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New tuberculosis vaccine to support
tuberculosis elimination

Fransisca Chondro
Department of Physiology Faculty of Medicine, Trisakti University

The Sustainable Development Goals have
prioritized ending the epidemic of tuberculosis by
2030.(1) Around one-third of the world population
is infected with Mycobacterium tuberculosis
(MTBC), but is asymptomatic, a conditon known
as late nt T B. (2 ) According to the global
tuberculosis report, in 2017 there were 5-15% of
1.7 billion  persons infected with MTBC, who
will develop TB in their lives.(1) Around 10% of
latent TB will develop into active TB disease, with
a higher risk in patients with immunodeficiencies
such as HIV, undernutrition, diabetes mellitus,
smoking, and habitual alcohol consumption. As a
result there are annually an estimated 8.8 million
new TB cases, with a TB mortality of 1.1 million
and deaths from TB and HIV coinfection of 350
thousand cases.(1,3) The World Health Organization
has planned a number of strategies for TB
elimination in the year 2030, such as developing
rapid and accurate diagnostic tests, new regimens
for the treatment of drug-susceptible or drug-
resistant TB, prevention of transmission of M.
tuberculosis through infection control, new
vaccine candidates to prevent the development
of TB, and to help improve the outcomes of
treatment for TB disease.(1)

Based on the estimated incidence of TB,
the WHO published a list of countries with the
highest numbers of cases of TB, TB-HIV, and
multi-drug resistant TB (MDR-TB). Indonesia
is included in all categories; in other words,
Indonesia belongs to the 20 countries with the
highest incidence of TB, TB-HIV, and MDR-
TB.(1)

Natural infection induces the production of
antibodies against Mycobacterium tuberculosis
(MTBC). Studies show that 90% of TB patients
have a higher serum immunoglobulin titer against
MTBC at the onset of the clinical symptoms of
the disease. However, there are a wide variety
of antigens that produce the target antibody. One
of the studies show that among 10 culture results
of MTBC protein filtrates, there was not one
antigen that is found in the serum of patients
with active MTBC.(1)

In the last few decades, several DNA
fingerprinting techniques have been used to
differentiate between a number of MTBC
s t r a i n s.  Re st r i c t io n  f r a gment  l e n gt h
polymorphism (RFLP) is based on the number
of DNA copies and the genomic location of the
IS6110 insertion sequence. This technique is the
gol d  st a n da r d  f o r  e x a min i n g t he  a c t u a l
transmission stage of MTBC bacteria in the
patient’s body, for differentiating between
relapse and reinfection in the patient, and for
detecting cross-contamination in the laboratory.
IS6110 is an insertion sequence of 1361 base
pairs, with inverted repeats of 28 base pairs at
e a c h e nd . Re s tr i c t io n  f r a gme n t  l e n gt h
polymorphism analysis of IS6110 depends on the
d ige s t i on of  D NA ge n e t i c  mat e r i a l  b y
endonucleases followed by electrophoretic
separation of the DNA fragments, which are
then transferred to a nylon or nitrocellulose
membrane. The fragments on the membrane are
then subjected to Southern blot hybridization with
a labeled DNA probe, which will adhere to the

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IS6110-specific DNA fragment. Two limitations
of this technique are the difficulty of obtaining
comparable results in different laboratories and
the need for DNA of good quality in large
a mou n t s.  T h e r e f or e ,  s e ve r a l PCR-b a s e d
methods have been developed to assist in the
identification of MTBC strains using relatively
small amounts of DNA. In this category belong
spoligotyping and mycobacterial interspersed
repeat units (MIRUs) typing, both of which are
considered the new gold standards in molecular
epidemiological studies of MTBC.(3,4)

To date many studies seek to evaluate the
effect of MTBC strain variations on virulence
and immunogenicity. Virulence of TB may be
influenced by the ability of the bacteria to survive
after facing the host immune response, to damage
the lungs, to survive aerosolization outside the host,
and to be transmitted to healthy persons. Studies
in humans and experimental animals have shown
that TNF-alpha, gamma interferon, IL-12 and IL-
17 are important mediators for the formation of
the immune response of the patients against
MTBC.(4) Other mediators such as IL-10 are also
thought to play a role in limiting the development
of MTBC at the initial stages of the immune
response. Previously it was concluded that the
more severe the inflammatory response, the more
severe the damage to the lungs, increasing the
efficiency of MTBC transmission. However,
several studies found that the increase in MTBC
virulence was associated with a decreased and/
or delayed inflammmatory response, possibly as
a result of considerable bacterial proliferation in
the early stages of infection and leading to
increased MTBC virulence in the final stages.(5,6)

The Ba cille Ca lme tte-Guérin (BCG)
vaccine, which was developed almost 100 years
ago and has been shown to prevent severe forms
of TB in children, is still widely used. However,
there is currently no vaccine that is effective in
preventing TB disease in adults, either before
or after exposure to TB infection.

The BCG vaccine is considered to be less
effective, since it protects only against TB
infection in childhood, but does not influence the

development of TB infection or reinfection in
adults. In addition, the vaccine shows variable
efficacy due to differences in the BCG strain
used. Therefore, there are currently several
initiatives, such as the development of a better
vaccine than the present BCG vaccine, the
administration of a booster with a second dose
of BCG or the administration of a BCG vaccine
containing a different strain.

To date there are 12 types of vaccine under
study. For phase I studies, there are 3 vaccines,
i.e. i). Ad5 Ag85A – adenovirus serotype 5
expre ss ing Ag85 A. T his vac c ine will  be
administered by the intramuscular route after it
has been demonstrated to be safe, is tolerated,
and increases the patient’s immune level with a
higher immunogenicity if administered to patients
wh o  h a ve  pr e vi o us l y r e c e i ve d t he  BCG
vaccine;ii). ChAdOx185A – MVA85A. This
vaccine is a combination of a simian adenovirus
and a recombinant pox virus, both of which
express the 85A antigen. The ChAdOx185A
vaccine is for intramuscular administration and
has been tested in a phase I trial. At present the
phase I trial for its administration in aerosol form
is ongoing;iii) MTBVAC. This is a live MTBC
strain attenuated through deletions in the genes
phoP and fadD26. The main target population
of this vaccine are the neonates (for replacing
the current BCG vaccine). In addition, this
vaccine may also be administered to adolescents
and adults as repeat vaccine (booster).

For phase II and III studies, there are 9
vaccines under development: i). DAR-901
b oo s te r  is  a  va c c i n e  t ha t  con s i st s  of
nontuberculous mycobacteria, in whole-cell and
heat-inactivated form;ii). H4:IC31 is a booster
vaccine containing a fusion protein of Ag85B
and TB10.4 with IC31 adjuvant. This vaccine is
under trial to evaluate its efficacy in preventing
infection in adolescents at high risk for MTBC
infection, and has been tested for administration
to infants;iii). H56:IC31 is a vaccine comprising
a combination of three MTBC antigens (Ag85B,
ESAT-6, and Rv2660c) with IC31 adjuvant. This
vaccine has been tested, proven to be safe and



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possesses substantial immunogenicity;iv). ID93
+ GLA-SE is a vaccine consisting of 4 MTBC
antigens associated with virulence (Rv2608,
Rv3619 and Rv3620) or latency (Rv1813), and
the adjuvant GLA-SE;v). M72/AS01E is a
subunit vaccine containing 2 MTBC antigens
(32A and 39A) with an adjuvant (AS01E);vii).
RUTI® is a therapeutic vaccine containing
MTBC cell-wall fragments for co-administration
with short-term antibiotics. The main targets of
this vaccine are patients with MDR-TB;vii). TB/
FLU -04L i s  a  muc osa l-ve ct or e d va cc ine
containing influenza virus with a replication
d ef i ci e nc y tha t has  be e n a tt e nua t ed  an d
expresses the Ag85A and ESAT-6 antigens. This
vaccine is intended as prophylactic boost
vaccine for infants, adolescents, and adults; viii).
Vac cae™ is an immunothera peutic agent
intended to shorten the therapeutic period in
patients with MTBC infections that are still
susceptible  to the basic MTBC therapy; and
ix) . V PM 10 02 is a r ec ombi na nt  vac ci ne
containing  live MTBC bacteria. This vaccine is
u nd e r  tr i al  t o e va l u a t e  i t s  s a f e ty a n d
immunogenicity in neonates exposed to the HIV
virus and those unexposed to HIV.(1)

It is hope d that with the increased
understanding and knowledge about the host and
the MTBC bacteria, the goal of developing a

suitable vaccine may be achieved, so that TB may
be expected to be eliminated in the year 2030.

REFERENCES

1. World Health Organiztaion. Global tuberculosis
report 2017. Geneva: World Health Organization;
2017.

2. Achkar JM, Casadevall A. Antibody-mediated
immunity against tuberculosis: implications for
vaccine development. Cell Host Microbe 2013;
13:250-62. doi: http://dx.doi.org/10.1016/j.chom.
2013.02.009.

3. Fogel N. Tuberculosis: a disease without
boundaries. Tuberculosis 2015;95:527-31. doi:
http://dx.doi.org/10.1016/j.tube.2015.05.017.

4. Coscolla M, Gagneux S. Consequences of
genomic diversity in Mycobacterium
tuberculosis. Seminars Immunology 2014;26:431–
44. doi: http://dx.doi.org/10.1016/j.smim.2014.09.
0121044-5323.

5. Mbugi EV, Katale BZ, Siame KK, et al. Genetic
diversity of Mycobacterium tuberculosis isolated
from tuberculosis patients in the Serengeti
ecosystem in Tanzania. Tuberculosis. 2015;95:
170-8. doi: http://dx.doi.org/10.1016/j.tube.2014.
11.006.

6. Cadmus S, Hill V, van Soolingen D, et al.
Spoligotype profile of Mycobacterium
tuberculosis complex strains from HIV-positive
and -negative patients in Nigeria: a comparative
analysis. J Clin Microbiol 2011;49:220-6. doi:
10.1128/JCM.01241-10.

Univ Med 2018;37:85-7. DOI: http://dx.doi.org/10.18051/UnivMed.2018.v37.85-87