Q&A: Understanding challenges behind developing second TB vaccine

Currently, the Bacillus Calmette-Guérin vaccine from 1921 is the only available vaccine for tuberculosis, according to a press release from the European Society of Clinical Microbiology and Infectious Diseases.

As Healio previously reported, WHO’s 2022 global report showed that 10.6 million people were diagnosed with TB in 2021, a 4.5% increase from 2020 that demonstrates how the disease has become even more widespread over recent years.

According to the Stop TB Partnership, five new TB vaccine candidates are being tested in phase 3 trials as of November 2022. These TB vaccines show promise, but long study periods followed by regulatory evaluation and approval are required before they can be manufactured and put into use.

To learn more about TB and the challenges associated with vaccine development, Healio spoke with Frank Cobelens, MD, MSc, PhD, professor of global health at University of Amsterdam and chair of the executive board of the Amsterdam Institute for Global Health and Development in the Netherlands, who recently gave a presentation on the topic at the 2023 European Congress on Clinical Microbiology & Infectious Diseases.

Healio: What does the TB epidemic look like in today’s world? How effective is the current TB vaccine in preventing the disease?

Cobelens: TB is still a major cause of suffering and death globally. Although high income countries, where TB was still rampant in the first half of the 20th century, have seen enormous reductions in TB incidence and the disease has become more or less something of the past, most low-income countries still have very high rates of TB. This is due to poor living conditions, HIV infection, other comorbidities such as diabetes, and poorly functioning health systems.

TB is a treatable condition. Although treatment takes at least 6 months, most patients are cured. Despite this, mortality due to TB remains high because the disease is typically chronic and sometimes difficult to diagnose, and many people who have TB remain untreated. Over the past 20 years, despite control efforts, the global incidence of TB has only declined to very limited extent.

The current TB vaccine, Bacillus Calmette-Guérin (BCG), is used as a preventive vaccination shortly after childbirth. It has rather high efficacy (75%-85%) against disseminated TB in infants, but inconsistent efficacy against pulmonary TB which is the most important clinical presentation from the ages of 12 to 15 years onward and is the form of the disease that is infectious to others. BCG is therefore rarely used beyond childhood.

Healio: Why has it been challenging to develop new and effective vaccines for TB?

Cobelens: There are two reasons for this, and the first one is scientific reasons. We have insufficient understanding about the immune mechanisms that define protection against disease. The animal models that are being used to test candidates preclinically (mice, guinea pigs, nonhuman primates) are currently not very good at predicting how well a vaccine candidate will provide clinical protection in humans. We also don’t have agreed correlates of protection, that is laboratory assays that indicate that an individual is protected against infection with Mycobacterium tuberculosis or against TB disease once infected. Together, this means we can only have a reliable indication of whether a vaccine candidate will offer protection in humans when we test them in large, expensive clinical trials.

The second reason is a lack of funding. To put things in perspective, although globally deaths from TB surpass the number of deaths from HIV, the amount of funding available for TB vaccine development is several-fold less than for HIV vaccine development.

Healio: In a press release from the European Society of Clinical Microbiology and Infectious Diseases, you said that WHO looks for evidence of prevention of disease (POD) when licensing TB vaccines but several trials in progress are not looking at this outcome. What is difference between POD, prevention of infection and prevention of recurrence? Why are the researchers behind these clinical trials not looking for POD?

Cobelens: POD is in the end what you want a TB vaccine to do. However, trials that measure POD as the primary outcome need to be large and of long duration, which means they are expensive and difficult to conduct. Trials that look at prevention of infection (POI) or recurrent TB (POR) as outcomes can be much smaller and shorter. In POI trials, one compares the rate of infection tests (eg, interferon-gamma release assays, or IGRA) becoming positive over time between the vaccine and a control group, and these rates are much higher than for TB disease. In POR, one compares the rate of TB recurrence in people who have just been successfully treated. This rate is also much higher than if one would follow individuals who have never had TB. That is why researchers often try such trials first before moving to a large POD trial. The problem, however, is that we cannot be sure that a vaccine that shows POI or POR in such “proof-of-concept” trials will eventually show POD in a large regulatory trial and vice versa.

Healio: What benefits will come with more licensed TB vaccines? How will the vaccines ease the burden of TB on patients and clinicians?

Cobelens: If we would have one or more vaccines that are effective in preventing TB disease at adolescent or adult age and can be effectively delivered to the population in countries and regions where TB rates are still high, this would help to substantially reduce the incidence of the disease and thereby of suffering, mortality and likely of onward transmission of the infection to others.

For more information:

Frank Cobelens, MD, MSc, PhD, can be reached at f.cobelens@aighd.org.

References:

• More than 100 years after the first TB vaccine, why are we still waiting for a second? https://www.eurekalert.org/news-releases/979833. Published Feb. 15, 2023. Accessed Feb. 16, 2023.
• Stop TB Partnership: TB Vaccine Pipeline. https://newtbvaccines.org/tb-vaccine-pipeline/. Updated Nov. 2, 2022. Accessed Feb. 21, 2023.