28 Devastating Infectious Diseases

Every Year, Tuberculosis Kills Over A Million People. Can A New Vaccine Turn The Tide?

It's 2024, and people are still dying from ... Consumption.

This ancient disease, known today as tuberculosis or TB, has plagued humanity for thousands of years, and as recently as a few hundred years ago, was thought to be responsible for some 25 percent of all deaths in Europe and North America.

Today, TB is both preventable and treatable — there's a century-old vaccine, effective antibiotics, and known behavioral and sanitation safeguards that disrupt transmission. Yet in 2022, more than 10 million people globally still fell ill from TB and 1.3 million died, making it the second deadliest infectious disease that year. (More people die from TB generally, but Covid-19 temporarily outpaced it.) More than 80 percent of those TB cases and deaths occur in low- and middle-income countries.

That's largely because people in those countries are more likely to suffer from contributing risk factors to TB, such as malnourishment and HIV.

But beyond those factors, when it comes to preventing illness and death in these regions, physicians, researchers, and public health officials say that the available vaccine and treatments don't do enough: The vaccine is given to infants and only offers protection in the first few years of life, leaving large swaths of people at risk, while antibiotic treatments take months to cure the disease.

"TB is a disease of poverty," explained Helen McShane, professor of vaccinology at the University of Oxford, where she and her team are developing a new TB vaccine among other TB research. "There have been decades of neglect where there was no funding for new drugs or new vaccines for TB."

But for the first time, promising new vaccines are now in the pipeline and may help prevent TB in adolescents and adults who currently have no such protection. These vaccines might also be more effective than what we have right now. Several are undergoing phase 3 trials — the last step before vaccine makers can apply to international and national agencies for approval.

"It is excellent news," said Matteo Zignol, unit head of the WHO's Global Tuberculosis Programme. The success of the first wave of vaccines has helped usher in more support and funding to the field, but many researchers say we will need more than just a few effective vaccines. "We all wish [the M72/AS01E vaccine trial] is going to be a successful trial, but in any case, this is going to be like a first generation sort of new vaccine, and we really need more candidates to be able to help the epidemic."

It'll likely still take years for the vaccines to be rolled out, but if approved, the new vaccines have the potential to save hundreds of thousands of lives, making an enormous dent in a disease that has killed humans for millennia.

Why do we need another TB vaccine?

One of the strange things about tuberculosis is that having the bacterium that causes TB doesn't mean you have the disease. In a 2016 paper published in PLOS Medicine, researchers estimated that nearly 25 percent of the world's population has a latent TB infection. For most people, though, the bacteria remain dormant and never go on to cause disease.

Basic preventative measures — such as improving sanitation, ensuring proper ventilation in hospitals and laboratories, and proactively identifying and treating high-risk patients — helped greatly reduce TB cases in developed countries like the US, where there were around 8,000 TB cases reported in 2022. Many lower-income countries, unfortunately, still have underdeveloped public health systems and lack the resources to implement the multipronged approach necessary to stamp out TB. That is where vaccination can be a critical tool.

The world's first and only available TB vaccine, the Bacille Calmette-Guérin (BCG) vaccine, was created in 1921. Given the low burden of TB in the US, BCG is not routinely given to infants, but it is commonly used in many other countries. In Africa and Southeast Asia — the regions with the highest TB burden — 80 and 91 percent of 1-year-olds received the BCG vaccine in 2022, respectively, according to estimates by the WHO.

The BCG vaccine is considered safe with rare side effects, but it's not very effective. One meta-analysis of 26 studies reported that when the BCG vaccine was given during infancy, it was 37 percent effective against all forms of TB during the first five years of life, but did not offer protection among adolescents and adults.

The way TB infects someone also plays a role in how contagious the disease can be and limits the vaccine's ability to prevent disease. Usually, TB infects the lungs — that's pulmonary TB. But Mycobacterium tuberculosis can infect the liver, bones, spinal cord, brain, urinary tract, bladder, kidneys, and even the intestines. When TB infects organs other than the lungs, it's called extrapulmonary TB. Individuals with extrapulmonary disease don't usually infect others, while those with TB in their lungs can more easily spread the bacterium to others by breathing, coughing, or sneezing.

Pulmonary infections account for the majority of TB morbidity and mortality. Exact percentages vary by country, but globally around 63 percent of all TB cases were pulmonary in 2021, according to the WHO. BCG vaccine efficacy against pulmonary TB infections still remains a bit of a mystery as studies have reported efficacy rates ranging from 0 to 80 percent and efficacy tends to be lowest in high-burden countries close to the equator.

Researchers are not quite sure why this is. One theory is that those who live closer to the equator are more likely to be exposed to non-tuberculous mycobacteria, which are similar to the pathogen that causes TB. This exposure confers preexisting immunity which may actually hinder the BCG vaccine from doing its job, McShane said.

All in all, researchers estimate that the BCG vaccine prevents only 5 percent of all vaccine-preventable deaths due to TB. For comparison, vaccines for measles, smallpox, and polio are 93, 95, and 90 percent effective in preventing disease, respectively.

So why now? What can a new TB vaccine actually accomplish?

Despite the limitations of the BCG vaccine, no new vaccine candidates have emerged in the past 100 years. M. Tuberculosis is notoriously difficult to make a vaccine for because the bacterium has an adept ability to evade the human immune system. As Vox's Dylan Matthews reported last year, "TB is a hard disease to vaccinate against. While most vaccines target viruses, TB is a bacterium, and one with a strange lifecycle."

Economic and political factors play a role as well. After many high-income countries made huge strides in reducing TB in the late 1990s and early 2000s, they allocated few resources to further research and development of new vaccines and treatments, focusing instead on other health threats such as cancer and cardiovascular disease. TB fell into the category of neglected diseases.

McShane recalled when her team conducted the first trials of a new generation TB vaccine in 2002. "At the time, there were about 50 candidate vaccines being tested for malaria and about 50 for HIV," she said. "Of course, for both of those pathogens, there is a Western market. There is no Western market for a TB vaccine."

Since then, however, there have been renewed efforts to eradicate TB. The emergence of drug-resistant TB has threatened to reverse what global gains against TB have been made and may even cause a TB resurgence in the US and other low-burden countries, spurring more attention and funding to the disease. The Global Fund and the Stop TB Partnership have also launched major advocacy campaigns to bring more attention to the epidemic.

Additionally, in 2016, the World Health Organization set a goal to end the TB epidemic by 2030. The US government has also ramped up investments in global TB eradication efforts. In the 2023 fiscal year, the US contributed more than $400 million to the cause, nearly double its total investments for global TB in fiscal year 2013.

As of last year, there are 16 new TB vaccine candidates in development, four of which are in phase 3 clinical trials — which, if successful, would likely be the last phase of trials before FDA or WHO approval. Some vaccines aim to replace the BCG vaccine altogether while other candidates will serve as boosters to the BCG vaccine among adolescents and adults, McShane explained.

One vaccine, M72/AS01E, seems to be the most promising candidate, buoyed by support and funding from the Bill and Melinda Gates Foundation. In a phase 2B clinical trial conducted in South Africa, Kenya, and Zambia, more than 3,500 adults with latent TB were randomly assigned to receive either two doses of the M72/AS01E vaccine or a placebo. Initial vaccine efficacy was 54 percent. Three years later, a follow-up analysis revealed that the vaccine had prevented active TB cases in 49.7 percent of people who received the vaccine.

Most other TB vaccine candidates have demonstrated similar efficacy rates. "It's unlikely that we're going to get a vaccine against tuberculosis that is 100 percent effective anytime soon," McShane said.

But even a TB vaccine with low efficacy can have profound global implications. If the M72/AS01E vaccine demonstrates safety and efficacy in the ongoing phase 3 trial, then for the first time, the world could prevent at least a good portion of infections among adolescents and adults.

"One of the big issues is that even if we'll have a vaccine, it'll be a game changer, but the effectiveness is around 50 percent. So it's not one of the best, but it is something," said Eliud Wandwalo, head of TB at the Global Fund to Fight AIDS, Tuberculosis and Malaria.

Given the relatively low efficacy rates, these new TB vaccines are not a silver bullet for eradicating TB globally. For most of the world, improvements in sanitation, infrastructure, and medication are also urgently needed. Currently, it takes six months of ongoing therapy to cure TB, and as drug-resistant strains of TB become more common, existing antibiotics will become less and less useful. The vaccine will be just one of the tools in the toolbox, Wandwalo said.

"If you look at the trajectory and projections, if we continue the same pace with the same tools, we'll be ending TB in the next 180 years," he said. "It's a dire projection. But I think with a vaccine, we are likely to be able to end TB in our lifetime."

Tuberculosis Vaccines — An Update

Tuberculosis (TB), a disease which is both curable and preventable, still kills 2–3 million people every year. After decades of neglect, the immense public health impact of TB is now widely recognized, and the development of new tools to combat and control the epidemic has become an international priority. The current strategy for TB control is based on reducing the spread of infection through effective treatment of individuals with active disease and vaccination of children. The WHO has initiated the directly observed therapy (DOTS) campaign in many regions, but so far this programme has not been able to control the global TB epidemic or prevent the increase in multidrug resistant (MDR) strains of Mycobacterium tuberculosis1.

The current TB vaccine Mycobacterium bovis bacillus Calmette–Guérin (BCG) is the most widely used vaccine worldwide. BCG provides efficient protection against TB in newborns, but does not prevent the establishment of latent TB or reactivation of pulmonary disease in adults. Being a viable organism, the activity of BCG depends on its initial replication, and it therefore cannot be used as a booster in an adult population that is already sensitized by prior BCG vaccination, exposure to environmental mycobacteria or latent TB2. A novel, effective vaccination strategy against adult pulmonary TB is therefore a crucial goal and an active field of research, development and clinical evaluation.

Global distribution and disease burden

In 2004, approximately 9 million people developed active TB. Although this places TB as one of the most important global health problems, active disease represents only the tip of the iceberg, as it has been estimated that one-third of the world's population is latently infected with M. Tuberculosis. Globally, the incidence of TB is growing, mainly owing to the spread of HIV in Africa, where it has been estimated that 13% of adults with newly diagnosed TB are also co-infected with HIV3. However, in recent years, the increasing TB problem in Eastern European countries has contributed to the worsening global epidemic. Africa has the highest estimated incidence (356 per 100,000 population per year), but major parts of Asia also have a significant TB problem1 (Fig. 1). In most of these regions, the incidence of TB has now reached such a magnitude that it is overwhelming the limited resources available to identify and treat active contagious pulmonary TB. Furthermore, by primarily targeting the working population, TB is a major roadblock to healthy economic development in many developing countries.

Figure 1: The distribution of tuberculosis in 2003.

Immunity to M. Tuberculosis

M. Tuberculosis infection remains latent with no overt clinical symptoms throughout life in more than 90% of infected individuals. Progressive mycobacterial infection in patients with deficient interferon-γ (IFN-γ) and tumour necrosis factor (TNF) signalling provides convincing evidence for the importance of these cytokines in the control of TB. The major source of these cytokines are CD4+ T cells, the most important lymphocyte population in the protective immune response and the main target for most vaccination strategies4. The role of CD8+ T cells is less clear. They are induced during natural M. Tuberculosis infection, and although they do not seem to have a major role in the initial control of the infection, they might be more involved in the later, chronic stages of the disease5. To target this lymphocyte subset, some of the new vaccines are delivered through live carriers such as viral vectors or genetically modified strains of BCG. In the 5–10% of latently infected individuals who go on to develop active TB, the balance between the natural immunity of the host and the pathogen is thought to change, for example, following an immunosuppressive event, resulting in massive bacterial replication and reactivation of the disease.

All of the new TB vaccine candidates that are under clinical evaluation (Table 1) are designed as pre-exposure vaccines and, hence, are aimed at stimulating an immune response that controls subsequent infection more efficaciously than the immune response that is stimulated during natural infection, thereby delaying reactivation. It is not known whether post-exposure administration of these vaccines to already latently infected individuals would prolong host containment of latent TB and prevent reactivation, or whether this would require specially designed post-exposure vaccines based on antigens that are expressed by the bacteria during latency, as recently discussed elsewhere6.

Table 1 The leading tuberculosis vaccine candidates in clinical trials

Vaccine concepts and clinical trials

Current attempts to develop improved TB vaccination strategies can be divided into two approaches — replacing or boosting BCG. The first strategy aims to replace BCG with a more effective vaccine. This is generally believed to demand an improved, attenuated mycobacterial vaccine strain, obtained either through the generation of gene-deletion mutants of M. Tuberculosis, or by re-introducing important antigens or other factors into the existing BCG vaccine strain. Viable, attenuated mycobacterial vaccines obviously present a broad variety of antigens and will potentially cover a combination of different T-cell populations, but such vaccines must be not only more potent than BCG, but also at least as safe, in order to be considered as candidates for clinical trials7.

The second strategy involves the development of a booster vaccine that takes advantage of BCG priming vaccination in childhood, and is given to increase the immune response and prolong immunity to also cover the adult population. It is generally agreed that such a vaccination strategy can be best accomplished with a subunit vaccine. Subunit vaccines are based on a restricted number of antigens and hence on a highly focused immune response for protection. In several of the leading vaccine candidates, the individual antigens are fused into polyproteins, something that both increases the immunogenicity of the individual antigens and has obvious advantages from a manufacturing point of view. The success of the booster strategy is underpinned by recent advances in adjuvant development. Until recently, the only adjuvants appropriate for use in TB vaccines were either ineffective at stimulating T-cell responses or were too toxic for human use. This situation has rapidly changed in recent years, and a number of novel, promising T-cell adjuvants such as the IC31 adjuvant, cationic liposomes, the AS2 formulation and LTK63 (for mucosal delivery) are now under late-preclinical or clinical development in TB vaccines (Table 1).

Eventually, the ultimate vaccine strategy could be based on a combination of both approaches, that is, a prime–boost vaccination regime that comprises priming with the best possible viable vaccine candidate and boosting with the best possible subunit vaccine candidate4.

BCG replacement vaccines

rBCG30. RBCG30 is a recombinant BCG vaccine in which the well-known and well-characterized antigen 85B (Ag85B) is overexpressed. This 30 kDa enzyme, which is involved in outer cell-wall synthesis, is a key component in several TB vaccines, and although Ag85B is already abundantly secreted by BCG, overexpression appears to increase responses to this important antigen8. RBCG30 has been tested in a Phase I trial in humans and was well tolerated.

rBCG ΔureC:Hly. To amplify the CD8+ T-cell response induced by BCG, a recombinant BCG mutant has been constructed that expresses listeriolysin (Hly), which can perforate the phagosome membrane. The gene (ureC) encoding the urease enzyme that increases the pH of the phagosome containing BCG was additionally deleted to avoid neutralizing the phagosome, as this would reduce the activity of Hly9. Surprisingly, apoptosis of infected macrophages and cross-priming of dendritic cells seems to be the major mechanisms responsible for the increased activity of this vaccine10. A clinical Phase I trial is planned to commence by the end of 2007.

BCG booster vaccines

Ag85B–ESAT6/TB10.4 fusion molecules. The Ag85B–ESAT6 fusion molecule (H1) is made up of the two secreted antigens Ag85B and ESAT6. These individual antigens both have an impressive track record of studies confirming their antigenicity in humans and their vaccine potential. H1 has shown promise both for parenteral (in IC31 or cationic liposomes) and mucosal (in LTK63) delivery11,12. In addition to being a valuable vaccine component, ESAT6 (the component of H1 localized in the region that was deleted during the original attenuation of BCG, and which is therefore absent from all BCG vaccine strains) is a key component in a new generation of diagnostic tests for M. Tuberculosis infection13. An alternative fusion construct, called H4, has been engineered and consists of Ag85B and the TB10.4 antigen, which is also from the ESAT family of small secreted antigens14. TB10.4 has similar immunological properties to ESAT6, but it is highly expressed and immunodominant in BCG. H4 is a powerful booster vaccine for BCG, whereas the H1 vaccine for comparison, in addition to boosting Ag85B responses, will supplement the BCG antigen repertoire with the important ESAT6 antigen component.

H1 is currently in clinical trials administered both parenterally and through the mucosal route. The first clinical trial in Leiden, Holland (Dissel and Ottenhoff, unpublished data) evaluated the vaccine in a conventional parenteral vaccination strategy, using the IC31 adjuvant. This trial was conducted in purified protein derivative (PPD)-negative individuals and the vaccine was shown to be both safe and strongly immunogenic. The H1/IC31 vaccine is currently being evaluated in PPD-positive BCG-vaccinated individuals at the same site. Another trial that has recently started will test the nasal administration of the H1 antigen, using the LTK63 adjuvant. The H4/IC31 vaccine will commence clinical trials in mid-2007 in Sweden.

MTB72f. The MTB72f vaccine is a fusion molecule consisting of two antigens that are strong targets for T helper 1 (TH1) cells in PPD-positive individuals. Rv1196 (MTB32) is inserted into the middle of the serine protease Rv0125 (MTB39), which is thus present as two fragments15. MTB72F in the AS02A adjuvant formulation has recently completed two Phase I trials in healthy PPD-negative adults in the United States and Belgium. The vaccine was well tolerated and safe, and could induce both antigen-specific humoral and cell-mediated immune responses.

MVA85A. MVA85A is a modified vaccine virus Ankara (MVA) strain expressing antigen 85A, another member of the Ag85 family of protective antigens. In Phase I studies in humans, MVA85A was found to be safe and well tolerated, and this vaccine has induced strong immune responses, particularly in previously BCG-vaccinated individuals16.

Conclusions

With increasing investment from public funds such as the European Union, National Institutes of Health and the Bill & Melinda Gates Foundation in recent years, TB vaccine research, development and evaluation has become an active area, with several vaccines in various stages of early clinical development. Most of this work is conducted by public research organizations and public–private partnerships, but a recent re-analysis and demonstration of the significant commercial value of a novel TB vaccine17 will probably result in a larger investment from private industry. This will promote streamlined development and the eventual global distribution of a novel vaccine. Although a new, improved vaccination strategy against TB is finally on the horizon, its eventual success will still depend on continued close integration with information from basic research. The identification of reliable correlates of protection, as well as the answers to more basic immunological questions relating to immunological memory and the relative importance of different T-cell subsets, will be important for the potential modification of the leading TB vaccines, the generation of second-generation products and the selection of which vaccines to move forward into expensive efficacy trials (Box 1). It will furthermore be a high priority for the clinical development programmes to evaluate whether the current vaccines, all of which have been designed for pre-infection administration, will also prevent reactivation of TB if administered post-exposure to the large proportion of the global population already latently infected with TB.

Box 1Key areas for tuberculosis (TB) vaccine development

Determine the correlates of vaccine induced protective immunity

Determine the requirements for post-exposure TB vaccines

Understand vaccine-induced T-cell memory to Mycobacterium tuberculosis

Determine the role of CD8+ T cells in M. Tuberculosis infection and immunity

Path To A Better TB Vaccine Runs Through Montana

Jim Robbins

(KFF) A team of Montana researchers is playing a key role in the development of a more effective vaccine against tuberculosis, an infectious disease that has killed more people than any other.

The BCG (Bacille Calmette-Guérin) vaccine, created in 1921, remains the sole TB vaccine. While it is 40% to 80% effective in young children, its efficacy is very low in adolescents and adults, leading to a worldwide push to create a more powerful vaccine.

One effort is underway at the University of Montana Center for Translational Medicine. The center specializes in improving and creating vaccines by adding what are called novel adjuvants. An adjuvant is a substance included in the vaccine, such as fat molecules or aluminum salts, that enhances the immune response, and novel adjuvants are those that have not yet been used in humans. Scientists are finding that adjuvants make for stronger, more precise, and more durable immunity than antigens, which create antibodies, would alone.

Eliciting specific responses from the immune system and deepening and broadening the response with adjuvants is known as precision vaccination. "It's not one-size-fits-all," said Ofer Levy, a professor of pediatrics at Harvard University and the head of the Precision Vaccines Program at Boston Children's Hospital. "A vaccine might work differently in a newborn versus an older adult and a middle-aged person."

The ultimate precision vaccine, said Levy, would be lifelong protection from a disease with one jab. "A single-shot protection against influenza or a single-shot protection against covid, that would be the holy grail," Levy said.

Jay Evans, the director of the University of Montana center and the chief scientific and strategy officer and a co-founder of Inimmune, a privately held biotechnology company in Missoula, said his team has been working on a TB vaccine for 15 years. The private-public partnership is developing vaccines and trying to improve existing vaccines, and he said it's still five years off before the TB vaccine might be distributed widely.

It has not gone unnoticed at the center that this state-of-the-art vaccine research and production is located in a state that passed one of the nation's most extreme anti-vaccination laws during the pandemic in 2021. The law prohibits businesses and governments from discriminating against people who aren't vaccinated against covid-19 or other diseases, effectively banning both public and private employers from requiring workers to get vaccinated against covid or any other disease. A federal judge later ruled that the law cannot be enforced in health care settings, such as hospitals and doctors' offices.

In mid-March, the Bill & Melinda Gates Medical Research Institute announced it had begun the third and final phase of clinical trials for the new vaccine in seven countries. The trials should take about five years to complete. Research and production are being done in several places, including at a manufacturing facility in Hamilton owned by GSK, a giant pharmaceutical company.

Known as the forgotten pandemic, TB kills up to 1.6 million people a year, mostly in impoverished areas in Asia and Africa, despite its being both preventable and treatable. The U.S. Has seen an increase in tuberculosis over the past decade, especially with the influx of migrants, and the number of cases rose by 16% from 2022 to 2023. Tuberculosis is the leading cause of death among people living with HIV, whose risk of contracting a TB infection is 20 times as great as people without HIV.

"TB is a complex pathogen that has been with human beings for ages," said Alemnew Dagnew, who heads the program for the new vaccine for the Gates Medical Research Institute. "Because it has been with human beings for many years, it has evolved and has a mechanism to escape the immune system. And the immunology of TB is not fully understood."

The University of Montana Center for Translational Medicine and Inimmune together have 80 employees who specialize in researching a range of adjuvants to understand the specifics of immune responses to different substances. "You have to tailor it like tools in a toolbox towards the pathogen you are vaccinating against," Evans said. "We have a whole library of adjuvant molecules and formulations."

Vaccines are made more precise largely by using adjuvants. There are three basic types of natural adjuvants: aluminum salts; squalene, which is made from shark liver; and some kinds of saponins, which are fat molecules. It's not fully understood how they stimulate the immune system. The center in Missoula has also created and patented a synthetic adjuvant, UM-1098, that drives a specific type of immune response and will be added to new vaccines.

One of the most promising molecules being used to juice up the immune system response to vaccines is a saponin molecule from the bark of the quillay tree, gathered in Chile from trees at least 10 years old. Such molecules were used by Novavax in its covid vaccine and by GSK in its widely used shingles vaccine, Shingrix. These molecules are also a key component in the new tuberculosis vaccine, known as the M72 vaccine.

But there is room for improvement.

"The vaccine shows 50% efficacy, which doesn't sound like much, but basically there is no effective vaccine currently, so 50% is better than what's out there," Evans said. "We're looking to take what we learned from that vaccine development with additional adjuvants to try and make it even better and move 50% to 80% or more."

By contrast, measles vaccines are 95% effective.

According to Medscape, around 15 vaccine candidates are being developed to replace the BCG vaccine, and three of them are in phase 3 clinical trials.

One approach Evans' center is researching to improve the new vaccine's efficacy is taking a piece of the bacterium that causes TB, synthesizing it, and combining it with the adjuvant QS-21, made from the quillay tree. "It stimulates the immune system in a way that is specific to TB and it drives an immune response that is even closer to what we get from natural infections," Evans said.

The University of Montana center is researching the treatment of several problems not commonly thought of as treatable with vaccines. They are entering the first phase of clinical trials for a vaccine for allergies, for instance, and first-phase trials for a cancer vaccine. And later this year, clinical trials will begin for vaccines to block the effects of opioids like heroin and fentanyl. The University of Montana received the largest grant in its history, $33 million, for anti-opioid vaccine research. It works by creating an antibody that binds with the drug in the bloodstream, which keeps it from entering the brain and creating the high.

For now, though, the eyes of health care experts around the world are on the trials for the new TB vaccines, which, if they are successful, could help save countless lives in the world's poorest places.

---