In a critical global public health development, a vaccine candidate has been created for tuberculosis (TBC) using a gene editing approach.
Why not underestimate tuberculosis
Tuberculosis remains the leading cause of death from infectious diseases globally, with South Africa having one of the highest incidence rates in the world.
Although the BCG vaccine used to prevent TB is widely available for newborns, no vaccine has demonstrated long-lasting protection. BCG is also the only effective vaccine in existence.
“South Africa is committed to achieving the sustainable development goal of ending the tuberculosis epidemic by 2030. While we are doing relatively well as a country – tuberculosis deaths have fallen since 2015 – we need to do much better to achieve these goals,” says the professor. Bavesh Kana.
Kana, dean of the School of Pathology and former director of the Center of Excellence for Biomedical Tuberculosis Research at Wits University, contributed to the new study published in eLife.
Researchers modified the BCG vaccine to make it more effective at controlling the growth of M. tuberculosis. Mice injected with the modified BCG vaccine had less growth of M. tuberculosis in their lungs than mice that received the original vaccine.
“We can now offer a new vaccine candidate in the fight against this deadly disease,” says Kana. “The work also demonstrates that gene editing is a powerful way to develop vaccines. This is especially important for researchers working on vaccine development.”
The BCG vaccine is given to babies at birth and is effective in preventing tuberculosis disease. However, BCG does not protect adolescents and adults and has not been effective in eradicating tuberculosis.
This has spurred the need to develop new tuberculosis vaccine candidates to replace or augment BCG.
“We also see that BCG can evade the immune system and that this reduces its effectiveness as a vaccine,” Kana says. She noted that the importance of vaccines cannot be overstated.
When humans get sick, the body’s defense system detects particular signs, called PAMPs (pathogen-associated molecular patterns), on the outside of bacteria, viruses or other harmful germs.
This helps the body distinguish between the invaders and its own cells and thus begin to fight the infection.
Vaccines work by resembling germs, so they can initiate the first defense without making a person sick.
Kana lamented the funding gap in developing tools to eliminate tuberculosis, a disease that dates back more than 9,000 years. “Until recently, our diagnostic approaches were a century old. With some new vaccine candidates in the pipeline, we can finally begin to adequately address this devastating disease.”
It’s time for innovation
Tuberculosis is one of the oldest infectious diseases ever recorded in history. Most people with TB live in low- and middle-income countries where the disease is a leading cause of death. This is especially distressing given that tuberculosis is preventable, treatable and curable. But there is currently only one approved vaccine against tuberculosis. And it’s 100 years old.
The first dose of the Bacille Calmette-Guérin (BCG) vaccine was administered on 18 July 1921. Conversation Africa’s Ina Skosana asks key questions to Bavesh Kana, one of South Africa’s leading tuberculosis researchers.
The BCG vaccine was developed from a strain of bacteria called Mycobacterium bovis. These organisms closely resemble the bacteria that cause tuberculosis in humans ( Mycobacterium tuberculosis ) and are usually found in animals suffering from tuberculosis-type disease.
The vaccine was generated over a 13-year period (roughly 1908 to 1921) by two French scientists, Albert Calmette and Camille Guérin, hence the name Bacillus Calmette-Guérin.
Little did they know at the time that it would become one of the most widely administered vaccines in human history. BCG has been used worldwide to protect against the development of tuberculosis. However, because TB has primarily been a disease of the poor, there has been insufficient investment in the development of new vaccines over the past century.
Currently, BCG remains the only widely available vaccine against tuberculosis. This is sad, as the rapid mobilization to develop a Covid-19 vaccine over the past year has demonstrated that the world has the capacity to quickly create vaccines.
Yet a new tuberculosis vaccine has languished for decades due to poor funding, insufficient resources and diminished political will. Millions of people have died, which I believe we now appreciate with a new urgency in the context of COVID-19.
Vaccine innovation is needed for tuberculosis because the protection provided by the existing vaccine fades over time and is not fully effective in adults.
Developing vaccines and treatments is an incredibly expensive undertaking. Conducting multicenter clinical trials to demonstrate safety and efficacy in diverse populations over a period of years can cost billions. This requires concerted investments through partnerships with all stakeholders, including governments of TB endemic countries.
BCG is usually given only to newborns, soon after birth, in countries with a high incidence of tuberculosis. The vaccine therefore produces an early immune response which has been shown to protect children from severe forms of TB. In particular, BCG protects very well against the development of widespread forms of tuberculosis. TB usually occurs in the lungs, but the bacteria can also be found in other parts of the body: this phenomenon is called dissemination.
In children, bacteria can be found in the brain: this disease is called tuberculous meningitis. The BCG vaccine is very effective in protecting against tuberculous meningitis and is a great example of how vaccines can be of enormous benefit.
This immunity usually wanes during adolescence and later. The protection provided by BCG in adults is highly variable, ranging between 0% and 80% depending on the country and environment. The reasons for this remain a mystery, and much effort has recently gone into developing biomarkers that will identify which new vaccines will ultimately produce long-lasting immunity.
Biomarkers are signals that can be detected in blood or other clinical samples that give a predictive sense of a vaccine’s effectiveness. If a certain set of signals in the blood predicts good protection, we can test whether a new vaccine also induces the same set of signals.
We still have a long way to go. There have been two promising developments recently.
The first is a study showing that revaccination with BCG actually provides protection against tuberculosis disease. This is exciting since BCG is an approved vaccine and if this approach demonstrates long-lasting, long-lasting protection, rolling out mass vaccination campaigns will be easier than starting with a new vaccine.
The second comes from a study showing that a new vaccine from GSK (M72/AS01E) provided good protection in a clinical trial setting. In 2020, this vaccine was licensed to the Bill & Melinda Gates Medical Research Institute for continued development.
Better treatment
Today tuberculosis is treated with antibiotics. Treatment is often long-lasting and not everyone recovers. Researchers at the Statens Serum Institute in Denmark have been working on developing new vaccines against TB for many years.
A new study conducted at Oslo University Hospital shows that the so-called H56:IC31 vaccine, developed in Denmark, can also be administered to people who have already fallen ill. The vaccine can help the immune system attack and fight tuberculosis bacteria and may represent a relevant treatment option in addition to antibiotics.
“The most important finding of our study is that it is safe to administer what we call a therapeutic vaccine, that is, a vaccine used as a treatment, to patients who have ongoing tuberculosis disease. The study also shows that the vaccine strengthens the part of the immune system that has to fight tuberculosis bacteria,” explains Anne Margarita Dyrhol-Riise, who led the study.
Dyrhol-Riise is an adjunct professor at the Institute of Clinical Medicine and chief physician at the Department of Infectious Diseases at Oslo Ullevål University Hospital.
The immune system plays a key role in the development of tuberculosis disease. Individuals who become ill very often have been infected with the tuberculosis bacterium at some point in their lives. In areas with a lot of tuberculosis, people are often infected in childhood.
However, most people do not get sick, but contract a condition called latent tuberculosis. A small residue of the tuberculosis bacterium therefore remains in the body.
“The immune system keeps the infection under control and the person appears to be completely healthy. However, later in life, some people’s immune systems may be weakened by illness or as the person ages. Then, immune cells can no longer protect the body infection from tuberculosis bacteria. Only then does the person get sick,” explains Dyrhol-Riise.
Danish researchers had initially developed the vaccine to have a preventive effect, that is, to prevent people infected with the tuberculosis bacteria from getting sick. However, Dyrhol-Riise and the study team wanted to see whether it is possible to use the vaccine to treat tuberculosis when the person has already become ill.
The results of the new study indicate that this is indeed the case. The study shows that the vaccine can help the immune system attack and fight tuberculosis bacteria in sick patients.
“We saw that patients who received the vaccine had a greater number of immune cells, i.e. T cells, which can fight the tuberculosis bacterium,” he says.
Dyrhol-Riise says the study results indicate that more tuberculosis patients can be cured and/or recover more quickly if they receive the vaccine in addition to antibiotics.
This is especially true for patients who have developed multidrug-resistant tuberculosis, meaning that the bacteria that cause tuberculosis have become resistant to several types of antibiotics.
The antibiotics we have today are not effective enough to treat all individuals with resistant tuberculosis.
“The aim of the project was to demonstrate that a therapeutic vaccine should be included in a treatment regimen alongside antibiotics for patients with resistant tuberculosis,” he says.
He hopes the vaccine will allow more individuals to be treated and provide better care.
It is conceivable that the vaccine, as part of treatment in addition to antibiotics, could shorten treatment times even for those patients who have not developed resistant tuberculosis,” says Dyrhol-Riise. “But we need to study this further in larger groups of patients, including those with resistant tuberculosis bacteria, before we can finally conclude with such an effect.”
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