Articles about the ongoing effort to create a vaccine for the novel coronavirus often include talk of "phases," as if vaccine production were akin to the moon. For instance, CNN reported earlier this month that Johnson & Johnson's coronavirus vaccine was "fourth to begin Phase 3 trials in the United States." NBC News reported earlier this week that "AstraZeneca's phase 3 clinical trial was put on hold in early September after a study participant in the U.K. developed a spinal cord injury." A headline from Fierce Pharma proclaimed, "Moderna, now wrapped on phase 3 enrollment, touts diversity of vaccine trial participants."
For those who don't work in the pharmaceutical industry, understanding the different phases of a vaccine, and what that means, can be confusing. And any similarities to the moon's phases are superficial: vaccine candidates don't wax and wane, per se.
Yet given the urgency with which a vaccine will let our lives continue as normal, following the internecine twists and turns of vaccine production has suddenly become front-page news. What exactly they mean is crucial for understanding what's going on. Here's a brief primer on what vaccine "phases" mean, and why it's important.
The meaning of clinical trial "phases"
Before any vaccine candidate can be released to the public, it first has to go through several stages of study, which researchers organize into discrete phases. Typically, "phase" is capitalized. Before any phase begins, scientists work to develop a vaccine candidate. Once that candidate exists, they produce a small number of trial vaccines.
Then comes the first phase. In Phase I, a trial vaccine is administered to a small group of people for initial testing. (The phases are sometimes referred to with Roman numerals, and sometimes with numbers; research institutions don't seem particularly consistent here.)
If Phase I goes well — meaning that "the vaccine appears safe and the people who get it mount a detectable immune response," according to Dr. Justin Lessler, an associate professor of epidemiology at Johns Hopkins Bloomberg School of Public Health — scientists can move on to Phase II. As Lessler added, however, "These trials are usually limited to healthy adult volunteers, but the exact composition will depend on the disease and who is at most risk."
"Generally, people that have the disease you are trying to prevent are not included," Dr. Georges Benjamin, executive director of the American Public Health Association, wrote to Salon. "Also, anyone that would be known to have a reaction to the vaccine or any of its components. For example, people with egg allergies are excluded from Influenza vaccine trials since the virus used is grown in eggs. Also, if it is a live virus that is used for the vaccine, you would exclude anyone that could get sick from this like a person on steroids or with an immune dysfunction. If they live with someone who might get sick from the live virus vaccine. Usually kids and pregnant women are excluded. [They] may also exclude by gender depending on the vaccines goal."
On to Phase II
Phase II expands that clinical study to include people from groups who are in particular need for a vaccine using, criteria such as age and health. According to Dr. Alfred Sommer, dean emeritus and professor of epidemiology at Johns Hopkins Bloomberg School of Public Health, these phases contain "larger number of healthy folks – to get better assessment (since now seemingly worth studying larger number) to better establish what was studied in smaller numbers" during the initial clinical trial phase.
"What would stop it there is the seeming lack of the responses you would like to see, or an abundance or severity of those you wouldn't," Sommer said. "If a trial of a therapy for disease you would hope to see some impact on small numbers of those involved who are infected. But for a vaccine – want to see good response but insufficient to have any idea whether it would be protective in real life."
During Phase II, as Medical Xpress explains, "these studies are usually not large enough for us to confirm the vaccine actually does what it needs to do, and that is to protect people from the infection it's designed to provide protection from." They instead serve the purpose of being as sure as possible that a vaccine candidate is safe.
Phase III is where things get exciting (and safer)
Phase III involves an even further expansion of that group, usually involving thousands of patients.
"Ideally diversity is always wanted throughout but it is essential to get gender and diversity addressed here in order to not miss concerns or efficacy concerns," Benjamin wrote to Salon. "Anything can go wrong from serious health complication to it is not as effective as the earlier study suggested with a smaller pool. Generally, we are still only including generally health people, but you might include people with some chronic diseases at some point because you want to know if the vaccine is protective in people with certain chronic diseases. [It] depends on the protocol and the vaccine."
He added that "once you show it is safe to use you still must show it prevents the disease." Benjamin observed that this can be done in two ways: "Put them in the real world around people that could infect them and see who does and does not get infected. The other thing you can do is infect them on purpose. Very controversial approach and most ethicists say you can only do this if you have an effective treatment or cure for the disease you are trying to prevent with a vaccine. This would not be appropriate for COVID-19 since we don't have effective antiviral agents."
Dr. Russell Medford, Chairman of the Center for Global Health Innovation and Global Health Crisis Coordination Center, told Salon, reinforced that view.
"In Phase III, scientists are directly asking the question for the first time whether the vaccine protects people against SARS-CoV2 and whether or not there are serious side effects not yet detected in the smaller, earlier Phase 1 and Phase 2 trials," Medford wrote to Salon. "To do this, a large population (thousands) is studied that better reflects the diversity of people likely to receive the vaccine once it is approved. Further additional studies are often required to look at specific populations such as the immunocompromised, elderly and children."
He added, "In a typical Phase 3 study design, volunteers are randomized to receive either the vaccine or a placebo. Scientists then monitor all the volunteers over time (months) to see who becomes infected or develops potential side effects. Neither the volunteers nor the scientists conducting the study know which volunteer has received the vaccine or placebo. It is only at pre-specified times, such as at the end of the study, that 'the blind is broken' and the number of infections and potential side effects is compared between the vaccine and placebo groups." For a Phase III trial to be considered successful according to Food and Drug Administration (FDA) guidelines, "the vaccine group must demonstrate a statistically significant 50% or greater reduction in COVID-19 cases compared with the placebo group" and "the vaccine group must demonstrate no significant increase in serious, life-threatening side effects compared with the placebo group."
The final phase is Phase IV
Finally, if a vaccine is approved and licensed after Phase III, many companies will continue through Phase IV of testing to make sure a given drug is effective and safe. If a drug reaches Phase IV, that means it has been approved by the FDA. According to the National Comprehensive Cancer Network (NCCN), this means that "the drug is tested in several hundreds or thousands of patients," which "allows for better research on short-lived and long-lasting side effects and safety." This phase will often continue well after a vaccine is in widespread, common use.
I see stories about vaccine makers doing multiple phases at once. How does that work?
Yes, phases can also be blurred together.
"The phases are discreet — one, two and three — but sometimes companies can enter into approval with the Food and Drug Administration to combine elements of a safety study with an efficacy study," Medford told Salon. "That would be called a Phase I/II. And in Phase II/III, it's an agreement with the regulatory agency that will not only establish a dose finding, shall we say, but the study will be a sufficient size that efficacy results and safety results may be incorporated into a final package for a consideration for approval. It's not unusual to combine them."
What happens if you rush a vaccine without doing all these steps, as Russia and other countries appear to be doing?
"These steps reflect long years of experience and lessons learned by scientists, doctors, statisticians and government regulators in the US and the world in developing safe and effective vaccines against many of the world's most serious infectious diseases," Medford told Salon. "Today's extraordinarily rapid development and testing of COVID-19 vaccines in the US and Europe is based on new science, technologies and approaches that embrace and build upon these lessons. However, by ignoring these lessons, such as the approval of a vaccine without a large scale Phase 3 clinical trial to assess safety and efficacy, we run the risk of deploying a vaccine to millions of people that is neither protective against SARS-Cov-2 nor safe."
Dr. Lessler added, "The biggest risk is you get an ineffective, or even dangerous, vaccine. This can not only be dangerous in and of itself, but can make it harder to get a future vaccine approved or widely used by the population."
What are vaccines made of? How do they work?
A vaccine is a medical tool used to either prevent or therapeutically treat specific infectious diseases. Most vaccines work by containing agents that resemble microorganisms which normally cause diseases; usually they are either weakened forms of the bacteria or virus that cause the disease, or else they contain the surface proteins and toxins associated with those microorganisms. The underlying goal is to help the body develop a proper immune response so that it will be able to protect itself from other diseases like it.
This is a painstaking process, one that requires repeated trial and error so that scientists can both guarantee that a given vaccine is effective and so that they will not accidentally give someone a drug that makes them sick, or perhaps even kills them. Rushing a vaccine can lead to "inflammatory reactions in the body when the body rushes to try to generate antibodies and T-cells against the 'antigens' or proteins in the vaccine formulation," Dr. Monica Gandhi, infectious disease doctor and professor of medicine at the University of California–San Francisco, told Salon last month.
For vaccines to work, however, a large number of people must actually use them. One of the major concerns held by scientists today is that anti-vaccine conspiracy theories will scare people off of getting a coronavirus vaccine if and when one is developed.
"We very clearly know that, if we don't get 70-something percent of the population covered, we will probably not get to herd immunity," Benjamin told Salon in May. "There are some people that think that, with this virus, we might be able to achieve it with 50 percent, so that's not 100 percent. But I'm thinking that 70-something percent is about where we need to be, and it's because I've looked at some of the data. We may achieve it with 50 percent, but the bottom line is we'd run the risk of not getting herd immunity with the vaccine."
What is herd immunity?
"Herd immunity, or community immunity as I like to call it, is the indirect protection we get because people around us are immune to the disease," Dr. Lessler wrote to Salon. "The basic idea is if there are fewer people around me who can get sick, then there will be fewer people around who can infect me, so I will be less likely to get infected even if I am not immune to the disease myself. Herd immunity is a more general concept, but when people use the term they often mean herd protection; which is the point where there is so much immunity in the population that a community would not be able to start an epidemic if someone in that community got infected."
He added, "For SARS-CoV-2 it seems reasonable rough estimate of this amount of immunity needed to achieve this is 50-80% of people being immune."
Medford expressed a similar thought, writing to Salon that "herd immunity occurs when the spread of a disease, such as COVID-19, from person to person becomes unlikely because a high percentage of the community in which the person lives (approximately 70%) is immune to the SARS-CoV-2 virus, primarily through vaccination but also by contracting and surviving the COVID-19 disease itself. In this manner, herd immunity could help protect the rest of the community (up to 30% of the population) that is not immune to the SARS-CoV-2 virus."
Why has the novel coronavirus presented such a tough challenge?
The main problem, as Dr. H. Cody Meissner wrote for American Academy of Pediatrics News, is that the SARS-CoV-2 virus is very poorly understood. Vaccines take a long time to develop even when a disease has been around for a while, but because SARS-CoV-2 entered human beings less than a year ago, scientists have more work to do than would otherwise be the case.
This does not mean we should lose hope, however.
"It is encouraging to see so many players in the field, many using very different platforms (forms of vaccines)," Sommer told Salon by email last month. "This clearly increases the likelihood that at least one if not more of these vaccine candidates will prove safe and effective. Some are likely to prove more effective than others at reducing the risk of subsequent infection, and provide such protection for longer periods of time. The lessons we learn from each approach might well increase the likelihood, and the speed, at which even more effective vaccines are developed."
Which vaccine candidates are showing the most progress?
According to MarketWatch, there are only four major vaccine candidates right now that are currently in Phase III trials. These include one being developed by AstraZeneca in partnership with the University of Oxford, one being developed by BioNTech and Pfizer Inc., one being developed by Johnson & Johnson and one being developed by Moderna. AstraZeneca currently says they expect data by the end of the year, although they halted trials in the United States in early September due to an adverse event;
Last week Pfizer CEO Albert Bourla announced that the pharmaceutical giant may apply for emergency federal approval of its coronavirus vaccine by as soon as late November. This marks the first time a drug company has offered a possible specific time for a vaccine to be ready for public use.