Vaccine profiles: Tuberculosis
Efforts to fight the world’s biggest infectious killer are about to get a boost, with new vaccines on the horizon.
- 24 October 2023
- 7 min read
- by Linda Geddes
Tuberculosis is the world's biggest infectious killer, claiming approximately three lives every minute. Growing resistance to antibiotics is also making it harder to treat. Besides the fear of dying from the disease, in many communities a diagnosis can sentence someone to months or years of and social isolation, which can delay them seeking care or adhering to treatment. Not only does TB kill an estimated 1.5 million people every year, but it also destroys families and livelihoods.
More than 100 years since the first administration of the BCG vaccine, hopes are building that a vaccine that could protect all age groups against all types of TB may finally be in reach.
Despite efforts to control the disease in recent decades, TB remains the 13th leading cause of death worldwide, and the leading infectious killer. Growing resistance to drugs is also making the disease deadlier and more difficult to treat. While the Bacillus Calmette–Guérin (BCG) vaccine provides significant protection against TB disease in infants and young children, new vaccines that block infection and prevent TB disease in adolescents and adults, who account for the greatest burden of disease, are urgently needed. Fortunately, several vaccine candidates are now in late-stage clinical trials, raising hopes that an affordable and effective vaccine may soon be within reach.
Ancient scourge
TB is thought to be as old as humanity itself, infecting our early human ancestors before they even migrated out of Africa 70,000 years ago. It is caused by a bacterium called Mycobacterium tuberculosis, which usually attacks the lungs, but may also attack other tissues, including the kidneys, brain, bones, or skin. Globally, around a quarter of people are thought to have been infected with TB bacteria, but these can remain dormant for many years (a latent infection) and only 5–10% of infected individuals will ever develop TB disease.
Symptoms of TB disease include a prolonged cough (sometimes with blood), chest pain, fever, night sweats, fatigue, weakness, and weight loss. People become contagious if they develop TB disease, but because their symptoms may be mild for many months, it is easy for them to infect others without knowing it.
In 2021, an estimated 10.6 million people fell ill with TB, and 1.6 million died from it – including 187,000 people with HIV. TB and HIV are a particularly lethal combination, as HIV weakens people's immune systems, making it easier for TB to take hold. Diabetes, tobacco use and being malnourished also increase people's risk of developing TB disease.
Early discoveries
M. tuberculosis wasidentified in 1882 by the German microbiologist Robert Koch. Within 20 years, a Danish physician called Niels Finsen had developed an effective treatment for the disfiguring skin form of tuberculosis, which involved exposing people to ultraviolet light. Light therapy was a mainstay of treatment until antibiotics against TB were discovered in the 1940s, with people being sent to sanatoria both to prevent transmission of the disease, and to aid recovery through a combination of sunshine, fresh air and exercise.
Today, both TB infection and disease are treated with antibiotics, but these must be taken for four to six months to be effective. Stopping these drugs early can be dangerous because it increases the risk of treatment-resistant infections. Multidrug-resistant tuberculosis (MDR-TB) is TB that does not respond to the two most effective first-line antibiotics. Second-line drugs exist, but they are more expensive and toxic. However, more extensively drug-resistant TB is a growing problem. If it develops, patients are left with limited treatment options.
Vaccine development
The BCG vaccine was developed by Albert Calmette and Camille Guérin at the Pasteur Institute in Lille, France, in the early 20th Century, using a cattle strain of the bacterium, called Mycobacterium bovis. In 1908 Calmette and Guérin began growing these bacteria in their laboratory, transferring a subculture to fresh growth medium every three weeks to keep them alive. Over time, the researchers discovered that the ability of these bacteria to cause disease was changing. Thirteen years and 230 subcultures later, they had a strain that no longer made cattle ill, but equipped them and other animals with immunity against tuberculosis.
In 1921, an oral dose of the vaccine was given to a human infant whose mother had died from tuberculosis a few hours after giving birth. The infant survived, and over the next three years hundreds more infants received the vaccine. In 1924, this BCG vaccine began to be mass produced, with millions of infants immunised during the 1920s and '30s.
Modern BCG vaccines
Today's BCG vaccines are based on different attenuated strains of M. bovis and they are given by injection just under the skin (intradermally), rather than by mouth. These vaccines are recommended for newborns in countries with high burden of TB and are among the most widely used of all vaccines, reaching more than 80% of infants in countries where the BCG vaccine is included in routine childhood immunisation programmes.
However, while it has saved many lives, the BCG vaccine is not perfect: Estimates of its efficacy in preventing TB and how long immunity lasts for vary between countries, but according to a recent review and meta-analysis published in The Lancet Global Health, BCG vaccination at birth provides significant protection against TB disease until children are around five years old, which is important because tuberculosis in children is a highly debilitating and severe disease.
Have you read?
Unfortunately, this protection was shown to wane as children get older and the vaccine provided no protection for adolescents or adults – who account for the bulk of TB infections and disease transmission. The BCG vaccine also doesn't prevent people from becoming infected with M. tuberculosis, meaning it can still spread through communities. To end the TB epidemic, vaccines are needed that are effective against all forms of TB in all age groups, and which prevent transmission of the bacteria that cause it.
Future vaccines
In 2014 and 2015, World Health Organization (WHO) member states and the United Nations committed to ending the TB epidemic through their adoption of WHO's End TB Strategy, which aims to reduce TB incidence by 80% and TB deaths by 90% by 2030. Achieving this will require the introduction of major technological breakthroughs by 2025, such as a vaccine that is effective both before and after exposure, WHO said.
There are currently at least 20 TB vaccines for adults and adolescents in clinical pipeline. Of particular interest to Gavi, the Vaccine Alliance, is the M72/AS01E (M72) candidate vaccine, which, it is hoped, could receive WHO prequalification (a prerequisite for purchase by United Nations agencies and Gavi) by 2030, subject to Phase 3 trial results. Immunocompromised individuals living with HIV are being included in these trials, which is important because if they are successful, it would allow these high-risk groups to also be vaccinated against TB.
M72 is a protein subunit vaccine combining two M. tuberculosis antigens with an adjuvant system (AS01E) that enhances the immune response to the vaccine. It is designed to be given by intramuscular injection to 15- to 44-year-olds, with two doses spaced a month apart.
In a recent Phase 2b trial, M72 showed approximately 50% efficacy in reducing pulmonary TB in adults with latent TB infection (where people are infected with the bacteria that cause TB, but they are in a dormant state). In June 2023, Wellcome and the Bill & Melinda Gates Foundation announced funding to advance the vaccine through a Phase 3 trial involving approximately 26,000 people, including people living with HIV and without TB infection, at more than 50 trial sites in Africa and Southeast Asia.
Other candidates of potential interest to Gavi include the VPM1002 vaccine, which uses a live attenuated strain of M. bovis that has been genetically modified so that immune cells can better recognise and respond to it; and the MTBVAC vaccine, which uses a genetically modified live attenuated strain of M. tuberculosis. Because MTBVAC is based on the human TB bacterium, rather than the cattle one, it is hoped it will trigger a broader immune response.
More than 100 years since the first administration of the BCG vaccine, hopes are building that a vaccine that could protect all age groups against all types of TB may finally be in reach. Humans have been fighting this ancient pathogen for millennia, but it seems the battle may finally be swinging in our favour.
More from Linda Geddes
Recommended for you
