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Key recent advances in TB vaccine development and understanding of protective immune responses against Mycobacterium tuberculosis

Thomas j. scriba.

a South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa

Mihai G. Netea

b Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Centre, Nijmegen, Geert Grooteplein 8, 6525 GA Nijmegen, the Netherlands

c Department of Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Germany

Ann M. Ginsberg

d Bill & Melinda Gates Foundation, Division of Global Health, Washington DC, United States

• • Highly efficacious TB vaccines would make a crucial impact in epidemic control.
• • Elucidating mycobacteria-induced immune responses is expanding our understanding of vaccine-induced protection.
• • Rigorous BCG revaccination trials are providing novel insights into TB vaccinology.
• • A novel vaccine’s efficacy has launched TB vaccinology into the next wave of trials.
• • Effort to identify nonhuman primate and human correlates of protection is advancing.

Tuberculosis is the leading infectious disease killer globally due to a single pathogen. Despite wide deployment of standard drug regimens, modern diagnostics and a vaccine (bacille Calmette Guerin, BCG), the global tuberculosis epidemic is inadequately controlled. Novel, effective vaccine(s) are a crucial element of the World Health Organization End TB Strategy. TB vaccine research and development has recently been catalysed by several factors, including a revised strategy focused first on preventing pulmonary TB in adolescents and adults who are the main source of transmission, and encouraging evaluations of novel efficacy endpoints. Renewed enthusiasm for TB vaccine research has also been stimulated by recent preclinical and clinical advancements. These include new insights into underlying protective immune responses, including potential roles for ‘trained’ innate immunity and Th1/Th17 CD4+ (and CD8+) T cells. The field has been further reinvigorated by two positive proof of concept efficacy trials: one evaluating a potential new use of BCG in preventing high risk populations from sustained Mycobacterium tuberculosis infection and the second evaluating a novel, adjuvanted, recombinant protein vaccine candidate (M72/AS01 E ) for prevention of disease in adults already infected. Fourteen additional candidates are currently in various phases of clinical evaluation and multiple approaches to next generation vaccines are in discovery and preclinical development. The two positive efficacy trials and recent studies in nonhuman primates have enabled the first opportunities to discover candidate vaccine-induced correlates of protection, an effort being undertaken by a broad research consortium.

1. Introduction

1.1. tb global epidemiology.

Even in the time of SARS-CoV-2, tuberculosis (TB) is to date the leading global infectious killer due to a single pathogen (i.e., the bacterium, Mycobacterium tuberculosis (Mtb)), and one of the world’s top ten causes of death. According to the World Health Organization [ 1 ], there were an estimated 10 million new cases and 1.4 million deaths due to TB in 2019. Substantial improvement in TB mortality rates, but only minimal global progress in decreasing TB incidence, have been achieved over the past 20 years [ 1 ]. COVID-19-related disruptions in TB services are predicted to cause a significant increase in global TB morbidity and mortality in coming years [ [1] , [2] , [3] ]. Compounding the urgency of the TB epidemic is the spreading challenge of drug resistant-TB: approximately 500,000 cases in 2019 of which 78% were multidrug-resistant [ 1 ].

1.2. The current vaccine for TB prevention: bacille Calmette-Guérin (BCG)

Reaching WHO’s End TB ambitious strategic goal of ending the TB epidemic by 2035 [ 4 ] will require effective vaccine(s) that can block the cycle of transmission. The only currently licensed vaccine to prevent TB is bacille Calmette-Guérin (BCG), which was first administered in Paris in 1921 by Dr. Benjamin Weill-Halle to a child, using the oral route [ 5 ]. BCG is still administered today (parenterally) to infants in most countries as part of the WHO’s Expanded Programme on Immunization. While infant BCG is moderately effective in preventing severe, extrapulmonary forms of TB in young children, it has had varied efficacy in preventing TB in adolescents and adults in multiple clinical trials [ 6 ], and has been ineffective in controlling the global epidemic.

1.3. Target populations and indications for novel TB vaccines to maximize public health impact

Adolescents and adults primarily develop pulmonary TB and are the leading drivers of TB transmission. Given the urgent need for novel, highly effective TB vaccines, these age groups have become the leading priority target population for TB vaccine development. Preventing TB among adolescents and adults will, by preventing transmission, help to protect all age groups most quickly. The same or other novel vaccines are also being developed, nonetheless, for other age groups. Additionally, the fastest global decreases in morbidity and mortality will result from implementing vaccine(s) that prevent TB when administered both before Mycobacterium tuberculosis (Mtb) (pre-infection vaccine) and after infection is already established but before active TB disease develops (post-infection vaccine). It has been estimated [ 7 ] that one quarter of the world population has been infected with Mtb. This represents a very large reservoir of potential cases of future active TB. The impact of each vaccine type in a given population will depend on whether the epidemic is primarily driven by recent infections or by reactivation of established, asymptomatic infections (typically referred to, although imprecisely, as latent TB infection or LTBI) [ [8] , [9] , [10] , [11] ]. A pre-infection vaccine may initially be evaluated for a prevention of infection (POI) indication, but ultimately should be evaluated for its ability to prevent disease (POD), as this is the only TB endpoint clearly established to prevent morbidity and mortality. A third target indication, prevention of TB recurrence (POR) and/or as an adjunct to TB treatment is being pursued for some vaccine candidates. In the POR case, candidate vaccines are being evaluated for their ability to decrease rates of TB relapse and/or reinfection in TB patients after cure, which has been estimated at 2–8 % for standard treatment of drug-sensitive TB in various studies [ [12] , [13] , [14] , [15] ]. Vaccines as adjuncts to TB treatment might increase cure rates, especially for MDR-TB or XDR-TB, and/or shorten duration of TB treatment, which is still a minimum of six months and typically up to two years for MDR and XDR-TB. The WHO has issued Preferred Product Characteristics for each of these types of novel TB vaccines [ 16 , 17 ].

1.4. The TB vaccine pipeline of clinical candidates

Currently, the global TB vaccine pipeline, to the best of our knowledge, includes 16 distinct candidates in various stages of clinical development, ranging from Phase 1 through Phase 3 (for definitions of phases of clinical development see [ 18 ]).

The global portfolio of clinical candidates is summarized and referenced in Table 1 and has been the subject of several recent reviews (for example, [ 19 , 20 ]), so only those candidates with published mid- or late-stage human efficacy data are discussed here.

TB Vaccine Candidates in Clinical Development.

There is also a (frequently changing) number of candidates in discovery and preclinical stages of R&D. Two of these, CMV-TB and intravenous (i.v.) BCG, have been selected for discussion below because they have recently demonstrated unprecedented levels of protection in nonhuman primates and are spurring development of the next generation of novel candidates and discovery of potential vaccine-induced, immune correlates of protection.

Nonetheless, the TB vaccine R&D process remains hampered by insufficient global investment [ 21 ] and a lack of complete understanding of the human protective immune response to this complex pathogen and an absence of both validated animal models predictive of human vaccine efficacy and correlates of protection (see below). Despite the resulting requirement for a largely empiric vaccine development process, two positive proof of concept efficacy trials for TB vaccine candidates have recently been completed: one evaluating a potential new use of BCG – to protect a high-risk population from Mtb infection [see below; [ 22 ]], and one evaluating a novel adjuvanted recombinant protein vaccine candidate, M72/AS01 E , to protect latently Mtb-infected adults from developing active TB disease [ 23 , 24 ]. Results from a recently completed POI efficacy trial in adolescents in Tanzania of a third candidate, DAR-901 (an inactivated form of the non-tuberculous mycobacterium, M. obuense ), did not demonstrate statistically significant efficacy against either the primary or secondary trial endpoint [ 25 ]. The other 13 clinical candidates, as noted in Table 1 , include additional mycobacterial candidates (both live attenuated and inactivated or lysates) and subunit candidates (virally vectored as well as adjuvanted recombinant protein candidates). Each of these candidates is currently being evaluated in the clinic for use in one or more age groups (infants, adolescents, adults) and for one or more target indications (prevention of Mtb infection, prevention of Mtb disease, prevention of TB disease recurrence or as an adjunct to TB treatment).

1.5. Recent results catalysing progress

1.5.1. interventional studies.

Two positive proof-of-concept clinical efficacy trials of novel TB vaccine candidates were published in 2018–2019 and are currently galvanizing TB vaccine R&D. The first [ 23 , 24 ] was a Phase 2b trial evaluating the adjuvanted recombinant protein candidate, M72/AS01E, in LTBI+, HIV- adults (see section 1.5.1.1 , below). The second [ 22 ] evaluated the ability of a novel subunit vaccine, H4:IC31, or BCG revaccination to prevent Mtb infection in a high risk of infection adolescent population (see section 1.5.1.2 , below). These results, respectively, provide for the first time a catalyst to catapult a novel subunit TB vaccine candidate into late stage development for prevention of TB disease and to evaluate further a novel use of the hundred year old TB vaccine, BCG, for a potential policy recommendation to provide protection against Mtb infection in some high-risk populations.

1.5.1.1. M72/AS01E proof of concept Phase 2b trial

M72/AS01 E is comprised of two Mtb antigens (Mtb32A and Mtb39A) in a recombinant fusion protein and the GSK proprietary adjuvant system, AS01, [ [26] , [27] , [28] , [29] , [30] , [31] , [32] ] also used in GSK’s Shingrix® vaccine and the malaria vaccine, RTS,S. In this randomized, double-blinded, controlled efficacy trial, 3575 Mtb-infected (Interferon Gamma Release Assay-positive (IGRA+)) adults in Africa without active TB or HIV infection were randomized 1 to 1 to receive either two doses of M72/AS01E or placebo, one month apart and followed for a total of three years for microbiologically confirmed active, pulmonary TB without evidence of HIV infection (primary endpoint). At the primary analysis, two years after the second vaccination, M72/AS01 E demonstrated 54.0 % vaccine efficacy (95 %CI: 2.9–78.2) [ 24 ]. At the final analysis, conducted after a median follow-up period of 2.7 years after the second vaccination, vaccine efficacy was 49.7 % (95 % CI: 2.1–74.2). The frequencies of severe adverse events, potentially immune-mediated diseases and deaths were similar between the two groups. Antibody and T cell responses were evaluated in an according-to-protocol subgroup of 244 participants (M72/AS01E - 120; placebo - 124). All participants in the M72/AS01E arm of this subcohort had IgG antibody responses to the M72 protein by month 2 and remained seropositive through month 36. Vaccine-induced, M72-specific CD4 T cells that co-expressed two or more cytokines, defined as “polypositive”, were observed in 23.5 % (95 %CI 12.8–37.5) of M72/AS01E vaccinees after the first vaccination and in 53.7 % (95 % CI 39.6–67.4) by month 36. These CD4 T cells expressed primarily interferon-γ, interleukin-2 or tumor necrosis factor-α or any combination of these cytokines. CD40L expression was low at all timepoints and CD8 T cell responses were not detected in any participants [ 23 ]. The large majority of trial participants provided biospecimens under informed consent for a substudy to discover potential correlates of risk and protection, which was underway at the time of this writing. Of interest, a study of BCG prime vaccination followed by boosting with intramuscular M72/AS01 E in a rhesus macaque model [ 33 ] also evaluated vaccine-induced immune responses and protection. No vaccine efficacy against Mtb challenge above that induced by BCG alone was demonstrated. It is important to note that the rhesus macaque model used in this study has several important differences compared to the phase 2b trial, including that the trial participants were Mtb-infected at baseline (IGRA+) and had received BCG as infants (if at all) approximately 18–50 years before being vaccinated with M72/AS01E (or placebo). By comparison, the NHPs were Mtb-uninfected at the time of vaccination and M72/AS01E was administered 16 and 20 weeks post-BCG. Moreover, the challenge dose of Mtb (16–20 cfu) was administered to the animals via bronchoscope. With this methodology, typically all unvaccinated animals become infected with Mtb and develop active TB disease, whereas humans typically inhale a single infectious Mtb bacterium in the form of airborne droplet nuclei to become infected and it is estimated that only 5–10 % of infected humans develop active TB disease. As a result, it is perhaps not surprising that the NHP model did not replicate the human results. Whether this model will accurately, consistently and reproducibly predict efficacy for TB vaccine candidates that protect Mtb-uninfected humans remains to be determined. Only one such vaccine, BCG, exists to date and both human and NHP studies of BCG have produced variable results [ 34 , 35 ]. The lack of a validated animal model predictive of human vaccine efficacy remains an important impediment to TB vaccine development.

1.5.1.2. Intradermal BCG efficacy trials

Two potential new uses of BCG are currently under active investigation in clinical efficacy trials. The first, as noted above, is based on initial evidence that BCG delivered to Mtb-uninfected adolescents who were BCG-vaccinated as infants and at high risk of becoming Mtb infected were moderately protected from infection by being revaccinated with BCG [ 22 ]. This randomized, controlled, partially blinded trial (designated C-040-404; {"type":"clinical-trial","attrs":{"text":"NCT02075203","term_id":"NCT02075203"}} NCT02075203 ) was designed to evaluate the ability of BCG revaccination or of a novel adjuvanted recombinant protein vaccine candidate, H4:IC31, to prevent initial or sustained Mtb infection, as indicated by conversion from negative to positive of an Mtb-specific IGRA – each compared to placebo (the trial was not powered to compare these two vaccine candidates to each other). The trial enrolled 990 adolescents in the Western Cape of South Africa randomized equally across the three arms. Neither candidate demonstrated statistically significant protection against the primary endpoint of initial IGRA conversion but BCG demonstrated 45.4 % (p = 0.03; 95 % CI = 6.4, 68.1) efficacy in preventing sustained conversion (secondary endpoint), interpreted as reflecting prevention of LTBI. H4:IC31 demonstrated only 30.5 % (p = 0.16; 95 % CI=-15.8, 58.3) vaccine efficacy and its further development was terminated. A follow-up study characterised the breadth, function and phenotype of innate and adaptive cellular responses induced by BCG revaccination in a subset of participants of the C-040-404 trial [ 36 ]. BCG revaccination increased the magnitude of CD4 T cell subsets that expressed Th1 cytokines or IL-22, and also modestly increased IFN-γ-producing NK cells. Thus, protection against sustained Mtb-infection conferred by BCG may be dependent on multiple immune cell subsets. A study that aims to identify immunological correlates of protection in samples collected from C-040-404 trial participants is now underway (see Section 2.3 and Table 2 ).

Major hypothesized immune correlates of protection against TB.

BCG revaccination is currently undergoing evaluation in a second, larger trial in IGRA-negative South African adolescents (1800 participants assigned 1:1 to either BCG or placebo) with sustained IGRA conversion as primary endpoint, to confirm and extend these results ( {"type":"clinical-trial","attrs":{"text":"NCT04152161","term_id":"NCT04152161"}} NCT04152161 ). Because BCG is an already licensed, inexpensive intervention with a very long and robust safety record in immunocompetent individuals, BCG revaccination could represent a useful tool for controlling Mtb infection in populations with high risk of infection, if the ongoing trial successfully confirms vaccine efficacy. Safety in HIV-infected, immunocompromised adolescents and adults remains an open question needing further evaluation before widespread implementation of BCG revaccination in this population.

Three large, community-based trials had previously evaluated BCG revaccination in a large range of age groups without demonstrating substantial overall protective efficacy against active TB disease, with the exception of some limited sub-groups (younger children in one of two geographic regions in Brazil and an uninfected sub-cohort in the India trial) [ [37] , [38] , [39] ]. However, it is important to note that these trials had significant methodologic and design differences from the C-040-404 trial including that the majority of participants in these trials were individuals of unknown Mtb infection status and the efficacy endpoints were TB disease rather than prevention of sustained infection as indicated by IGRA. In addition, the role of BCG strain diversity remains unclear, although differences in microbiological and immunological properties between the strains have been suggested [ 40 ]. For example, a meta-analysis of randomized controlled BCG efficacy trials concluded that there was not strong evidence that BCG strain was associated with efficacy [ 6 ], while an analysis of pediatric TB incidence in Kazakhstan over a four-year period in which three different strains of BCG (from Japan, Serbia and Russia, respectively) were administered concluded that BCG source did impact effectiveness [ 41 ].

The second potential new use of BCG is based on the hypothesis that non-specific effects of BCG, through induction of trained innate immune responses, may provide some protection from severe heterologous respiratory infections, including COVID-19 disease (see below) [ 42 , 43 ]. A number of clinical efficacy trials are underway in multiple countries to test this hypothesis (see, for example, clinicaltrials.gov and WHO clinical trials registry).

1.5.2. Key preclinical advances

1.5.2.1. intravenous bcg in mice and nonhuman primates.

There has been a continuous interest to compare the effect of the BCG route of administration, with various studies suggesting that alternative routes to subcutaneous (s.c.) or the commonly used intradermal (i.d.) route are more effective. Both aerosol [ 44 ] or intravenous (i.v.) vaccinations [ 45 ] have been suggested to provide increased protection against TB. A series of more recent studies have expanded this work, and an increased research interest in i.v. administration of BCG has emerged. In mice, i.v. administration of BCG resulted in potent T-cell responses, although they were poorly correlated with efficacy of the vaccine [ 46 ]. A recent study on the other hand demonstrated long-term effects by i.v. BCG administration not only in the lymphoid cell lineage, but also in the myeloid lineage and the precursors in the bone marrow [ 47 ]. In addition, this study showed that the protective effect by myeloid cells against Mtb can be transferred to naïve mice by adoptive transfer. These murine studies have been recently complemented with investigations in non-human primates (NHP), that also suggest important advantages of i.v. administration. When comparing intradermal, intratracheal and intravenous administration of BCG in NHP, Sharpe and colleagues observed that the most effective protection against TB was achieved by i.v. administration [ 48 ]. This was also associated with the strongest induction of multifunctional CD4 T cells producing TNF and IFNg in the i.v.-vaccinated macaques, and subsequently lowest organ pathology. These data are supported by recent studies that also showed that macaques vaccinated i.v. with BCG displayed increased protection against TB, compared to animals vaccinated through i.d. or aerosol route [ 49 ]. Although these experiments do not allow ascertainment of the exact mechanisms of protection, primarily because the i.v route was so protective that it precluded identification of immune responses associated with levels of protection [ 49 ], they do provide very important hypotheses that can be tested. I.v BCG induced very high numbers and frequencies of antigen-specific, bronchoalveolar Th1/Th17 cytokine-expressing CD4 (and CD8) T cells. Antigen-specific Th1/Th17 cells in the lung were also associated with protection against Mtb in another NHP study that delivered BCG by bronchoscope into the airways [ 50 ], while an NHP study of Mtb infected macaques also identified this cell subset as correlating with the degree of Mtb control in granulomas [ 51 ]. These studies highlight antigen-specific Th1/Th17 cells as a promising candidate correlate of protection (CoP) (See section 2.2 and Table 2 ).

1.5.2.2. CMV-TB in nonhuman primates

Another promising preclinical result was achieved with a rhesus macaque CMV-vectored recombinant protein candidate, rhCMV/TB, when evaluated for immunogenicity and protection in a low-dose Mtb rhesus challenge model [ 52 ]. Two independent challenge experiments were reported to demonstrate a decrease in combined extra-pulmonary and pulmonary Mtb infection and disease of 68% compared to unvaccinated controls after one year of follow-up post-first vaccination. The vaccine induced and maintained high frequencies of highly-differentiated, Mtb-specific circulating and tissue-resident CD4 and CD8 T cell responses, but an antibody response was not detected. Unprecedentedly for any other peripherally delivered TB vaccine candidate to date, 14 of 34 vaccinated animals (41%) had no detectable TB disease by CT scan or at necropsy (in the two studies combined) compared to zero of 17 unvaccinated controls following challenge with the highly virulent Erdman strain of Mtb. In ten of these RhCMV/TB-vaccinated animals, Mtb was undetectable in all tissues tested at necropsy. RhCMV/TB is currently in pre-IND development by Vir Biotechnology (Vir-2020).

1.5.3. Cohort studies and biosignatures of TB risk and disease progression

Animal studies provide opportunities to manipulate the exact timing, dose and route of Mtb infection and allow access to relevant tissue sites such that investigation of the complex interactions and kinetics that define immunologic mechanisms of protection can be performed. The elegant studies in animal models discussed above thus provide critical insights into the immune cells, their phenotypes and functions that mediate protection against Mtb in a manner that is not possible in humans. These studies have also generated hypotheses about the immune responses that mediate protective immunity against Mtb infection or TB disease. However, it is clear that the immunopathogenesis of Mtb in humans is complex, extremely heterogenic and subject to a very large variety of environmental and biological factors to such a degree that exact recapitulation with experimental animal models is not possible. Clinical studies of human cohorts therefore provide key opportunities to study human immunopathogenesis of Mtb and can advance our understanding of mechanisms that mediate risk of disease as well as protective immunity. A number of clinical studies have followed human participants with Mtb infection or known exposure to Mtb for months or years to characterise immunological changes that represent correlates of risk of TB disease. Analysis of blood transcriptomes, plasma proteomes and cellular phenotypes have shown that Mtb-infected but asymptomatic individuals who ultimately develop disease present with elevated inflammation and type I/II IFN responses [ [53] , [54] , [55] , [56] , [57] , [58] ], activation of the complement cascade [ 54 ] and T cell activation [ 54 , 59 ]. Other studies have applied intensive clinical, phenotypic and radiological examination to identify asymptomatic study participants with radiological or microbiological evidence of subclinical disease and found that such individuals presented with similar blood inflammatory signals [ 60 , 61 ]. These inflammatory signals are consistent with those typically observed during microbiologically confirmed, clinical TB disease [ [62] , [63] , [64] , [65] ]. It is thus clear that progression from Mtb infection to active TB proceeds through at least two intermediate asymptomatic stages, namely minimal or “incipient” TB, characterised by elevated inflammatory signals in the absence of radiological or microbiological evidence of disease, and subclinical TB, characterised by the presence of either radiological or microbiological evidence of disease, or both [ 11 ].

Based on this premise, many investigators have developed concise transcriptomic or proteomic signatures, or correlates of risk that can identify individuals with incipient or subclinical TB [ 53 , [55] , [56] , [57] , [58] , 66 ]. These tests may allow exclusion of individuals from clinical trials (for example, because a prophylactic vaccine may not be able to protect someone who has already progressed to incipient or subclinical TB) or, conversely, may allow selective inclusion of those with incipient or subclinical TB (for example, to determine if a therapeutic vaccine can reverse disease progression or as an adjunct to therapy, accelerate therapy).

Other innovative and novel approaches to studying protective immunity and the immunopathogenesis of Mtb in humans are being explored in the context of experimental medicine studies. For example, a recent study of bronchoscopic instillation of live BCG or PPD into the lungs of healthy participants allowed assessment of cellular immune responses and changes in gene expression at the site of Mtb infection in humans [ 67 ]. Small phase I trials have also investigated safety and immunogenicity after aerosol administration of novel TB vaccine candidates [ 68 , 69 ]. Such small, intensive and carefully controlled experimental trials provide important opportunities to define the host immune response and inform vaccine design and development, and may ultimately lead to a human challenge model for TB [ 70 ]. However, such invasive interventions are not generally considered to be practical delivery platforms for mass vaccination campaigns against TB.

2. Advances in understanding protective immune responses

2.1. trained innate immunity.

Development of vaccines in the last half century or more has been based on induction of specific adaptive immune responses endowed with long-term memory. The concept behind this approach is to induce priming of antigen-specific naïve B and T cells and subsequently generation of memory B and T cells. These memory lymphocytes will initiate a rapid and robust immune response upon re-infection with the same pathogen, thus leading to long-lasting protection (sometimes for the entire life) against the target infection.

However, recent studies provide evidence that some types of vaccines, especially live attenuated ones, also induce a long-term improvement in the anti-microbial function of innate immune cells, and this effect can also contribute to protection from reinfection. The reprogramming of the innate immune cells (e.g. myeloid and NK-cells) has been termed ‘ trained immunity’, and represents a de facto innate immune memory [ 71 ]. The induction of trained immunity by live attenuated vaccines induces an integration of immunological signals, metabolic rewiring of cell metabolism, and epigenetic reprogramming, all processes necessary to mediate the induction of improved innate immune responses [ 72 ].

Induction of trained immunity has been reported to be an important component of the biological effects of BCG vaccination, which induces epigenetic and metabolic rewiring of myeloid cells though an NOD2-dependent mechanism [ 73 , 74 ]. Moreover, recent studies have also demonstrated long-term functional and transcriptional reprogramming of myeloid cell progenitors in the bone marrow, which explains the long-term effect of BCG on circulating myeloid cells [ 47 , 75 ]. The increase in the anti-mycobacterial function of the myeloid cells such as monocytes and macrophages has been suggested to contribute to the beneficial effects of BCG against TB [ 76 ]. Not only myeloid cells, but also other innate immune cell populations such as NK cells undergo an increase in their function after BCG vaccination [ 77 ] and NK-memory responses have been correlated with BCG effects in humans [ 78 ]. It would thus be tempting to speculate that vaccines able to induce both innate and adaptive memory responses would be more efficient against TB. Of the novel TB vaccine candidates, MTBVAC also has been shown recently to be able to induce trained immunity [ 79 ], and evidence of its efficacy is eagerly anticipated. No additional data are available regarding the capacity of other TB vaccine candidates or relevant adjuvants to induce trained immunity, and additional future studies are warranted.

2.2. Approaches to discovering human correlates of protection against Mtb infection and TB disease

Publication of positive efficacy results from the proof-of-concept trials of BCG revaccination and M72/ASO1 E vaccination marked an important turning point from a somewhat negative undercurrent that characterised TB vaccine development until 2018 [ 80 ]. This negativity was amplified by results of the first, large phase IIb efficacy trial of a “new-generation vaccine candidate”, MVA85A, in infants published in 2013. The trial did not demonstrate statistically significant efficacy of MVA85A vaccination of previously BCG-vaccinated 4–6-month-old infants against Mtb infection or active TB [ 81 ]. Demonstration of protection by BCG revaccination or M72/ASO1 E vaccination thus provided the first opportunity to identify immunological correlates of protection (CoP). Crucially, a limited set of blood samples that were specifically earmarked for this purpose were collected and stored with informed consent in the BCG revaccination and M72/ASO1 E phase 2b trials and an international ‘TB Immune Correlate Program’ consortium, led by the Gates Medical Research Institute and supported by vaccine manufacturers, sponsors of the two phase 2b trials, key funding agencies and trial investigators, has been launched. This consortium is charged with identifying and executing a strategy to test a number of a priori hypotheses that are informed by existing knowledge and results from recent animal models and clinical studies ( Table 2 ). The desire to identify immunological CoP for TB has been great for decades because measurement of an immunological outcome rather than accrual of clinical endpoints in large and expensive clinical trials could significantly accelerate vaccine development. It also has potential to reveal putative mechanisms of protection, which are likely to spark more rational design to improve the efficacy of next generation vaccines.

However, the relatively small number of participants that reached clinical endpoints (57 participants had sustained QFT conversion in the C-040-404 trial and 39 participants developed TB disease in the M72/ASO1 E trial) in the phase 2b proof-of-concept trials restrict statistical power of these CoP discovery approaches. This limitation emphasizes the importance of larger, follow-up studies to confirm and strengthen evidence of vaccine efficacy, while providing an opportunity to validate the CoP identified in the currently ongoing efforts.

3. Discussion and conclusions

These recent successes in TB vaccine research illustrate that deployment of a highly efficacious vaccine against TB is likely within this decade. It is critical that TB vaccine development accelerates towards phase 3 licensure trials with innovative designs and the necessary urgency. Crucially, identification of correlate(s) of protection could be hugely valuable in speeding optimization and an expansion of target populations for M72/AS01E and also in streamlining triage and evaluation of next generation candidates. The remarkable “warp-speed” at which COVID-19 vaccines are being developed demonstrates what real urgency can achieve and serves as a benchmark for the TB field. Given the morbidity and mortality that is suffered globally due to TB, it is time to accelerate commitment, investment and implementation to stop the infectious disease that has killed the most human beings.

This review article did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors received salary support as follows: AMG – Bill & Melinda Gates Foundation; MGN – supported by an ERC Advanced Grant (#833247) and a Spinoza grant of the Netherlands Organization for Scientific Research; TJS – supported from research grants to University of Cape Town from South African Medical Research Council, Bill & Melinda Gates Foundation, National Institutes of Health, European and Developing Countries Clinical Trials Partnership.

Declaration of Competing Interest

Mihai G. Netea – declares patent applications/registration of nanobiologics to stimulate or inhibit trained immunity, and he is a scientific founder of Trained Therapeutix and Discovery; Thomas Scriba – declares patent applications/registrations of transcriptomic and proteomic biosignatures of TB risk and disease progression and research grants to University of Cape Town from South African Medical Research Council, Bill & Melinda Gates Foundation, National Institutes of Health, European and Developing Countries Clinical Trials Partnership; Ann Ginsberg - none

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Research Article

The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study

Roles Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America

Roles Data curation, Formal analysis, Writing – original draft, Writing – review & editing

Affiliations TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom, Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom

Roles Conceptualization, Formal analysis, Methodology, Writing – review & editing

Roles Formal analysis, Writing – review & editing

Affiliations TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom, Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom, KNCV Tuberculosis Foundation, The Hague, the Netherlands

Affiliations TB Modelling Group, London School of Hygiene and Tropical Medicine, London, United Kingdom, Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom, Coalition for Epidemic Preparedness Innovations, London, United Kingdom

Roles Methodology, Writing – review & editing

Affiliations Market Access, Global Alliance for TB Drug Development, New York, New York, United States of America, Global Access, International AIDS Vaccine Initiative, New York, New York, United States of America

Roles Resources, Writing – review & editing

Affiliation Global TB Programme, World Health Organization, Geneva, Switzerland

Affiliation Department of Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland

Roles Data curation, Methodology, Writing – review & editing

Roles Data curation, Writing – review & editing

Affiliations Centre for the Mathematical Modelling of Infectious Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom, Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, United Kingdom, School of Public Health, University of Hong Kong, Hong Kong SAR, China

Roles Conceptualization, Formal analysis, Funding acquisition, Methodology, Supervision, Writing – original draft, Writing – review & editing

¶ ‡ These authors are joint senior authors on this work.

•  [ ... ],

Affiliations Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America

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• Published: January 24, 2023
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Tuberculosis (TB) is preventable and curable but eliminating it has proven challenging. Safe and effective TB vaccines that can rapidly reduce disease burden are essential for achieving TB elimination. We assessed future costs, cost-savings, and cost-effectiveness of introducing novel TB vaccines in low- and middle-income countries (LMICs) for a range of product characteristics and delivery strategies.

Methods and findings

We developed a system of epidemiological and economic models, calibrated to demographic, epidemiological, and health service data in 105 LMICs. For each country, we assessed the likely future course of TB-related outcomes under several vaccine introduction scenarios, compared to a “no-new-vaccine” counterfactual. Vaccine scenarios considered 2 vaccine product profiles (1 targeted at infants, 1 at adolescents/adults), both assumed to prevent progression to active TB. Key economic inputs were derived from the Global Health Cost Consortium, World Health Organization (WHO) patient cost surveys, and the published literature. We estimated the incremental impact of vaccine introduction for a range of health and economic outcomes. In the base-case, we assumed a vaccine price of $4.60 and used a 1× per-capita gross domestic product (GDP) cost-effectiveness threshold (both varied in sensitivity analyses). Vaccine introduction was estimated to require substantial near-term resources, offset by future cost-savings from averted TB burden. From a health system perspective, adolescent/adult vaccination was cost-effective in 64 of 105 LMICs. From a societal perspective (including productivity gains and averted patient costs), adolescent/adult vaccination was projected to be cost-effective in 73 of 105 LMICs and cost-saving in 58 of 105 LMICs, including 96% of countries with higher TB burden. When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult vaccine could produce $283 to 474 billion in economic benefits by 2050. Limited data availability required assumptions and extrapolations that may omit important country-level heterogeneity in epidemiology and costs.

Conclusions

TB vaccination would be highly impactful and cost-effective in most LMICs. Further efforts are needed for future development, adoption, and implementation of novel TB vaccines.

Author summary

Why was this study done.

• Previous studies have highlighted the economic impact of tuberculosis (TB) and the potential economic impact that novel TB vaccines could have on reducing this burden in specific low- and middle-income countries (LMICs).
• The cost and cost-effectiveness of novel TB vaccines, which depend on vaccine price and delivery strategy that may vary by country, are needed by vaccine developers, manufacturers, and potential purchasers to guide investment decisions.
• No modeling studies have estimated the cost and cost-effectiveness of novel TB vaccine products with country-specific assumptions for medical and non-medical costs, indirect costs, vaccine delivery costs, and delivery strategies across a wide range of LMICs.

What did the researchers do and find?

• We estimated the costs, cost-effectiveness, and incremental net monetary benefit (iNMB) of TB vaccine introduction from both the health system and societal perspective, in order to inform global-level decision-making for novel TB vaccine investment and introduction.
• Using mathematical and economic models, we assessed scenarios for the introduction of novel TB vaccines with a wide range of characteristics and a diverse set of health and economic outcomes, including country-specific introduction years from 2028 to 2047.
• Our analysis projected that an effective new TB vaccine could offer large potential health and economic benefits over 2028 to 2050. From a societal perspective, vaccination was projected to be cost-effective in 73 LMICs compared to a 1× per-capita gross domestic product (GDP) threshold.
• When considering the monetized value of health gains, we estimated that introduction of an adolescent/adult TB vaccine could produce $283 to 474 billion in health and economic benefits by 2050, with greater benefits in LMICs with elevated TB incidence.

What do these findings mean?

• Introduction of a new TB vaccine was found to be impactful and cost-effective for a range of assumptions on vaccine price and delivery strategies, with aggregate health and economic benefits of similar scale to the most influential health interventions in LMIC settings in recent years.
• The results of these analyses can be used by global and country stakeholders to inform TB vaccine policy and introduction preparedness, as well as decision-making around future development, adoption, and implementation of novel TB vaccines.

Citation: Portnoy A, Clark RA, Quaife M, Weerasuriya CK, Mukandavire C, Bakker R, et al. (2023) The cost and cost-effectiveness of novel tuberculosis vaccines in low- and middle-income countries: A modeling study. PLoS Med 20(1): e1004155. https://doi.org/10.1371/journal.pmed.1004155

Academic Editor: Megan B. Murray, Harvard Medical School, UNITED STATES

Received: May 23, 2022; Accepted: December 9, 2022; Published: January 24, 2023

Copyright: © 2023 Portnoy et al. This is an open access article distributed under the Creative Commons Attribution IGO License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. https://creativecommons.org/licenses/by/3.0/igo/ . In any use of this article, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article’s original URL.

Data Availability: Analytic code is available at https://doi.org/10.5281/zenodo.6421372 .

Funding: This study was funded by the World Health Organization (2020/985800-0 to RGW), the Bill & Melinda Gates Foundation (INV-001754 to RAC, RGW; OPP1084276 to RGW; OPP1135288 to RGW), the Canadian Centennial Scholarship Fund (to RAC), UK Research & Innovation Medical Research Council (MR/N013638/1 to CKW; CCF17-7779 via SET Bloomsbury to RGW), the Wellcome Trust (218261/Z/19/Z to RGW), the National Institutes of Health (1R01AI147321-01 to RGW), European and Developing Countries Clinical Trials Partnership (RIA208D-2505B to RGW), UK Research & Innovation Economic and Social Research Council (ES/P008011/1 to RGW). Members of the funder participated as authors on the study. All authors had the opportunity to access and verify the data, and all authors were responsible for the decision to submit the manuscript for publication.

Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Members of the funder (NG, MZ, SYS, RH, IGB, NN) participated as authors on the study and critically reviewed the analysis, reviewed and revised the manuscript, and approved the final manuscript as submitted. All other authors have declared that no competing interests exist.

Abbreviations: AFR, WHO African region; ART, antiretroviral therapy; COVID-19, Coronavirus Disease 2019; DALY, disability-adjusted life-year; DS, drug-susceptible; GDP, gross domestic product; GLM, generalized linear regression model; GNI, gross national income; HPV, human papillomavirus; ICER, incremental cost-effectiveness ratio; iNMB, incremental net monetary benefit; LMIC, low- and middle-income country; RR, rifampicin-resistant; SEAR, WHO Southeast Asian region; TB, tuberculosis; WHO, World Health Organization; YLD, years lost due to disability

Introduction

Tuberculosis (TB) is one of the world’s leading causes of infectious disease death [ 1 ]. It remains the leading cause of death for people living with HIV and a major contributor to antimicrobial-resistance-related deaths. The Coronavirus Disease 2019 (COVID-19) pandemic has reversed years of progress in providing TB services and, consequently, the number of people who died from TB increased to 1.5 million in 2020 [ 1 ].

The World Health Organization (WHO)’s End TB Strategy targets a 90% reduction in TB mortality and 80% decline in TB incidence by 2030, compared to 2015 [ 2 ]. Achieving these targets will require a comprehensive multisectoral response, along with transformational new tools. The cost of not meeting the End TB Targets by 2030 and facing the excess deaths resulting from COVID-19-related disruptions to TB services may translate into 31.8 million TB deaths globally corresponding to an economic loss of $17.5 trillion between 2020 and 2050 [ 3 ]. Developing new safe, affordable, and effective TB vaccines is critical for achieving these targets. While promising candidates exist (for example, the M72/AS01 E candidate vaccine [ 4 ]), limited market incentives to invest in TB prevention has delayed the development of novel TB vaccines.

The WHO promotes the Full Value of Vaccines Assessment framework to improve decision-making around vaccine development and use [ 5 , 6 ]. As part of a Full Value of Vaccines Assessment of novel TB vaccines, we estimated the costs, cost-effectiveness, and net monetary benefit of TB vaccine introduction, from health system and societal perspectives, to inform global-level decision-making for novel TB vaccine investment and introduction [ 5 , 6 ].

Analytic overview

We estimated a range of outcomes quantifying the health and economic impact of new vaccine introduction for affected countries. To do so, we used linked epidemiological and economic models to project changes in healthcare utilization, health outcomes, and healthcare costs for various vaccine introduction scenarios compared to a “no-new-vaccine” counterfactual. (Full epidemiological model details have been previously reported by Clark and colleagues [ 7 ] and are briefly described in Exhibit A in S1 Appendix . Any changes to the analysis that were required are also described; no prospective analysis plan was developed.) We estimated outcomes for each of 105 low- and middle-income countries (LMICs) over a 2028 to 2050 evaluation period (Exhibit B in S1 Appendix ). We summarized results as the incremental costs, cost-effectiveness, and incremental net monetary benefits (iNMBs) of vaccine introduction. Results are presented for a range of analytic assumptions and introduction scenarios, organized by major country groupings (WHO region, World Bank income level [ 8 ], and WHO high-TB burden grouping [ 9 ]).

Vaccination scenarios

We constructed a “no-new-vaccine” baseline with current TB interventions continuing into the future at current levels. Compared to this baseline, we evaluated 2 different vaccine product profiles: an infant “pre-infection” prevention of disease vaccine (i.e., efficacious for individuals uninfected at time of vaccination) with 80% efficacy targeting neonates and an adolescent/adult “pre- and post-infection” prevention of disease vaccine (i.e., efficacious in all individuals aside from those with active TB at time of vaccination) with 50% efficacy, based on WHO Preferred Product Characteristics for New Tuberculosis Vaccines [ 10 ]. For both vaccine product profiles, we assumed an average 10-year duration of protection, with exponential waning. We assumed the infant vaccine would be delivered through the routine vaccination program, with vaccine delivery at fixed sites following a standard dosing schedule. We assumed the adolescent/adult vaccine would be delivered through routine vaccination of 9-year-olds plus a one-time vaccination campaign for ages 10+. In the base-case scenario, we assumed countries would achieve linear scale-up to a specified coverage over 5 years. Based on consultation with global stakeholders, we assumed a coverage target of 85% for the infant vaccine (average coverage of diphtheria-tetanus-pertussis third dose for LMICs [ 11 ]), 80% for routine delivery of adolescent/adult vaccine, and 70% of the adolescent/adult vaccination campaign [ 12 ]. We selected 2028 as the earliest country-specific introduction year to align with anticipated product availability following TB vaccine candidate trial completion. We assumed country-specific introduction years from 2028 to 2047, determined based on indicators for disease burden, immunization capacity, classification of the country as an “early adopter/leader,” lack of regulatory barriers, and commercial prioritization [ 7 ]. Further details regarding vaccination scenarios are provided in the appendix.

Epidemiological outcomes and health service utilization

We projected future TB epidemiology and health service utilization using an age-structured TB transmission model calibrated to reported demography, TB burden estimates, and TB service utilization in each modeled country [ 7 ]. Out of 135 LMICs [ 8 ], we excluded 20 due to lack of critical calibration data and 10 due to unsuccessful calibration results (details provided in Exhibit A in S1 Appendix ). We analyzed the remaining 105 countries (Exhibit B in S1 Appendix ), representing 93.3% of global TB burden [ 13 ]. In countries in which the proportion of TB cases among people living with HIV was greater than or equal to 15%, and the HIV prevalence in the country was greater than 1%, the model included the effects of HIV and antiretroviral therapy (ART) on TB infection and progression risks (Exhibit A in S1 Appendix ). Using this model, we estimated changes in TB epidemiology and related service utilization for each modeled scenario.

Summary health outcomes

We estimated disability-adjusted life-years (DALYs) averted to quantify the health gains achieved by vaccination. To calculate years lost due to disability (YLDs), we assigned each modeled health state a disability weight from the Global Burden of Disease classification system (Exhibit C in S1 Appendix ) [ 14 ]. For each scenario and year, total YLDs were calculated by summing life-years lived across all health states, weighted by the disability weight for each state. For each scenario and year, years of life lost were calculated by multiplying deaths at each year of age by reference life expectancy at that age [ 15 ] and summing across all ages.

Cost outcomes

We estimated the costs of vaccine introduction, as well as changes in the costs of other health services (TB care, HIV care) by multiplying health service volume indicators (vaccines delivered, TB cases diagnosed and treated, ART patient-years) by country-specific unit costs. Diagnostics costs for drug-susceptible (DS) and rifampicin-resistant (RR) TB were obtained from published literature as average values for each country income level [ 16 ], which were assigned to each LMIC in the associated country income level grouping [ 8 ]. Unit costs for TB treatment were calculated as an average of country-level DS-TB [ 17 ] and income-level RR-TB [ 16 , 18 ] treatment costs, weighted by country-level RR-TB prevalence [ 1 ].

For ART costs, direct non-medical costs (travel, accommodation, food, nutritional supplements) to the patient, and productivity costs (income loss experienced by patients during TB care), we derived unit costs by extrapolating estimates reported by the Global Health Cost Consortium [ 19 ] (sample size = 39) and WHO patient cost surveys (sample size = 20) [ 20 , 21 ] with meta-regression models for the respective outcomes specified as generalized linear regression models (GLMs), assuming a Gamma distributed outcome, a log link function, and gross domestic product (GDP) per capita as the predictor [ 22 ]. The previous unit costs were inflated to 2020 values in local currency using the country consumer price index [ 23 ] and converted to 2020 US dollars using market exchange rates [ 24 ].

Productivity costs due to premature death were estimated as the incremental number of life-years gained under a given vaccination scenario, multiplied by 2020 per-capita GDP as an approximation of income.

As the per-dose cost for novel TB vaccines is unclear while products are still under development, the base-case used an LMIC price of human papillomavirus (HPV) vaccine ($4.60) for a novel vaccine proxy with an injection supply cost per dose of $0.11 and 5% wastage [ 25 , 26 ]. Country-specific vaccine delivery costs were based on a meta-analysis of childhood [ 27 ] and HPV vaccine delivery unit costs for the infant and adolescent/adult vaccines, respectively, plus additional one-time vaccine introduction costs ($0.65 and $2.40 per targeted individual in the first year of introduction for infant and adolescent/adult vaccines, respectively) [ 28 ]. Costs are reported in 2020 US dollars.

Cost-effectiveness analysis

Incremental cost-effectiveness ratios (ICERs) were calculated from health system and societal perspectives, with a 3% discount rate, across the 2028 to 2050 evaluation period. We also reported a specification in which costs are discounted but not health outcomes. The health system perspective considered costs of vaccine introduction, plus the costs of TB and HIV services indirectly affected by vaccine introduction. The societal perspective additionally included patient non-medical and productivity costs. ICERs were compared to a range of country-specific cost-effectiveness thresholds to reflect the lack of consensus for a single threshold, including multiples of per-capita GDP [ 29 ] (assuming 1× per-capita GDP as a proxy for willingness to pay in the base-case), recent estimates of the opportunity cost of healthcare spending [ 30 , 31 ], and the WHO’s universal “Best Buy” threshold of $100 per DALY averted. This study is reported as per the Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) statement (Exhibit D in S1 Appendix ) [ 32 ].

Return on investment

We quantified the return on investment as the iNMB from the societal perspective of each vaccine scenario compared to baseline for a range of willingness-to-pay thresholds [ 29 – 31 ]. iNMB was calculated as the sum of monetized health gains (DALYs averted multiplied by the estimated willingness-to-pay per DALY averted) minus incremental costs. We estimated the market size for each vaccine product profile, summing all individuals across 2028 to 2050 who were vaccinated in the model in the base-case scenario in countries in which the vaccine was cost-effective (ICER less than per-capita GDP). We also estimated market size based on countries in which vaccination was cost-saving under the societal perspective.

Statistical analysis

We explored estimation uncertainty using a second-order Monte Carlo simulation [ 33 ]. We constructed probability distributions representing uncertainty in economic inputs and disability weights, specified as Gamma distributions for parameters defined over [0, ∞], and Beta distributions for parameters defined over [0, 1]. For each parameter, the distribution mean was set equal to the point estimate, and the dispersion was set so an equal-tailed 95% interval reproduced the reported interval width. For parameters estimated from a meta-regression model (ART costs, patient costs), we simulated parameter values from each fitted regression model. We drew 1,000 random values for each uncertain parameter. We represented uncertainty in healthcare utilization and epidemiological outcomes (counts of each outcome by scenario, year, and population stratum) using 1,000 results sets from the transmission-dynamic model. This analysis generated 1,000 estimates for each outcome of interest, which we summarized as equal-tailed 95% uncertainty intervals.

Sensitivity analysis

Compared to the base-case coverage targets (85%, 80%, 70% for routine infant vaccine delivery, routine adolescent vaccine delivery, and campaign adolescent/adult vaccine delivery, respectively), we examined a low-coverage scenario (75%, 70%, and 50%, respectively) and a high-coverage scenario (95%, 90%, and 90%, respectively).

We examined 2 alternative vaccine delivery scenarios. First, we modeled an accelerated scale-up scenario in which all countries introduced vaccination in 2025 and achieved instantaneous scale-up to the specified coverage target. Second, we modeled a routine-only scenario that removed the one-time campaign-delivery component of the adolescent/adult base-case scenario.

We examined 3 alternative vaccine price scenarios, including scenarios in which the base-case vaccine price of $4.60 was both halved ($2.30) and doubled ($9.20), respectively. A third scenario examined high-middle-tier vaccine pricing, with higher prices for middle-income countries based on UNICEF vaccine pricing data ($10.25 for non-Gavi countries with gross national income (GNI) per capita less than $3,995 and $14.14 for non-Gavi countries with GNI per capita greater than $3,995; Exhibit B in S1 Appendix ) [ 25 ].

Compared to the base-case scenario assuming 1 vaccine dose, we estimated results assuming that 2 vaccine doses were required to achieve the same level of efficacy, i.e., a full vaccination course required 2× the base-case vaccine price of $4.60 and 2× the delivery cost.

We also estimated results with an alternative set of assumptions about TB incidence trends in the no-new-vaccine baseline, with incidence assumed to decline more rapidly through the scale-up of existing preventive treatment and case detection, meeting the 2025 “End TB” incidence reduction target without introduction of a new vaccine [ 2 ].

Compared to the base-case assumption of 10-year duration of protection, we also examined lifelong duration of protection conferred by vaccination.

Finally, compared to the base-case assumption of 50% efficacy for the adolescent/adult vaccine, we also examined 75% efficacy conferred by this vaccine.

Costs and cost-effectiveness analysis

A summary of the unit costs by country income level is provided in Table 1 . In the no-new-vaccine baseline, over 2028 to 2050, total undiscounted (i.e., without a 3% annual discount rate) costs of TB diagnosis and treatment were estimated to be $20.7 (95% uncertainty interval: 12.8 to 31.2) billion for DS-TB and $19.2 (15.6 to 23.1) billion for RR-TB (Exhibit E in S1 Appendix ). For the infant vaccine scenario, vaccine introduction costs were $11.8 (9.6 to 16.9) billion, and averted TB diagnosis and treatment costs were $342 (223 to 489) million for DS-TB and $299 (251 to 351) million for RR-TB over 2028 to 2050 (Exhibit F in S1 Appendix ). For the adolescent/adult vaccine scenario, vaccine introduction costs were $50.5 (38.1 to 75.9) billion, and averted TB diagnosis and treatment costs were $3.5 (2.2 to 5.2) billion for DS-TB and $3.2 (2.6 to 3.8) billion for RR-TB over 2028 to 2050 (Exhibit G in S1 Appendix )—greater than the averted disease costs in the infant vaccine scenario. There would also be $13.4 (9.5 to 19.2) million and $362 (281 to 466) million in additional ART costs under the infant and adolescent/adult vaccine scenarios, respectively, due to extended survival among people living with HIV (Exhibits H and I in S1 Appendix ).

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https://doi.org/10.1371/journal.pmed.1004155.t001

There was greater, and more rapid, impact from an adolescent/adult vaccine compared to an infant vaccine over the study period (Exhibits J and K in S1 Appendix ). Across 2028 to 2050, infant vaccine costs were projected to increase smoothly from the year of vaccine introduction, whereas the adolescent/adult vaccine scenario required major upfront investments during vaccine introduction and 5-year campaign roll-out, then decreased substantially after campaigns were completed.

In the base-case analysis, from the health system perspective, we found that infant vaccination would be cost-effective (ICER below 1-times per-capita GDP) compared to no vaccination in 47 of 105 modeled LMICs (45%) and 24 of 27 with high-TB burden (89%). Using the same assumptions, we found that adolescent/adult vaccination would be cost-effective in 64 out of 105 countries (61%) and all 27 with high-TB burden. Neither vaccine strategy would be cost-saving in any country. Fig 1 displays the distribution of country-level cost-effectiveness results from the health system perspective for infant and adolescent/adult vaccines, stratified by TB incidence level. Vaccine introduction was more likely to be cost-effective in countries with higher TB incidence.

Note: Points represent each of 105 LMICs analyzed in the base-case scenario, stratified by TB incidence per 100,000. Line represents a cost-effectiveness threshold of 1× per-capita GDP in 2020. Vaccine introduction would be considered cost-effective for countries falling underneath this line. DALY, disability-adjusted life year; GDP, gross domestic product; LMIC, low- and middle-income country; TB, tuberculosis.

https://doi.org/10.1371/journal.pmed.1004155.g001

From the societal perspective, the infant vaccine was cost-effective in 56 out of 105 countries (53%), including all with high-TB burden, and cost-saving in 46 countries (44%). Similarly, the adolescent/adult vaccine was cost-effective in 73 out of 105 countries (70%), remaining cost-effective in all with high-TB burden, and cost-saving in 58 countries (55%). Fig 2 displays the percentage of the modeled population that live in countries where vaccination was cost-effective based on different cost-effectiveness thresholds (Exhibit L in S1 Appendix shows the percentage of countries where vaccination was cost-effective; Exhibits M and N in S1 Appendix present tabular results).

Note: Countries include 105 LMICs analyzed. Population includes vaccinated individuals 2028–2050. GDP per capita estimates from 2020. GDP, gross domestic product per capita; LMIC, low- and middle-income country.

https://doi.org/10.1371/journal.pmed.1004155.g002

Tables 2 and 3 report summary health outcomes, costs, and cost-effectiveness of the base-case vaccination scenarios. Across all 105 analyzed countries, the majority of TB cost-savings accrued in high-TB-burden settings, particularly in lower middle-income settings and WHO African region (AFR) and Southeast Asian region (SEAR). Assuming 0% discounting on health outcomes decreased ICERs (indicating greater cost-effectiveness) for the infant vaccine by approximately 76% and for the adolescent/adult vaccine by approximately 69% from the health system perspective (Exhibits O and P in S1 Appendix ).

https://doi.org/10.1371/journal.pmed.1004155.t002

https://doi.org/10.1371/journal.pmed.1004155.t003

With each averted DALY valued at per-capita GDP and costs assessed from the societal perspective, we estimated a cumulative $68.6 (range: $44.5 to 100 across examined thresholds) billion iNMB globally for infant vaccine introduction in countries where introduction was cost-effective at 1-times per-capita GDP ( Fig 3 ; tabular results in Exhibit Q in S1 Appendix ). For the adolescent/adult vaccine, we estimated iNMB of $372 billion for countries in which vaccination was cost-effective (range: $283 to 474 billion). These benefits were concentrated in regions (AFR, SEAR) with higher disease burden. For the infant vaccine, the market size (i.e., the vaccinated population in countries in which the vaccine would be cost-effective at per-capita GDP from the societal perspective) would be 1.431 (1.430 to 1.432) billion individuals, while for the adolescent/adult vaccine, this population size would be 5.182 (5.180 to 5.183) billion individuals. Under a more restrictive assumption where the vaccine is only introduced in countries where the societal ICER is cost-saving, the market size would be 1.316 (1.315 to 1.317) billion individuals for the infant vaccine, and 4.642 (4.617 to 4.644) billion individuals for the adolescent/adult vaccine. The largest markets were in the WHO SEAR and WPR regions (Exhibits R and S in S1 Appendix ).

Note: Estimates include the iNMB from the countries that are cost-effective at the respective threshold [ 29 – 31 ]. GDP per capita estimates from 2020. GDP, gross domestic product per capita; iNMB, incremental net monetary benefit.

https://doi.org/10.1371/journal.pmed.1004155.g003

From both health system and societal perspectives, DALYs averted and costs decreased in the low-coverage scenario, and increased in the high-coverage scenario, for both the infant and the adolescent/adult vaccine, with evidence of diminishing returns as coverage increases (Exhibits T and W in S1 Appendix ).

Compared to the base-case vaccination introduction and delivery scenario, the accelerated scale-up scenario had greater health impact (DALYs averted) and better cost-effectiveness (assuming per-unit vaccination costs were unchanged), with vaccination being cost-effective in all 105 LMICs for both the infant and adolescent/adult vaccine compared to a per-capita GDP threshold (Exhibits X–AA in S1 Appendix ). Conversely, the routine-only scenario had a much smaller health impact and modestly worse cost-effectiveness profile, as compared to the base-case analysis (Exhibit BB in S1 Appendix ).

Reducing the vaccine price by half decreased infant vaccination costs from $11.8 to $7.6 billion (36% decrease) and adolescent/adult vaccination costs from $50.5 to $36.4 billion (28% decrease; Exhibits CC–LL in S1 Appendix ). Doubling the vaccine price increased infant vaccination costs to $20.2 billion (71% increase) and adolescent/adult vaccination costs to $78.8 billion (56% increase). Switching to high-middle-tier vaccine pricing (higher vaccine prices for middle-income countries) increased infant vaccine costs to $16.9 billion (44% increase) and adolescent/adult vaccination costs to $72.1 billion (43% increase). From the health system perspective, reducing the vaccine price by half increased the number of countries in which infant vaccination was cost-effective at a per-capita GDP threshold from 47 to 51, whereas doubling the vaccine price decreased the number of cost-effective countries to 32. Assuming higher vaccine prices for middle-income countries reduced the number of countries in which the infant vaccine was cost-effective at a per-capita GDP threshold from 47 to 41. Similarly, the half-price scenario, double-price scenario, and high-middle-tier-price scenario changed the number of countries in which the adolescent/adult vaccine was considered cost-effective from the health system perspective at a per-capita GDP threshold from 64 in the base-case, to 70, 52, and 55, respectively.

Assuming a two-dose vaccination course increased infant vaccination costs to $23.3 billion (Exhibit CC in S1 Appendix ) and adolescent/adult vaccination costs to $100 billion (Exhibit DD in S1 Appendix ). From the health system perspective, a two-dose vaccination course decreased the number of countries in which infant vaccination was cost-effective at a per-capita GDP threshold from 47 to 31 and in which adolescent/adult vaccination was cost-effective from 64 to 46 (Exhibits MM and NN in S1 Appendix ).

Assuming the no-new-vaccine baseline with faster incidence reductions through strengthening of current TB interventions to meet the 2025 End TB targets, a number of countries remained cost-saving from the societal perspective (9 countries for infant vaccine and 20 countries for adolescent/adult vaccine; Exhibits OO and PP in S1 Appendix ).

An infant vaccine with lifelong duration of protection averted 30.0 (26.1 to 34.5) million DALYs, a 66% increase compared to the base-case assumption of 10-year protection (Exhibit QQ in S1 Appendix ). An adolescent/adult vaccine with lifelong duration of protection averted 138 (127 to 150) million DALYs (46% greater than the base-case; Exhibit RR in S1 Appendix ). Both vaccine products remained cost-saving from the societal perspective, assuming lifelong duration of protection decreased the ICER by approximately 42% and 36% for the infant and adolescent/adult vaccine, respectively (health system perspective).

An adolescent/adult vaccine with 75% efficacy also averted 138 (127 to 150) million DALYs (45% greater than the base-case; Exhibit SS in S1 Appendix ), but decreased the ICER to a greater degree than lifelong duration of protection at 53%.

An effective novel TB vaccine would offer large potential health and economic benefits over 2028 to 2050. The results of this analysis demonstrate that, when available, TB vaccines could be cost-effective in a majority of LMICs, particularly from the societal perspective, and in essentially all high-burden countries. Introducing novel TB vaccines could also offer high value in terms of iNMB to patients, the health system, and society, particularly in countries with high burden of TB, HIV-associated TB, and/or multidrug-resistant/RR-TB.

For both vaccine product profiles, vaccination was more likely to be cost-effective in lower middle-income countries (relative to low-income and upper middle-income countries), as countries in this income group are more likely to have both significant TB burden and sufficient economic resources to justify additional TB investments without displacing other important health interventions. Vaccination was more frequently cost-effective in AFR and SEAR regions and the adolescent/adult vaccine was estimated to be cost-effective in all countries in the 27 modeled high-TB burden countries that accounted for 81.8% of global incident TB cases and 80.9% of global TB deaths in 2020 [ 9 , 13 ]. This relationship of ICERs decreasing as disease burden increases has also been shown for several licensed vaccines, including HPV, malaria, and rotavirus [ 34 – 36 ]. Although vaccines can be economically less viable for manufacturers, we estimated large potential markets for vaccinees in high-burden, middle-income settings. We estimated cost-effectiveness using a range of cost-effectiveness benchmarks, based on recent discussion of the validity of conventional standards [ 31 , 37 – 39 ]. Final decisions about vaccine adoption will be made by local decision-makers, based on the values placed on health benefits, opportunity costs, the relative timing of health outcomes and costs, and other context-specific considerations.

There was greater, and more rapid, impact from an adolescent/adult vaccine over the 2028 to 2050 time horizon compared to an infant vaccine, as this vaccine is targeted to a population with the highest burden of TB, and the delay between vaccination and TB prevention impact is shorter with the adolescent/adult vaccine. For the adolescent/adult vaccine, we estimated major short-term costs from introduction and one-time vaccination campaigns, with the highest costs incurred during the 10 years following vaccine introduction. In contrast, the cost-savings from averted TB cases were realized gradually over 2028 to 2050, growing in magnitude towards the end of the time horizon. By assuming the no-new-vaccine baseline meeting the End TB targets, the remaining TB burden that could be averted by vaccination was estimated to be smaller, yielding results that were less cost-effective.

There are several factors that distinguish this analysis from past studies [ 40 – 43 ]: firstly, the steps taken to construct a realistic vaccine adoption timeline, based on an analysis of factors affecting country adoption decisions and stakeholder consultation. As a result, this analysis provides a more robust estimate of the potential timing of vaccine impact compared to past analyses, which is particularly important given the expected role of vaccines in contributing to the attainment of TB elimination targets for specific calendar years. Secondly, this study examined a wide range of scenarios for vaccine introduction, illustrating how the pace and extent of scale-up affect overall impact by 2050. In particular, the comparison of the base-case scenario to an accelerated scale-up scenario demonstrates the additional health and economic gains that would be possible with more rapid vaccine introduction. Thirdly, this study estimated iNMB as a single measure summarizing the health and economic benefits of TB vaccine introduction. Combined with the large number of countries modeled, this analysis quantifies the overall global benefits of TB vaccination in a way that can be set against the costs and other challenges that must be overcome to develop a new vaccine. This is particularly important for justifying the investments that still need to be made in vaccine development and preparation for deployment.

This analysis had several limitations. We were constrained by data availability, with only 105 countries successfully parameterized and calibrated. However, these 105 countries represent 93.3% of LMIC TB incidence and 93.6% of LMIC TB mortality globally in 2020 [ 13 ]. As a “pre- and post-infection” vaccine, the adolescent/adult vaccine was assumed to be equally effective regardless of previous infection status, which may have led to an overestimation of averted TB cases and deaths if the vaccine is less effective in infected vaccinees. We also restricted the analysis to focus on vaccine products that would prevent development of active TB, and did not examine the possible impact of vaccine products that would prevent infection, such as recombinant BCG vaccines [ 44 ]. If successfully developed, such vaccines could provide another effective tool for accelerating TB control. We also extrapolated from published literature [ 16 – 18 ] for several major unit cost inputs, potentially omitting important country-level heterogeneity in these costs. The sample size of patient cost surveys used for non-medical and productivity costs was small (20); therefore, the extrapolation to other country settings may not capture the level of potential variation in these costs. We did not investigate targeting high-risk subgroups for vaccination; vaccination could still be cost-effective when targeted to subgroups in settings where vaccination was not estimated to be cost-effective in a national roll-out. In our main analysis, we used 1× per-capita GDP as a threshold to approximate willingness-to-pay per DALY averted, based on its historical broad utilization in economic evaluation studies. However, recent evidence suggests that a more stringent cost-effectiveness threshold may be appropriate [ 30 , 31 ], in which case vaccination would be cost-effective in fewer countries and estimates of return on investment would be lower. Finally, we did not consider all possible product and introduction scenarios, such as varying ages of vaccination, vaccine coverage targets by country, and scale-up trends by country, but demonstrated the potential value of novel TB vaccines according to specified characteristics. Future work developing detailed country-level models could take into account the health system capacity of each country and the underlying country-specific TB epidemiology by age to inform more realistic delivery scenarios.

Across this analysis, introduction of a novel TB vaccine was found to be impactful and cost-effective for a range of assumptions on vaccine price and delivery strategies, with aggregate health and economic benefits of similar scale to the most influential health interventions in LMIC settings in recent years [ 45 ]. TB vaccines are still under development, so their potential effectiveness and impact are uncertain. Accelerating the timeline for vaccine introduction, decreasing the vaccine price, or increasing vaccine efficacy could all impact the cost-effectiveness profile of vaccination and increase the magnitude of the benefits, directly improving the welfare of individuals and households that would otherwise experience the health and economic consequences of TB in coming years. Future work should investigate country-level vaccine policy questions to support introduction preparedness. The results of these analyses can be used by global and country stakeholders to inform these questions, as well as decision-making around future development, adoption, and implementation of novel TB vaccines.

Supporting information

S1 appendix..

https://doi.org/10.1371/journal.pmed.1004155.s001

Acknowledgments

We thank all the attendees at the WHO meetings on the Full Value Assessment of TB Vaccines for insightful advice and direction. The views expressed are those of the authors and do not necessarily represent the views of their respective organizations.

Ethics approval and consent to participate

Not applicable.

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Research Advances of Tuberculosis Vaccine and its Implication on COVID-19

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Tuberculosis (TB) is a global infectious disease caused by the Mycobacterium tuberculosis complex. The number of deaths caused by TB is second only to COVID-19. Therefore, vaccination plays an essential role in the prevention and control of TB. However, the efficacy of currently licensed TB vaccine, bacilli ...

Keywords : Tuberculosis, immune mechanism, progress, vaccine, BCG, COVID-19

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Tuberculosis — United States, 2023

Weekly / March 28, 2024 / 73(12);265–270

Paula M. Williams, DrPH 1 ,2 ; Robert H. Pratt 2 ; William L. Walker, DVM, PhD 2 ; Sandy F. Price 2 ; Rebekah J. Stewart, MSN, MPH 2 ; Pei-Jean I. Feng, MPH 2 ( View author affiliations )

What is already known about this topic?

For years, the United States has had one of the lowest tuberculosis (TB) rates in the world. In the first year of the COVID-19 pandemic, reported TB case counts dropped substantially, followed by increasing case counts every year since 2020.

What is added by this report?

During 2023, tuberculosis case counts increased among all age groups, among U.S-born and non-U.S.–born persons, and in most reporting jurisdictions. Overall, cases increased from 8,320 in 2022 to 9,615 in 2023, an increase of 1,295 cases. The rate also increased from 2.5 per 100,000 persons in 2022 to 2.9 in 2023.

What are the implications for public health practice?

Continued progress toward TB elimination will require strong public health systems that are capable of maintaining essential disease prevention and control activities and prepared to withstand the next pandemic or other large-scale crisis.

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After 27 years of declining U.S. tuberculosis (TB) case counts, the number of TB cases declined considerably in 2020, coinciding with the COVID-19 pandemic. For this analysis, TB case counts were obtained from the National TB Surveillance System. U.S. Census Bureau population estimates were used to calculate rates overall, by jurisdiction, birth origin, race and ethnicity, and age group. Since 2020, TB case counts and rates have increased each year. During 2023, a total of 9,615 TB cases were provisionally reported by the 50 U.S. states and the District of Columbia (DC), representing an increase of 1,295 cases (16%) as compared with 2022. The rate in 2023 (2.9 per 100,000 persons) also increased compared with that in 2022 (2.5). Forty states and DC reported increases in 2023 in both case counts and rates. National case counts increased among all age groups and among both U.S.-born and non-U.S.–born persons. Although TB incidence in the United States is among the lowest in the world and most U.S. residents are at minimal risk, TB continues to cause substantial global morbidity and mortality. This postpandemic increase in U.S. cases highlights the importance of continuing to engage communities with higher TB rates and their medical providers in TB elimination efforts and strengthening the capacity in public health programs to carry out critical disease control and prevention strategies.

Introduction

Despite being both preventable and curable, tuberculosis (TB) remains one of the world’s leading infectious disease killers ( 1 ). The United States has one of the lowest TB rates globally ( 1 ) and has a goal of eliminating TB (elimination defined as less than one case per 1 million population) by 2035 ( 2 ). During 1995–2014, health departments and CDC TB control efforts prevented as many as 300,000 persons from developing TB disease and averted up to $14.5 billion in costs ( 3 ). After 27 years of declining U.S. TB cases, the number of TB cases declined considerably in 2020 to 7,171, coinciding with the COVID-19 pandemic ( 4 ); however, TB case counts and rates increased in 2021 and 2022. This report provides provisional TB surveillance data for 2023 in the United States.

Tuberculosis Case Counts and Incidence

The 50 U.S. states and DC report each TB case that meets the Council of State and Territorial Epidemiologists’ surveillance case definition* to CDC’s National Tuberculosis Surveillance System (NTSS). † National case counts, along with counts by jurisdiction, birth origin, § race and ethnicity, and age group, were obtained from NTSS. National and jurisdictional TB rates per 100,000 persons were calculated using the midyear U.S. Census Bureau population estimates, ¶ and rates by birth origin (i.e., U.S.-born versus non-U.S.–born), race and ethnicity, and age group were calculated using the Current Population Survey** midyear estimates. Percentage changes in TB case counts and rates for 2023 compared with 2022 were calculated overall and by jurisdiction and demographic characteristics. Annual number and rate of TB cases are reported by birth origin for 2013 through 2023. SAS software (version 9.4; SAS Institute) was used for all analyses. This activity was reviewed by CDC, deemed not research, and was conducted consistent with applicable federal law and CDC policy. ††

Population Characteristics

Self-reported race and ethnicity were categorized according to federal guidelines. §§ Persons of Hispanic or Latino (Hispanic) origin might be of any race but are categorized as Hispanic; all racial groups are non-Hispanic. Non-Hispanic persons who reported more than one race were categorized as “multiple race.”

Tuberculosis Incidence by Jurisdiction

In 2023, the 50 U.S. states and DC provisionally reported 9,615 TB cases, an increase of 1,295 cases (16%) compared with the 8,320 cases reported in 2022, an 8% increase compared with the 2019 prepandemic case count (8,895), and the highest number of cases reported since 2013 (9,556) ( Figure ). Overall, the U.S. TB rate increased by 15%, from 2.5 per 100,000 persons in 2022 to 2.9 in 2023 ( Table 1 ). Forty states and DC reported an increase in both case counts and rates compared with those in 2022. As in 2022, California reported the highest number of cases in 2023 (2,113), and Alaska reported the highest rate (10.6). Eight states and DC reported TB rates higher than the national rate of 2.9 per 100,000 in 2023.

Tuberculosis Incidence by Demographic Characteristics

In 2023, among 9,573 TB cases in persons for whom birth origin was known, 7,259 (76%) occurred among non-U.S.–born persons, an 18% increase compared with the 6,177 such cases reported in 2022 ( Table 2 ). The number of cases in U.S.-born persons in 2023 increased 9%, from 2,131 in 2022 to 2,314. ¶¶ The rate increased among non-U.S.–born persons from 13.1 in 2022 to 15.0 in 2023, and the rate among U.S.-born persons remained at 0.8 cases per 100,000 persons.

Among U.S.-born persons with TB, 33% (753) identified as Black or African American (Black), 27% (614) as Hispanic, 26% (591) as White, 6% (130) as Asian, 5% (106) as American Indian or Alaska Native, 3% (62) as Native Hawaiian or other Pacific Islander, and 1% (18) as multiple race. Among U.S.-born persons, the rate of TB in 2023 compared with 2022 increased 20% (11 cases) among Native Hawaiian or other Pacific Islander, 12% (81 cases) among Black, 11% (72 cases) among Hispanic, and 4% (22 cases) among White persons, and the rate declined 9% (–7 cases) among American Indian or Alaska Native, and 12% (–12 cases) among Asian persons. Among non-U.S.–born persons with TB, 40% (2,876) identified as Hispanic, 39% (2,804) as Asian, 13% (922) as Black, 4% (300) as White, 2% (115) as Native Hawaiian or other Pacific Islander, 1% (64) as multiple race, and 0.1% (six) as American Indian or Alaska Native persons. Among non-U.S.–born persons, the TB rate in 2023 compared with 2022 increased 29% (10 cases) among Native Hawaiian or other Pacific Islander, 28% (272 cases) among Black, 23% (598 cases) among Hispanic, and 10% (26) among White persons, among non-U.S.–born Asian persons, the rate declined 2% (65 cases).***

TB incidence increased in every age group in 2023 compared with 2022, with the largest relative increase among children aged 5–14 years (68 cases, corresponding to a 42% increase in case count and a 45% increase in rate). Among the 83% (8,013) of persons with TB in 2023 for whom HIV status was known, 5% were coinfected with TB and HIV.

Provisional national surveillance data show that TB case counts and rates have increased since the COVID-19 pandemic, returning to the number of cases last observed in 2013 ( 4 ). Increases occurred in every age group and all except 10 U.S. states. Case counts increased among both U.S.-born and non-U.S.–born persons, with the most substantial increase, 18%, among non-U.S.–born persons (1,082 cases).

The United States has one of the lowest TB rates in the world ( 1 ) and most U.S. residents are at minimal risk for TB ( 2 , 4 ). The overall epidemiology of TB continues to reflect persistent disparities by birth origin, and race and ethnicity in the United States. TB rates in 2023 were highest among non-U.S.–born persons which is consistent with prepandemic trends. Among U.S.-born persons, rates remained <1.0 overall but were highest among those who identified as Native Hawaiian or other Pacific Islander, American Indian or Alaska Native, or Black.

Approximately 85% of TB cases in the United States are attributed to reactivation of latent TB infection (LTBI) rather than recent transmission ( 2 , 4 ). Therefore, sustained transmission of TB in the United States leading to outbreaks is uncommon. Essential TB elimination activities include TB testing among populations at risk and treating persons with LTBI or TB disease. To prevent transmission and reduce morbidity, TB disease must be detected quickly; effective treatment must be initiated promptly; and all exposed persons identified, evaluated, and treated if infected ( 5 ). This approach led to a 66% reduction in TB cases and 73% reduction in the TB rate in the United States in the first 25 years of implementation ( 4 ).

TB prevention and control interventions are primarily conducted by staff members in state and local public health programs. The decades-long downward trend in TB in the United States and the high TB disease treatment completion rates ( 4 ) underscore the success of these TB programs. However, during the COVID-19 pandemic, TB programs were severely taxed with many staff members and activities diverted to the COVID-19 response ( 6 ). Timely diagnosis and treatment of TB disease also suffered because of pandemic-related disruptions in health care access and health care workers focusing on identifying persons with COVID-19, who often have symptoms similar to those of pulmonary TB ( 7 ). These factors, along with changes in migration volume ( 8 ), probably contributed to the decrease in the number of cases observed in 2020, and to the subsequent rise in case counts and rates since 2020. Identification of TB cases possibly increased after the pandemic because of renewed attention to infectious diseases other than COVID-19.

The number of persons who received a new TB diagnosis has also risen globally. In 2022, the World Health Organization reported a second consecutive year of increasing TB case counts, with the global estimate of TB cases equaling that of 2016 ( 1 ). TB is not the only preventable communicable disease resurging after the COVID-19 pandemic. For example, influenza ( 9 ) and measles ( 10 ) have also experienced postpandemic surges. Setbacks to TB elimination in the United States illustrate the power of pandemics and other large-scale crises to have long-lasting effects on public health, a phenomenon also observed at the onset of the HIV epidemic when the number of TB cases increased after 3 decades of decline ( 4 ). Renewed progress toward TB elimination will require strengthened capacity of public health programs to carry out critical TB control and prevention strategies and engagement of providers and affected communities in TB elimination efforts. In addition, because most TB cases in the United States occur among non-U.S.–born persons, collaboration of public health entities in the United States with international partners is important to reduce TB morbidity globally.

Limitations

The findings in this report are subject to at least two limitations. First, this analysis is limited to provisional surveillance data for 2023, and case counts might change before CDC’s annual TB surveillance report is published. Second, rates are based on midyear population estimates from the U.S. Census Bureau that are subject to ongoing refinement.

Implications for Public Health Practice

The U.S. TB case count increases in 2023 underscores the ongoing global TB-associated morbidity and mortality. Renewed progress toward TB elimination will require strong public health systems both domestically and globally that are responsive to health disparities, capable of maintaining essential disease prevention and control activities, and prepared to withstand the next pandemic or other large-scale crisis.

Acknowledgments

State and local health department personnel; Surveillance Team, Cynthia Adams, Shanita Clemmons, Stacey Parker, Jeanette Roberts, Katrina Williams, Peraton; Justin Davis, Maryam Haddad, Kimberly Schildknecht, Julie Self, Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, CDC.

Corresponding author: Paula M. Williams, [email protected] .

1 Epidemic Intelligence Service, CDC; 2 Division of Tuberculosis Elimination, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, CDC.

All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. William L. Walker reports being a board member of the National Association of Federal Veterinarians. No other potential conflicts of interest were disclosed.

* https://ndc.services.cdc.gov/case-definitions/tuberculosis-2009

† This report is limited to National Tuberculosis Surveillance System data verified as of February 17, 2024. Updated data will be available in CDC’s annual TB surveillance report later in 2024.

§ Persons born in the United States or certain U.S. territories or elsewhere to at least one U.S. citizen parent are categorized as U.S.-born. All other persons are categorized as non-U.S.–born.

¶ Short-term projections from the monthly population estimates by age, sex, and race and ethnicity were used for the 2023 population. Vintage 2022 Estimates were used for 2023 and 2022, and Vintage 2010 Estimates were used for 2013–2019. https://www.census.gov/programs-surveys/popest/data/tables.html

** https://www.census.gov/programs-surveys/cps.html

†† 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.

§§ https://www.census.gov/topics/population/race/about.html

¶¶ Proportions using birth origin are calculated excluding 12 cases in 2022 and 42 cases in 2023 for which birth origin was missing or unknown.

*** Percentage change is calculated from unrounded numbers. For demographic groups with small populations (e.g., non-U.S.–born American Indian or Alaska Native), changes in rates should be interpreted cautiously because of the increased volatility of these rates.

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• Nabity SA, Marks SM, Goswami ND, et al.; National Tuberculosis Controllers Association/CDC TB-COVID-19 Collaboration. Characteristics of and deaths among 333 persons with tuberculosis and COVID-19 in cross-sectional sample from 25 jurisdictions, United States. Emerg Infect Dis 2023;29:2016–23. https://doi.org/10.3201/eid2910.230286 PMID:37647628
• Department of Homeland Security. 2022 yearbook of immigration statistics. Washington, DC: US Department of Homeland Security, Office of Homeland Security Statistics; 2023. https://www.dhs.gov/ohss/topics/immigration/yearbook/2022
• CDC. Influenza (flu): weekly U.S. influenza surveillance report. Atlanta, GA: US Department of Health and Human Services, CDC; 2023. https://www.cdc.gov/flu/weekly/index.htm#FluSurvNet
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FIGURE . Annual number* and rate † of cases of tuberculosis disease, by birth origin § — United States, 2013–2023

* Case counts are based on data from the National Tuberculosis Surveillance System as of February 17, 2024.

† Annual tuberculosis rate is calculated as cases per 100,000 persons. The Current Population Survey provides the population denominators used to calculate tuberculosis rate according to birth origin. https://www.census.gov/programs-surveys/cps.html (Accessed February 2, 2024).

§ Persons born in the United States or certain U.S. territories or elsewhere to at least one U.S. citizen parent are categorized as U.S.-born. All other persons are categorized as non–U.S.–-born. Persons for whom birth origin was unknown (range = 7 [2013] to 42 [2023]) are not included in this figure.

* Case counts are based on data reported to the National Tuberculosis Surveillance System as of February 17, 2024. † Annual tuberculosis rate is calculated as cases per 100,000 persons using midyear population estimates from the U.S. Census Bureau. Short-term projections from the monthly population estimates by age, sex, and race and ethnicity were used for the 2023 population. Vintage 2022 estimates were used for 2022 and 2023. https://www.census.gov/programs-surveys/popest/data/tables.html § Percentage change in rate was calculated with unrounded numbers.

Abbreviation: TB = tuberculosis. * Case counts are based on data reported to the National Tuberculosis Surveillance System as of February 17, 2024. † Annual tuberculosis rate is calculated as cases per 100,000 persons using midyear population estimates from the U.S. Census Bureau. Short-term projections from the monthly population estimates by age, sex, and race and ethnicity were used for the 2023 population. Vintage 2022 estimates were used for 2022 and 2023. https://www.census.gov/programs-surveys/popest/data/tables.html § Percentage change in rate was calculated with unrounded numbers. ¶ Age was missing or unknown for zero cases in 2022 and six cases in 2023. ** Persons born in the United States or certain U.S. territories or elsewhere to at least one U.S. citizen parent are categorized as U.S.-born. All other persons are categorized as non-U.S.–born. †† Birth origin was missing or unknown for 12 cases in 2022 and 42 cases in 2023. §§ Race and ethnicity was missing or unknown for 22 cases in 2022 and 40 cases in 2023 among U.S.-born persons. ¶¶ Race and ethnicity was missing or unknown for 63 cases in 2022 and 172 cases in 2023 among non–U.S.–-born persons. *** No TB cases reported among American Indian or Alaska Native persons in 2022.

Suggested citation for this article: Williams PM, Pratt RH, Walker WL, Price SF, Stewart RJ, Feng PI. Tuberculosis — United States, 2023. MMWR Morb Mortal Wkly Rep 2024;73:265–270. DOI: http://dx.doi.org/10.15585/mmwr.mm7312a4 .

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Tuberculosis vaccine may enable elimination of the disease in cattle by reducing its spread

by University of Cambridge

Vaccination not only reduces the severity of TB in infected cattle, but reduces its spread in dairy herds by 89%, research finds. The research, led by the University of Cambridge and Penn State University, improves prospects for the elimination and control of bovine tuberculosis (TB), an infectious disease of cattle that results in large economic costs and health impacts across the world. The study is published in the journal Science .

This is the first study to show that BCG-vaccinated cattle infected with TB are substantially less infectious to other cattle. This remarkable indirect effect of the vaccine beyond its direct protective effect has not been measured before.

The spillover of infection from livestock has been estimated to account for about 10% of human tuberculosis cases. While such zoonotic TB (zTB) infections are most commonly associated with gastrointestinal infections related to drinking contaminated milk, zTB can also cause chronic lung infections in humans. Lung disease caused by zTB can be indistinguishable from regular tuberculosis, but is more difficult to treat due to natural antibiotic resistance in the cattle bacteria.

TB remains endemic in many countries around the world, including in Europe and the Americas, where its control costs farmers and taxpayers hundreds of millions of dollars each year.

In the study, carried out in Ethiopia, researchers examined the ability of the vaccine, Bacillus Calmette-Guérin (BCG), to directly protect cattle that receive it, as well as to indirectly protect both vaccinated and unvaccinated cattle by reducing TB transmission. Vaccinated and unvaccinated animals were put into enclosures with naturally infected animals, in a novel crossover design performed over two years.

"Our study found that BCG vaccination reduces TB transmission in cattle by almost 90%. Vaccinated cows also developed significantly fewer visible signs of TB than unvaccinated ones. This suggests that the vaccination not only reduces the progression of the disease, but that if vaccinated animals become infected, they are substantially less infectious to others," said Andrew Conlan, Associate Professor of Epidemiology at the University of Cambridge's Department of Veterinary Medicine and a corresponding author of the study.

Using livestock census and movement data from Ethiopia, the team developed a transmission model to explore the potential for routine vaccination to control bovine tuberculosis.

"Results of the model suggest that vaccinating calves within the dairy sector of Ethiopia could reduce the reproduction number of the bacterium—the R 0 —to below 1, arresting the projected increase in the burden of disease and putting herds on a pathway towards elimination of TB," Conlan said.

The team focused their studies in Ethiopia, a country with the largest cattle herd in Africa and a rapidly growing dairy sector that has a growing burden of bovine tuberculosis and no current control program, as a representative of similarly situated transitional economies.

"Bovine tuberculosis is largely uncontrolled in low- and middle-income countries , including Ethiopia," said Abebe Fromsa, associate professor of agriculture and veterinary medicine at Addis Ababa University in Ethiopia and the study's co-lead author. "Vaccination of cattle has the potential to provide significant benefits in these regions."

"For over a hundred years, programs to eliminate bovine tuberculosis have relied on intensive testing and slaughtering of infected animals," said Vivek Kapur, professor of microbiology and infectious diseases and Huck Distinguished Chair in Global Health at Penn State and a corresponding author of the study.

He added, "This approach is unimplementable in many parts of the world for economic and social reasons, resulting in considerable animal suffering and economic losses from lost productivity, alongside an increased risk of spillover of infection to humans. By vaccinating cattle, we hope to be able to protect both cattle and humans from the consequences of this devastating disease."

Professor James Wood, Alborada Professor of Equine and Farm Animal Science in the University of Cambridge's Department of Veterinary Medicine, noted that despite TB being more prevalent in lower-income countries, the United Kingdom, Ireland and New Zealand also experience considerable economic pressures from the disease which continues to persist despite intensive and costly control programs.

Wood said, "For over 20 years the UK government has pinned hopes on cattle vaccination for bovine tuberculosis as a solution to reduce the disease and the consequent costs of the controls. These results provide important support for the epidemiological benefit that cattle vaccination could have to reduce rates of transmission to and within herds."

Journal information: Science

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TB vaccine may enable elimination of the disease in cattle by reducing its spread

Vaccination not only reduces the severity of TB in infected cattle, but reduces its spread in dairy herds by 89%, research finds.

The research, led by the University of Cambridge and Penn State University, improves prospects for the elimination and control of bovine tuberculosis (TB), an infectious disease of cattle that results in large economic costs and health impacts across the world.

This is the first study to show that BCG-vaccinated cattle infected with TB are substantially less infectious to other cattle. This remarkable indirect effect of the vaccine beyond its direct protective effect has not been measured before.

The spillover of infection from livestock has been estimated to account for about 10% of human tuberculosis cases. While such zoonotic TB (zTB) infections are most commonly associated with gastro-intestinal infections related to drinking contaminated milk, zTB can also cause chronic lung infections in humans. Lung disease caused by zTB can be indistinguishable from regular tuberculosis, but is more difficult to treat due to natural antibiotic resistance in the cattle bacteria.

TB remains endemic in many countries around the world, including in Europe and the Americas, where its control costs farmers and taxpayers hundreds of millions of dollars each year.

The study is published today in the journal Science .

In the study, carried out in Ethiopia, researchers examined the ability of the vaccine, Bacillus Calmette-Guérin (BCG), to directly protect cattle that receive it, as well as to indirectly protect both vaccinated and unvaccinated cattle by reducing TB transmission. Vaccinated and unvaccinated animals were put into enclosures with naturally infected animals, in a novel crossover design performed over two years.

"Our study found that BCG vaccination reduces TB transmission in cattle by almost 90%. Vaccinated cows also developed significantly fewer visible signs of TB than unvaccinated ones. This suggests that the vaccination not only reduces the progression of the disease, but that if vaccinated animals become infected, they are substantially less infectious to others," said Andrew Conlan, Associate Professor of Epidemiology at the University of Cambridge's Department of Veterinary Medicine and a corresponding author of the study.

Using livestock census and movement data from Ethiopia, the team developed a transmission model to explore the potential for routine vaccination to control bovine tuberculosis.

"Results of the model suggest that vaccinating calves within the dairy sector of Ethiopia could reduce the reproduction number of the bacterium -- the R 0 -- to below 1, arresting the projected increase in the burden of disease and putting herds on a pathway towards elimination of TB," Conlan said.

The team focused their studies in Ethiopia, a country with the largest cattle herd in Africa and a rapidly growing dairy sector that has a growing burden of bovine tuberculosis and no current control program, as a representative of similarly situated transitional economies.

"Bovine tuberculosis is largely uncontrolled in low- and middle-income countries, including Ethiopia," said Abebe Fromsa, associate professor of agriculture and veterinary medicine at Addis Ababa University in Ethiopia and the study's co-lead author. "Vaccination of cattle has the potential to provide significant benefits in these regions."

"For over a hundred years, programs to eliminate bovine tuberculosis have relied on intensive testing and slaughtering of infected animals," said Vivek Kapur, professor of microbiology and infectious diseases and Huck Distinguished Chair in Global Health at Penn State and a corresponding author of the study.

He added: "This approach is unimplementable in many parts of the world for economic and social reasons, resulting in considerable animal suffering and economic losses from lost productivity, alongside an increased risk of spillover of infection to humans. By vaccinating cattle, we hope to be able to protect both cattle and humans from the consequences of this devastating disease."

Professor James Wood, Alborada Professor of Equine and Farm Animal Science in the University of Cambridge's Department of Veterinary Medicine, noted that despite TB being more prevalent in lower-income countries, the United Kingdom, Ireland and New Zealand also experience considerable economic pressures from the disease which continues to persist despite intensive and costly control programmes.

Wood said: "For over twenty-years the UK government has pinned hopes on cattle vaccination for bovine tuberculosis as a solution to reduce the disease and the consequent costs of the controls. These results provide important support for the epidemiological benefit that cattle vaccination could have to reduce rates of transmission to and within herds."

• Veterinary Medicine
• Cows, Sheep, Pigs
• Agriculture and Food
• Food and Agriculture
• Dairy cattle
• Vaccination
• Vegetarianism
• Reindeer (Caribou)

Story Source:

Materials provided by University of Cambridge . The original text of this story is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License . Note: Content may be edited for style and length.

Journal Reference :

• Abebe Fromsa, Katriina Willgert, Sreenidhi Srinivasan, Getnet Mekonnen, Wegene Bedada, Balako Gumi, Matios Lakew, Biniam Tadesse, Berecha Bayissa, Asegedech Sirak, Musse Girma Abdela, Solomon Gebre, Tesfaye Chibssa, Maroudam Veerasami, H. Martin Vordermeier, Douwe Bakker, Stefan Berg, Gobena Ameni, Nick Juleff, Mart C. M. de Jong, James Wood, Andrew Conlan, Vivek Kapur. BCG vaccination reduces bovine tuberculosis transmission, improving prospects for elimination . Science , 2024; 383 (6690) DOI: 10.1126/science.adl3962

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CDC Report: Tuberculosis Cases Increase in U.S.

While the U.S. has one of the lowest rates of tuberculosis in the world, researchers found that cases increased 16% from 2022 to 2023.

CDC: Tuberculosis Cases Increasing

Elizabeth S. Mingioli | AP

This 1966 microscope photo provided by the U.S. Centers for Disease Control and Prevention shows Mycobacterium tuberculosis bacilli, the organism responsible for causing the disease tuberculosis.

Tuberculosis cases are on the rise in the U.S., according to a report published Thursday by the Centers for Disease Control and Prevention.

While the country has one of the lowest rates of TB in the world, according to the report, researchers found that cases increased 16% from 2022 to 2023, with over 9,600 provisionally reported last year.

Tuberculosis cases in the U.S. had declined for close to three decades, the report says, with a particularly notable drop occurring in 2020 that coincided with the COVID-19 pandemic.

Since then, cases have increased annually, topping 8,300 in 2022 and hitting 9,615 in 2023 That provisional figure marks the highest number of cases reported in the country in at least a decade, as the U.S. saw 9,556 TB cases in 2013.

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“This postpandemic increase in U.S. cases highlights the importance of continuing to engage communities with higher TB rates and their medical providers in TB elimination efforts and strengthening the capacity in public health programs to carry out critical disease control and prevention strategies,” researchers wrote in the report .

Researchers also noted that TB programs suffered during the pandemic as resources were diverted to addressing COVID-19. Disruptions in health care during the pandemic affected timely diagnosis and treatment of TB as well, they said.

“These factors, along with changes in migration volume, probably contributed to the decrease in the number of cases observed in 2020, and to the subsequent rise in case counts and rates since 2020,” the report states. “Identification of TB cases possibly increased after the pandemic because of renewed attention to infectious diseases other than COVID-19.”

Among people with TB whose place of birth was known, researchers said the vast majority of cases – 76% – occurred among those born outside the U.S. The rate was also highest among that group at 15 cases per 100,000 – up from 13.1 in 2022 – compared with a steady year-over-year rate of 0.8 per 100,000 among people born in the U.S.

Among people born in the U.S., rates were highest among Native Hawaiians or other Pacific Islanders and American Indian or Alaska Native people. Among those born outside the country, rates also were highest among NHOPI people, followed by Asian people.

Certain spots in the U.S. saw higher rates of TB than others. The five states with the highest rates of TB in 2023, based on the provisional data, were:

• Alaska – 10.6
• Hawaii – 8.1
• California – 5.4
• New York – 4.6

Tuberculosis is caused by a bacteria that typically attacks the lungs. Symptoms include a bad cough that lasts three weeks or longer, chest pain and coughing up blood, according to the CDC. It spreads through the air from person to person, but it’s both a treatable and preventable disease.

Not everyone infected by TB bacteria will develop disease and be contagious, and the CDC report notes most cases in the U.S. are tied to reactivation of “latent” bacteria within a person, rather than “recent transmission.” Still, TB is one of the world’s leading infectious disease killers.

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Tuberculosis (TB) is an infectious disease caused by strains of bacteria known as mycobacteria. The disease most commonly affects the lungs and can be fatal if not treated. However, most infected individuals show no disease symptoms. One third of the world’s population is thought to have been infected with TB.

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Tuberculosis is the leading cause of death from a single infectious agent, with over 25% of these occurring in the African region. Multi-drug resistant strains which do not respond to first-line antibiotics continue to emerge, putting at risk numerous public health strategies which aim to reduce incidence and mortality. Here, we speak with Professor Valerie Mizrahi, world-leading researcher and former director of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, regarding the tuberculosis burden in South Africa. We discuss the challenges faced by researchers, the lessons that need to be learnt and current innovations to better understand the overall response required to accelerate progress.

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