Contrasting The Effectiveness Of Vaccine And Drug Based

Published Date: 02 Nov 2017

MB2050/SSM

Government Scientific Report Assessment

Contrasting the effectiveness of vaccine and drug-based strategies for the control and treatment of tuberculosis

TEO KAH WEE

MD11336

Introduction

Tuberculosis (TB) is an infectious disease caused by Mycobacterium Tuberculosis. Primary tuberculosis is mainly asymptomatic in most of the individuals. However, the mortality rate of tuberculosis is high without treatment. It is the world’s second leading cause of death from a single infectious disease, only behind to AIDS. According to Public Health England, the incident rate is 14.4 per 100000 populations in the United Kingdom. (1)

Globally, the burden of tuberculosis is slowly declining. However, with 1.4 million deaths in 2011 and 8.7 million new cases, TB remains a global scourge.(2) The common risk factors are AIDS, the use of immunosuppressive drugs, low socio-economic conditions and immigration of persons from area of high tuberculosis prevalence.

Classically, tuberculosis presents with persistent cough, fever towards the end of the day, weight loss and general debility. TB infections can be investigated by several clinical procedures. Lesions with cavitation can be seen in chest x-ray. However, in military tuberculosis, the acute disseminated form of tuberculosis, chest x-ray may be entirely normal. Mantoux skin test can be performed, and patients with positive Mantoux skin test will be offer interferon-gamma testing.

Tuberculosis is diagnosed by clinical and radiological features, along with the identification of Mycobacterium tuberculosis in body fluid by direct smear and subsequently culture.

Pathophysiology

Tuberculosis is caused by Mycobacterium Tuberculosis. M. tuberculosis is rod-shaped, non-spore forming bacteria. It has a thick waxy coating that is made up of mycolic acid covalently attached to the underlying peptidoglycan-bound polysaccharide arabinogalactan.(3) This characteristic made the bacteria impervious to Gram staining. Acid fast detection techniques (Zeihl-Neelsen staining) are used instead. Even though mycobacteria do not retain the crystal violet stain, it is still classified as Gram-positive bacteria due to absence of outer lipopolysaccharide wall.

Figure 1: Mycobacteria cell wall are made of (2)

Outer lipids layer

Mycolic acid layer

Arabinogalactan polysaccharides

Peptidoglycan

Plasma membrane

Lipoarabinomannan

Phosphatidylinositol monoside

Cell wall skeleton.https://upload.wikimedia.org/wikipedia/commons/thumb/a/a2/Mycobacterial_cell_wall_diagram.png/300px-Mycobacterial_cell_wall_diagram.png

Mycobacterium tuberculosis is aerobic and requires oxygen to survive. This allows the bacteria to strive in the respiratory tract especially the lungs. The mycolic acid coating prevents the fusion of the phagosome with lysosome. This is a key virulence factor that enables the bacteria to evade digestion by the macrophages.

Mycobacterium tuberculosis is spread by aerosol droplets, called droplet nuclei, produced during coughing, sneezing or talking of a person with the disease. The transmission is influenced by number of bacteria in the droplets, virulence factors of the bacteria, exposure to ultraviolet light, depth of inhalation and occasions for aerosolization. Once inhaled, the respiratory system is infected.

The primary complex comprises the reaction at the site of initial infection, together with that which develops in the regional lymph nodes. The most common example is a primary pulmonary focus, accompanied by tuberculosis hilaradenopathy. This develops within few weeks. It can be asymptomatic. In young people, the lymph node may become much enlarged due to inflammation process.

In the initial reaction, the alveolar macrophages ingest the bacteria. As they are not digested, the bacteria proliferate inside the cells. The survival and persistence of the bacteria depend on their ability to actively inhibit the death by apoptosis of infected host cells. It is made possible by a virulence factor encoded by nuoG gene. (4)

The infected macrophages release chemokines and cytokines to attract other inflammatory cells such as neutrophils and monocytes. The adaptive immunity is then initiated when the macrophages present the processed antigen protein to T lymphocytes. Type 4 (delayed) hypersensitivity reaction occurs, resulting in the formation of classical caseous necrosis. The granulomatous lesions consist of a central necrotic area surrounded by epitheliod histiocytes and Langhans giant cells. Eventually the caseated lesions undergo fibrosis. In the calcified primary lesions, the bacteria remain dormant and capable of reactivation when the host immune system is weakened. This leads to post-primary tuberculosis.

If mycobacterium tuberculosis is not completely eradicated in a patient due to non-adherence to drug treatment, the bacteria start to acquire resistance towards the drugs. When the bacteria are resistant to isoniazid and rifampicin, they are classified as multi-drug-resistant tuberculosis (MDR-TB). Tubercle bacillus acquires drug resistance via several strategies:

Decreased permeability of cell wall for drugs.

Production of drug modifying and inactivating enzymes against drugs.

Increased affinity of drug efflux systems.

Spontaneous mutation such that targeted sequence of bacteria no longer fit into the active sites of drugs.

Tuberculosis vaccinations

Currently, the only available vaccination for TB is bacillus Calmette-Guerin (BCG). It is a live attenuated vaccine derived from Mycobacterium Bovis. The virulence factors are lost after growth in laboratory for many passages. The concept is that the weakened antigen is not potent enough cause a TB infection, but is strong enough to invoke an adaptive immune response from the host immune system. The host, now having immune memory, is able to launch a stronger and faster immune reaction upon re-exposure of antigen.

BCG immunisation is highly effective in preventing TB in young children, especially effective against military tuberculosis and tuberculous meningitis. (5) Therefore, mass immunisation of children are helpful in prevent the development of infection in two different way. The ‘direct’ effect is that it prevents the vaccinated individuals from getting infected. The ‘indirect’ method is by breaking the chain of transmission among population, such that unvaccinated individuals are protected as well.

While being up to 80% effective in preventing TB in young children, the efficacy of BCG vaccine against pulmonary tuberculosis in adult varies from 0% to 80%. (6)This variation can be due to:

Genetic variation in the vaccine strains provoking different degree of immunologic response.

Genetic variation in population causing immunologic polymorphism.

Interference by other non-tuberculous mycobacteria such as M. avium, M. marinum and M. intracellulare.

Depletion of Th1 response due to concurrent parasitic infection.

Despite the massive variation of the efficacy of BCG vaccine, a meta-analysis had shown that BCG reduces the risk of infecting TB by an average of 50%. (7) This has proven to be very cost effective in managing the incidence of TB world-wide. However, for area with low TB incidence such as UK, a universal BCG vaccination is not as cost effective.

Nation-wide neonatal BCG vaccination had been stopped in many area of the UK. It is only provided to neonates from primary care organisations with high incidence of TB. Routine BCG vaccination is no longer recommended for children aged 10-14. Instead, BCG vaccines are offered to new entrants from high-incidence areas, healthcare workers, contacts of people with active TB and people with increased risk of exposure to TB.

Being the most widely used vaccine across the world, BCG has relatively less adverse effects. The main con of BCG vaccine is formation of keloids at site of injection. However, if BCG is given to patient with depressed immune system (such as those with AIDS or SCID), it may lead to fatal disseminated BCG infection. Thus, people identified for BCG vaccination that are also considered to be at increased risk of being HIV positive, should be offered HIV testing before BCG vaccination.

Potential vaccines

There are several potential TB vaccines under development.

MVA85A. Recombinant modified vaccinia virus Ankara 85A has been shown to induce substantially higher levels of antigen specific IFN-y secreting T cells in BCG vaccinated individuals. (8) This means that boosting vaccinations with MVA85A can provide a practical and effective way to produce higher levels of long-lasting cellular immunity.

rBCG30. Live recombinant BCG vaccine is made by overexpressing the 30kDa major secretory protein of M. tuberculosis. It has shown to induce significantly increased immunology response in terms of blood lymphocyte proliferation, IFN-y producing T cells, and amount of memory T cells and activation of macrophages that inhibit mycobacterial intracellular multiplication. (7) Thus, rBCG30 are capable of inducing strong protective immunity against TB.

Mtb72F. Mtb72F is a fusion protein composed of Rv0125 and Rv1196 proteins form M. tuberculosis. Immunization by Mtb70F elicits strong IFN-y response, antibody response and CD8 response. It had shown to prolong the survival of guinea pig by more than one year after aerosol challenge with virulent M. tuberculosis compared to that of BCG vaccinated subject. (9)

Drug-based treatment of tuberculosis

The treatment of active Tb is a six-month, four-drug regimen. It is composed of 6 months of rifampicin and isoniazid medication, supplemented in in the first 2 months with pyrazinamide and etambutol. For patients with tuberculous meningitis, a 12-month regimen is provided instead.

Rifampicin. Rifampicin is a bactericidal antibiotic that acts as an nucleic acid inhibitor. It targets the RNA synthesis by inhibiting mycobacterial RNA polymerase. Rifampicin physically blocking the path of elongating RNA beyond a length of 2-3 nucleotides, a condition known as ‘steric occlusion. (10) There are several side effects for rifampicin. It has hepatotoxicity, thus patients’ liver function should be monitored. Rifampicin induces the up-regulation of liver cytochrome P450 enzyme, causing concomitant drug treatment to be less effective. For example, women taking oral contraceptive pills are still at risk of getting pregnant. Body secretions such as sweat and urine may stain orange-red colour.

Figure 2: structure of rifampicin. (10) http://www.newdruginfo.com/pharmacopeia/usp28/v28230/uspnf/pub/images/v28230/g-747.gif

Isoniazid. Isoniazid is a cell envelop antibiotic that targets the mycolic acid layer of M. tuberculosis. As a prodrug, Isoniazid needs to be activated by KatG in M. tuberculosis, a bacterial catalase peroxidase enzyme. (11) Activated form of isoniazid blocks the action of fatty acid synthase, inhibits the synthesis of mycolic acid, causing a break-down of mycobacterial cell wall. For this, isoniazid is bactericidal in rapidly dividing cells, and bacteriostatic for static cells. Isoniazid has few unwanted effects, such as occasional hypersensitivity reaction in the form of rash and fever. Rarely, it can cause fatal hepatitis.

Figure 3: structure of isoniazid. (11)http://upload.wikimedia.org/wikipedia/commons/thumb/4/48/Isoniazid_skeletal.svg/160px-Isoniazid_skeletal.svg.png

Pyrazinamide. Unlike other drugs, pyrazinamide does not has a specific target of action. The accumulation of its active form (protonated pyrazinoic acid) in mycobacteria under acidic condition causes cellular damage. (12) At high dosage, pyrazinamide will cause hepatic toxicity. It reduces renal excretion of uric acid, thus increase the risk of getting hyperuricaemic gout.

Figure 4: Structure of pyrazinamide. (12) http://www.newdruginfo.com/pharmacopeia/usp28/v28230/uspnf/pub/images/v28230/g-728.gif

Etambutol. Etambutol is a cell envelope antibiotic that targets the arabinogalactan layer. It inhibits the enzyme arabinosyl transferases that are involved in arabinogalactan synthesis. (13) This disrupts the mycobacterial cell wall. At high dose, Ethambutol cancause optic retrobulbar neuritis that presents with colour blindness for green, reduction in visual acuity and central scotoma. (14)

Figure 5: Structure of ethambutol. (13)Full-size image (2 K)

Future drugs

The Global Alliance for TB Drug Development (TB Alliance) is a non-profit organisation aims to discover and develop better, faster-acting, and affordable drugs to fight tuberculosis. New drugs are designed to:

Shorten and simplify duration of treatment;

Increase effectiveness against multidrug-resistant strains;

Increase compatibility with anti-retroviral therapy for people with TB-HIV co-infection;

Increase suitability for paediatric populations;

Improve the treatment of latent infection.

There are quite a few new drugs being developed.

SQ109. SQ109 is a call envelop antibiotic that targets arabinogalactan layer. It has shown to be effective against both TB and MDR-TB. One study semonstrated that SQ109 displays promising antitubercular activity with favourable targeted tissue distribution properties. (15)

Figure 6: structure of SQ109 (15)http://upload.wikimedia.org/wikipedia/commons/thumb/d/db/AntitubercularSQ109.svg/200px-AntitubercularSQ109.svg.png

Bedaquiline (R 207910) is a new anti-tuberculosis drug that is specifically developed to treat MDR-TB. It is now under Phase IIa development. Bedaquiline targets the energy metabolism of bacteria by affecting the proton pump for ATP synthase. It has shown stronger bactericidal effect than rifampicin and isoniazid. (16)

Figure 7: Structure of Bedaquiline (16)http://upload.wikimedia.org/wikipedia/commons/thumb/5/53/Bedaquiline.svg/220px-Bedaquiline.svg.png

Discussion

For short-term (1-3 years) funding priorities, drug-based treatment seems to be a better option. This is because the low incidence of TB in UK has render vaccination not cost-effective. As the incidence of TB will not change significantly over 1 to 3 years, vaccination will remain not feasible. The emergence of MDR-TB has prompted the call for newer and stronger drugs to overcome these threats. New drugs that can shorten the duration of treatment can also decrease the incidence of MDR-TB. They are already many on-going researches for new drugs, thus funding is required to keep these development going.

For long term (5-10 years) however, funding priority should be set on developing new vaccine. BCG vaccine has already been administered for decades, yet unable to eradicate TB totally. WHO had set the target to eradicate TB completely from human population by year 2050. In order to achieve this goal, stronger and more effective vaccine is required. When a more effective vaccine is available, it will then be more cost effective to immunise the entire nation to prevent any new cases of TB.

(2078 words)