Tuberculosis is an old foe. A 500,000-year-old human fossil discovered in Turkey bears telltale signs of the disease, which today continues to wreak havoc, killing an estimated 2 million per year, according to the World Health Organization.
Josephine Clark-Curtiss, a researcher at Arizona State University’s Biodesign Institute has been exploring new lines of attack against Mycobacterium tuberculosis, causative agent of tuberculosis. In work carried out at the Institute’s Center for Infectious Diseases and Vaccinology, under the directorship of her husband, Roy Curtiss III, a new class of vaccine candidates is being investigated.
Recently, Clark-Curtiss and her colleagues have demonstrated the
effectiveness of several recombinant attenuated Salmonella vaccine (or
RASV) strains in two studies appearing in the journal Infection and
Immunity. The team’s results underline the promise of new vaccines
against the disease that provide better protection than immunization with
Mycobacterium bovis Bacillus Calmette-Guérin BCG – the
currently available vaccine – along with improved practicality,
flexibility of use, and importantly, cost.
Tuberculosis is one
of the three leading infectious diseases, (along with malaria and AIDS),
classified as serious global health threats. While advances in the
developed world have been largely effective in combatting tuberculosis,
once a major killer in the US and Europe, the pace of new TB cases in much
of the developing world continues on a frightening upswing.
M.
tuberculosis is responsible for more deaths than any other single
bacterial pathogen and its occurrence in conjunction with other deadly
microbes – particularly the HIV virus – has cut a broad swath
of destruction through many regions of the globe whose medical resources
are ill-equipped to deal with the flood of cases. In 2009 alone, the World
Health Organization reported 9.4 million new cases of the disease, and
notes that roughly one third of the world’s population has been
infected with M. tuberculosis.
Carriers of the bacteria are
vulnerable to developing the disease should their immune systems become
compromised due to age, poor nutrition or some medical condition. Prior to
this, the bacteria are able to persist in the body in a non-replicating
state of dormancy for years at a time.
Four standard
first-line drugs are usually used to treat the illness, though multi-drug
resistant strains of M. tuberculosis are becoming more prevalent, and
recent years have seen the emergence of extensively drug-resistant M.
tuberculosis (XDR-TB) – strains resistant to essentially all anti-TB
drugs.
A more thorough understanding of tuberculosis is
essential for the formulation of better therapeutics to treat the disease
and more effective protective vaccines.
Recombinant attenuated
Salmonella vaccines (RASV) hold much promise in the fight against a range
of deadly diseases, including hepatitis B, cholera, typhoid fever, AIDS
and pneumonia. To formulate such vaccines, Salmonella bacteria are
modified, eliminating the virulence factors associated with their
notorious disease-causing abilities and outfitting them with key protein
antigens from the pathogen to be vaccinated against.
Genes
encoding bacterial, viral, tumor or parasitic antigens may be inserted
into Salmonella, making the bacterium a particularly versatile vaccine
vector. Such RASV strains can be manufactured at low cost, do not require
refrigeration during distribution and are delivered orally – huge
advantages, particularly in the developing world.
While other
types of pathogens have been similarly applied as cargo vessels to carry
disease antigens for vaccination, Salmonella is particularly well-suited
for the purpose. Ingestion of the Salmonella-based vaccine stimulates all
three branches of the immune response, conferring mucosal, humoral and
cellular immunity, following colonization of the intestinal tract, lymph
nodes, liver and spleen.
The Curtiss group has fine-tuned
various versions of RASV systems, increasing their safety, efficacy,
tolerability and immunogenicity. Through clever genetic
manipulation, the attenuation, antigen synthesis and lysis of the
Salmonella vector can be precisely controlled, significantly improving the
vaccine’s effectiveness.
Delaying Salmonella attenuation
ensures that the bacterium elicits a robust, system-wide immune response
before its virulence falls off. Synthesis of the disease antigen is also
tightly controlled temporally, for maximum immunological impact. Finally,
the Salmonella carrier ship may be set to self-destruct in vivo once its
antigen-production activities have been successfully completed. This
cellular lysis occurs because the modified strains require specialized
sugars available in the lab, but absent in the human body. Once the
bacterium exhausts its stores of specialized sugar, it is unable to
sustain the integrity of its cell wall, and bursts.
The current
studies appearing in Infection and Immunity describe the latest efforts at
designing effective RASV strains against tuberculosis. Using a mouse
model, the group, spear-headed by the efforts of Dr. Maria Dolores
Juárez-Rodríguez, demonstrated that oral immunization with
an RASV strain synthesizing a fusion of protein antigens to tuberculosis
provided significant protection against aerosol challenge with M.
tuberculosis, comparable to immunization with M. bovis BCG administered
subcutaneously.
In one of the two studies, the protective
efficacy imparted by RASV vaccine strains was compared with the dose of
antigen each strain expressed and delivered to the cytoplasm of host
cells. RASV strains designed to engage the responses of protective T cells
were shown to be highly effective, significantly reducing the quantities
of M. tuberculosis bacteria in the lungs and spleens of immunized
mice.
Further modification incorporating regulated delayed
lysis and regulated delayed antigen synthesis improved the vaccine’s
protective properties, outpacing the performance of the BCG vaccine.
Inoculation with RASV-M. tuberculosis vaccines also acts to induce gamma
interferon (IFN-) and tumor necrosis factor alpha (TNF-), important
cytokines, which are implicated in controlling infection by intracellular
pathogens like M. tuberculosis.
The traditional BCG vaccine,
in use for over 80 years, is effective at protecting newborns and children
from complications of the disease, including meningitis, but does not
confer long-term protection from infection. Further, effectiveness of the
BCG vaccine in adults varies considerably from 0 to 80 percent. By
contrast, an orally-delivered RASV vaccine is expected to be broadly
effective in populations. The Clark-Curtiss/Curtiss TB research team are
continuing to develop improved RASV-M. tuberculosis systems into safe,
efficacious vaccines that confer long-lasting protection against infection
with M. tuberculosis.
HealthCanal.com
http://www.healthcanal.com/infections/29769-Halting-tuberculosis-stubborn-ascent.html