10 Injury Treatment Priorities at the Emergency Room

Tuberculosis Vaccines — An Update

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

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

Global distribution and disease burden

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

Figure 1: The distribution of tuberculosis in 2003.

Immunity to M. Tuberculosis

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

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

Table 1 The leading tuberculosis vaccine candidates in clinical trials

Vaccine concepts and clinical trials

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

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

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

BCG replacement vaccines

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

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

BCG booster vaccines

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

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

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

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

Conclusions

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

Box 1Key areas for tuberculosis (TB) vaccine development

Determine the correlates of vaccine induced protective immunity

Determine the requirements for post-exposure TB vaccines

Understand vaccine-induced T-cell memory to Mycobacterium tuberculosis

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

Following Koch's Example

Robert Koch (1843–1910) is one of the founding fathers of medical microbiology and is probably most well known for his guidelines for establishing a microorganism as the causative agent of an infectious disease. The principles behind Koch's postulates are still considered relevant today, although subsequent developments, such as the discovery of microorganisms that cannot grow in cell-free culture, including viruses and obligate intracellular bacterial pathogens, have caused the guidelines themselves to be reinterpreted for the molecular era1,2,3.

The details of Koch's research career and his contribution to microbiology have recently been elegantly recounted by Stefan Kaufmann and colleagues4,5. Here, we thought it would be interesting to look at Koch's career with the aim of devising an alternative version of Koch's postulates, this time for microbiologists rather than microorganisms — that is, what are the characteristics of Koch's approach to research that could spell success for microbiologists today? In our opinion, the three qualities that stand out are his multidisciplinary approach, his persistence and his teaching ability.

Koch's postulates aside, Robert Koch is also known for his work on the aetiology of anthrax and tuberculosis. In 1876, Koch published a paper giving the first demonstration that a living microorganism (Bacillus anthracis) was the causative agent of an infectious disease (anthrax) and in 1882, he isolated Mycobacterium tuberculosis and proved it was the causative agent of tuberculosis. Perhaps less well known is the fact that he discovered Vibrio cholerae, the causative agent of cholera, and was among the first to develop and implement public-health measures to control the disease, and that he also worked extensively on tropical diseases including African trypanosomiasis and malaria.

Contrary to what one might have expected for the nineteenth century, Koch did not have a privileged background. He was the third son of 13 children who taught himself to read and had to work hard to reach university. Even once he had qualified as a doctor, Koch's success did not come easily. His research on anthrax was carried out in his spare time in a primitive laboratory at home. Undaunted by his lack of facilities, Koch improvised materials where possible and, in addition to his description of anthrax, he made major strides in developing solid culture media and staining techniques, which would be instrumental in his discovery of M. Tuberculosis. Working outside the university system, Koch was aware that it would be difficult to be taken seriously and, in a move that will be familiar to students and postdocs today, he actively sought the patronage of a well known researcher, not only to validate his work, but also to help him get it published. Koch's persistence paid off and the publication of his work on anthrax marked the start of his movement into the scientific elite in Germany.

In setting out Koch's postulates, Robert Koch was not only attempting to establish guidelines for his peers to follow but also wanted to influence their thinking and persuade them that the use of more rigorous criteria to prove that microorganisms cause disease was required to win over the sceptics. Once established in Germany, Koch was generous with his knowledge and techniques and nurtured the careers of many researchers who went on to become prominent figures in their own right, including Paul Erlich.

These days, of course, access to higher education in many countries is more open, and it would be unusual for even the biggest microbiology laboratories to work on such a diverse group of organisms. However, it is apparent that the principles that were important to Robert Koch still ring true: cast your net wide, work hard and pass on your knowledge to others.

Fall River Sees Slight Uptick In Tuberculosis Cases. How The City's TB Clinic Handles It.

(This story has been updated to include additional information.)

FALL RIVER — Tuberculosis is rare in Fall River, though rates of the disease are higher here than the country's average — and it was classified by the World Health Organization as the world's deadliest disease in 2023.

Fall River has a TB clinic with a constant presence year-round, serving adult and pediatric patients alike.

The clinic has operated for decades under different roofs and practitioners before being housed on the fourth floor in room 431 of the Government Center, and run by Dr. Naresh Mansharamani, the medical director of the Fall River Tuberculosis Clinic, and Dr. Zoe Vazquez, associate medical director. Mansharamani and Vazquez are pulmonary medicine providers at Southcoast Health and see these patients at 1030 President Ave. In suite 210 in Fall River.

"I first began working at this clinic in 1999, and we joined Southcoast Health in 2014," Mansharamani saidvia email.

"Unfortunately, a lot of the state-run clinics have closed," said City Nurse Deb Kosior, who investigates and oversees infectious diseases for the city. She recalls a hospital-run TB clinic closing in Fall River, and a new one just opened in a physician's office in Attleboro, though they don't treat pediatric patients.

"But besides that, the closest TB clinic in Massachusetts is probably Boston Medical," Kosior said. "That's how far it is."

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How big of a risk does TB pose to Fall River?

According to the Department of Public Health's Bureau of Infectious Diseases report that tracks TB cases in the state's top 25 largest cities, Fall River had approximately 8.5 cases out of every 100,000 residents in 2023; a major uptick after the year before, when none were counted.

That compares to the United States average of 2.5 cases per 100,000 that same year.

TB most often affects the lungs, and is commonly spread by coughing, spitting and sharing air with someone carrying the disease.

TB is very communicable in winter months, Kosior said, which is partly the reason for the 105 CMR state mandate, which dictates stringent measures of managing TB outside of hospitals in outpatient settings.

Though TB is relatively rare in the United States, it is common in many Asian, African and Latin American countries.

"A lot of times there's more cases in areas where there's a lot of immigration into the city," Kosior said, but maintained that "there's not quite a high risk of TB here." She said advanced healthcare standards and infrastructure means a healthier environment, one that's less likely to host pathogens and communicable disease.

Like other respiratory illnesses, TB spikes "comes in ebbs and flows," and could be more rampant when communities are housed in close quarters, like public housing.

Vazquez said her patients include "many adults and children that have newly immigrated to the United States," but that there are certain "risk factors that increase an individual's risk of contracting TB. It is important that we are actively screening for and remain aware of this treatable disease," she said via email.

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Fall River's tuberculosis clinic is in Government Center.

Fall River's TB clinic has been serving the SouthCoast for over 60 years

Having a state-run clinic in the SouthCoast allows for patients who are "diagnosed with TB, whether a latent TB infection or TB disease," Kosior said, to fall under the umbrella of the Massachusetts Department of Public Health and the TB DOT (directly observed therapy) program.

This entitles patients — healthcare professionals, cancer patients who are beginning new treatments, and any community members who have an increased risk for this infectious disease— to "medications at either no cost no or no copays," Kosior said. "They get radiology exams and blood work … and doctor's visits for the course of this therapy," she added, listing the obvious benefits in store for receiving treatment at a state sponsored TB clinic.

"Public health nurses are mandated by the state … to follow pediatric TB cases — whether infection or disease — as well as any TB disease patients," she said.

Kosior "applauds" Mansharamani's and Vazquez's contribution of their time and expertise, as they run about two clinics per month. Testing is free for children attending school in Fall River, and $10 for adults living in the city.

The clinic follows a "test and plant on Tuesday, read on Thursday" pattern that mandates patients visit the clinic on Tuesday and return on Thursday, 48 hours later, to receive test results. Patients are reminded on the city's Health and Human Services webpage to bring identification and proof of their Fall River residence to the clinic, open between 9 a.M. And noon on Tuesdays and Thursdays. If a patient's skin test comes back positive, x-rays may be ordered to ensure the patient doesn't have an active infection.

"If they're new to the country, or if they've traveled out of the country for three weeks or more, or recently had contact with somebody with TB," it validates taking a test to ensure no infection is present, Kosior said.

Given the diversity of patient demographics, Kosior mentioned language barriers that, at times, stalls what could be "a patient every 15 minutes," though Mansharamani and Vasquez work diligently to serve anyone who walks in.

TB is 'treatable,' and recovery is supported by state resources

Mansharamani said he is thankful to work in tandem with the state, which bolsters the city's response with "essential services," he said. "While TB is a contagious disease, we have great treatments available for it."

Vazquez echoed this, mentioning that by partnering with the Department of Health, the clinic is able to serve a "wide variety of patients that have been referred to us," she said.

"Most of the primary care providers in the city refer patients to Dr. Mansharamani," Kosior said.

Once patients are admitted under state-mandated TB protocol, they are eligible to receive mostly free benefits, including lab work, x-rays, medication, and routine follow-up care overseen by Mansharamani and Vazquez.

This article originally appeared on The Herald News: Tuberculosis clinic in Fall River open year round: How it works

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