19 in areas where the highest rates of viral transmission are.

In preparation for this phase of the study, Janssen worked with leading epidemiologists and modelers around the world to predict these hot spots.

In September, Janssen scientists plan to administer the SARS-CoV-2 vaccine to tens of thousands of healthy people, as well as those particularly vulnerable to COVID-19.

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Before volunteers are vaccinated, they will be tested to make sure they currently do not have the SARS-CoV-2 virus. Half of the group will be assigned to receive the vaccine; the other half will receive a placebo. Then they will all be followed closely for up to two years to see if they do develop COVID-19-related symptoms, such as fever, headache, shortness of breath, dry cough or gastrointestinal distress.

"It may be that some people do go on to develop COVID-19, even after having been vaccinated, but they may have substantially milder symptoms than those who develop COVID-19 in a control group,” Dr. Douoguih says.

As in previous phases, adverse events can potentially occur and are not uncommon, particularly in large studies like this. If an unexpected serious adverse event (SAE) occurs, recruitment or medication dosing may be paused so all pertinent medical information can be reviewed before deciding whether to restart the clinical trial. A clinical study might also be required to go on a regulatory hold by a regulatory health authority, such as the U.S. Food and Drug Administration (FDA).

Phase 3 trials can sometimes take years. But Janssen hopes to get results much sooner—in a year or less—by creating as large a trial as possible, with up to 60,000 people.

4.

Regulatory approval and licensure: Is it ready for the world?

After a successful Phase 3 trial, vaccine manufacturers submit an application to regulatory bodies such as the European Commission or the U.S. Food and Drug Administration (FDA). At this stage, clinical trial data is reviewed to make sure the vaccine is safe and effective.

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Janssen’s investigational vaccine candidate in a manufacturing facility in Leiden, the Netherlands

For FDA approval, “among the things we have to show is that the manufacturing process is consistent, and that we can produce consecutive batches of vaccine that induce the same immunity in people," Dr. Douoguih says.

Once the vaccine is approved, enough of the product needs to be manufactured to immunize those who need it. And in this case, Janssen will need to demonstrate that it can provide a supply of doses worldwide to the public, including underserved populations, on a not-for-profit basis for emergency pandemic use—a commitment it made in March as part of a landmark partnership with the Biomedical Advanced Research and Development Association (BARDA), part of the Office of the Assistant Secretary for Preparedness and Response (ASPR) at the U.S. Department of Health & Human Services.

The company aims to meet this goal by beginning to ramp up commercial scale manufacturing while clinical trials are still ongoing, with help from partners around the globe.

The vaccines will be produced at Janssen's facility in Leiden, the Netherlands, as well as in the U.S. and Italy.

5.

Phase 4: Will it stay safe down the road?

The end result: A potentially life-saving vaccine for COVID-19 that’s been developed in months, which is something that, up until now, has been virtually unheard of.

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Even after the vaccine is approved and licensed, regulatory agencies stay involved, continuing to monitor production; inspecting manufacturing facilities; and testing vaccines for potency, safety and purity.

The FDA also monitors adverse events that may occur related to receiving the vaccine, including through its Vaccine Adverse Event Reporting System and Phase 4 clinical trials—optional studies pharmaceutical companies may be required to perform after a vaccine is licensed to continue to monitor safety and effectiveness.

The end result: A potentially life-saving vaccine for COVID-19 that’s “been developed in months, which is something that, up until now, has been virtually unheard of,” Dr. Redlich says. “But there is an urgent medical need for us to do this, and do it safely.”

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Volunteers from diverse groups are needed to research an investigational vaccine.
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