Therapeutic Vaccines to Improve Tuberculosis Treatment Outcomes

WHO/IVB/18.06

WHO Preferred Product Characteristics for Therapeutic Vaccines to Improve Tuberculosis Treatment Outcomes

DEPARTMENT OF IMMUNIZATION, VACCINES AND BIOLOGICALS

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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 ex- WHO Secretariat pert, stakeholder and public consultation process. Through- Nebiat Gebraselassie, Lewis Schrager (consultant), Johan Ve- out, the WHO Tuberculosis Vaccine Working Group (Padma kemans, Matteo Zignol. Chandrasekaran (National Institute of Research in Tubercu- losis, India), Bernard Fritzell (Tuberculosis Vaccine Initiative, Overall coordination and document writing The Netherlands), Mark Hatherill (University of Cape Town, Re- Johan Vekemans (WHO). public of South Africa), Paul-Henri Lambert (University of Ge- neva, Switzerland), Helen McShane (Oxford University, United Image credits Kingdom), Nadia Tornieporth (Hannover University of Applied Cover: U.S. Centers for Disease Control and Prevention- Sciences & Arts, Germany)) provided critical input. We thank Medical Illustrator, Public Health Image Library Payam Nahid (University of California, USA), Kelly Dooley Page 5 WHO (John Hopkins School of Medicine) and Norbert Ndjeka (De- Page 8 WHO/Olivier Asselin partment of Health , South Africa) for input. Kathryn Rutkows- Page 10 Riccardo Venturi ki (IAVI) provided sample size estimates. We are grateful to all who attended a WHO consultation meeting on Tuberculo- sis vaccine development in Geneva on the 3rd and 4th Octo- ber 2017, to all who provided input on draft versions, and to the members of the WHO Product Development for Vaccines Advisory Committee. Summary

Treating tuberculosis (TB) requires a multidrug course of treat towards completion of a prescribed course of drug therapy or ment lasting 6 months, or longer for drug-resistant TB, which at certain time(s) during treatment, could improve outcomes is difficult to complete and often not well tolerated. Treatment through immune-mediated control and even clearance of failure and recurrence after end-of-treatment can have dev- bacteria, potentially prevent re-infection, and provide an op- astating consequences, including progressive debilitation, portunity to shorten and simplify drug treatment regimens. death, the transmission of Mycobacterium tuberculosis — The preferred product characteristics (PPC) for therapeutic TB the infectious agent responsible for causing TB — to others, vaccines described in this document are intended to provide and may be associated with the development of drug-resis- guidance to scientists, funding agencies, public and private tant TB. The burden on health systems is important, with stiff sector organizations developing such vaccine candidates. economic consequences. Vaccines have potential to serve as This document presents potential clinical end-points for ev- immunotherapeutic adjuncts to antibiotic treatment regimens idence generation and discusses key considerations about for TB. A therapeutic vaccine for TB patients, administered potential clinical development strategies. 6 WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES

1. Introduction

Tuberculosis burden

Developing interventions against tuberculosis (TB), includ- active TB in the first 18 months after initial infection while an ing new TB vaccines, represents a critical global health pri- additional 5% would be expected to develop TB over the re- ority (1). TB is the leading cause of death globally from a maining years of their lives (3). The transmission of TB caused single infectious agent, Mycobacterium tuberculosis (Mtb), by Mtb strains resistant to TB drugs represents a growing killing approximately 1.6 million persons in 2017, including threat to public health. An estimated 558.000 people devel- approximately 300,000 HIV-infected people (2). An estimat- oped drug-resistant TB in 2017, 82% being multidrug-resis- ed 10 million people developed TB in 2017. Approximate- tant. 230.000 deaths were due to drug-resistant TB. Globally, ly 1.7 billion people — 23% of the world’s population — har- 3.5% of new TB cases and 18% of previously treated cases bour latent TB infection (LTBI) (2). Approximately 5% develop had drug-resistant TB (2).

Drug treatment recommendations and outcomes

Active TB is most commonly a disease of the lungs, but can longer (7), sometimes requiring injections. The toxicity of the be extra-pulmonary and disseminated (3). If untreated, TB drugs included in the regimens can be devastating, with po- often results in months to years of progressively diminishing tential hearing loss, nephrotoxicity, skin rashes and neurolog- productivity, while the cough serves to spread Mtb through ical disorders (7). Additionally, the costs of treating patients the air, putting persons sharing the same home, school, social with MDR-TB and XDR-TB are very high (2, 8). or work environment at risk of Mtb infection. Without treatment, the TB case-fatality rate in HIV-uninfected individuals Globally, an estimated 85% of cases of drug-sensitive TB, is approximately 70% within 10 years of disease onset (4). and only 55% of cases of drug-resistant TB and 30% in XDR-TB, are successfully cured, at the end of the initiated The first use of streptomycin against TB in 1944, and subse- treatment (2). Adverse outcomes considered here include quent development of multiple other compounds, provided treatment failure and recurrences. Outcome definitions are hope for patients (5). Despite the availability of antimycobac- presented in the Panel. Recurrence can occur either due reac- terial drugs, treating TB remains a long and difficult endeav- tivation of the incompletely eliminated initial infecting organ- or. Even in cured patients, there can be pulmonary sequelae ism, or from reinfection (9, 10). Reports of recurrence rates and respiratory disability (6). Due to the slow rate of replica- vary, often between 2 and 15%, with higher rates seen in tion of Mtb and the difficulty that some of the drugs have in countries demonstrating high TB incidence and poor TB con- reaching and maintaining therapeutic concentrations with- trol (10—13). Individual patient risks for recurrence include in tissue involved with active TB infection, multiple drugs, irregular compliance with the initial drug regimen, initial in- over several months, are recommended for treatment of TB, fection with a drug-resistant strain, smoking, HIV infection, based on a careful analysis of the balance between efficacy cavitation (1, 8). Most recurrence occur between 6 months and the burden associated to treatment length, complexity and two years of completing treatment (11—14). and toxicity. The recommended first line regimen for treating pulmonary TB comprises an intensive phase of 2 months of New strategies in treating drug-resistant TB, utilizing drug isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and eth- combinations that include more recent TB drugs such as be- ambutol (EMB) followed by a continuation phase of 4 months daquiline, delamanid, and linezolid offer the hope for better of INH and RIF. The emergence and transmission of drug-re- treatment of drug-resistant TB cases, but strains resistant to sistant Mtb strains, including multidrug-resistant TB (MDR-TB) each of these new drugs have already been identified, sound- and extensively drug-resistant TB (XDR-TB), has further com- ing a note of caution against reliance on drug therapy to cure plicated attempts to treat TB disease, requiring a combina- drug-resistant TB well into the future (15—18). tion of five or more drugs be administered for nine months or WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES 7

Given the challenges inherent in drug treatment of TB, in- outcomes of drug treatment regimens for persons with TB cluding the development of multidrug-resistant Mtb strains, caused by either drug-sensitive or drug-resistant strains rep- developing vaccine strategies with the potential to improve resents an important global public health imperative.

Therapeutic vaccination

Therapeutic vaccines are administered to persons who have of the present report. WHO Preferred Product Characteristics for already manifested signs and symptoms of infection by the vaccines aimed at preventing primary pulmonary TB in subjects targeted organism. This contrasts with prophylactic vaccines with and without LTBI have been described elsewhere (20). aimed to prevent primary infections. The scope of this report relates to therapeutic vaccination against TB intended to stim- The potential for therapeutic vaccine strategies to improve ulate an individual’s immune response in combination with drug TB treatment outcomes has been recognized since the time treatment, in an effort to improve treatment outcome (19). A re- of Robert Koch and his attempt to use tuberculin to treat dis- lated TB vaccine indication relates to the prevention of progres- ease, prior to the advent of antibiotic treatment (21, 22). Sev- sion to TB disease in individuals with LTBI, sometimes referred eral vaccine candidates are presently considered for use as to as a post-exposure vaccine strategy. This is an important therapeutic TB vaccines, including attenuated and inactivat- vaccine target indication when considering the need to protect ed-whole organisms, fragmented mycobacteria and adjuvant- exposed contacts, some of whom can be identified as recent ed protein subunit molecules (23). converters by diagnostic tests for LTBI, but this is not in scope

Biologic feasibility

Although the immunological mechanisms of in vivo killing of • Vaccination of Mtb infected individuals: Primary results Mtb are poorly understood, several observations argue in fa- from a phase 2B clinical trial assessing the effect of 2 dos- vor of the feasibility of development of a therapeutic vacci- es of the M72/AS01E candidate TB vaccine on rates of nation for TB: progression to TB disease in individuals with LTBI demonstrated 54% efficacy at 2.3 years following vaccination • Effective immunity resulting from natural exposure: Fol- for the primary endpoint of bacteriologically confirmed lowing natural Mtb exposure, an estimated 90% of individ- active pulmonary TB (95% CI, 2.9 to 78.2; P=0.04) (30). uals do not progress to active disease, showing evidence of These results show that this vaccine generates an immune host capacity to limit TB progression (24–26). Boosting pro- response capable of preventing LTBI or new infections tective host responses through immunization during treat- from developing into overt, active pulmonary TB disease. ment for active disease could enhance killing of mycobac- Whether such an immune response can be stimulated in teria during ongoing drug treatment, thereby reducing the persons already receiving drug treatment for active TB, proportion of subjects at risk of relapse due to residual, vi- and, if so, whether it contributes to the effectiveness of the able mycobacteria following treatment cessation. drug regimen, remains to be explored. Additionally, a meta-analysis of data from more than 40 studies assessing • Animal models support the therapeutic vaccination strat- the ability of Vaccae™, derived from Mycobacterium vac- egy: Studies of therapeutic vaccination in animal TB cae and licensed in China as an immunotherapeutic ad- models indicate potential for improved drug treatment junct to drug treatment of TB in adults, suggested the po- outcomes (27, 28). Observed changes that may have con- tential therapeutic utility of this vaccine (31, 32) although tributed include a reduced number of myeloid-derived sup- the strength of evidence, based on data currently available pressor cells in the lung, an increased number of natural kill- in the public domain, is limited. er 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 pre- dictive of protection in humans is however unknown. 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 of persons required to receive extended periods of treat- the rate of recurrence following completion of a full course ment, particularly with second-line and third-line inject- of drug therapy; increasing the proportion of patients cured; able drugs, thereby potentially reducing the risk of seri- shortening the necessary treatment duration and number of ous, potential debilitating adverse effects associated with drugs to achieve a cure, all both for TB caused by drug-sen - these drugs. Prevention of long-term pulmonary disability sitive and drug-resistant Mtb strains. is also an important patient-centered goal.

1. Reducing the rate of recurrence following completion 3. Shortening the duration of drug treatment and/or of a full course of drug therapy reducing the number of drugs necessary to affect cure This goal, often referred to as prevention of recurrent dis- The many months required for treating drug-sensitive ease (PoR), which may result from relapse or re-infection, TB and furthermore MDR-TB and XDR-TB frequently re- represents an important public health outcome. In addi- sult in poor patient compliance with necessary drug reg- tion to providing benefit for the patient, reducing rates of imens (34). Lengthy and complex drug regimens needed recurrent disease would also reduce the chance of Mtb to treat drug-resistant Mtb frequently result in drug-relat- transmission to family members, friends and co-workers, ed toxicities that also diminish compliance and increase medical personnel and the community at large that oth- the possibility of both treatment failure and the develop- erwise could occur if these individuals once again devel- ment of resistant Mtb strains. Shortening and/or simplify- oped active pulmonary TB. ing treatment regimens is considered an essential public health goal, but, in absence of reliable animal or early clin- 2. Increasing the proportion of patients surviving to cure ical models for therapeutic vaccines and in order to man- This would represent a major advance for public health, age risk in study participants, proof-of-principle for thera- particularly in cases of drug-resistant TB given the poor peutic vaccine efficacy should first be established in study rates of cure when treating MDR-TB and, particularly, XDR- participants receiving standard of care drug regimens, be- TB (33). Increasing cure rates would reduce the number fore attempts are made to shorten or simplify new drug regimens in combination with vaccination.

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 drug- resistant 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 al- lowed 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 safe- Although subjects with drug-resistant TB represent a very im- ty and efficacy data interpretability and manage risk expo- portant potential target for therapeutic vaccines, the large sure in a vulnerable, sick population, proof-of-concept testing variation between individuals in disease course and types of may be best done in adults with TB and without comorbidi- resistance is likely to influence treatment outcome, increas- ties known to either reduce the likelihood of curing their TB ing background variability and potentially affecting estima- disease or diminish the potential effectiveness of a vaccine. tion of the vaccine effect. Additionally, enrolling a cohort of When proof-of-concept is established, when appropriate, ef- persons with drug-resistant TB into large-scale clinical effi- fectiveness in special population groups should also be eval- cacy trials is likely to prove difficult, requiring multiple sites uated (e.g., HIV infection, diabetes, pregnant women, the el- and high costs. Such an investment may be more responsi- derly, young children), as no-one should be excluded from ble after proof-of-concept is established in individuals with potentially benefitting from this intervention, if proven safe drug-sensitive TB. and effective.

Timing of immunization

A therapeutic vaccine could be administered to TB patients treatment would not provide an opportunity to study the vac- around the time of completion of drug treatment. Assessing cine effect on cure rates or options to simplify and/or short- the efficacy of a vaccine administered at this time necessari- en drug treatment regimens but could constitute a first step ly would focus on reducing the rate of TB recurrence. This may for establishing proof-of-concept of beneficial vaccine activi- correspond to a time at which the load of viable bacteria po- ty before investigating the effects of vaccine administration at tentially able to cause relapse may be minimal, and immune an earlier time-point in the treatment course. If multiple vac- functions restored following a time of suppression associ- cine doses are required, the question of compliance with im- ated with overt disease and bacterial replication, altogeth- munization schedule will require careful consideration, and er allowing for a most effective immune effector response. it may be desirable to plan for all doses to be delivered be- Administering a therapeutic vaccine at the end of standard fore 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

THERAPEUTIC VACCINES FOR USE WITH STANDARD RECOMMENDED TB DRUG TREATMENT

Diagnosis and treatment initiation

Sputum screen, Mtb characterization if positive END OF TREATMENT Sputum screen, Mtb characterization if positive END OF FOLLOW-UP

INTENSIVE PHASE CONTINUATION PHASE FOLLOW UP

Possible vaccination Possible vaccination timepoint for cure timepoint for PoR* and PoR* endpoints endpoint Proportion of subjects Proportion free of recurrence after of cure 12 months or more

* PoR – Prevention of recurrence Measurable endpoints 10 WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES

Another potential time for therapeutic vaccine administra- affected by the profound impact of active TB disease on in- tion is around the conclusion of the initial, intensive phase nate immunity (35). Also, symptoms associated to TB may of drug treatment. This relatively early point of immunization obscure the ability to characterize vaccine safety. may provide an opportunity for the immune response engen- dered by the vaccine to act in concert with drug treatment to Early vaccine administration during treatment may have the kill remaining live Mtb organisms and offer the potential to potential to influence immune-pathology leading to long term increase cure rates in addition to reduce rates of recurrence. pulmonary disability, which should be evaluated. Eventually, in a secondary step, vaccination at this time point also would provide the opportunity to investigate the poten- Whatever the timing of therapeutic vaccination, it will be im- tial for a therapeutic vaccine to reduce the duration and num- portant to prospectively obtain and bank mycobacterial spec- ber of drugs required for treatment. imens prior to the onset of initial drug treatment to support strain characterization in the context of outcome monitoring. A third possible time for administering a therapeutic vaccine More specifically differentiating relapse from re-infection dur- would be at or around the time of TB diagnosis or initiation of ing the post-treatment phase, and de novo emergence of drug- treatment. However, vaccine responses administered at this resistant strains, will provide valuable information. time of maximal mycobacterial load have the potential to be

Standards of care, efficacy and effectiveness

Before confirmation of any therapeutic vaccine efficacy in on the assumption of an interaction between drug treatment a proof-of-concept trial, standard TB drug treatment rec- and an immunotherapeutic vaccine effect (illustrated by the ommendations for drug-sensitive TB (36) or drug-resistant fact that a therapeutic vaccine would not be expected to pro- TB (7) should be followed. It would be ethically inappropriate vide protection alone, replacing the need for treatment), ca- to provide participants with a shortened or simplified treat- pacity strengthening efforts leading to increased access and ment regimen before any demonstration of vaccine-induced delivery of care may affect the generalizability of the effect increased cure rates and/or reduction of relapses, in absence of therapeutic vaccines as measured in a trial to real life set- of reliable pre-clinical or early clinical models establishing tings. The administration of vaccines at the end of treatment strong confidence in protective immunotherapeutic effects in individuals enrolled only after end of treatment delivered of a specific vaccine candidate. Participants should have ac- in a routine setting, for initial proof-of-concept generation, cess to local delivery of care in a routine setting according to may be an appropriate way of mitigating the generalizability national and WHO recommendations, with local ethics com- question associated to a possible statistical interaction be- mittee oversight. tween the drug and vaccine effect.

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 mo- ments 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 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.

Cum. Inc. True VE = 50% True VE = 75% LTFU / Excl. (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

10%/10% 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

Safety considerations

The potential for the injection of antigenic components of Mtb vaccine studies conducted to date (19, 30, 39, 40), but en- precipitating a delayed-type (Type IV) hypersensitivity reac- rollment in a phase 2 trial of the M72/AS01E vaccine candi- tion, resulting in necrosis at the site of injection, in persons date was interrupted prematurely after the observation of lo- with Mtb infection or active TB (37) represents a possibility cal reactions (pain, redness, swelling) larger than expected in that must be considered when testing therapeutic TB vaccines tuberculosis patients (41). A careful safety risk management on persons with active TB disease. The possibility of pulmo- plan should be instituted to identify and mitigate potential nary and systemic inflammatory reactions (38), and the break- risks. Safety data will need to be interpreted in context of co- down of granuloma structure potentially resulting in Mtb dis- administered drug treatment to sick individuals. The potential semination should be considered and monitored. Respiratory severity of TB, as compared to vaccines aimed for healthy peo- function tests may be useful to monitor lung safety. Mostly mi- ple at minimal risk of health outcomes, may justify consider- nor adverse events have been observed in most therapeutic ing acceptable safety thresholds differently. 12 WHO PREFERRED PRODUCT CHARACTERISTICS FOR NEW TUBERCULOSIS VACCINES

Panel

CASE DEFINITIONS, AS PER AVAILABLE WHO RECOMMENDATIONS (42)

Preferred endpoint for TB vaccine efficacy assessment. A bacteriologically Bacteriologically confirmed case is one from whom a biological specimen is confirmed positive confirmed case of TB by culture or WHO-approved rapid diagnostic method.

Defined as Mtb isolates resistant to the two, first-line treatments MDR-TB for TB: rifampicin (RIF) and isoniazid (INH).

Defined as Mtb isolates resistant to INH and RIF, as well as any fluoroquinolone and at XDR-TB least one of the three injectable second-line drugs (amikacin, kanamycin or capreomycin).

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 Cure treatment and on at least one previous occasion. For drug-resistant cases - treatment com- pleted 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.

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 Recurrence reactivation of the incompletely eradicated Mtb strain responsible for the initial epi- sode 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 WHO PPCs are developed following a consensus-generating entities involved in the development of therapeutic vaccines for wide consultation process involving experts and stakehold- improvement of TB treatment outcomes. This PPC is present- ers in the field. Key policy considerations are highlighted, but ed as a complement to the existing WHO PPC on the develop- preferred attributes expressed here do not pre-empt future ment of TB vaccines intended to prevent TB disease (20), pro- policy decisions. The PPC criteria proposed are aspirational viding guidance to scientists, funding agencies, and public and in nature. Some aspects of a potentially effective therapeutic private sector organizations developing therapeutic TB vaccine vaccine may diverge from those proposed in this PPC, which candidates. It is anticipated that PPCs provide a framework would not necessarily preclude successful licensure and pol- for developers to design their development plan and define in icy decision for clinical application. more details specific target product profiles. 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 Reducing the cumulative incidence of recurrence after initial, drug-mediated cure, recurrence, following and increasing the proportion of cure at the end of drug treatment represents the initial cure. highest priorities to demonstrate in clinical studies. The possibility of reducing the number of drugs and treatment duration are essential long-term goals. Ethical Increase the proportion standards would require that initial proof-of-concept be established while TB pa- of cure at end of drug tients receive a standard recommended treatment regimen. Changes to the treat- treatment. ment regimen could be investigated after an initial demonstration of efficacy.

Target All persons being treated Initial proof-of-concept might best be established in subjects with no specific, in- population for active TB, both drug- creased risk of adverse outcome with drug-sensitive tuberculosis. After initial sensitive and drug- demonstration of efficacy and safety, investigations in cases of MDR-TB and XDR- resistant Mtb strains. TB, as well as studies in special populations (children, pregnant women, subjects with HIV/AIDS and other high-risk individuals), should be started promptly.

Outcome 50% or greater efficacy in These preference levels are selected by analogy with other severe diseases and measure reducing the rate of recur- expert opinion. Further research is required on the correspondence between vac- and efficacy rent TB after a standard cine efficacy and Mtb transmission and the TB epidemic as a whole including the course of drug treatment, spread of drug-resistant TB. Further research is also required to define strategy and/or 50% or greater re- and targets for reduction in the number of drugs needed for treatment, and the duction in treatment fail- duration of drug therapy, as long-term objectives. See panel for case definitions. ure at the end of drug Impact on long term pulmonary function should be evaluated. treatment.

Duration Initial proof-of-concept for Recurrence can result from both reactivation and reinfection. Most reactivations of Protec- prevention of recurrence occur in the first year post treatment. tion against could be demonstrated recurrence on the basis of one year of follow-up.

Safety A safety and reactogenic- The benefit/risk balance will need to be considered. Given the severity and public ity profile similar to other health concern associated to the target disease, mitigations may be considered current WHO-recommend- for mild reactions or rare events. ed routine vaccines for use in adolescents and adults would be preferred.

Schedule A minimal number of doses A requirement for more than three doses to achieve immunization would not be required. desirable due to logistical and cost concerns.

Co- N/A Issues generally relevant to co-administration of a preventive vaccine with other administration 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/ Little is presently known about immune determinants of protection, and no con- surrogate of protection, us- firmed correlate/surrogate of clinical efficacy of a TB vaccine currently exists. The ing a validated assay. 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 General guidance from Beyond the minimum requirements for WHO prequalification, innovation related suitability and WHO expectations about to programmatic suitability, such as ease of administration and thermostability, prequalification clinical evaluation of would lead to major public health benefits and is strongly encouraged. vaccines should be followed (43). The WHO defined criteria for programmatic suitability of vaccines should be met, following guidance on vaccine presentation, packaging, thermostability, formu- lation and disposal (44). The vaccine should be pre- qualified to support pur- chasing by United Nations agencies (45).

Value Dosage, regimen, and cost Modelling public health value and impact of TB vaccines with various characteris- proposition of goods should be amena- tics on the TB epidemic in general, and on drug-resistant TB specifically, as well as ble to affordable supply. on TB-associated anti-mycobacterial drug use would be valuable. The vaccine im- Favourable cost-effective- pact on health systems (such as reduction of TB-related medical attendance and ness should be established hospitalization) and other aspects of implementation science should be evaluated and price should not be a in both modelling and real vaccine use studies. barrier to access, including in low-and middle-income countries.

5. Conclusions and strategic goals

Achieving proof-of-concept for a therapeutic vaccine based end-of-treatment. While initial proof-of-concept may best be on the ability of the vaccine to reduce recurrence rates over generated in patients with drug-sensitive tuberculosis, re- one year or more following a drug-mediated cure represents ducing the emergence of drug-resistant TB represents an im- the preferred short-term strategic goal of therapeutic TB vac- portant strategic goal. Investigations in special population cine development. Assessing the efficacy of a vaccine deliv- groups should be initiated rapidly after initial demonstration ered at some point during treatment, possibly at the end of of efficacy. The potential for shortening and simplifying drug the initial intensive treatment phase, against end-treatment regimens represent essential long-term goals. Proof-of-con- failure and recurrence, may also be considered as a short- cept should imperatively trigger vaccine evaluation for other term goal. Initial studies should be conducted in the context indications including prevention of TB in the general popula- of standard recommended drug treatment. Mtb samples ob- tion or in recently exposed individuals. Initial demonstration tained prior to the initiation of treatment should be available of vaccine efficacy in other target populations should trigger to assess whether a recurrence that may occur is due to re- evaluation of a potential therapeutic adjunct, as these vari- activation of the same, initially infecting Mtb strain, or wheth- ous indications are of importance to public health. er it results from a de novo, Mtb infection that occurred post References

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