Chapter7.2.indd 1094 11/02/14 1:10 PMtbvaccines.usm.my/finlay/sites/default/files/Chapter...

Chapter7.2.indd 1094 11/02/14 1:10 PM

TUBERCULOSIS VACCINE CLINICAL TRIAL SITE DEVELOPMENT AND

CLINICAL TRIALSHassan Mahomed, Willem Hanekom,

Gregory D Hussey

CHAPTER 7.2

The possibility of evaluating vaccine candidates in a high burden population allows us to choose the more efficacious

one that can be used in the future for the control of the disease in this population.

'And I don't know how to jump from the river side from today to the river side of tomorrow.'

GardenJuan Ramon Jimenez

From the series DreamerRoberto FabeloOil on canvas; 160 � 120 cm

Chapter7.2.indd 1095 11/02/14 1:10 PM

Chapter7.2.indd 1096 11/02/14 1:10 PM

INTRODUCTIONTB is a major global health problem particularly in developing countries (1). The BCG vaccine is the only licensed vaccine used to prevent TB. However, its ef�cacy is disputed (2). There is general agreement that it does provide protection against disseminated disease among children but its ef�cacy in preventing pulmonary TB in adults has varied widely from 0 per cent to 80 per cent. In recent years, there has been renewed interest in �nding alternative` vaccines against TB given a worsening of the TB epidemic due to the HIV pandemic and a reversal of gains previously made in reducing TB incidence (3).

DEVELOPMENT PLAN FOR TB VACCINE TRIALS

Preclinical developmentThe initial steps involve molecule discovery; most new vaccines comprise speci�c TB antigens. Some vaccine models have involved attaching these antigens to vectors while others have created fusion proteins mixed with adjuvants. Still others have modi�ed BCG to create recombinant forms of the vaccine. One form of vaccine consists of a killed non-TB mycobacterial species with cross-reacting antigens with MTB. The next steps involve experimental testing of the product in animals looking at safety, immunogenicity, toxicity and ef�cacy, often with comparisons to BCG.

Phase I trials

The �rst phase of testing of the vaccine in healthy TB naive adult humans focuses on the safety and immunogenicity of the vaccine. Dose escalation testing may also be done at this stage. Some examination of the effects in BCG vaccinated individuals may also be carried out at this point.

CHAPTER 7.2TUBERCULOSIS VACCINE CLINICAL TRIAL SITE DEVELOPMENT AND CLINICAL TRIALS

Chapter7.2.indd 1097 11/02/14 1:10 PM

1098 SECTION 7 PRECLINICAL AND CLINICAL EVALUATION

Phase II trials

The primary goals of Phase II trials are to evaluate vaccine safety and immunogenicity in potential target groups. These groups include adolescents, infants, HIV positive individuals and latent TB infected individuals. A phase IIb study is a proof of concept study designed not only to focus on safety and immunogenicity but is also statistically powered to get an indication of potential ef�cacy using clinical endpoints so that a decision can be made about whether to proceed to a phase III study.

Phase III trials

This level of trial is designed to evaluate vaccine ef�cacy, and is conducted in the target group of interest. More recently, HIV negative adults have been prioritized as a target group since this would be a means of reducing transmission of the disease. HIV infected individuals, infants and adolescents are also important groups for vaccine testing because they are at high risk (HIV infected persons and infants) or precede a peak in incidence (adolescents). If ef�cacy is demonstrated at this stage, the application for licensure of the new TB vaccine product for public use can then occur.

Phase IV trials

As with any product, post-marketing surveillance for rare adverse events and the measurement of vaccine effectiveness would occur during this phase. Observational study designs may be used. Studies for new indications or evaluation in new target groups may also occur at this stage.

Clinical trial site developmentSafety and immunogenicity testing may be done in a high or low TB burden population since only the direct physiological and immunological effects of a vaccine are being evaluated. However, since there is currently no immune correlate of protection for TB, a phase III vaccine trial site would need to be carefully selected in an area where TB is prevalent as the prevention of the occurrence of disease would be the prime measure of vaccine ef�cacy. Based on the experiences of the South African TB Vaccine Initiative (SATVI) of the University of Cape Town that has been conducting TB vaccine trials since 2001, the following requirements for a phase III vaccine trial site are proposed.

Chapter7.2.indd 1098 11/02/14 1:10 PM

1099 CHAPTER 7.2TUBERCULOSIS VACCINE CLINICAL TRIAL SITE DEVELOPMENT AND CLINICAL TRIALS

TABLE 7.2.1 Requirements for Phase III TB vaccine trial sitesEpidemiological

• Adequate rates of TB in the target populations (>0.5 per cent per annum).

• Ability to detect, investigate and document a very high proportion of signi�cant health events which may occur for safety evaluation.

• Good surveillance systems with the ability to detect every case of TB which occurs.

Clinical

• Ability to diagnose TB infection and disease as accurately as possible including microbiological TB culture capacity.

• Competent clinical research team willing and able to prioritize TB vaccine studies.

• Adequate referral structures for detected cases of infection and disease.

Immunology laboratory

• Ability to at least process and dispatch blood specimens for analysis of immunogenicity.

Ethics and regulatory authorities

• Competent and ef�cient local and national ethical and regulatory authorities.

General

• Conducive environment: roads, telecommunications, power, security.

• Political stability and commitment.

• Established relationship with the local community.

Epidemiological

In order to measure ef�cacy, the incidence of the disease at a proposed trial site will determine the sample size. The higher the rate of disease, the lower the sample size requirements and vice versa. Internationally, few agencies are willing to fund TB vaccine trials, so funding for such trials is limited. Thus, an area with a high rate of disease would be more suitable for vaccine trials because the sample size required would better match the resources available to do such trials.

Health occurrences such as deaths, hospitalizations and TB disease events will need to be measured in clinical trials. The standard method of detecting these events through follow up visits would be applied in any trial. However, these events often occur in between visits. Surveillance mechanisms are thus needed to monitor death registers, hospital admissions and, health service evaluation and diagnosis of TB

Chapter7.2.indd 1099 11/02/14 1:10 PM


cases. A co-operative arrangement with a reasonably well functioning health care system would be a requirement.

An organized system for monitoring deaths either utilizing government based death registration systems or specially set up demographic surveillance areas are needed to monitor these. Regulators will have serious concerns not only about the ability of a trial site to detect deaths but also mechanisms to determine the cause of death. Regulators will be reluctant to register products where deaths have not clearly been shown not to be related to trial products.

Clinical

The capacity to diagnose TB with the implied laboratory infrastructure is needed. Sputum smear and culture and/ or GeneXpert (Xpert MTB/RIF, Cepheid)) are important components of TB diagnosis. The diagnosis of TB in children is particularly dif�cult because the disease is pauci-bacillary. SATVI performs gastric washings and induced sputum procedures for smear and culture when investigating a child for TB. In addition, good quality X-rays are important in diagnosing paediatric TB. SATVI utilizes an expert paediatric radiologist panel to read the X-rays of infant TB suspects. A good clinical history and examination, and tests for TB infection such as the TST and more recently, the IFN-� release assays are all important diagnostic aids. Once TB is diagnosed, a participant would need to be treated. Well-functioning experienced TB health care services should be available for the management of such patients.

Training

Staff involved in clinical trials are required to undergo training in Good Clinical Practice (GCP) or Good Clinical Laboratory Practice (GCLP). The capacity to conduct such training is needed. Protocol training needs to be conducted and training in study procedures is needed. Staff turnover is normal in any setting so the ongoing ability to provide training is an important component of any trial site. Thus, an in-house training unit or suitable accessible external training providers are needed for clinical trial sites.

Immunology

Although no markers of protection have been identi�ed, the immune response is monitored as part of vaccine trials and work is already ongoing to investigate potential correlates of protection. Immune testing is still usually done to determine the impact of vaccination on human subjects even if it is still uncertain whether these responses will be protective. Thus, either an immunology laboratory with competent staff is needed to manage these tests or, alternatively, the capacity

Chapter7.2.indd 1100 11/02/14 1:10 PM


to manage the storage and transport of specimens for immunological analysis is needed as these specimens often require special storage and transport.

Ethics and regulatory authorities

All trials require both institutional ethical approval and national regulatory approval. For the ultimate registration of any new product, all the trials prior to that point would need to have been managed in a way that is acceptable internationally. Any new TB vaccine would need to be used in many different countries. Local and national ethical and regulatory bodies thus have to ensure that trials are conducted in such a way so that not only international requirements are met but also local populations are protected where experimental products are being tested. Populations in developing countries are vulnerable to abuse and with the support of the necessary ethics and regulatory agencies, it is up to researchers to ensure that such abuse does not occur. Some vaccines are genetically modi�ed products and many countries have speci�c regulations with respect to the import and export of such substances.

Ef�ciency is an important component of processing regulatory applications. Many regulatory agencies, due to inadequate resources, often take long to process trial applications. This would limit the ability of researchers to conduct trials in a timely manner and it would be a disincentive to sponsors to fund trials where the trial approval processes are lengthy.

Quality assurance and quality control

Most trials are subject to ongoing external monitoring and ad hoc audits by national and international agencies. The capacity to do internal monitoring is advisable to prevent problems from occurring as well as for early identi�cation of problems. The regulatory environment for clinical trials is quite strict and both internal and external monitoring are needed to ensure conformity with regulatory requirements but these are also opportunities for growth and development of site personnel.

Capacity development

Large epidemiological cohort studies on TB involving 5,000–10,000 participants with 2-3 year follow up can be used to help develop Phase III clinical trial capacity. What this achieves is:

- It allows capacity to be built in the setting of a ‘mock trial’ with regard to e.g. - Good clinical practice - Data management

Chapter7.2.indd 1101 11/02/14 1:10 PM


- Clinical procedures, e.g. tuberculin skin test (TST), gastric lavage, sputum induction

- Surveillance for TB and other important events - Quality assurance and internal monitoring mechanisms - It allows prevalence and incidence of TB infection and disease at the site to be

accurately gauged.

General

Trials involve �eldwork to recruit participants and to conduct follow up visits. A good road infrastructure makes a big difference in facilitating such activities. While access to water, sanitation, electricity and telecommunications may be taken for granted, many developing countries struggle with these infrastructural issues particularly in rural areas. All are basic requirements in order for good clinical trials to be conducted. Trials cannot be conducted in an environment of political instability. Study timelines, visit schedules and after hours work would all be affected by instability and would undermine the success of any trial if these activities are severely affected in any way. Engaging with community representatives and stakeholders is an important part of trial site development particularly if many trials or long trials are to be conducted at a site. Language, culture, and power dynamics all need to be taken cognizance of where TB vaccine �eld trials are to be conducted.

THE SATVI EXPERIENCEResearch site selectionSATVI conducted a trial between 2001 and 2006, comparing the administration of BCG via the percutaneous route to the intradermal route and almost 12,000 infants were enrolled into this trial (5). SATVI’s research site is situated in the Boland Region of the Western Cape Province, South Africa. At the start of SATVI’s involvement in 2001, the total population of the study area was of�cially 266,825. Of the households, 89.8 per cent had access to a telephone, 84.3 per cent, access to electricity, 79.6 per cent, access to a �ush toilet, and 91.5 per cent had access to water either in their dwelling or elsewhere on the site (Census 2001, Statistics South Africa).

The reported incidence rates of adult and childhood TB in the area were extremely high. In 2000, the reported incidence rate of smear positive TB for the whole area was 531 per100,000 population (4). The area had a good primary health care and referral network. This was important to be able to run the studies in partnership with the public health services, relying on them to perform certain essential functions such as vaccination of

Chapter7.2.indd 1102 11/02/14 1:10 PM


trial participants and the provision of treatment for TB in any cases diagnosed by SATVI. There are around 25 ‘�xed’ clinics in the area and more remote areas are serviced by mobile teams. There are three ‘district’ hospitals, a referral hospital, and a dedicated TB hospital. Patients from the Boland who cannot be managed by the above are referred to one of three academic hospitals in Cape Town, some 100 km away. Reliable and ef�cient land and air ambulance services are available. All these factors led to this site being chosen as a �eld site for TB vaccine trials.

Recruitment and professional development of staffLike many rural areas in South Africa, the Boland is not well supplied with physicians, nurses, laboratory technologists, and other categories of staff necessary for the execution of large �eld trials. Nevertheless, SATVI has been relatively successful in attracting staff through competitive salary packages and good employment conditions. An important factor was the appointment of Clinical Research Workers (CRWs) to support the clinical research activities at the site combined with a strong training department or Professional Development Programme as it is referred to at SATVI. Staff were trained in GCP to meet regulatory requirements and this enabled them to have a clearer insight into the special requirements of clinical trials.

Vital registration and morbidity surveillanceThe regional Department of Health had good routine systems in place to monitor births (most of which took place in health care facilities) and to record deaths so that important events for TB vaccine trials were available for planning and surveillance purposes.

The surveillance system SATVI devised included the following elements.

Weekly lists of all admissions were obtained from the TB hospital, the referral hospital, and the three district hospitals in the study area. The names were cross- checked with the database of study participants. The medical �les of study participants were then drawn and copied (consent for access to study participant medical records was obtained at study entry). These were later reviewed by one of the study medical of�cers. Participants with serious adverse events (SAEs) were followed up further if more data were required and any TB suspects were investigated in depth.

Because the routine mortality surveillance system can only provide very basic data, the system was augmented by study staff conducting verbal autopsies and collecting clinical records for any hospital admissions prior to death. A study medical of�cer, having reviewed all available information, assigned the ‘most likely’ main and underlying causes of death (6).

Chapter7.2.indd 1103 11/02/14 1:10 PM


Tuberculosis surveillance and case veri�cationA reasonably sensitive but less speci�c public health system is available in the Boland for TB diagnosis and management in infants and young children. Some cases are diagnosed in hospital and, depending on which hospital, the grounds for treatment might include clinical signs and symptoms, tuberculin skin test (TST) results, gastric washing and/or extra-pulmonary body �uid TB culture results or biochemical changes, and chest radiography. Occasionally, diagnosis is based on more specialized investigations such as CT scan, ultrasound or histology. The levels of expertise of physicians in assessing patients, reading radiographs, and ordering treatment, range from newly quali�ed to experienced specialists. Many children diagnosed with TB are managed in clinics.

SATVI decided, in co-operation with the TB hospital, to equip and staff a ward into which children with suspected TB could be admitted, along with their primary caregiver, for a period of 48 hours. During this time the children had the following done: a comprehensive clinical history was taken and an examination was performed by a specially trained registered nurse. An HIV test was done. A �nger prick rapid test (Abbott Determine©) was used and if the result was positive, a laboratory ELISA as well as an HIV-polymerase chain reaction (PCR) test were performed if the child was under 18 months old. A TST was performed. All children had two gastric washings and two induced sputa samples taken on consecutive days sent for TB culture, drug susceptibility, and biochemical and molecular speciation to exclude BCG disease. At one stage in the trial, blood samples were sent for TB culture but this was discontinued due to the very low yield. A chest radiograph was taken: routine antero-posterior (AP) and lateral �lms were taken and these were reviewed �rst by the medical of�cer in charge of the paediatric ward at Brewelskloof Hospital, and later by a panel of specialists experienced in the radiological diagnosis of TB in young children and infants.

Cohort retentionOne of the reasons that the Boland was chosen as the site for the trial was that the population appeared to be fairly stable: there is seasonal migration due to the availability of work on the farms during the harvest and not at other times of the year, but labourers tend to return to the same farms, and there is no other large-scale migration documented. To make sure that this was the case, outmigration surveys were conducted at regular intervals. The outmigration rate in all surveys undertaken was low (cumulatively less than 5 per cent).

Chapter7.2.indd 1104 11/02/14 1:10 PM


Monitoring and quality control

Standard operating procedures

Standard operating procedures (SOPs) were drawn up under the supervision of the quality assurance/ control department. These were largely generic and work practice documents are drawn up when procedures are applied to speci�c studies. All documents are managed under a formal document control system which involves a special numbering system, version control, and document storage. Where necessary, specialists in the �eld are consulted. Once �nalized, training of staff in the performance of the tasks described in the SOPs is done by study staff. All SOPs are periodically revisited and updated as experience is gained and inconsistencies become evident. SOPs covering the following procedures have been developed: recruitment, informed consent and enrolment, vaccination, vaccine management, vaccine reaction follow up and surveillance, adverse event surveillance and reporting, TB surveillance, case veri�cation and review, outmigration surveys, database management, and needlestick injury management.

Internal monitoring

Initially, a senior research nurse with a strong background in clinical research and GCP was appointed as the study internal monitor, reporting directly to the principal investigator. With input from the data manager, a system was developed for monitoring a random 10 per cent sample of case report forms once a month and providing feedback on the results to the trial management for action. Fields were divided into critical and non-critical. If inconsistencies were found of greater than one per cent in critical or greater than 10 per cent in non-critical �elds in any particular sample, this triggered a full audit of all records for that month. Many sponsors now use electronic data capture systems and staff are mainly involved in following up queries generated by these systems. Internal monitoring focuses now mainly on informed consent forms and source documents.

External monitoring

Community Advisory Board

A community advisory board (CAB) was constituted at the start of SATVI’s work and this was later expanded to broaden its representation. One of the site’s challenges is to maintain a fully functional community advisory board. The CAB has given input on a number of study related issues. The CAB has undergone GCP training covering trial management concepts but also infectious disease modules.

Chapter7.2.indd 1105 11/02/14 1:10 PM


External Monitors and Audits

The site has routine external monitoring of all its trials and problems picked up through monitoring visits are dealt with. SATVI has undergone sponsor- arranged audits as well as audits by the national regulatory authority in South Africa, the Medicines Control Council. These have provided valuable developmental experiences for the site.

Institutional Review Boards/Independent Ethics Committees

All protocols and other relevant study documents are approved by the local University of Cape Town Human Research Ethics Committee and by sponsor institutional review boards (IRBs) in some instances. Trials of new TB vaccines also need to be approved by the South African Medicines Control Council (South Africa’s FDA equivalent). Annual reports are submitted to the IECs (independent ethics committees)/IRBs which include a summary of all serious adverse events. All serious adverse events are, in addition, reported to the local safety monitor or data safety monitoring committee and the sponsor’s chief medical of�cer, weekly. Six monthly reports on adverse events are required to be submitted to the medicines regulatory authority in South Africa. More rapid reporting is required for any serious adverse events.

Database managementInitially, a database manager designed databases using Microsoft Access for SATVI studies but more recently, more advanced databases provided by sponsors are being used with remote data entry as one mechanism of entering data. Where SATVI has designed the database, data entry is done on site in Worcester by dedicated data capturers and weekly backup copies of the database are kept both in Worcester and in Cape Town. Access to the databases is by password and this is restricted to the database manager, data capturers, study co-ordinators and the investigators.

CLINICAL TRIALS OF TUBERCULOSIS VACCINESA number of vaccines have been developed in recent years (7, 8, 9) and some are going through clinical trials. Table 7.2.2 sets out those TB vaccines in human clinical trials at the time of writing.

Chapter7.2.indd 1106 11/02/14 1:10 PM


TABL

E 7.

2.2

Curr

ent T

B va

ccin

es in

clin

ical

tria

ls (2

011)

Stat

us

Prod

ucts

Pr

oduc

t de

scri

ptio

n [C

itat

ions

]Sp

onso

rIn

dica

tion

Type

of

Vac

cine

Ta

rget

Po

pula

tion

s

Phas

e III

Mw

[M.

indi

cus

pran

ii (M

IP)]

Who

le c

ell s

apro

phyt

ic n

on-

DTB

myc

obac

teriu

m [1

–3]

Depa

rtm

ent o

f Bi

otec

hono

logy

(M

inis

try

of S

cien

ce &

Te

chno

logy

, Gov

ernm

ent

of In

dia)

, M/s

. Cad

ila

Phar

mac

eutic

als

Ltd.

ITW

hole

cel

l, In

activ

ated

or

Disr

upte

d–

Phas

e IIb

MVA

85A/

AERA

S‐48

5

Mod

ified

vac

cini

a An

kara

ve

ctor

exp

ress

ing

Mtb

an

tigen

85A

[4–8

]

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

Vira

l Ve

ctor

ed

BCG

‐va

ccin

ated

in

fant

s an

d ad

oles

cent

s; HI

V‐in

fect

ed

adul

ts

AERA

S‐40

2/Cr

ucel

l Ad3

5

Repl

icat

ionÐ

defic

ient

ad

enov

irus

35 v

ecto

r ex

pres

sing

Mtb

ant

igen

s 85

A, 8

5B, T

B10.

4 [9

–13]

Cruc

ell,

Aera

s, ED

CTP,

NIH

BVi

ral

Vect

ored

BCG

‐va

ccin

ated

in

fant

s, ch

ildre

n an

d ad

ults

Chapter7.2.indd 1107 11/02/14 1:10 PM


TABL

E 7.

2.2

Curr

ent T

B va

ccin

es in

clin

ical

tria

ls (2

011)

Stat

us

Prod

ucts

Pr

oduc

t de

scri

ptio

n [C

itat

ions

]Sp

onso

rIn

dica

tion

Type

of

Vac

cine

Ta

rget

Po

pula

tion

s

Phas

e II

M72

+ A

S01

Reco

mbi

nant

pro

tein

co

mpo

sed

of a

fusi

on o

f Mtb

an

tigen

s Rv

1196

and

Rv0

125

& a

djuv

ant A

S01

[14–

17]

GSK

, Aer

asB

PI

Reco

mbi

nant

Pr

otei

nAd

oles

cent

s/ad

ults

, nfa

nts

Hybr

id-I+

IC31

Adju

vant

ed re

com

bina

nt

prot

ein

com

pose

d of

Mtb

an

tigen

s 85

B an

d ES

ATÐ6

[1

8–22

]

Stat

ens

Seru

m In

stitu

te

(SSI

), TB

VI, E

DCTP

, In

terc

ell

P B

PI

Reco

mbi

nant

Pr

otei

nAd

oles

cent

s; ad

ults

VPM

100

2

rBCG

Pra

gue

stra

in

expr

essi

ng li

ster

ioly

sin

and

carr

ies

a ur

ease

del

etio

n m

utat

ion

[23–

27]

Max

Pla

nck,

Vak

zine

Pr

ojek

t Man

agem

ent

Gm

bH, T

BVI

P B

Reco

mbi

nant

Liv

e–

RUTI

Frag

men

ted

Mtb

cel

ls

[28–

32]

Arch

ivel

Far

ma,

S.L

..B

PI

ITW

hole

cel

l, In

activ

ated

or

Disr

upte

d

HIV+

ad

ults

, LTB

I di

agno

sed

Chapter7.2.indd 1108 11/02/14 1:10 PM


TABL

E 7.

2.2

Curr

ent T

B va

ccin

es in

clin

ical

tria

ls (2

011)

Stat

us

Prod

ucts

Pr

oduc

t de

scri

ptio

n [C

itat

ions

]Sp

onso

rIn

dica

tion

Type

of

Vac

cine

Ta

rget

Po

pula

tion

s

Phas

e I

AdAg

85A

Repl

icat

ion-

defic

ient

ad

enov

irus

5 ve

ctor

ex

pres

sing

Mtb

ant

igen

85A

[3

3–37

]

McM

aste

r Uni

vers

ityP

B P

IVi

ral V

ecto

red

Infa

nts;

adol

esce

nts;

HIV+

Hybr

id‐

I+CA

F01

Adju

vant

ed re

com

bina

nt

prot

ein

com

pose

d of

Mtb

an

tigen

s 85

B an

d ES

AT-6

[1

9–20

, 38–

40]

SSI,

TBVI

P B

IT

Reco

mbi

nant

Pr

otei

n Ad

oles

cent

s, ad

ults

Hybr

id 5

6 +

IC

31

Adju

vant

ed re

com

bina

nt

prot

ein

com

pose

d of

Mtb

an

tigen

s 85

B, E

SAT-

6 an

d Rv

2660

[41–

42]

SSI,

Aera

s, In

terc

ell

P B

PI

Reco

mbi

nant

Pr

otei

n Ad

oles

cent

s, ad

ults

HyVa

c 4/

AERA

S‐40

4, +

IC

31

Adju

vant

ed re

com

bina

nt

prot

ein

com

pose

d of

a fu

sion

of

Mtb

ant

igen

s 85

B an

d TB

10.4

[43–

46]

SSI,

sano

�‐pa

steu

r,

Aera

s, In

terc

ell

BRe

com

bina

nt

Prot

ein

Infa

nts

ID93

/GLA

‐SE

Subu

nit f

usio

n pr

otei

n co

mpo

sed

of 4

Mtb

ant

igen

s [9

9Ð10

0]

Infe

ctio

us D

isea

se

Rese

arch

Inst

itute

(IDR

I),

Aera

sB

PI

ITRe

com

bina

nt

Prot

ein

Adol

esce

nts,

adul

ts

(Sou

rce:

htt

p://w

ww

.sto

ptb.

org/

wg/

new

_vac

cine

s/do

cum

ents

.asp

whi

ch a

lso

prov

ides

upd

ates

of t

his

tabl

e)

Chapter7.2.indd 1109 11/02/14 1:10 PM


MEASURING SAFETY AND IMMUNOGENICITY ENDPOINTS

Assessing safety in human trialsLocal, systemic, and serious adverse events would need to be measured in any safety vaccine study. Symptoms, signs, and laboratory measures are all evaluated in safety studies. Tables for grading severity have been developed by e.g FDA as mild, moderate or severe and these are used by many clinical trialists as it enables a standardised way of measuring such events. In TB vaccine trials, local reactions at the injection site are common and it would be important to measure how severe these are. The so-called ‘Koch’ phenomenon is also of concern. This hypothesised effect relates to where a person has TB disease or infection and the administration of TB antigens somehow aggravates the disease or brings about a severe reaction in those individuals who have been exposed. No trials to date have observed this phenomenon but this was observed when Robert Koch administered tuberculin to TB patients towards the end of the 19th century as he thought this was a potential treatment for TB.

An important issue is whether an observed adverse event is related to a particular product. The association of adverse events (AEs) to investigational products is judged by study investigators and, therefore, is subject to clinical judgement. The related adverse events form an important part of the pro�le of a vaccine and will impact on its acceptability by regulators and consumers.

Assessing immunogenicity in human trialsAs biomarkers of a protective immune response against TB are not known, the immune response induced by a novel vaccine should best be termed “vaccine take”. Current assessment of vaccine take focuses on T cell immunity thought to be important for protection. Speci�c CD4 T cells able to produce IFN-� are critical for protection against TB, as shown in congenital and acquired human immune de�ciency, and in experimental models of mycobacterial disease. Therefore, speci�c IFN-� production by CD4 T cells is measured in all current phase I or IIa trials of novel TB vaccines, either by an IFN-� ELISPOT assay or by an intracellular cytokine staining (ICS) assay.

The IFN-� ELISPOT detects production of IFN-� by individual cells – each cell making the cytokine can be detected as a “spot” in a well (10). Each spot represents cytokine production by a single cell, following incubation of peripheral blood

Chapter7.2.indd 1110 11/02/14 1:10 PM


mononuclear cells (PBMC) with speci�c vaccine antigens within the well. It is likely that most spots originate from speci�c CD4 T cells, although natural killer cells may contribute. In contrast, �ow cytometric ICS assays detect IFN-� production speci�c to CD4 T cells, following incubation of whole blood or PBMC with speci�c antigens (10). Multi-parameter ICS assays allow assessment of multiple complementary T cell outcomes. For example, CD4 T cell production of IL-2 and TNF, as well as of the pro-in�ammatory cytokine IL-17 (11), cytokines that may contribute to protection against TB, may be measured within the same sample. Additionally, activation of CD8 T cells, which may also be important for protection, can be measured by the ability to produce IFN-�, IL-2 and/or TNF, following speci�c stimulation.

ELISPOT and ICS assays are classic examples of shorter term assays, in which cells do not have time to proliferate, allowing a more quantitative assessment of outcome. Many other assays may be used to measure the T cell response (recently summarized in [12]). Some assays have longer periods of incubation (5-7 days), which may allow better assessment of cells that may require longer periods for activation, such as central memory T cells. The lymphocyte proliferation assay is a classic longer term assay: PBMC are pre-stained with a dye such as carboxy �uorescein succinimidyl ester (CFSE), incubated with speci�c antigens for 5-7 days, and proliferation of CD4 or CD8 T cells measured by �ow cytometry (13). Every time the cell replicates it loses 50% of the original �uorescence intensity of the CFSE, allowing easy detection of expanded, speci�c cells.

Multiple variables determine assay success (summarised in [12]). For example, following blood collection, delay of incubation into assays or of PBMC isolation may compromise outcome. Also, the use of freshly isolated PBMC will allow greater sensitivity in measuring an immune response, compared with the use of thawed PBMC after cryopreservation. Selecting peptide vs. recombinant protein vs. whole bacterial (e.g., BCG) antigen, as well as the dose of the antigen, may signi�cantly impact assay results.

More on the induced immune response, and biomarkers of protection The exact nature of immunological mechanisms that mediate protection at different stages of MTB infection remain incompletely understood. T cell mechanisms other than those described above may be important, for example, cytotoxic activity, regulatory activity or activity of non-traditional T cells, such as �� T cells. Innate cells, including macrophages, natural killer (NK) cells, and dendritic cells, may

Chapter7.2.indd 1111 11/02/14 1:10 PM


be critically important. The dogma that antibodies, complement, or other host components are not critical players in immune control may simply re�ect our lack of understanding of the complexity of the response to mycobacteria. Regardless, the emerging evidence of a well-balanced T cell response, which includes effector and regulatory arms, may be important for protection. Therefore, a quantitatively greater effector T cell response, following vaccination, is not necessarily ideal. Animal models of TB disease have taught us that speci�c IFN-� production early after vaccination, particularly when determined in lung or local lymph node CD4 T cells, may correlate with protection (reviewed in [14]). However, results from multiple recent experimental studies caution against use of IFN-� production as a sole vaccination-induced immune correlate of protection (15-17): in many cases, IFN-� production merely re�ects bacterial load and/or in�ammatory status.

In humans, no vaccination-induced correlates of protection against TB, or correlates of risk of TB disease, using modern immunological tools, exist today. The TST reaction following BCG vaccination is a poor correlate of protection. Only one large study of biomarkers of protection against TB following BCG vaccination of newborns is currently ongoing, at the SATVI group in Cape Town, South Africa; preliminary results suggest that the classical T cell markers used to determine vaccine take, i.e., CD4 T cell production of IFN-�, or even a polyfunctional CD4 T cell response (cells that make IFN-�, IL-2 and TNF together, proposed to be a correlate of protection against intracellular pathogens), when measured at 10 weeks of age following newborn BCG vaccination, did not correlate with protection. Proliferation responses did not correlate with protection either. Other preliminary results suggest unbiased screening methods, such as DNA microarray analysis of gene expression, may yield patterns that are associated with protection – these approaches may ultimately allow discovery of novel correlates. These correlates may only be validated in placebo-controlled ef�cacy (phase III) trials of new TB vaccines, if ef�cacy is demonstrated.

SAFETY AND IMMUNOGENICITY FEATURES OF NEW TB VACCINESA summary of key safety and immunological features of new TB vaccines currently in human trials is set out below (direct comparisons of vaccines is not possible because of different de�nitions and methods used for measuring adverse events and immunology outcomes).

Chapter7.2.indd 1112 11/02/14 1:10 PM


AERAS-402

Safety

The safety pro�le of AERAS-402 developed so far (personal communication, Aeras Foundation) in adults consists of mild to moderate local injection site in�ammatory �ndings with some cases of severe injection site pain, some moderate to severe constitutional symptoms, mild changes in liver enzymes, and mild to moderate changes in leukocyte parameters with some severe decreases in neutrophil count. It appears that there may be a dose-dependent increase in the frequency and severity of injection site reactions. There also appears to be an increased incidence of mild to moderate fever and myalgia in adult subjects receiving the highest dose level of AERAS-402 (1 x 1011 vp) compared to those receiving lower dose levels of AERAS-402. Aeras 402 has been described as well tolerated with no vaccine-related serious adverse events reported in an adult trial with this vaccine (10).

In the �rst study in healthy BCG-vaccinated infants, AERAS-402 provoked mild to moderate local injection site reactions. Mild to moderate constitutional symptoms related to AERAS-402, most commonly malaise, rhinitis, body temperature increase (fever), and fatigue, were also seen. A dose-dependent increase in the frequency of injection site pain, malaise, and fever was observed. Some changes in laboratory parameters were also attributed to AERAS-402, the most common (occurred in 2 or more infants) being hemoglobin decrease, ALT increase, and neutrophil count decrease. Most of the laboratory changes considered related to AERAS-402 were mild, although some infants had a moderate hemoglobin increase and one infant had a transient severe neutrophil count decrease. Instances of increased respiratory rate (tachypnoea) and rapid onset local erythema have been reported with a subsequent multicenter dose-�nding trial in infants. The tachypnoea was reported as a severe unexpected serious adverse reaction (SUSAR) but all infants recovered within a short period of this reaction occurring. The erythematous reactions were self-limiting and no evidence of allergy was found. This vaccine was initially tested as a single dose vaccine then as a 2 dose vaccine (one month apart) and more recently, a third dose has been added 6 months after the �rst dose. There are 7 completed or ongoing trials of this vaccine in adults (35).

Immunogenicity

AERAS-402 is capable of inducing high levels of CD8+ T cells that respond to vaccine peptides in vitro in some volunteers. The CD4 response is measurable but less prominent. There is a general trend of increased immunogenicity with higher dose

Chapter7.2.indd 1113 11/02/14 1:10 PM


levels. Polyfunctionality in T-cell responses has been an important �nding with this vaccine. The CD8 responses were described as robust and durable in adults (18).

GSK M72/AS01The M72 antigen is a fusion of 2 immunogenic proteins, MTB32A and MTB39A, formulated with GSK’s proprietary AS01 Adjuvant Systems (personal communication, O Ofori-Anyinam [GSK]). MTB32A and MTB39A are speci�cally expressed in BCG and MTB and induce proliferation and production of IFN-g by PBMC from PPD-positive donors. AS01 is composed of two immunostimulants, MPL and QS21, and a liposomal preparation. Following extensive preclinical evaluation, M72/AS01 has been tested in PPD- negative, PPD-positive, and HIV-positive adults (36, 37). It has now also been tested in infants and adolescents. A multicentre phase IIb ef�cacy trial in adults is planned.

Safety

Transient injection-site pain, redness, and swelling were local reactions reported for this vaccine. Constitutional symptoms such as fatigue and an in�uenza-like illness, headache or malaise have also been reported. These events generally decreased in severity or resolved within two days. No clinically signi�cant abnormal laboratory results related to vaccination have been observed to date. There were no serious adverse events related to the vaccine that were reported.

Immunogenicity

The vaccine induces marked and persistent M72-speci�c humoral and polyfunctional cellular responses following administration of two doses. The second vaccine dose boosted the speci�c immune responses induced by the �rst dose. The pro�le of cytokine expression showed a signi�cant frequency of M72-speci�c CD4+ T cells expressing two or more immune markers, among which are CD40L, IL-2, TNF-a, and IFN-g upon short- term in vitro stimulation. Additional characterization of the cellular response one week post vaccination on subjects living in endemic areas showed speci�c CD8+ T cell responses induced/boosted in subjects at seven days post dose 1 and to a lesser extent at seven days post dose 2.

Hybrid-1-IC31 (H1IC)Ag85B-ESAT-6 (Hybrid-1) is the recombinant fusion protein of Ag85B and ESAT-6, developed and manufactured by Statens Serum Institute (Copenhagen, Denmark)

Chapter7.2.indd 1114 11/02/14 1:10 PM


(personal communication, Ingrid Kromann, Statens Serum Institut). IC31® is a two-component adjuvant system developed by Intercell AG (Vienna, Austria), composed of the cationic polyaminoacid KLK and the oligodeoxynucleotide ODN1a.

Three phase I studies with this vaccine have been conducted in adults and two further trials are in progress, one in adolescents and one in HIV positive adults.

Safety

Vaccination to date has caused mainly local reactions such as transient soreness but also mild systemic symptoms.

Immunogenicity

The vaccine elicited strong antigen-speci�c T cell responses against H1 and both the Ag85B and the ESAT-6 components. In one study the volunteers from one group was followed up for immunogenicity after 2.5 year and the strong responses persisted through the 2.5 years, indicating the induction of a substantial memory response in the vaccine recipients (19, 20, 21).

Hyvac4-IC31Ag85B-TB10.4 (Hyvac-4) is the recombinant fusion protein of Ag85B and TB 10.4, developed and manufactured by Statens Serum Institute (Copenhagen, Denmark) (personal communication, Ingrid Kromann, Statens Serum Institut). IC31® is a two-component adjuvant system developed by Intercell AG (Vienna, Austria), composed of the cationic polyaminoacid KLK and the oligodeoxynucleotide ODN1a (22). Four phase I studies have been conducted with this vaccine in adults with the latest being a trial in BCG vaccinated adults. Overall the vaccine has been shown to be well tolerated and immunogenic. No data on clinical trials for this vaccine has been published in the scienti�c literature at the time of writing. A trial in infants is being planned.

MVA85A

Safety

This vaccine which is administered intradermally commonly causes local reactions of redness and swelling initially, which then leads to scaling at the injection site which resolves within a few weeks. Less commonly, systemic reactions are experienced such as fever, headache, and cough (10, 23, 24). The safety pro�le in

Chapter7.2.indd 1115 11/02/14 1:10 PM


subjects latently infected with MTB is comparable to that seen in BCG-vaccinated subjects (25). This vaccine has also be shown to be safe in HIV positive adults both on and off antiretroviral treatment who had CD4 levels >300 cells/mm3 (38). A trial in infants similarly showed this vaccine to be safe (39).

Immunogenicity

The main way in which the immunological response to MVA85A has been evaluated so far in the clinical trials conducted to date is the ex-vivo IFN-� ELISPOT assay. MVA85A induced high levels of antigen-speci�c IFN-� secreting T cells in BCG-naïve adults, and signi�cantly higher levels in adults previously vaccinated with BCG (10, 23, 24). This boosting seems to be regardless of length of time between BCG and boosting with MVA85A (23). Immunogenicity results were similar in BCG-vaccinated adolescents and adults latently infected with MTB. In BCG-vaccinated adults, adolescents, children and infants, signi�cant levels of antigen-speci�c T cells have been observed. In BCG- vaccinated adults in South Africa and the UK, BCG-speci�c CD4+ T cells boosted by MVA85A comprised multiple populations expressing combinations of IFN-g, TNF-a, IL-2, and IL-17, as measured by �ow cytometry (10, 25). IFN-g-expressing and polyfunctional IFN-g+TNF-a+IL-2+ CD4+ T cells were boosted during the peak BCG-speci�c response, which occurred seven days after vaccination (25, 26, 27). A trial assessing interference with other routinely given vaccines in infancy showed the vaccine’s immune responses to be reduced by these routine vaccinations but the converse was not true (40).

Ef�cacy

This vaccine has been evaluated in a phase IIb trial in infants in South Africa for ef�cacy, the �rst new TB vaccine to undergo such an evaluation in infants. No evidence of ef�cacy against TB infection or disease was shown at the dose tested (41). While this result was disappointing, the trial provides a benchmark for further ef�cacy trials and many operational lessons were learnt (42).

Mycobacterium vaccae

This is the only new TB vaccine that has been through a phase III trial. Five doses of MV reduced de�nite TB by 39% in HIV positive adults and was immunogenic (28). This was consistent with immunogenicity from a preceding Phase II trial in Finland (29). Immunization was safe and had no adverse effects on HIV viral load or CD4 cell count in both trials. A broth production method for this vaccine

Chapter7.2.indd 1116 11/02/14 1:10 PM


is now underway at Aeras. Interestingly, immune responses did not correlate with protection in the phase III trial (30).

rBCG∆ureC::Hly (VPM1002)VPM1002-speci�c human data are available from two clinical trials. In the �rst clinical trial conducted in Germany, healthy male Caucasian adult volunteers with or without pre-exposure to BCG were vaccinated with VPM1002 (N=30 + 30) or BCG (N=10 + 10) followed by a six month follow-up period. This study revealed that a single vaccination with VPM1002 up to 5x10e5 CFU was safe and well tolerated. No Serious Adverse Event occurred. VPM1002 was also shown to be highly immunogenic; it induced multifunctional CD4+ and CD8+ T cell subsets. With regard to the multifunctional CD8+ T cells, VPM1002 showed a trend of superiority over BCG at a comparable dosage. In addition it showed also a potential for a boost vaccination on a pre-existing immune response induced by BCG.

In the second clinical trial, 24 healthy male or female adults, all with prior exposure to BCG and predominantly from the indigenous African population, were vaccinated in South Africa. The 2 month safety data concurred with that of the German clinical trial, demonstrating that a single vaccination with VPM1002 up to a dose of 5x10e5 CFU was safe and well tolerated. (Personal communication – Leander Grode, Vakzine Projekt Management). This vaccine is being further tested for safety in infants and further trials in HIV exposed and infected infants are planned.

rBCG30This vaccine is currently not in active development.

Safety

Similar responses were seen with rBCG30 as with BCG (20).

Immunogenicity

rBCG30 induced Ag85b-speci�c T cell responses involved both the CD4+ and CD8+ T cell components (31).

RUTIThe published results from a Phase I clinical trial report that “RUTI appeared to be well tolerated as judged by local and systemic clinical evaluation, though vaccine

Chapter7.2.indd 1117 11/02/14 1:10 PM


dose dependent local adverse reactions were recorded. T-cell responses of blood lymphocytes to PPD and a number of antigen subunits were elevated, when compared with controls subjects (32). This vaccine is planned for use as a therapeutic vaccine against latent tuberculosis infection in combination with INH therapy (33).

H56This vaccine is a variation of Hybrid-1-IC31mentioned above but includes an additional antigen, Rv 2660, which is a an antigen associated with latency. This vaccine has been developed to target individuals latently infected with TB. A phase I �rst in human trial has been completed in South Africa and no safety issues have been reported. Further trials are planned.

ID93/ GLA-SEThis fusion protein vaccine to be targeted at adults and adolescents has entered its �rst trial in the USA and this trial is ongoing. Depending on the results of this trial, further trials are planned in TB endemic countries.

MTBVACThis live attenuated vaccine based on M tuberculosis has entered its �rst clinical trial in Europe and the trial is ongoing. No data on progress is currently available.

CONCLUSIONSATVI has set up a successful site for the testing of new TB vaccines which is ready to conduct Phase III vaccine trials. Multiple centres will probably be needed to conduct Phase III trials of TB vaccines and other TB vaccine trial sites in Africa and also other parts of the world have been developed. The lessons learnt by SATVI are valuable for sites currently in development and for any organizations/ institutions wishing to develop such a site.

There are a number of new TB candidates that have been developed and a number of these are in clinical trials in humans. Results thus far are promising both in terms of immunogenicity and in terms of safety pro�le but we will only know if any of these candidates will be able to mount an effective challenge to the TB epidemic at the Phase III stage.

Chapter7.2.indd 1118 11/02/14 1:10 PM


ACKNOWLEDGEMENTSThe input of Dr Tony Hawkridge in the form of contributions, comments and suggestions on site development is hereby gratefully acknowledged.

REFERENCES

1. WHO. Global tuberculosis control: surveillance, planning, �nancing: WHO Report 2008. Geneva.

2. Trunz BB, Fine P, and Dye C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet, 2006; 367(9517): 1173–80.

3. Lönnroth K and Raviglione M. Global epidemiology of tuberculosis: prospects for control. Semin Respir Crit Care Med, 2008; 29(5): 481–91.

4. Groenewald P. Boland-Overberg Region, Annual Health Status Report 2001, Dept of Information Management, Boland-Overberg Regional Of�ce, Worcester, undated.

5. Hawkridge A, Hatherill M, Little F, Goetz MA, Barker L, Mahomed H, Sadoff J, Hanekom W, Geiter L, and Hussey G; South African BCG trial team. Ef�cacy of percutaneous versus intradermal BCG in the prevention of tuberculosis in South African infants: randomised trial. BMJ, 2008; 337: a2052.

6. Moyo S, Hawkridge T, Mahomed H, Workman L, Groenewald P, Minnies D, Geiter LJ, Verver S, Kibel M, and Hussey GD. Determining causes of mortality in children enrolled in a vaccine trial in a rural area. J Paediatr Child Health, 2007; 43(3): 178–83.

7. Skeiky YA and Sadoff JC. Advances in tuberculosis vaccine strategies. Nat Rev Microbiol, 2006; 4(6): 469–76. Review.

8. Hussey G, Hawkridge T, and Hanekom W. Childhood tuberculosis: old and new vaccines. Paediatr Respir Rev, 2007; 8(2): 148–54. Epub 2007 Jun 4. Review.

9. Ly LH and McMurray DN. Tuberculosis: vaccines in the pipeline. Expert Rev Vaccines, 2008; 7(5): 635–50.

10. Hawkridge T, Scriba TJ, Gelderbloem S, Smit E, Tameris M, Moyo S, Lang T, Veldsman A, Hatherill M, van der Merwe L, Fletcher HA, Mahomed H, Hill AV, Hanekom WA, Hussey GD, and McShane H. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa. J Infect Dis, 2008; 198(4): 544–52.

Chapter7.2.indd 1119 11/02/14 1:10 PM


11. Scriba TJ, Kalsdorf B, Abrahams DA, Isaacs F, Hofmeister J, Black G, Hassan HY, Wilkinson RJ, Walzl G, Gelderbloem SJ, Mahomed H, Hussey GD, and Hanekom WA. Distinct, speci�c IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response. J Immunol, 2008; 180(3): 1962–70.

12. Hanekom WA, Dockrell HM, Ottenhoff TH, Doherty TM, Fletcher H, McShane H, Weichold FF, Hoft DF, Parida SK, and Fruth UJ. Immunological outcomes of new tuberculosis vaccine trials: WHO panel recommendations. PLoS Med, 2008; 5(7): e145.

13. Beveridge NE, Price DA, Casazza JP, Pathan AA, Sander CR, Asher TE, Ambrozak DR, Precopio ML, Scheinberg P, Alder NC,Roederer M, Koup RA, Douek DC, Hill AV, and McShane H. Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis-speci�c CD4+ memory T lymphocyte populations. Eur J Immunol, 2007; 37(11): 3089–100.

14. Hanekom WA. Maintenance of latent infection, with correlates of protective immunity. Kaufmann SHE, Britton WJ (eds): Handbook of tuberculosis: Immunology and cell biology, Weinheim: Wiley-VCH. 2008.

15. Bennekov T, Dietrich J, Rosenkrands I, Stryhn A, Doherty TM, and Andersen P. Alteration of epitope recognition pattern in Ag85B and ESAT-6 has a profound in�uence on vaccine-induced protection against Mycobacterium tuberculosis. Eur J Immunol, 2006; 36(12): 3346–55.

16. Forbes EK SC and Ronan EO. Multifunctional, high-level cytokine-producing Th1 cells in the lung, but not spleen, correlate with protection against Mycobacterium tuberculosis aerosol challenge in mice. J Immunol, 2008; 81(7): 4955–64.

17. Mittrucker HW SU and Kohler A. Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis. Proc Natl Acad Sci USA, 2007; 104(30): 12434–9.

18. Abel B, Tameris M, Mansoor N, Gelderbloem S, Hughes J, Abrahams D, Makhethe L, Erasmus M, de Kock M, van der Merwe L, Hawkridge A, Veldsman A, Hatherill M, Schirru G, Pau MG, Hendriks J, Weverling GJ, Goudsmit J, Sizemore D, McClain JB, Goetz M, Gearhart J, Mahomed H, Hussey GD, Sadoff JC, and Hanekom WA. The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults. Am J Respir Crit Care Med., 2010; 181(12): 1407–17. Epub 2010 Feb 18.

19. van Dissel JT, Soonawala D, Joosten SA, Prins C, Arend SM, Bang P, Tingskov PN, Lingnau K, Nouta J, Hoff ST, Rosenkrands I,Kromann I, Ottenhoff TH, Doherty

Chapter7.2.indd 1120 11/02/14 1:10 PM


TM, and Andersen P. Ag85B-ESAT-6 adjuvanted with IC31® promotes strong and long-lived Mycobacterium tuberculosis speci�c T cell responses in volunteers with previous BCG vaccination or tuberculosis infection. Vaccine, 2011; 29(11): 2100-9. Epub 2011 Jan 20.

20. van Dissel JT, Arend SM, Prins C, Bang P, Tingskov PN, Lingnau K, Nouta J, Klein MR, Rosenkrands I, Ottenhoff TH, Kromann I,Doherty TM, Andersen P. Ag85B-ESAT-6 adjuvanted with IC31((R)) promotes strong and long-lived Mycobacterium tuberculosis speci�c T cell responses in naïve human volunteers. Vaccine, 2010; 28(20): 3571-81. Epub 2010 Mar 11.

21. Ottenhoff TH, Doherty TM, van Dissel JT, Bang P, Lingnau K, Kromann I, and Andersen P. First in humans: A new molecularly de�ned vaccine shows excellent safety and strong induction of long-lived Mycobacterium tuberculosis-speci�c Th1-cell like responses. Human Vaccine, 6(12): 1007-15.

22. Skeiky YA, Dietrich J, Lasco TM, Stagliano K, Dheenadhayalan V, Goetz MA, Cantarero L, Basaraba RJ, Bang P, Kromann I, McMclain JB, Sadoff JC, and Andersen P. Non-clinical ef�cacy and safety of HyVac4:IC31 vaccine administered in a BCG prime-boost regimen. Vaccine, 2010; 28(4): 1084-

23. Pathan AA, Sander CR, Fletcher HA, Poulton I, Alder NC, Beveridge NE, Whelan KT, Hill AV, and McShane H. Boosting BCG with recombinant modi�ed Vaccinia Ankara expressing antigen 85A: different boosting intervals and implications for ef�cacy trials. PLoS ONE, 2007; 2(10): e1052.

24. Brookes RH, Hill PC, Owiafe PK, Ibanga HB, Jeffries DJ, Donkor SA, Fletcher HA, Hammond AS, Lienhardt C, Adegbola RA, McShane H, and Hill AV. Safety and immunogenicity of the candidate tuberculosis vaccine MVA85A in West Africa. PLoS ONE, 2008; 3(8): e2921.

25. Sander CR, Pathan AA, Beveridge NE, Poulton I, Minassian A, Alder N, Van Wijgerden J, Hill AV, Gleeson FV, Davies RJ, Pasvol G, and McShane H. Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals. Am J Respir Crit Care Med, 2009; 179(8): 724–33. Epub 2009 Jan 16.

26. Scriba TJ, Tameris M, Mansoor N, Smit E, van der Merwe L, Isaacs F, Keyser A, Moyo S, Brittain N, Lawrie A, Gelderbloem S, Veldsman A, Hatherill M, Hawkridge A, Hill AV, Hussey GD, Mahomed H, McShane H, and Hanekom WA. Modi�ed vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells. Eur J Immunol, 2010; 40(1): 279–90.

Chapter7.2.indd 1121 11/02/14 1:10 PM


27. de Cassan SC, Pathan AA, Sander CR, Minassian A, Rowland R, Hill AV, McShane H, and Fletcher HA. Investigating the induction of vaccine-induced Th17 and regulatory T cells in healthy, Mycobacterium bovis BCG-immunized adults vaccinated with a new tuberculosis vaccine, MVA85A. Clin Vaccine Immunol, 2010;17(7): 1066–73. Epub 2010 May 19.

28. von Reyn CF, Mtei L, Arbeit RD, Waddell R, Cole B, Mackenzie T, Matee M, Bakari M, Tvaroha S, Adams LV, Horsburgh CR, and Pallangyo K; DarDar Study Group. Prevention of tuberculosis in Bacille Calmette-Guérin-primed, HIV-infected adults boosted with an inactivated whole-cell mycobacterial vaccine. AIDS, 2010; 24(5): 675–85

29. Vuola JM, Ristola MA, Cole B, Järviluoma A, Tvaroha S, Rönkkö T, Rautio O, Arbeit RD, and von Reyn CF. Immunogenicity of an inactivated mycobacterial vaccine for the prevention of HIV-associated tuberculosis: a randomized, controlled trial. AIDS, 2003; 17(16): 2351–5.

30. Lahey T, Arbeit RD, Bakari M, Horsburgh CR, Matee M, Waddell R, Mtei L, Vuola JM, Pallangyo K, and von Reyn CF. Immunogenicity of a protective whole cell mycobacterial vaccine in HIV-infected adults: a phase III study in Tanzania. Vaccine, 2010; 28(48): 7652-8. Epub 2010 Sep 25.

31. Hoft DF, Blazevic A, Abate G, Hanekom WA, Kaplan G, Soler JH, Weichold F, Geiter L, Sadoff JC, and Horwitz MA. A new recombinant bacille Calmette-Guérin vaccine safely induces signi�cantly enhanced tuberculosis-speci�c immunity in human volunteers. J Infect Dis, 2008; 198(10): 1491–501.

32. Vilaplana C, Montané E, Pinto S, Barriocanal AM, Domenech G, Torres F, Cardona PJ, and Costa J. Double-blind, randomized, placebo-controlled Phase I Clinical Trial of the therapeutical antituberculous vaccine RUTI. Vaccine, 2010; 28(4): 1106-16. Epub 2009 Oct 22.

33. Cardona PJ. RUTI: a new chance to shorten the treatment of latent tuberculosis infection. Tuberculosis (Edinb), 2006; 86(3-4): 273–89. Epub 2006 Mar 20.

34. Scriba TJ, Tameris M, Smit E, van der Merwe L, Hughes EJ, Kadira B, Mauff K, Moyo S, Brittain N, Lawrie A, Mulenga H, de Kock M, Gelderbloem S, Veldsman A, Hatherill M, Geldenhuys H, Hill AVS, Hawkridge A, Hussey GD, Hanekom WA, McShane H, and Mahomed H. A phase IIa trial of the new TB vaccine, MVA85A,in HIV and/or M. tuberculosis infected adults. Am J Respir Crit Care Med, 2012; 185(7):769-78. Epub 2012 Jan 26.

35. Hoft DF, Blazevic A, Stanley J, Landry B, Sizemore D, Kpamegan E, Gearhart J, Scott A, Kik S, Pau MG, Goudsmit J, McClain JB, Sadoff J. A recombinant adenovirus expressing immunodominant TB antigens can signi�cantly enhance BCG-induced human immunity. Vaccine, 2012; 30(12):2098-108. Epub 2012 Jan 30.

Chapter7.2.indd 1122 11/02/14 1:10 PM


36. Leroux-Roels I, Forgus S, De Boever F, Clement F, Demoitié MA, Mettens P, Moris P, Ledent E, Leroux-Roels G, Ofori-Anyinam O; M72 Study Group. Improved CD4- T cell responses to Mycobacterium tuberculosis in PPD-negative adults by M72/AS01 as compared to the M72/AS02 and Mtb72F/AS02 tuberculosis candidate vaccine formulations: a randomized trial. Vaccine, 2013; 31(17):2196-206. Epub 2012 May 27.

37. Day CL, Tameris M, Mansoor N, van Rooyen M, de Kock M, Geldenhuys H, Erasmus M, Makhethe L, Hughes EJ, Gelderbloem S, Bollaerts A, Bourguignon P, Cohen J, Demoitié MA, Mettens P, Moris P, Sadoff JC, Hawkridge A, Hussey GD, Mahomed H, Ofori-Anyinam O, Hanekom WA. Induction and regulation of T cell immunity by the novel TB vaccine M72/AS01 in South African adults. Am J Respir Crit Care Med, 2013; Jan 10. Epub ahead of print.

38. Scriba TJ, Tameris M, Smit E, van der Merwe L, Hughes EJ, Kadira B, Mauff K, Moyo S, Brittain N, Lawrie A, Mulenga H, de Kock M, Makhethe L, Janse van Rensburg E, Gelderbloem S, Veldsman A, Hatherill M, Geldenhuys H, Hill AV, Hawkridge A, Hussey GD, Hanekom WA, McShane H, Mahomed H. A phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-infected adults. Am J Respir Crit Care Med, 2012; 185(7):769-78. Epub 2012 Jan 26.

39. Scriba TJ, Tameris M, Mansoor N, Smit E, van der Merwe L, Mauff K, Hughes EJ, Moyo S, Brittain N, Lawrie A, Mulenga H, de Kock M, Gelderbloem S, Veldsman A, Hatherill M, Geldenhuys H, Hill AV, Hussey GD, Mahomed H, Hanekom WA, McShane H. Dose-�nding study of the novel tuberculosis vaccine, MVA85A, in healthy BCG-vaccinated infants. J Infect Dis, 2011; 15;203(12):1832-43.

40. Ota MO, Odutola AA, Owiafe PK, Donkor S, Owolabi OA, Brittain NJ, Williams N, Rowland-Jones S, Hill AV, Adegbola RA, McShane H. Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants. Sci Transl Med, 2011; 3(88):88ra56.

41. Tameris, MD, Hatherill M, Bernard LS, Scriba TJ, Snowden MA, Lockhart S, Shea JE, McClain JB, Hussey GD, Hanekom WA, Mahomed H, McShane H. Safety and ef�cacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: A randomized, placebo-controlled phase 2b trial. Lancet, 2013.

42. Tameris M, McShane H, McClain JB, Landry B, Lockhart S, Luabeya AK, Geldenhuys H, Shea J, Hussey G, van der Merwe L, de Kock M, Scriba T, Walker R, Hanekom W, Hatherill M, Mahomed H. Lessons learnt from the �rst ef�cacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edinb), 2013; 93(2):143-9. Epub 2013 Feb 12.

Chapter7.2.indd 1123 11/02/14 1:10 PM

Chapter7.2.indd 1094 11/02/14 1:10 PMtbvaccines.usm.my/finlay/sites/default/files/Chapter...

Documents

Transcript of Chapter7.2.indd 1094 11/02/14 1:10 PMtbvaccines.usm.my/finlay/sites/default/files/Chapter...