chapter5.15.indd 948 11/02/14 1:09 pmtbvaccines.usm.my/finlay/sites/default/files/chapter...

Chapter5.15.indd 948 11/02/14 1:09 PM

NEW TB VACCINES: WHAT IS IN THE PIPELINE?

Michael J. Brennan, Amy R. Sweeny, Jennifer Woolley, Bartholt Clagett, Lewellys F. Barker

CHAPTER 5.15

The uncertainty about the success of any vaccine candidate under evaluation determines the need to keep the pipeline of TB vaccine

development well filled.

‘Lets give time to the time:in order for the glass to overflow,

first it has to be filled.’

Antonio Machado

The ChoirEduardo Roca Salazar (Choco)Oil on canvas; 90 � 110cm

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Chapter5.15.indd 950 11/02/14 1:09 PM

INTRODUCTION The health and economic burdens that TB places on patients and health systems across the globe are considerable, and the current tools and methods to control the disease, while valuable, are in need of improvement and have not abolished the impact of the disease. The World Health Organization (WHO) estimates that one-third of the world’s population is infected with TB and 1.7 million people die from the disease each year (1). Modeling studies suggest that TB imposes considerable economic costs, particularly in high-burden, developing countries. Directly Observed Therapy – Short course (DOTS), the primary method of control, has been shown to be an effective treatment measure for TB disease, in terms of both health impact and cost, but DOTS alone would not be suf�cient to achieve global TB elimination (2). Another control measure, Bacille Calmette-Guérin (BCG) vaccine, is effective in protecting against serious forms of childhood TB, such as miliary TB and tuberculous meningitis, when given to infants at birth. However, the protective ef�cacy of infant BCG vaccination against adult pulmonary TB is considered unreliable and inadequate to help control the global TB epidemic (3-7). New and more effective TB vaccines could have the potential to be highly bene�cial and cost-effective measures for disease control (8). Accordingly, the development of new improved TB vaccines is a promising approach to signi�cantly reduce the health and economic impact of TB.

APPROACHES TO VACCINE DEVELOPMENT In 2010, the Stop TB Partnership reviewed and revised its Global Plan to Stop TB for 2011-2015. This is a comprehensive plan toward the elimination of TB by 2050, with elimination de�ned as less than one case per million people per year. The plan outlines a set of enhanced control measures and targets for the research and development of new, more effective technologies, including the development of a safe, effective and affordable TB vaccine, which has the potential for a signi�cant public health impact (9).

NEW TB VACCINES: WHAT IS IN THE PIPELINE? CHAPTER 5.15

Chapter5.15.indd 951 11/02/14 1:09 PM

952 SECTION 5 DEVELOPMENT OF NEW VACCINES AGAINST TB

Researchers have identi�ed a number of approaches to vaccine development. First, BCG could be replaced by a similar, but improved vaccine to be given to infants at birth (10). WHO currently recommends against the administration of BCG to HIV-infected infants, related to concerns over the risk of BCG disease in these infants (11). A modi�ed BCG or live attenuated vaccine that is safer and more effective presents one target for development. Second, a new TB vaccine could be introduced into a heterologous prime-boost regimen following vaccination of infants with BCG or an improved replacement for BCG, or in adolescents and adults previously primed with BCG. Because nearly 80% of newborns worldwide are inoculated with BCG as a prime, a new booster vaccine, to be given later to infants or young children and again in adolescence, could enhance immunity to TB and increase protective ef�cacy against the disease. Finally, a post-infection or immunotherapeutic vaccine, administered during or after treatment of individuals with latent or active TB, may decrease the incidence of active disease or relapse, or reduce the duration and improve the outcome of chemotherapy.

DRIVERS AND BARRIERS TO TB VACCINE DEVELOPMENT There are a number of scienti�c and clinical hurdles on the path to the development and licensure of a new TB vaccine (12). For example, it is not known whether the animal models used to test vaccines suf�ciently mimic the immune response and TB disease in humans to predict the ef�cacy of vaccines from preclinical studies. Similarly, the natural immune response to MTB infection which protects most people from progressing to TB disease is not well understood. Also research has not identi�ed correlates of protection from vaccination that could give clues to a protective immune response to TB from investigational vaccines. Consequently, the best scienti�c approaches to vaccine development may not become clear until after the evaluation of data from successful clinical trials. To conduct these clinical trials, a number of other barriers must be overcome. As accurate TB diagnosis is dif�cult for the identi�cation of TB in infants, it is challenging to establish endpoints for trials that test new vaccines in this population. Furthermore, there is a shortage of sites with the capacity to conduct large scale Phase IIb and III trials and a large gap in funding for the conduct of such trials (9). These trials are required to evaluate human safety and protection on a scale suf�cient to support TB vaccine development and licensure.

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953 CHAPTER 5.15NEW TB VACCINES: WHAT IS IN THE PIPELINE?

Epidemiological modeling studies suggest that vaccines with modest ef�cacy have the potential to reduce the TB burden over time, and economic studies show that such vaccines are likely to be cost-effective [13-18]. Perhaps more importantly, it appears that there is demand for a better TB vaccine among high level decision-makers in endemic countries. A 2010 survey of such individuals in eight TB high-burden countries reports that a new, improved TB vaccine that is more ef�cacious than current BCG is likely to be adopted in these countries within a few years of its licensure [19]. It is likely that the development of new, improved TB vaccines, in combination with other measures, speci�cally new drugs and diagnostics, will be a highly effective strategy to minimize the current serious global impact of TB.

VACCINES IN THE PIPELINETo assist with tracking activity and progress in TB vaccine research and development, the Stop TB Partnership Working Group on New TB Vaccines publishes an inventory of new vaccines at various stages of development. This listing is updated annually with information collected from vaccine developers, and can be found at the home page of the Vaccines Working Group of the Stop TB Partnership website: http://www.stoptb.org/wg/new_vaccines/.

Signi�cant progress has been made toward the goal to develop new, more effective vaccines as set out by the Partnership, as shown in Table 5.15.1. The global portfolio of candidates targets a variety of different patient populations, and includes priming candidates, boosting candidates, and those intended for post-infection, immunotherapeutic use. It also includes a range of scienti�c approaches to vaccine development, including recombinant live bacterial, viral vectored subunits, recombinant protein subunits, and whole cell inactivated or disrupted candidates. As of 2012, seventeen candidates had entered the clinic with two candidates, Oxford MVA85A/AERAS-485 and AERAS-402/Crucell Ad35, in Phase IIb proof-of concept trials. Results published in 2013 of the MVA-85A trial showed safety but failed to show ef�cacy in infants who had received BCG (43); the AERAS-402 trial was also modi�ed in 2013 to a large safety trial without expansion to determine ef�cacy. Six more candidates, M72, VPM 1002, Hybrid-1+IC31, Hybrid 56 +IC3, RUTI, and SSI HyVac 4/AERAS-404 are in Phase II trials. Six candidates are currently in Phase I safety trials, including AdAg85A, MTBVAC, SSI Hybrid-I+CAF01, and ID93+GLA-SE. Five candidates, rBCG30, AERAS 422, M. vaccae, Mw and M. smegmatis, have completed either Phase I or beyond Phase I trials. Beyond those vaccines in clinical

Chapter5.15.indd 953 11/02/14 1:09 PM


trials, there are many other candidates that are in the discovery and preclinical stages of development, including DNA and other vaccine types, which utilize different scienti�c approaches to those seen in the clinic.

In the following table, TB vaccine candidates are presented in three categories:

Candidates Tested in Clinical Trials-2011(Section I): TB vaccine candidates that are in clinical studies. Certain candidates that have been in clinical studies but are not currently in clinical trials are listed as ‘completed.’

Candidates in Preclinical Studies & GMP-2011 (Section II): TB vaccine candidates that as of 2011 are not yet in clinical trials, but have been manufactured under good manufacturing practice (GMP) for clinical use and/or have undergone some advanced preclinical testing that meets regulatory standards.

Next Generation Candidates- 2011 (Section III): TB vaccine candidates that are in the discovery, research and development stage with some preclinical testing performed to show that they may confer protection and become product candidates.

Vaccine candidates are further divided into speci�c Vaccine Types: Recombinant Live; Viral Vectored; Recombinant Protein; Whole Cell Inactivated or Disrupted or Other and a brief description is provided. The Table lists vaccines intended to be used as a Prime ( P ) or Booster ( B ) vaccine, as a Post-infection vaccine ( PI ) or in immunotherapy ( IT ).

The information on vaccine candidates was provided and updated by the vaccine developers unless otherwise indicated. In cases where an update regarding a previously listed vaccine candidate was not received in 2011, the 2010 listing was retained.

Chapter5.15.indd 954 11/02/14 1:09 PM


TABL

E 5.

15.1

Tub

ercu

losi

s va

ccin

e ca

ndid

ates

– 2

011

SECT

ION

I: C

andi

date

s Te

sted

in C

linic

al T

rial

s Ty

pe o

f Va

ccin

ePr

oduc

ts

Prod

uct

desc

ript

ion

Spon

sor

Indi

cati

onSt

atus

as

of 2

011

Cita

tion

s

Reco

mbi

nant

Li

ve

VPM

100

2rB

CG P

ragu

e st

rain

exp

ress

ing

liste

rioly

sin

and

carr

ies

a ur

ease

de

letio

n m

utat

ion

Max

Pla

nck,

Vak

zine

Pr

ojek

t Man

agem

ent

Gm

bH, T

BVI

P B

Phas

e II

[10,

20–

23]

rBCG

30rB

CG T

ice

stra

in e

xpre

ssin

g

30 k

Da M

TB a

ntig

en 8

5B; p

hase

I c

ompl

eted

in U

.S.

UCL

A, N

IH, N

IAID

, Aer

asP

Phas

e I

[com

plet

ed]

[24–

28]

AERA

S-42

2

Reco

mbi

nant

BCG

exp

ress

ing

mut

ated

Pfo

A an

d ov

erex

pres

sing

ant

igen

s 85

A,

85B,

and

Rv3

407

Aera

sP

Phas

e I

[com

plet

ed]

[29–

31]

MTB

VAC

[∆ph

oP, ∆

fad

D26]

Live

vac

cine

bas

ed o

n at

tenu

atio

n of

MTB

by

stab

le

inac

tivat

ion

by d

elet

ion

of p

hoP

and

fad

D26

gene

s

Uni

vers

ity o

f Zar

agoz

a,

Inst

itute

Pas

teur

, BI

OFA

BRI,

TBVI

PPh

ase

I[3

2–36

]

Vira

l Vec

tore

d

Oxf

ord

MVA

85A

/ AE

RAS-

485

Mod

ified

vac

cini

a An

kara

vec

tor

expr

essi

ng M

tb a

ntig

en 8

5A

Oxf

ord

Emer

gent

Tu

berc

ulos

is C

onso

rtiu

m

(OET

C), A

eras

, EDC

TP,

Wel

lcom

e Tr

ust

B P

I IT

Phas

e IIb

[37–

43]

AERA

S-40

2/

Cruc

ell A

d35

Repl

icat

ion-

defic

ient

ade

novi

rus

35 v

ecto

r exp

ress

ing

MTB

an

tigen

s 85

A, 8

5B, T

B10.

4

Cruc

ell,

Aera

s, ED

CTP,

NIH

BPh

ase

IIb[2

9-30

,44–

46]

AdAg

85A

Repl

icat

ion-

defic

ient

ade

novi

rus

5 ve

ctor

exp

ress

ing

MTB

an

tigen

85A

McM

aste

r Uni

vers

ityP

BPh

ase

I[4

7–51

]

Reco

mbi

nant

Pr

otei

nM

72 +

AS0

1

Reco

mbi

nant

pro

tein

com

pose

d of

a fu

sion

of M

TB a

ntig

ens

Rv11

96 a

nd R

v012

5 &

adj

uvan

t AS

01

GSK

, Aer

asB

PI

Phas

e II

[52–

55]

Chapter5.15.indd 955 11/02/14 1:09 PM


TABL

E 5.

15.1

Tub

ercu

losi

s va

ccin

e ca

ndid

ates

– 2

011

SECT

ION

I: C

andi

date

s Te

sted

in C

linic

al T

rial

s Ty

pe o

f Va

ccin

ePr

oduc

ts

Prod

uct

desc

ript

ion

Spon

sor

Indi

cati

onSt

atus

as

of 2

011

Cita

tion

s

Hybr

id-I+

IC31

Ad

juva

nted

reco

mbi

nant

pro

tein

co

mpo

sed

of M

TB a

ntig

ens

85B

and

ESAT

-6

Stat

ens

Seru

m In

stitu

te

(SSI

), TB

VI, E

DCTP

, In

terc

ell

P B

PI

Phas

e II

[56–

60]

Hybr

id-

I+CA

F01

Adju

vant

ed re

com

bina

nt p

rote

in

com

pose

d of

MTB

ant

igen

s 85

B an

d ES

AT-6

SSI,

TBVI

P B

PI

Phas

e I

[56,

59,6

1–63

]

HyVa

c 4/

AERA

S-40

4,

+IC

31

Adju

vant

ed re

com

bina

nt p

rote

in

com

pose

d of

a fu

sion

of M

TB

antig

ens

85B

and

TB10

.4

SSI,

Sano

�-Pa

steu

r, Ae

ras,

Inte

rcel

lB

Phas

e I

[64–

67]

Hybr

id 5

6 +

IC

31

Adju

vant

ed re

com

bina

nt p

rote

in

com

pose

d of

MTB

ant

igen

s 85

B,

ESAT

-6 a

nd R

v266

0SS

I, Ae

ras,

Inte

rcel

lP

B P

IPh

ase

IIa[6

8–69

]

ID93

in G

LA-

SE a

djuv

ant

Subu

nit f

usio

n pr

otei

n co

mpo

sed

of 4

MTB

ant

igen

sIn

fect

ious

Dis

ease

Re

sear

ch In

stitu

teB

PI

ITPh

ase

I[7

0–71

]

Who

le C

ell,

Inac

tivat

ed o

r Di

srup

ted

M. v

acca

e

Inac

tivat

ed w

hole

cel

l non

-TB

myc

obac

teriu

m; p

hase

III i

n BC

G-p

rimed

HIV

+ p

opul

atio

n co

mpl

eted

; ref

orm

ulat

ion

pend

ing

NIH

, Im

mod

ulon

B

PI

ITPh

ase

III

[com

plet

ed]

[72–

76]

Mw

[M.

indi

cus

pran

ii (M

IP)]

Who

le c

ell s

apro

phyt

ic n

on-T

B m

ycob

acte

rium

Depa

rtm

ent o

f Bi

otec

hnol

ogy

(Min

istr

y of

Sci

ence

&

Tech

nolo

gy, G

over

nmen

t of

Indi

a), M

/s. C

adila

Ph

arm

aceu

tical

s Lt

d.

ITPh

ase

III

[com

plet

ed]

[77–

79]

Chapter5.15.indd 956 11/02/14 1:09 PM


SECT

ION

II: C

andi

date

s in

Pre

clin

ical

Stu

dies

& G

MP-

201

1Ty

pe o

f Va

ccin

ePr

oduc

ts

Prod

uct

desc

ript

ion

Spon

sor

Indi

cati

onCi

tati

ons

Reco

mbi

nant

Li

ve

MTB

[∆le

uCD

∆pan

CD

∆sec

A2]

Non

-rep

licat

ing,

MTB

str

ain

auxo

trop

hic

for l

euci

ne a

nd

pant

othe

nate

; att

enua

ted

for

secA

2

Albe

rt E

inst

ein

Colle

ge

of M

edic

ine

P[8

5–86

]

Reco

mbi

nant

Pr

otei

nHB

HA

Nat

ural

ly m

ethy

late

d 21

-kDa

pu

rified

pro

tein

from

M.b

ovis

BC

G

Inst

itute

Pas

teur

of L

ille,

IN

SERM

, TBV

I, Ae

ras

[87–

91]

Oth

er

HG85

ADN

A va

ccin

es—

Ag85

A Sh

angh

ai H

&G

Bio

tech

B I

T[9

2–96

]

Hsp

DNA

vacc

ine

Codo

n-op

timiz

ed h

eat s

hock

pr

otei

n fro

m M

. lep

rae,

a C

pG

isla

nd

Sequ

ella

, Sha

ngha

i Pu

blic

Hea

lth C

linic

al

Cent

erB

[97–

99]

1 Can

dida

te in

form

atio

n co

mm

unic

ated

by

the

Wuh

an In

stitu

te o

f Bio

logi

cal P

rodu

cts.

TABL

E 5.

15.1

Tub

ercu

losi

s va

ccin

e ca

ndid

ates

– 2

011

SECT

ION

I: C

andi

date

s Te

sted

in C

linic

al T

rial

s Ty

pe o

f Va

ccin

ePr

oduc

ts

Prod

uct

desc

ript

ion

Spon

sor

Indi

cati

onSt

atus

as

of 2

011

Cita

tion

s

RUTI

Frag

men

ted

MTB

cel

lsAr

chiv

el F

arm

a, S

.I.

B P

I IT

Phas

e II

[80–

84]

M. s

meg

mat

is1

Who

le c

ell e

xtra

ct; p

hase

I co

mpl

eted

in C

hina

–B

PI

ITPh

ase

I

[com

plet

ed]

–

Chapter5.15.indd 957 11/02/14 1:09 PM


SECT

ION

III:

Nex

t G

ener

atio

n Ca

ndid

ates

– 2

011

Typ

e of

Va

ccin

ePr

oduc

ts

Prod

uct

desc

ript

ion

Spon

sor

Indi

cati

onCi

tati

ons

Reco

mbi

nant

Li

ve

HG85

6-BC

GrB

CG o

vere

xpre

ssin

g ch

imer

ic E

SAT-

6/Ag

85A

DNA

fusi

on p

rote

inSh

angh

ai P

ublic

He

alth

Clin

ical

Cen

ter

B P

I I

T[1

00]

IKEP

LUS

M.

smeg

mat

is w

ith

ESX-

3 de

letio

n/

com

plem

enta

tion

Live

M. s

meg

mat

is w

ith d

elet

ion

of E

SX-3

enc

odin

g lo

cus

and

com

plem

enta

tion

with

MTB

locu

s

Albe

rt E

inst

ein

Colle

ge

of M

edic

ine,

Aer

asB

[101

]

paBC

G

BCG

with

redu

ced

activ

ity o

f an

ti-ap

opto

tic m

icro

bial

enz

ymes

in

clud

ing

SodA

, Gln

A1, t

hior

edox

in,

and

thio

redo

xin

redu

ctas

e

Vand

erbi

lt U

nive

rsity

P

[102

]

Proa

popt

otic

rBCG

Reco

mbi

nant

BCG

exp

ress

ing

mut

ated

Pfo

A an

d in

clud

ing

mut

atio

ns s

how

n at

AEC

OM

to

indu

ce m

acro

phag

e ap

opto

sis

Aera

s, Al

bert

Ein

stei

n Co

llege

of M

edic

ine

P

–

rBCG

(mbt

B)30

rBCG

with

lim

ited

repl

icat

ion

over

expr

essi

ng th

e 30

kDa

MTB

An

tigen

85B

UCL

A, N

IH, N

IAID

P[1

03]

rBCG

T+

B

rM. s

meg

mat

is T

+B

rBCG

and

rM. s

meg

mat

is e

xpre

ssin

g m

ultip

le T

and

B e

pito

pes

of M

TB

Finl

ay In

stitu

te,

Uni

vers

iti S

ains

M

alay

sia

P B

PI

[104

–106

]

rBCG

38rB

CG T

ice

stra

in o

vere

xpre

ss th

e 38

kD

a pr

otei

nU

nive

rsid

ad N

acio

nal

Autó

nom

a de

Méx

ico

P B

[107

–110

]

Chapter5.15.indd 958 11/02/14 1:09 PM


SECT

ION

III:

Nex

t G

ener

atio

n Ca

ndid

ates

– 2

011

Typ

e of

Va

ccin

ePr

oduc

ts

Prod

uct

desc

ript

ion

Spon

sor

Indi

cati

onCi

tati

ons

rBCG

Mex

38rB

CG M

exic

o st

rain

ove

rexp

ress

the

38 k

Da p

rote

inU

nive

rsid

ad N

acio

nal

Autó

nom

a de

Mex

ico

P B

[1

09, 1

11–1

13]

rM.m

icro

ti30

rM.m

icro

ti38

rM.m

icro

ti st

rain

ove

rexp

ress

the

30

or 3

8kDa

pro

tein

Uni

vers

idad

Nac

iona

l Au

tóno

ma

de M

exic

oP

[27,

114

–115

]

Stre

ptom

yces

live

ve

ctor

Reco

mbi

nant

str

epto

myc

es

expr

essi

ng m

ultip

le T

and

B e

pito

pes

from

M.tb

Finl

ay In

stitu

te,

Inst

itute

of P

harm

acy

and

Food

, Cub

aP

B P

I IT

[105

–106

,116

]

rBCG

85C

rBCG

ove

rexp

ress

ing

antig

en 8

5C o

f M

. tub

ercu

losi

s

Uni

vers

ity o

f Del

hi

Sout

h Ca

mpu

s an

d De

part

men

t of

Bio

tech

nolo

gy,

Gov

ernm

ent o

f Ind

ia

P[1

17]

Disr

uptio

n of

the

SapM

locu

sRe

com

bina

nt M

. bov

is B

CG in

whi

ch

the

SapM

locu

s ha

s be

en d

isru

pted

FW

O-G

hent

U

nive

rsity

-VIB

P[1

18]

BCG

zm

p 1

BCG

zm

p 1

dele

tion

mut

ant

Uni

vers

ity o

f Zur

ich,

TB

VIP

[119

–121

]

Reco

mbi

nant

Pr

otei

n

Late

ncy

fusi

on

prot

eins

Reco

mbi

nant

fusi

on p

rote

ins

com

pose

d of

ant

igen

s 85

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Chapter5.15.indd 959 11/02/14 1:09 PM


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Chapter5.15.indd 962 11/02/14 1:09 PM


AbbreviationsBCG – Bacille Calmette-Guérin

IL – Interleukin

GMP – Good Manufacturing Practices

GSK – GlaxoSmithKline Biologicals

M. bovis – Mycobacterium bovis

MTB – Mycobacterium tuberculosis

NIAID– National Institute of Allergy and Infectious Diseases

NIH – National Institutes of Health

OETC – Oxford-Emergent Tuberculosis Consortium, Ltd.

SSI – Statens Serum Institute

TBVI – Tuberculosis Vaccine Initiative

UCLA – University of California Los Angeles

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