David Lewinsohn
Working Group on New TB Vaccines

Clinical trials of vaccine candidates, including TB vaccine candidates, generally progress through three phases.

Phase 1 clinical trials are the first clinical trials conducted in humans. Phase 1 trials usually are conducted in small groups of healthy adult volunteers, typically 20 to 30 persons. The main goals of phase 1 trials are to demonstrate the safety of the vaccine candidate, and to get preliminary information about the ability of the vaccine candidate to stimulate the desired kind of immune response.

How effective a vaccine is in stimulating an immune response is called the immunogenicity of the vaccine. If phase 1 trials don't identify any safety concerns and the preliminary data suggest the vaccine candidate is immunogenic, it can advance to phase 2.

Phase 2 trials are conducted with larger groups of participants. Early phase 2 trials, sometimes referred to as phase 2a trials, typically involve from 100 to 200 participants, but they can be larger. The goals of phase 2 trials are to further study the safety and immunogenicity of the vaccine candidate. Another key goal of phase 2 studies is to identify the optimal dose.

Multiple phase 2 trials may be done to test the safety and immunogenicity of the vaccine candidate in different populations, such as different age groups, people with or without TB infection, people living with HIV, and other populations most likely to use the vaccine.

Sometimes the vaccine developers choose to conduct an additional study to get a sense of the ability of the vaccine candidate to achieve its efficacy goal before moving on to a large, expensive phase 3 study. We refer to a study like this as a phase 2b trial. It is also called a proof of concept efficacy trial. A phase 2b trial is larger than earlier phase 2 trials, often requiring the enrollment of several thousand volunteers.

Phase 3 trials are intended to provide proof of vaccine candidate safety and efficacy that is strong enough to allow the vaccine candidate to be licensed for use. Phase 3 trials for TB candidates require tens of thousands of participants who need to be
followed for between three and five years. That's because TB disease can take two or more years to develop after TB infection. This is a very different scenario compared to studying vaccine candidates against COVID-19 because COVID disease usually develops
days after infection.

Because of their size, phase 3 trials of TB vaccine candidates need to
be conducted at multiple trial sites and may be tested in multiple countries or regions of the world in order to gather evidence of vaccine efficacy in different populations.

Clinical trials of vaccine candidates are different from clinical trials of drug candidates in that vaccines are usually tested in healthy volunteers. Vaccine researchers are required to wait until a certain number of volunteers get infected by TB or develop TB disease. They
then look to see which of those people who got infected or sick had received the vaccine candidate versus those who had received a placebo. This lets them determine how well the vaccine worked in that population, a measure that we describe as the efficacy of the
vaccine.

Throughout this process, vaccine trials are being conducted directly in communities, working in collaboration with volunteers often over periods of several years. So it is critical to follow best practices for community engagement. These practices are outlined in the Good Participatory Practice Guidelines for TB Vaccine Research. You can find a link to these guidelines in your module guide.

By now you might be wondering how much does this all cost?
Vaccine clinical trials cost anywhere from several million dollars for a phase 1 study to several hundreds of million dollars in a phase 3. Enough funding needs to be available in order to conduct a clinical trial. And this is where your advocacy is so important. As an
advocate, you can help mobilize the funding that's needed to move vaccine candidates through the phases of clinical testing.

If a vaccine demonstrates efficacy in a phase 3 trial, the company or organization that is leading the research, what we call the vaccine sponsor, then submits an application to a government regulatory agency for approval. This process is known as licensure or
registration. Each country or region has its own regulatory agency, often referred to as the national regulatory authority or NRA, which is responsible for reviewing the data collected during the vaccine development process and evaluating the evidence regarding the safety and efficacy of the vaccine candidate. The relevant NRAs then decide whether to approve the vaccine for use.

In order for UN agencies to purchase and distribute vaccines, like UNICEF for example, the vaccine also has to be reviewed and approved by the WHO through a process known as pre-qualification.
Even after vaccines are approved the vaccine sponsor continues to collect data on the vaccine safety and effectiveness in the real world.

The NRA that approved a vaccine may also require the vaccine developer to continue studying the long-term effects of the
vaccine. These studies are referred to as phase 4 post-licensure studies and can provide important information such as the potential need for booster vaccinations. Such studies can also help identify any uncommon safety issues that were not identified during the
phase 1, 2 and 3 studies.