WHO/IVB/18.06
WHO Preferred Product Characteristics
for Therapeutic Vaccines
to Improve Tuberculosis Treatment Outcomes
DEPARTMENT OF IMMUNIZATION,
VACCINES AND BIOLOGICALS
Family, Womens’s and Children’s Health (FWC)
This document was produced by the Initiative for Vaccine Research (IVR)
of the Department of Immunization, Vaccines and Biologicals
Ordering code: WHO/IVB/19.05
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Published in Switzerland
Contents
Methodology, acknowledgments.................................................................................. 4
1. Introduction.............................................................................................................. 6
Tuberculosis burden....................................................................................................... 6
Drug treatment recommendations and outcomes....................................................... 6
Therapeutic vaccination................................................................................................. 7
Biologic feasibility........................................................................................................... 7
2. Public health goals, target population.................................................................... 8
Public health goals......................................................................................................... 8
Target population............................................................................................................ 8
3. Clinical development strategy................................................................................. 9
Timing of immunization.................................................................................................. 9
Standards of care, efficacy and effectiveness............................................................ 10
Safety considerations.................................................................................................. 11
4. The PPC for a Therapeutic Vaccine for TB.............................................................12
5. Conclusions and strategic goals............................................................................14
Methodology, acknowledgments
This work is the result of a consensus-generating wide expert, stakeholder and public consultation process. Throughout, the WHO Tuberculosis Vaccine Working Group (Padma
Chandrasekaran (National Institute of Research in Tuberculosis, India), Bernard Fritzell (Tuberculosis Vaccine Initiative,
The Netherlands), Mark Hatherill (University of Cape Town, Republic of South Africa), Paul-Henri Lambert (University of Geneva, Switzerland), Helen McShane (Oxford University, United
Kingdom), Nadia Tornieporth (Hannover University of Applied
Sciences & Arts, Germany)) provided critical input. We thank
Payam Nahid (University of California, USA), Kelly Dooley
(John Hopkins School of Medicine) and Norbert Ndjeka (Department of Health , South Africa) for input. Kathryn Rutkowski (IAVI) provided sample size estimates. We are grateful to
all who attended a WHO consultation meeting on Tuberculosis vaccine development in Geneva on the 3rd and 4th October 2017, to all who provided input on draft versions, and to
the members of the WHO Product Development for Vaccines
Advisory Committee.
WHO Secretariat
Nebiat Gebraselassie, Lewis Schrager (consultant), Johan Vekemans, Matteo Zignol.
Overall coordination and document writing
Johan Vekemans (WHO).
Image credits
Cover: U.S. Centers for Disease Control and PreventionMedical Illustrator, Public Health Image Library
Page 5 WHO
Page 8 WHO/Olivier Asselin
Page 10 Riccardo Venturi
Summary
Treating tuberculosis (TB) requires a multidrug course of tre­at­
ment lasting 6 months, or longer for drug-resistant TB, which
is difficult to complete and often not well tolerated. Treatment
failure and recurrence after end-of-treatment can have devastating consequences, including progressive debilitation,
death, the transmission of Mycobacterium tuberculosis —
the infectious agent responsible for causing TB — to others,
and may be associated with the development of drug-resistant TB. The burden on health systems is important, with stiff
economic consequences. Vaccines have potential to serve as
immunotherapeutic adjuncts to antibiotic treatment regimens
for TB. A therapeutic vaccine for TB patients, administered
towards completion of a prescribed course of drug therapy or
at certain time(s) during treatment, could improve outcomes
through immune-mediated control and even clearance of
bacteria, potentially prevent re-infection, and provide an opportunity to shorten and simplify drug treatment regimens.
The preferred product characteristics (PPC) for therapeutic TB
vaccines described in this document are intended to provide
guidance to scientists, funding agencies, public and private
sector organizations developing such vaccine candidates.
This document presents potential clinical end-points for evidence generation and discusses key considerations about
potential clinical development strategies.
6
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
1. Introduction
Tuberculosis burden
Developing interventions against tuberculosis (TB), including new TB vaccines, represents a critical global health priority (1). TB is the leading cause of death globally from a
single infectious agent, Mycobacterium tuberculosis (Mtb),
killing approximately 1.6 million persons in 2017, including
approximately 300,000 HIV-infected people (2). An estimated 10 million people developed TB in 2017. Approximately 1.7 billion people — 23% of the world’s population — harbour latent TB infection (LTBI) (2). Approximately 5% develop
active TB in the first 18 months after initial infection while an
additional 5% would be expected to develop TB over the remaining years of their lives (3). The transmission of TB caused
by Mtb strains resistant to TB drugs represents a growing
threat to public health. An estimated 558.000 people developed drug-resistant TB in 2017, 82% being multidrug-resistant. 230.000 deaths were due to drug-resistant TB. Globally,
3.5% of new TB cases and 18% of previously treated cases
had drug-resistant TB (2).
Drug treatment recommendations and outcomes
Active TB is most commonly a disease of the lungs, but can
be extra-pulmonary and disseminated (3). If untreated, TB
often results in months to years of progressively diminishing
productivity, while the cough serves to spread Mtb through
the air, putting persons sharing the same home, school, social
or work environment at risk of Mtb infection. Without treatment, the TB case-fatality rate in HIV-uninfected individuals
is approximately 70% within 10 years of disease onset (4).
The first use of streptomycin against TB in 1944, and subsequent development of multiple other compounds, provided
hope for patients (5). Despite the availability of antimycobacterial drugs, treating TB remains a long and difficult endeavor. Even in cured patients, there can be pulmonary sequelae
and respiratory disability (6). Due to the slow rate of replication of Mtb and the difficulty that some of the drugs have in
reaching and maintaining therapeutic concentrations within tissue involved with active TB infection, multiple drugs,
over several months, are recommended for treatment of TB,
based on a careful analysis of the balance between efficacy
and the burden associated to treatment length, complexity
and toxicity. The recommended first line regimen for treating
pulmonary TB comprises an intensive phase of 2 months of
isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) followed by a continuation phase of 4 months
of INH and RIF. The emergence and transmission of drug-resistant Mtb strains, including multidrug-resistant TB (MDR-TB)
and extensively drug-resistant TB (XDR-TB), has further complicated attempts to treat TB disease, requiring a combination of five or more drugs be administered for nine months or
longer (7), sometimes requiring injections. The toxicity of the
drugs included in the regimens can be devastating, with potential hearing loss, nephrotoxicity, skin rashes and neurological disorders (7). Additionally, the costs of treating patients
with MDR-TB and XDR-TB are very high (2, 8).
Globally, an estimated 85% of cases of drug-sensitive TB,
and only 55% of cases of drug-resistant TB and 30% in
XDR-TB, are successfully cured, at the end of the initiated
treatment (2). Adverse outcomes considered here include
treatment failure and recurrences. Outcome definitions are
presented in the Panel. Recurrence can occur either due reactivation of the incompletely eliminated initial infecting organism, or from reinfection (9, 10). Reports of recurrence rates
vary, often between 2 and 15%, with higher rates seen in
countries demonstrating high TB incidence and poor TB control (10—13). Individual patient risks for recurrence include
irregular compliance with the initial drug regimen, initial infection with a drug-resistant strain, smoking, HIV infection,
cavitation (1, 8). Most recurrence occur between 6 months
and two years of completing treatment (11—14).
New strategies in treating drug-resistant TB, utilizing drug
combinations that include more recent TB drugs such as bedaquiline, delamanid, and linezolid offer the hope for better
treatment of drug-resistant TB cases, but strains resistant to
each of these new drugs have already been identified, sounding a note of caution against reliance on drug therapy to cure
drug-resistant TB well into the future (15—18).
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
Given the challenges inherent in drug treatment of TB, including the development of multidrug-resistant Mtb strains,
developing vaccine strategies with the potential to improve
7
outcomes of drug treatment regimens for persons with TB
caused by either drug-sensitive or drug-resistant strains represents an important global public health imperative.
Therapeutic vaccination
Therapeutic vaccines are administered to persons who have
already manifested signs and symptoms of infection by the
targeted organism. This contrasts with prophylactic vaccines
aimed to prevent primary infections. The scope of this report
relates to therapeutic vaccination against TB intended to stimulate an individual’s immune response in combination with drug
treatment, in an effort to improve treatment outcome (19). A related TB vaccine indication relates to the prevention of progression to TB disease in individuals with LTBI, sometimes referred
to as a post-exposure vaccine strategy. This is an important
vaccine target indication when considering the need to protect
exposed contacts, some of whom can be identified as recent
converters by diagnostic tests for LTBI, but this is not in scope
of the present report. WHO Preferred Product Characteristics for
vaccines aimed at preventing primary pulmonary TB in subjects
with and without LTBI have been described elsewhere (20).
The potential for therapeutic vaccine strategies to improve
TB treatment outcomes has been recognized since the time
of Robert Koch and his attempt to use tuberculin to treat disease, prior to the advent of antibiotic treatment (21, 22). Several vaccine candidates are presently considered for use as
therapeutic TB vaccines, including attenuated and inactivated-whole organisms, fragmented mycobacteria and adjuvanted protein subunit molecules (23).
Biologic feasibility
Although the immunological mechanisms of in vivo killing of
Mtb are poorly understood, several observations argue in favor of the feasibility of development of a therapeutic vaccination for TB:
•
Effective immunity resulting from natural exposure: Following natural Mtb exposure, an estimated 90% of individuals do not progress to active disease, showing evidence of
host capacity to limit TB progression (24–26). Boosting protective host responses through immunization during treatment for active disease could enhance killing of mycobacteria during ongoing drug treatment, thereby reducing the
proportion of subjects at risk of relapse due to residual, viable mycobacteria following treatment cessation.
•
Animal models support the therapeutic vaccination strategy: Studies of therapeutic vaccination in animal TB
models indicate potential for improved drug treatment
outcomes (27, 28). Observed changes that may have contributed include a reduced number of myeloid-derived suppressor cells in the lung, an increased number of natural killer T-cells, CD4 T cell activation and TNF-α release. Favorable
results have also been found in animal models of post-exposure vaccination (29). Whether these observations are predictive of protection in humans is however unknown.
•
Vaccination of Mtb infected individuals: Primary results
from a phase 2B clinical trial assessing the effect of 2 doses of the M72/AS01E candidate TB vaccine on rates of
progression to TB disease in individuals with LTBI demonstrated 54% efficacy at 2.3 years following vaccination
for the primary endpoint of bacteriologically confirmed
active pulmonary TB (95% CI, 2.9 to 78.2; P=0.04) (30).
These results show that this vaccine generates an immune
response capable of preventing LTBI or new infections
from developing into overt, active pulmonary TB disease.
Whether such an immune response can be stimulated in
persons already receiving drug treatment for active TB,
and, if so, whether it contributes to the effectiveness of the
drug regimen, remains to be explored. Additionally, a meta-analysis of data from more than 40 studies assessing
the ability of Vaccae™, derived from Mycobacterium vaccae and licensed in China as an immunotherapeutic adjunct to drug treatment of TB in adults, suggested the potential therapeutic utility of this vaccine (31, 32) although
the strength of evidence, based on data currently available
in the public domain, is limited.
8
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
2. Public health goals, target population
Public health goals
Public health goals for therapeutic vaccines include reducing
the rate of recurrence following completion of a full course
of drug therapy; increasing the proportion of patients cured;
shortening the necessary treatment duration and number of
drugs to achieve a cure, all both for TB caused by drug-sensitive and drug-resistant Mtb strains.
of persons required to receive extended periods of treatment, particularly with second-line and third-line injectable drugs, thereby potentially reducing the risk of serious, potential debilitating adverse effects associated with
these drugs. Prevention of long-term pulmonary disability
is also an important patient-centered goal.
1. Reducing the rate of recurrence following completion
of a full course of drug therapy
This goal, often referred to as prevention of recurrent disease (PoR), which may result from relapse or re-infection,
represents an important public health outcome. In addition to providing benefit for the patient, reducing rates of
recurrent disease would also reduce the chance of Mtb
transmission to family members, friends and co-workers,
medical personnel and the community at large that otherwise could occur if these individuals once again developed active pulmonary TB.
3. Shortening the duration of drug treatment and/or
reducing the number of drugs necessary to affect cure
The many months required for treating drug-sensitive
TB and furthermore MDR-TB and XDR-TB frequently result in poor patient compliance with necessary drug regimens (34). Lengthy and complex drug regimens needed
to treat drug-resistant Mtb frequently result in drug-related toxicities that also diminish compliance and increase
the possibility of both treatment failure and the development of resistant Mtb strains. Shortening and/or simplifying treatment regimens is considered an essential public
health goal, but, in absence of reliable animal or early clinical models for therapeutic vaccines and in order to manage risk in study participants, proof-of-principle for therapeutic vaccine efficacy should first be established in study
participants receiving standard of care drug regimens, before attempts are made to shorten or simplify new drug
regimens in combination with vaccination.
2. Increasing the proportion of patients surviving to cure
This would represent a major advance for public health,
particularly in cases of drug-resistant TB given the poor
rates of cure when treating MDR-TB and, particularly, XDRTB (33). Increasing cure rates would reduce the number
Target population
Ultimately, the target population for therapeutic TB vaccines
is all persons, regardless of age, during or towards the end of
treatment for active TB disease, due to drug-sensitive or drugresistant strains. The medical need for a therapeutic vaccine
against TB is global. TB patients otherwise healthy as well as
patients with co-morbidities or other risk factors should be allowed to benefit from an intervention proven effective.
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
9
3. Clinical development strategy
In order to reduce background heterogeneity, maximize safety and efficacy data interpretability and manage risk exposure in a vulnerable, sick population, proof-of-concept testing
may be best done in adults with TB and without comorbidities known to either reduce the likelihood of curing their TB
disease or diminish the potential effectiveness of a vaccine.
When proof-of-concept is established, when appropriate, effectiveness in special population groups should also be evaluated (e.g., HIV infection, diabetes, pregnant women, the elderly, young children), as no-one should be excluded from
potentially benefitting from this intervention, if proven safe
and effective.
Although subjects with drug-resistant TB represent a very important potential target for therapeutic vaccines, the large
variation between individuals in disease course and types of
resistance is likely to influence treatment outcome, increasing background variability and potentially affecting estimation of the vaccine effect. Additionally, enrolling a cohort of
persons with drug-resistant TB into large-scale clinical efficacy trials is likely to prove difficult, requiring multiple sites
and high costs. Such an investment may be more responsible after proof-of-concept is established in individuals with
drug-sensitive TB.
Timing of immunization
A therapeutic vaccine could be administered to TB patients
around the time of completion of drug treatment. Assessing
the efficacy of a vaccine administered at this time necessarily would focus on reducing the rate of TB recurrence. This may
correspond to a time at which the load of viable bacteria potentially able to cause relapse may be minimal, and immune
functions restored following a time of suppression associated with overt disease and bacterial replication, altogether allowing for a most effective immune effector response.
Administering a therapeutic vaccine at the end of standard
treatment would not provide an opportunity to study the vaccine effect on cure rates or options to simplify and/or shorten drug treatment regimens but could constitute a first step
for establishing proof-of-concept of beneficial vaccine activity before investigating the effects of vaccine administration at
an earlier time-point in the treatment course. If multiple vaccine doses are required, the question of compliance with immunization schedule will require careful consideration, and
it may be desirable to plan for all doses to be delivered before end of treatment.
Figure 1. Overview of key design features for a double-blind, randomized, controlled proof-of-concept trial
of a therapeutic TB vaccine candidate
Sputum screen, Mtb characterization if positive
INTENSIVE PHASE
Sputum screen, Mtb characterization if positive
CONTINUATION PHASE
Possible vaccination
timepoint for cure
and PoR* endpoints
FOLLOW UP
Possible vaccination
timepoint for PoR*
endpoint
Proportion
of cure
* PoR – Prevention of recurrence
END OF FOLLOW-UP
Diagnosis and
treatment initiation
END OF TREATMENT
THERAPEUTIC VACCINES FOR USE WITH STANDARD RECOMMENDED TB DRUG TREATMENT
Proportion of subjects
free of recurrence after
12 months or more
Measurable endpoints
10
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
Another potential time for therapeutic vaccine administration is around the conclusion of the initial, intensive phase
of drug treatment. This relatively early point of immunization
may provide an opportunity for the immune response engendered by the vaccine to act in concert with drug treatment to
kill remaining live Mtb organisms and offer the potential to
increase cure rates in addition to reduce rates of recurrence.
Eventually, in a secondary step, vaccination at this time point
also would provide the opportunity to investigate the potential for a therapeutic vaccine to reduce the duration and number of drugs required for treatment.
A third possible time for administering a therapeutic vaccine
would be at or around the time of TB diagnosis or initiation of
treatment. However, vaccine responses administered at this
time of maximal mycobacterial load have the potential to be
affected by the profound impact of active TB disease on innate immunity (35). Also, symptoms associated to TB may
obscure the ability to characterize vaccine safety.
Early vaccine administration during treatment may have the
potential to influence immune-pathology leading to long term
pulmonary disability, which should be evaluated.
Whatever the timing of therapeutic vaccination, it will be important to prospectively obtain and bank mycobacterial specimens prior to the onset of initial drug treatment to support
strain characterization in the context of outcome monitoring.
More specifically differentiating relapse from re-infection during the post-treatment phase, and de novo emergence of drugresistant strains, will provide valuable information.
Standards of care, efficacy and effectiveness
Before confirmation of any therapeutic vaccine efficacy in
a proof-of-concept trial, standard TB drug treatment recommendations for drug-sensitive TB (36) or drug-resistant
TB (7) should be followed. It would be ethically inappropriate
to provide participants with a shortened or simplified treatment regimen before any demonstration of vaccine-induced
increased cure rates and/or reduction of relapses, in absence
of reliable pre-clinical or early clinical models establishing
strong confidence in protective immunotherapeutic effects
of a specific vaccine candidate. Participants should have access to local delivery of care in a routine setting according to
national and WHO recommendations, with local ethics committee oversight.
Access to care should include basic radiological and microbiological services to ensure that Mtb microbiological samples can be stored and locally or remotely typed. For vaccines
administered during drug treatment, monitoring of sputum
clearance and relapse should be planned at various moments including end-of-treatment. For vaccines administered towards the end-of-treatment, active or passive monitoring of recurrence should be planned, over at least one year
post treatment.
The degree of treatment adherence and quality of treatment
administration provided in the context of a trial will assuredly
impact cure and recurrence rates and the sample size needed
to demonstrate efficacy of a therapeutic vaccine (sample size
assumptions and estimates are presented in Table 1). Based
on the assumption of an interaction between drug treatment
and an immunotherapeutic vaccine effect (illustrated by the
fact that a therapeutic vaccine would not be expected to provide protection alone, replacing the need for treatment), capacity strengthening efforts leading to increased access and
delivery of care may affect the generalizability of the effect
of therapeutic vaccines as measured in a trial to real life settings. The administration of vaccines at the end of treatment
in individuals enrolled only after end of treatment delivered
in a routine setting, for initial proof-of-concept generation,
may be an appropriate way of mitigating the generalizability
question associated to a possible statistical interaction between the drug and vaccine effect.
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
11
Table 1.
Total sample sizes required for demonstration of vaccine efficacy against recurrence after treatment, according to assumptions about the baseline cumulative incidence (cum. Inc.), the true vaccine efficacy (VE), the desired lower bound of the 95%
confidence interval (LB), rates of lost to follow-up (LTFU) and ineligibility of cases for compliance with primary case definition
(excl.), for a trial with 80% power, a two-sided alpha = 0.05 (LB>25%, one-sided alpha = 0.025). The same sample sizes would
be required to estimate vaccine efficacy treatment failure instead of recurrence, using the same assumptions.
True VE = 50%
True VE = 75%
LTFU / Excl.
Cum. Inc.
(Control)
LB > 0%
LB > 25%
LB > 0%
LB > 25%
0%/0%
4%
2278
6744
844
1376
6%
1492
4428
552
906
8%
1100
3270
408
672
10%
864
2576
320
530
12%
708
2114
262
436
4%
2734
8093
1013
1651
6%
1790
5314
662
1087
8%
1320
3924
490
806
10%
1037
3091
384
636
12%
850
2537
314
523
10%/10%
Safety considerations
The potential for the injection of antigenic components of Mtb
precipitating a delayed-type (Type IV) hypersensitivity reaction, resulting in necrosis at the site of injection, in persons
with Mtb infection or active TB (37) represents a possibility
that must be considered when testing therapeutic TB vaccines
on persons with active TB disease. The possibility of pulmonary and systemic inflammatory reactions (38), and the breakdown of granuloma structure potentially resulting in Mtb dissemination should be considered and monitored. Respiratory
function tests may be useful to monitor lung safety. Mostly minor adverse events have been observed in most therapeutic
vaccine studies conducted to date (19, 30, 39, 40), but enrollment in a phase 2 trial of the M72/AS01E vaccine candidate was interrupted prematurely after the observation of local reactions (pain, redness, swelling) larger than expected in
tuberculosis patients (41). A careful safety risk management
plan should be instituted to identify and mitigate potential
risks. Safety data will need to be interpreted in context of coadministered drug treatment to sick individuals. The potential
severity of TB, as compared to vaccines aimed for healthy people at minimal risk of health outcomes, may justify considering acceptable safety thresholds differently.
12
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
Panel
CASE DEFINITIONS, AS PER AVAILABLE WHO RECOMMENDATIONS (42)
Bacteriologically
confirmed case of TB
Preferred endpoint for TB vaccine efficacy assessment. A bacteriologically
confirmed case is one from whom a biological specimen is confirmed positive
by culture or WHO-approved rapid diagnostic method.
MDR-TB
Defined as Mtb isolates resistant to the two, first-line treatments
for TB: rifampicin (RIF) and isoniazid (INH).
XDR-TB
Defined as Mtb isolates resistant to INH and RIF, as well as any fluoroquinolone and at
least one of the three injectable second-line drugs (amikacin, kanamycin or capreomycin).
Cure
For drug-sensitive cases — a pulmonary TB patient with bacteriologically confirmed TB at
the beginning of treatment who is smear-negative or culture-negative at the last month of
treatment and on at least one previous occasion. For drug-resistant cases - treatment completed as recommended by the national policy without evidence of failure AND three or more
consecutive cultures taken at least 30 days apart are negative after the intensive phase.
Treatment failure
Refers to a case where cure is not achieved.
Recurrence
In a bacteriologically confirmed case of TB, recurrence refers to reversion to sputum
positivity after successful end of treatment cure. Recurrence may include cases of
reactivation of the incompletely eradicated Mtb strain responsible for the initial episode of TB (here referred to as relapse), and cases of re-infection with a new Mtb
strain. These can be diffentiated through molecular Mtb strain characterization.
4. The PPC for a Therapeutic Vaccine for TB
The primary audience for this WHO PPC document includes all
entities involved in the development of therapeutic vaccines for
improvement of TB treatment outcomes. This PPC is presented as a complement to the existing WHO PPC on the development of TB vaccines intended to prevent TB disease (20), providing guidance to scientists, funding agencies, and public and
private sector organizations developing therapeutic TB vaccine
candidates. It is anticipated that PPCs provide a framework
for developers to design their development plan and define in
more details specific target product profiles.
WHO PPCs are developed following a consensus-generating
wide consultation process involving experts and stakeholders in the field. Key policy considerations are highlighted, but
preferred attributes expressed here do not pre-empt future
policy decisions. The PPC criteria proposed are aspirational
in nature. Some aspects of a potentially effective therapeutic
vaccine may diverge from those proposed in this PPC, which
would not necessarily preclude successful licensure and policy decision for clinical application.
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
13
Table 2. WHO Preferred Product Characteristics for Therapeutic TB Vaccines
Parameter
Preferred Characteristic
Comments
Indication
Protection against TB
recurrence, following
initial cure.
Reducing the cumulative incidence of recurrence after initial, drug-mediated cure,
and increasing the proportion of cure at the end of drug treatment represents the
highest priorities to demonstrate in clinical studies. The possibility of reducing
the number of drugs and treatment duration are essential long-term goals. Ethical
standards would require that initial proof-of-concept be established while TB patients receive a standard recommended treatment regimen. Changes to the treatment regimen could be investigated after an initial demonstration of efficacy.
Increase the proportion
of cure at end of drug
treatment.
Target
population
All persons being treated
for active TB, both drugsensitive and drugresistant Mtb strains.
Initial proof-of-concept might best be established in subjects with no specific, increased risk of adverse outcome with drug-sensitive tuberculosis. After initial
demonstration of efficacy and safety, investigations in cases of MDR-TB and XDRTB, as well as studies in special populations (children, pregnant women, subjects
with HIV/AIDS and other high-risk individuals), should be started promptly.
Outcome
measure
and efficacy
50% or greater efficacy in
reducing the rate of recurrent TB after a standard
course of drug treatment,
and/or 50% or greater reduction in treatment failure at the end of drug
treatment.
These preference levels are selected by analogy with other severe diseases and
expert opinion. Further research is required on the correspondence between vaccine efficacy and Mtb transmission and the TB epidemic as a whole including the
spread of drug-resistant TB. Further research is also required to define strategy
and targets for reduction in the number of drugs needed for treatment, and the
duration of drug therapy, as long-term objectives. See panel for case definitions.
Impact on long term pulmonary function should be evaluated.
Duration
of Protection against
recurrence
Initial proof-of-concept for
prevention of recurrence
could be demonstrated
on the basis of one year
of follow-up.
Recurrence can result from both reactivation and reinfection. Most reactivations
occur in the first year post treatment.
Safety
A safety and reactogenicity profile similar to other
current WHO-recommended routine vaccines for use
in adolescents and adults
would be preferred.
The benefit/risk balance will need to be considered. Given the severity and public
health concern associated to the target disease, mitigations may be considered
for mild reactions or rare events.
Schedule
A minimal number of doses
required.
A requirement for more than three doses to achieve immunization would not be
desirable due to logistical and cost concerns.
Coadministration
N/A
Issues generally relevant to co-administration of a preventive vaccine with other
vaccines are not applicable here given the intended administration of this therapeutic vaccine to individuals with active TB disease.
The potential for adverse interactions with drugs administered for treatment of TB
or comorbidities should be considered.
Immunogenicity
Identification of a correlate/
surrogate of protection, using a validated assay.
Little is presently known about immune determinants of protection, and no confirmed correlate/surrogate of clinical efficacy of a TB vaccine currently exists. The
identification of marker of risk if recurrence and immune correlates/surrogates of
protection should be included as immunogenicity objectives in TB vaccine efficacy studies. In the absence of established correlates of protection, markers of immune ‘take’ should be characterized. The conservation of biological specimen for
future use upon advances in technology and knowledge is encouraged.
14
WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES
Parameter
Preferred Characteristic
Comments
Programmatic
suitability and
prequalification
General guidance from
WHO expectations about
clinical evaluation of
vaccines should be followed (43). The WHO
defined criteria for programmatic suitability of
vaccines should be met,
following guidance on vaccine presentation, packaging, thermostability, formulation and disposal (44).
Beyond the minimum requirements for WHO prequalification, innovation related
to programmatic suitability, such as ease of administration and thermostability,
would lead to major public health benefits and is strongly encouraged.
The vaccine should be prequalified to support purchasing by United Nations
agencies (45).
Value
proposition
Dosage, regimen, and cost
of goods should be amenable to affordable supply.
Favourable cost-effectiveness should be established
and price should not be a
barrier to access, including
in low-and middle-income
countries.
Modelling public health value and impact of TB vaccines with various characteristics on the TB epidemic in general, and on drug-resistant TB specifically, as well as
on TB-associated anti-mycobacterial drug use would be valuable. The vaccine impact on health systems (such as reduction of TB-related medical attendance and
hospitalization) and other aspects of implementation science should be evaluated
in both modelling and real vaccine use studies.
5. Conclusions and strategic goals
Achieving proof-of-concept for a therapeutic vaccine based
on the ability of the vaccine to reduce recurrence rates over
one year or more following a drug-mediated cure represents
the preferred short-term strategic goal of therapeutic TB vaccine development. Assessing the efficacy of a vaccine delivered at some point during treatment, possibly at the end of
the initial intensive treatment phase, against end-treatment
failure and recurrence, may also be considered as a shortterm goal. Initial studies should be conducted in the context
of standard recommended drug treatment. Mtb samples obtained prior to the initiation of treatment should be available
to assess whether a recurrence that may occur is due to reactivation of the same, initially infecting Mtb strain, or whether it results from a de novo, Mtb infection that occurred post
end-of-treatment. While initial proof-of-concept may best be
generated in patients with drug-sensitive tuberculosis, reducing the emergence of drug-resistant TB represents an important strategic goal. Investigations in special population
groups should be initiated rapidly after initial demonstration
of efficacy. The potential for shortening and simplifying drug
regimens represent essential long-term goals. Proof-of-concept should imperatively trigger vaccine evaluation for other
indications including prevention of TB in the general population or in recently exposed individuals. Initial demonstration
of vaccine efficacy in other target populations should trigger
evaluation of a potential therapeutic adjunct, as these various indications are of importance to public health.
References
1. G20 Leaders’ Declaration: Shaping an Interconnected World. Hamburg, Germany, 8 July 2017
(http://europa.eu/rapid/press-release_STATEMENT-17-1960_en.htm, accessed 6 June 2019).
2. Global tuberculosis report 2018. Geneva: World Health Organization; 2018 (https://www.who.int/tb/publications/global_
report/, accessed 6 June 2019).
3. Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. N Engl J Med. 2013;368(8):745—55. doi:10.1056/NEJMra1200894.
4. Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJ. Natural history of tuberculosis: duration and
fatality of untreated pulmonary tuberculosis in HIV negative patients: a systematic review. PLoS One. 2011;6(4):e17601.
doi:10.1371/journal.pone.0017601.
5. Murray JF, Schraufnagel DE, Hopewell PC. Treatment of Tuberculosis. A Historical Perspective. Ann Am Thorac Soc 2015;
12(12):1749—59. doi:10.1513/AnnalsATS.201509-632PS.
6. Ravimohan S, Kornfeld H, Weissman D, Bisson GP. Tuberculosis and lung damage: from epidemiology to pathophysiology.
Eur Respir Rev. 2018;27(147). pii:170077. doi:10.1183/16000617.0077-2017.
7. WHO treatment guidelines for drug-resistant tuberculosis, 2016 update. October 2016 revision. Geneva: World Health Organization; 2016 (https://apps.who.int/iris/bitstream/handle/10665/250125/9789241549639-eng.pdf, accessed
6 June 2019).
8. Diel R, Nienhaus A, Lampenius N, Rüsch-Gerdes S, Richter E. Cost of multi drug resistance tuberculosis in Germany. Respir
Med. 2014;108(11):1677—87. doi:10.1016/j.rmed.2014.09.021.
9. Blumberg HM, Burman WJ, Chaisson RE, Daley CL, Etkind SC, Friedman LN et al. American Thoracic Society/Centers for
Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care
Med. 200 Feb 15;167(4):603—62. doi:10.1164/rccm.167.4.603.
10. Verver S, Warren RM, Beyers N, Richardson M, van der Spuy GD, Borgdorff MW et al. Rate of reinfection tuberculosis
after successful treatment is higher than rate of new tuberculosis. Am J Respir Crit Care Med 2005;171(12):1430—5.
doi:10.1164/rccm.200409-1200OC.
11. Nunn AJ, Phillips PPJ, Mitchison DA. Timing of relapse in short-course chemotherapy trials for tuberculosis. Int J Tuberc
Lung Dis 2010;14(2):241—2.
12. Imperial MZ, Nahid P, Phillips PPJ, Davies GR, Fielding K, Hanna D et al. A patient-level pooled analysis of treatmentshortening regimens for drug-susceptible pulmonary tuberculosis. Nat Med. 2018;24(11):1708—1715. doi:10.1038/
s41591-018-0224-2.
13. Lee H, Kim J. A Study on the Relapse Rate of Tuberculosis and Related Factors in Korea Using Nationwide Tuberculosis
Notification Data. Osong Public Health Res Perspect. 2014;5(Suppl):S8—S17. doi:10.1016/j.phrp.2014.11.001.
14. Thomas A, Gopi PG, Santha T, Chandrasekaran V, Subramani R, Selvakumar N et al. Predictors of relapse among pulmonary tuberculosis patients treated in a DOTS programme in South India. Int J Tuberc Lung Dis 2005;9(5):556—61.
15. Diacon AH, Pym A, Grobusch MP, de los Rios JM, Gotuzzo E, Vasilyeva I et al. TMC207-C208 Study Group. MultidrugResistant Tuberculosis and Culture Conversion with Bedaquiline. N Engl J Med. 2014;371(8):723—32. doi:10.1056/
NEJMoa1313865.
16. Pym AS, Diacon AH, Tang SJ, Conradie F, Danilovits M, Chuchottaworn C et al. TMC207-C209 Study Group. Bedaquiline in the treatment of multidrug- and extensively drug-resistant tuberculosis. Eur Respir J. 2016 Feb;47(2):564—74.
doi:10.1183/13993003.00724-2015.
17. Moodley R, Godec TR. Short-course treatment for multidrug-resistant tuberculosis: the STREAM trials. Eur Respir Rev.
2016;25(139):29—35. doi:10.1183/16000617.0080-2015.
18. Nguyen TVA, Anthony RM, Bañuls A-L, Nguyen TVA, Vu DH, Alffenaar J-WC. Bedaquiline Resistance: Its Emergence, Mechanism, and Prevention. Clin Infect Dis. 2018 May 2;66(10):1625—1630. doi:10.1093/cid/cix992.
19. Cardona P-J. The Progress of Therapeutic Vaccination with Regard to Tuberculosis. Front Microbiol. 2016;7:1536.
doi:10.3389/fmicb.2016.01536.
20. Schrager LK, Chandrasekaran P, Fritzell BH, Hatherill M, Lambert PH, McShane H et al. WHO preferred product characteristics for new vaccines against tuberculosis. Lancet Infect Dis. 2018;18(8):828—829. doi:10.1016/S1473-3099(18)30421-3.
21. Perciaccante A, Coralli A, Appenzeller O. Amedeo Modigliani and his “great secret”: a brief history of medical and social
aspects of tuberculosis in the nineteenth and early twentieth century. Infez Med 2018;26(3):280—2.
22. Daniel TM. The history of tuberculosis. Respir Med 2006;100(11):1862—70. doi:10.1016/j.rmed.2006.08.006
23. Schrager LK, Harris RC, Vekemans J. Research and development of new tuberculosis vaccines: a review [version 2; peer
review: 3 approved, 1 approved with reservations] F1000Research 2019, 7:1732 (https://doi.org/10.12688/f1000research.16521.2, accessed 6 June 2019).
24. Daniel TM. Hermann Brehmer and the origins of tuberculosis sanatoria. Int J Tuberc Lung Dis 2011;15(2):161—2, i.
25. Grose MJ. Landscape and children’s health: old natures and new challenges for the preventorium. Health Place 2011;
17(1):94—102. doi:10.1016/j.healthplace.2010.08.018.
26. Wallstedt H, Maeurer M. The history of tuberculosis management in Sweden. Int J Infect Dis 2015;32:179—82.
doi:10.1016/j.ijid.2015.01.018.
27. Coler RN, Bertholet S, Pine SO, Orr MT, Reese V, Windish HP et al. Therapeutic immunization against Mycobacterium tuberculosis is an effective adjunct to antibiotic treatment. J Infect Dis. 2013;207(8):1242—52. doi:10.1093/infdis/jis425.
28. Chahar M, Rawat KD, Reddy PVJ, Gupta UD, Natrajan M, Chauhan DS et al. Potential of adjunctive Mycobacterium w
(MIP) immunotherapy in reducing the duration of standard chemotherapy against tuberculosis. Indian J Tuberc
2018;65(4):335—44. doi:10.1016/j.ijtb.2018.08.004.
29. Aagaard C, Hoang T, Dietrich J, Cardona PJ, Izzo A, Dolganov G et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med. 2011;17(2):189—94. doi:10.1038/nm.2285.
30. Van Der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Van Brakel E et al. Phase 2b Controlled Trial of M72/
AS01 E Vaccine to Prevent Tuberculosis. N Engl J Med. 2018;379(17):1621—1634. doi:10.1056/NEJMoa1803484.
31. Yang X-Y, Chen Q-F, Li Y-P, Wu S-M. Mycobacterium vaccae as adjuvant therapy to anti-tuberculosis chemotherapy in never-treated tuberculosis patients: a meta-analysis. PLoS ONE 2011;6(9):e23826. doi:10.1371/journal.pone.0023826.
32. Huang C-Y, Hsieh W-Y. Efficacy of Mycobacterium vaccae immunotherapy for patients with tuberculosis: A systematic review and meta-analysis. Hum Vaccin Immunother 2017;13(9):1960—71. doi:10.1080/21645515.2017.1335374.
33. Global tuberculosis report 2017. Geneva: World Health Organization; 2017 (https://www.who.int/tb/publications/global_
report/gtbr2017_main_text.pdf, accessed 6 June 2019).
34. Munro SA, Lewin SA, Smith HJ, Engel ME, Fretheim A, Volmink J. Patient adherence to tuberculosis treatment: a systematic review of qualitative research. PLoS Med 2007;4(7):e238. doi:10.1371/journal.pmed.0040238.
35. Scriba TJ, Coussens AK, Fletcher HA. Human Immunology of Tuberculosis. Microbiol Spectr. 2017;5(1). doi:10.1128/microbiolspec.TBTB2-0016-2016.
36. Guidelines for treatment of drug-susceptible tuberculosis and patient care, 2017 update. Geneva: World Health Organization; 2017 (https://www.who.int/tb/publications/2017/dstb_guidance_2017/en/, accessed 6 June 2019).
37. Rook GA, al Attiyah R. Cytokines and the Koch phenomenon. Tubercle 1991;72(1):13—20.
38. Orme IM, Robinson RT, Cooper AM. The balance between protective and pathogenic immune responses in the TB-infected
lung. Nat Immunol. 2015 Jan;16(1):57—63. doi:10.1038/ni.3048.
39. Luabeya AK, Kagina BM, Tameris MD, Geldenhuys H, Hoff ST, Shi Z et al. First-in-human trial of the post-exposure tuberculosis vaccine H56:IC31 in Mycobacterium tuberculosis infected and non-infected healthy adults. Vaccine.
2015;33(33):4130—40. doi:10.1016/j.vaccine.2015.06.051.
40. Nell AS, D’lom E, Bouic P, Sabaté M, Bosser R, Picas J, Amat M et al. Safety, Tolerability, and Immunogenicity of the Novel
Antituberculous Vaccine RUTI: Randomized, Placebo-Controlled Phase II Clinical Trial in Patients with Latent Tuberculosis
Infection. PLoS One. 2014;9(2):e89612. doi:10.1371/journal.pone.0089612.
41. Gillard P, Yang PC, Danilovits M, Su WJ, Cheng SL, Pehme L et al. Safety and immunogenicity of the M72/AS01E candidate
tuberculosis vaccine in adults with tuberculosis: A phase II randomised study. Tuberculosis (Edinb). 2016;100:118—127.
doi:10.1016/j.tube.2016.07.005.
42. Definitions and reporting framework for tuberculosis — 2013 revision, updated December 2014. Geneva: World Health
Organization; 2014 (https://www.who.int/tb/publications/definitions/en/, accessed 6 June 2019).
43. Guidelines on clinical evaluation of vaccines: regulatory expectations. 2004. Geneva: World Health Organization; 2004
(WHO Technical Report, Series No. 924; http://www.who.int/biologicals/publications/trs/areas/vaccines/clinical_evaluation/035-101.pdf, accessed 6 June 2019).
44. WHO Vaccine Presentation and Packaging Advisory Group (VPPAG) [website]. Geneva: World Health Organization; 2017
(http://www.who.int/immunization/policy/committees/vppag/en/index2.html, accessed 6 June 2019).
45. A system for the prequalification of vaccines for UN supply [website]. Geneva: World Health Organization; 2017
(https://www.who.int/immunization_standards/vaccine_quality/pq_system/en/, accessed 6 June 2019).
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