SMGr up Tuberculosis Vaccine: Historical Perspectives on Tuberculosis Prevention and Novel Approaches to Vaccine Development Christopher da Costa* Aeras, 1405, Research Boulevard, USA

*Corresponding author: Christopher da Costa, Aeras, 1405, Research Boulevard, Rockville, USA, Email: [email protected] Published Date: January 23, 2016

GLOBAL EPIDEMIOLOGY OF TUBERCULOSIS: RECENT TRENDS Despite a 45% reduction in the mortality rate and a 41% reduction in the prevalence rate between 1990 and 2013, tuberculosis remains the second highest cause of death from an infectious disease worldwide. According to World Health Organization (WHO) estimates, in 2014 1.5 million worldwide people died of TB. Of these people 0.4 million people were positive for Human Immunodeficiency Virus (HIV) infection. Worldwide, deaths from TB currently exceed deaths from HIV. In 2014 1.2 million people died of HIV infection, including 0.4 million deaths in HIV positive people with TB. That year, there were an estimated 9.6 million new cases of TB worldwide, with an estimated 3.2 million cases and 480,000 TB deaths among women. In children during the same period there were also an estimated 1.0 million cases of TB and 140,000 deaths. There has also been an increasing incidence of multi- and extensively drug resistant TB. According to the WHO, in 2014 there were an estimated 480,000 new cases of Multi-Drug Resistant TB (MDR-TB) worldwide, with an estimated 190,000 deaths from MDR-TB.

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HISTORICAL PERSPECTIVES ON PREVENTION OF TUBERCULOSIS Mycobacterium tuberculosisis known to have existed for at least 15,000 years, and evidence

of TB has been found in remains from inhabitants of China, India and Egypt, notably in Egyptian

mummies, in whom spinal tuberculosis (Pott’s disease) has detected. The disease has been given a variety of epithets, including “Phthisis” (an ancient Greek word meaning to waste away, decline,

decay, or atrophy), the “White Plague” (due to severe pallor), and “Consumption” (due to extreme

weight loss). Scrofula is tuberculosis of the cervical lymph nodes and was first described in the middle Ages. It was also known as the “King’s evil” and there was widespread belief that scrofula

could be cured simply by the touch of English or French King. In the 18th century in Western Europe, tuberculosis reached its peak with a prevalence as high as 900 deaths per 100,000. Poor

socio-economic conditions, including poorly ventilated and overcrowded housing, primitive

sanitation, and malnutrition contributed significantly to this. The term “White Plague” emerged around this time. Robert Koch was the first to demonstrate that tubercle bacilli were the causative organism of TB, developing the Ziehl Neelsen stain, which identified the organisms as being “acid-fast”. In the late nineteenth century Jacques-Joseph Grancher, known as the father of TB

prevention, introduced the concept of a TB Preventorium, institutions where healthy children

were housed specifically for the purpose of preventing them from acquiring TB. Hermann Brehmer later developed the concept of keeping tuberculosis patients isolated in a sanatorium, to prevent spread of the disease and facilitate treatment with rest and improved nutrition. In

the early 20th century, the French scientists Albert Calmette and Camille Guérin developed the

first vaccine for TB by growing Koch’s bacillus in several mediums to progressively decrease its virulence and increase its capacity to induce immunity. It was first tested on cows in 1921, and

this led to the development of the vaccine known as Bacille Calmette-Guérin (BCG) named after the two founders. BCG was introduced in 1921 and later testedon 116,000 children at l’Hopital de la Charité in Paris in 1928, with some success. The advent of anti-tubercular drugs in the mid-20th

century spelled the beginning of an era of treatment hand-in hand with preventive efforts that

have seen limited success in reducing the global burden of tuberculosis over the ensuing decades.

The advent of HIV infection, along with increasing resistance to existing anti-tubercular drugs, have conspired with socio-economic factors and failed efforts at prevention to result in the need for a more effective vaccine that will help to successfully reduce the global burden of TB.

THE BCG VACCINE: SUCCESSES AND SHORTCOMINGS

The Mycobacterium bovis BCG vaccine currently being used to prevent TB in infants, despite

demonstrated efficacy in reducing the incidence of disseminated and more severe forms of TB,

has shown limited effectiveness in prevention of active disease, particularly in older children, adolescents and adults. The original BCG vaccine was first given to humans in 1921. Clinical trials in

the 1930s and 1940s provided some evidence for the effectiveness of BCG, given subcutaneously,

in protection against tuberculosis. In the 1950s the British Medical Research Council (BMRC)

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conducted further clinical trials in tuberculin negative 13 year olds that showed high degrees of efficacy in preventing tuberculosis. However these results were not confirmed by clinical

trials conducted by the United States Public Health Service (USPHS) using different strains of BCG (Park and Tice strains given to tuberculin-negative people of varying ages), in which little

or no protection was demonstrated.As a result, BCG was recommended for routine vaccination of tuberculin-negative adolescents in the UK, but not in the USA, where its use was restricted to certain high-risk populations. The majority of the rest of world followed the lead of Europe and the WHO, and introduced BCG for routine vaccination according to various schedules (e.g. at

birth, school entry or school leaving). The Netherlands and the USA both decided against routine BCG vaccination. Explanations for the differences in efficacy of BCG include variation between strains of BCG, and prior exposure to various environmental mycobacteria that imposed a limit on

vaccine efficacy. While BCG vaccine is thought to help reduce the severity of certain disseminated forms of TB such a TB meningitis in children, its overall efficacy in TB prevention has been widely

recognized as being inadequate, and the need for new, more effective vaccines has resulted in a wealth of vaccine candidates currently under investigation in clinical trials, as well as novel approaches to TB vaccine discovery and clinical development.

TUBERCULOSIS PIPELINE

VACCINE

DEVELOPMENT:

THE

CURRENT

The quest for a vaccine that could have a major impact in reducing the current global burden

of TB disease in humans continues to be extremely challenging. Significant gaps in our knowledge and understanding of the pathogenesis and immunology of tuberculosis continue to undermine efforts to break new ground, and traditional approaches to vaccine development have thus far met with limited success. Existing and novel candidate vaccines are being assessed in the context

of their ability to impact the various stages that culminate in disease transmission and an increase in the global burden of disease. Innovative methods of vaccine administration and delivery have provided a fresh stimulus to the search for the elusive vaccine. A major obstacle to more timely

development of an effective vaccine for tuberculosis is the absence of any known correlates of protection. The lack of viable surrogate biomarkers for use in clinical trials of candidate vaccines

calls for further research to explore patterns of immune responses associated with latent infection, active disease, and disease recurrence. At least 14 candidate TB vaccines have undergone or are currently in various phases of clinical development. They fall in to three broad categories:

1. Prime: Replacement of the existing BCG vaccine with either live recombinant BCG (rBCG)

or recombinant attenuated MTB with demonstrated improvement in safety and protective efficacy.

2. Prime-boost: Administration as a booster in recently- or remotely-BCG primed individuals or as a booster after previous administration of a non-BCG MTB candidate vaccine, e.g. viralvectored vaccines, adjuvanted subunit vaccines, and heat-inactivated whole cell vaccines.

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3. Immunotherapy: Therapeutic vaccines used as an adjunct to chemotherapy to reduce the duration of effective treatment for active TB disease or Latent Tuberculosis Infection (LTBI). These include whole-cell derived and fragmented mycobacteria. Table 1 provides an overview of these candidate vaccines. Name

Table 1: Candidate tuberculosis vaccines in clinical stage development. Type

Vaccine composition and functional attributes

Hybrid1-IC31

Adjuvanted subunit

Hybrid1-CAF01

Adjuvanted subunit

M72 +AS01E

Adjuvanted subunit

H4: IC31

Adjuvanted subunit

A recombinant fusion protein Ag85B and ESAT-6 adjuvanted with IC31 A recombinant fusion protein of Ag85B and ESAT-6 adjuvanted with a two-component CAF01 liposomal adjuvant system An immunogenic fusion protein (M72) derived from two MTB antigens (Mtb32A and Mtb39A) and the adjuvant AS01E. Mtb32 is a putative 32-kDa serine protease found in culture supernatants and lysates of MTB. Mtb39a is a 39-kDa membrane-associated protein with a putative role in MTB evasion A fusion protein of MTB antigens 85B and TB10.4, combined with adjuvant IC31

H56: IC31

Adjuvanted subunit

ID93 + GLA-SE

MVA85A

A fusion protein of three MTB antigens (85B, ESAT-6 and Rv2660c) formulated in the adjuvant IC31 A recombinant fusion-protein of four MTB antigens (virulence-associated Rv2608, Rv3619, Rv3620, and Adjuvanted latency-associated Rv1813). GLA-SE adjuvant is a Toll-like subunit receptor 4 agonist formulated in a squalene-based oil-inwater emulsion Attenuated Vaccinia virus MVA vector combined with MTB Viral vectored antigen 85A

Strategy

Study phase

Prime-Boost

I

Prime-Boost

I

Prime-Boost

IIb

Prime-Boost

II

Prime-Boost

II

Prime-Boost

I

Prime-Boost

IIb

Crucell Ad35/ Aeras 402

Viral vectored

A replication-deficient adenovirus (Ad35) vector containing the MTB antigens 85A, 85B and TB10.4

Prime-Boost

IIb

AdAg85A

Viral vectored

A replication-deficient serotype 5 Adenovirus vector expressing MTB antigen 85A

Prime-Boost

I

DAR 901

Whole cell

Heat-inactivated whole cell Mycobacterium obuense

Prime-Boost

I

Prime

II

Prime

I

VPM 1002 Recombinant (rBCGΔureC:HLY)

A recombinant BCG mutant expressing listeriolysin O. Perforation of the phagosomal membrane allows egress of recombinant BCG antigens into the cytosol, facilitating MHC**-mediated CD 8 T-cell priming A recombinant MTB mutant lacking expression of genes for several virulence factors, including ESAT6, as well as mutations in genes required for synthesis of bacterial cell wall components that protect MTB from host defenses

MTBVAC

Recombinant

M.vaccae

Whole cell

Heat-inactivated whole cell vaccine

Immunotherapy#

III (completed)

RUTI®

Fragmented MTB

Detoxified liposomal fragments of MTB

Immunotherapy#

II

NA. Non-adjuvanted. **MHC. Major Histocompatibility Complex. #Adjunctive to standard antiTB chemotherapy. *

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CONCLUSION: WHERE DO WE GO FROM HERE? Development of an efficacious vaccine against human TB remains a challenging goal, despite the wealth of candidate vaccines currently in various stages of clinical development. New paradigms for research and development call for increased emphasis on experimental medicine, biomarker discovery, and novel clinical proof of concept studies to streamline vaccine development and maximize the probability of success in late-stage trials. Emerging platforms and techniques for more effective delivery offer hope in paving the way for achieving the ultimate goal of breaking the infection-transmission-disease cycle, in an effort to substantially reduce the global burden of disease.

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