Innovations for Tackling Tuberculosis in the Time of COVID-19 Proceedings of a Workshop (2022) / Chapter Skim
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4 Vaccines and Therapeutics
4 Vaccines and Therapeutics
Pages 73-122
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From page 73... ...
The session began with presentations on strategies to make better use of existing tools and new technologies. Alex Schmidt, head of vaccine development at the Bill & Melinda Gates Medical Research Institute, discussed the history and current state of policies regarding the use of the Bacillus Calmette–Guérin (BCG)
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EXISTING TOOLS AND NEW TECHNOLOGIES Bacillus Calmette–Guérin Revaccination Presented by Alex Schmidt, Bill & Melinda Gates Medical Research Institute Schmidt discussed the history and current state of policies regarding the use of the BCG vaccine and whether BCG revaccination can play a role in TB elimination.1 Over the past century, most countries have implemented national BCG vaccination policies for all individuals (see Figure 4-1)
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. Overall, Schmidt considered, data from children and young adults with negative skin test results who received BCG vaccinations shows that the BCG vaccine provides protection from TB disease.
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Thus, BCG might offer some protection in climates with less abundance of environmental mycobacteria. A 2018 trial looked at the efficacy of a candidate subunit vaccine H4:IC31 compared with BCG revaccination in preventing Mycobacterium tuberculosis (MTB)
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An ongoing randomized controlled trial (BCG ReVax) is generating data to potentially support new policies for BCG revaccination.3 The primary objective of this trial is to demonstrate the efficacy of revaccination in preventing sustained MTB infection, and an important secondary objective is to explore or develop correlates of risk and protection.
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From page 78... ...
Schmidt emphasized that if robust correlates of risk and correlates of protection can be established for TB vaccines, the effect on vaccine development could be transformational, leading to faster, less expensive, and easier-to-iterate vaccines.5 Pathway to Effective Tuberculosis Vaccines: Promising New Adjuvants and Late-Stage Clinical Development of Vaccine Candidates Presented by Steven Reed, University of Washington and HDT Bio Reed discussed the breadth and diversity of ongoing research in the TB vaccine pipeline within which numerous vaccine candidates are being studied, including those based on live or whole-cell organisms, vector platforms, and recombinant proteins. He explained that there is a range of strategies and potential uses of TB vaccines (see Figure 4-2)
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SOURCES: Presented by Steve Reed on September 15, 2021; adapted from Bill & Melinda Gates Foundation. areas to further advance and accelerate TB vaccine development.
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He began with RNA vaccines, emphasizing lessons learned from the COVID-19 pandemic. RNA vaccine development has struggled in the past but demonstrated success during the COVID-19 pandemic, building in part on prior research that identified the target protein antigen.
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In addition, RNA vaccines may use either nonreplicating mRNA or self-replicating RNA.10 Reed believes that replicating RNA produces more proteins and generates more virus-like particles, resulting in more potent T-cell responses than mRNA vaccines and requiring smaller doses. Reed noted that his team is focusing on replicating RNA vaccines for these reasons.
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From page 82... ...
Kalman suggested that COVID-19 may increase deaths from bacterial infections by causing impaired antibacterial immune responses -- a condition that Kalman classified as "immune amnesia."11 Kalman worried that COVID-19-induced lymphopenia may have similar consequences, further surmising that COVID-19 patients with lung damage may be more susceptible to TB and vice versa. Moreover, COVID-19 pandemic response measures have led to reductions in TB control in Africa.
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From page 83... ...
. Use of Imatinib to Treat Tuberculosis Kalman explained that in addition to being safe and effective as a chemotherapeutic agent, imatinib is also effective in "resetting" the immune response to TB through stimulating emergency hematopoiesis and has shown promise of potentiating the efficacy of existing antibiotics against MTB (Napier et al., 2011, 2015)
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Because imatinib is off-patent (i.e., cheaper generics may be available if there is sufficient market demand) and its safety is well established (thus reducing the need for further expensive clinical trials)
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Each of these factors has implications for strategies for disease control. Immune Response to Mycobacterium Tuberculosis Many immune mechanisms have been proposed to control TB, including innate immune responses, antibodies, innate cell interactions by Fc receptors, and lung-resident T cells.
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and systemic responses across multiple interventions in preclinical and clinical models, combined with statistical analysis of immune responses. The resulting correlates of protection would help to accelerate the vaccine development pipeline and facilitate a 17 Progression to active TB is host dependent and is affected by factors such as host age.
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From page 87... ...
Uncertainty regarding the effect of prior BCG interventions on vaccine efficacy is another challenge for vaccine development. This can be addressed through the evaluation of vaccine efficacy and concurrent immune responses while accounting for planned BCG exposure (preclinical)
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She noted that the program organizers hope to back-translate human results into experimental models so they can be more rapidly advanced.20 TRANSFORMING TREATMENT OPTIONS Developing a New Treatment-Shortening Regimen for Drug-Susceptible Tuberculosis Presented by Payam Nahid, University of California, San Francisco Nahid described lessons learned from designing and conducting a trial that was successful in developing a new shorter regimen to advance TB treatment to serve as a potential blueprint for future treatment-shortening work. The Tuberculosis Trials Consortium Study 31/AIDS Clinical Trials Group 20 Back-translating refers to incorporation of new knowledge from the disease in humans to inform the improvement of existing or development of new animal models.
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More information about the Tuberculo sis Trials Consortium Study 31/AIDS Clinical Trials Group A5349 is available from https:// clinicaltrials.gov/ct2/show/NCT02410772 (accessed December 15, 2021)
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From page 90... ...
Nahid added that the results of 14 pre-specified sensitivity analyses, as well as pre-specified analyses conducted in the intention to treat per protocol, were all consistent in meeting noninferiority for this new experimental 17-week rifapentine-moxifloxacin regimen; the rifapentine-only regimen did not meet the noninferiority criteria throughout those analyses. The primary safety outcome -- experiencing any grade 3–5 adverse event during study treatment -- was comparable across the three study arms, experienced by 19.3 percent of participants in the control arm, FIGURE 4-3 Primary efficacy results for Tuberculosis Trials Consortium Study 31/ AIDS Clinical Trials Group A5349.
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The rifapentine-moxifloxacin regimen in TBTC Study 31/A5349 is the most potent regimen study to date and is the only regimen that has met noninferiority criteria for efficacy. Although the rifapentine-only regimen in TBTC Study 31/A5349 did not meet noninferiority criteria, it is still the second-most potent regimen compared to other recent trials of treatment-shortening regimens, including: (1)
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. Nahid added that on the clinical side, there is emerging value in looking across lesion pharmacokinetics and then integrating data and information from phase 2A studies and beyond, beginning a new chapter in TB regimen development.
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They also embedded substudies of innovative biomarkers, pharmacokinetics, and other investigations co-funded by NIH and others (e.g., intensive pharmacokinetics analyses from this data pool, TBTC Study 31A and 31B to analyze sputum transcriptomics, quantitative GeneXpert indications of treatment outcome, and bacterial drug susceptibility) to learn more from the trial even if the regimen had not proven to be safe and effective.
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From page 94... ...
2. Include experimental models -- such as murine studies, novel biomarkers, and new tools -- as nonnegotiable components of TB treatment regimen development.
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Thomas emphasized the role of USAID, the Stop TB Partnership's Global Drug Facility, WHO, and the Global Fund in supporting the donation program with flexibility, amplifying medical education for appropriate use, and building the infrastructure for ECG monitoring and resistance testing. Private-sector constituency partnerships have also played a large role in expanding access for TB treatment and diagnostic capability.
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For example, in 2021, J&J launched the Satellite Center for Global Health Discovery at the London School of Hygiene and Tropical Medicine. The Project to Accelerate New Treatments for Tuberculosis (PAN-TB)
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Stop TB Partnership's Global Drug Facility created a unique 188-pill bottle that contains a complete course of therapy with simplified regulatory language in four languages. This design enabled therapy availability in 140 countries through a regulatory waiver and a regulatory approval mechanism that accelerated access to patients.
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. In 2017, the success rate for treatment of RR TB and MDR TB was approximately 60 percent in South Africa, surpassing the global rate of about 57 percent.
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In addition to in-country work, the consortium also engaged with similar working groups around the world to better understand how to effectively roll out a new therapeutic and garner the necessary support. After developing the Bedaquiline Clinical Access Program, it was first implemented at five clinical sites prior to wider scale-up to additional sites.
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Partners also provided resources and support to improve electronic recording and reporting systems and to train health care workers on data and treatment management. Factors Contributing to Success in Implementation Ndjeka outlined several factors that contributed to the success in implementing the Bedaquiline Clinical Access Program.
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Effect of Bedaquiline Implementation Ndjeka presented data on the DR TB treatment initiation, outcomes, and success rates in South Africa before and after the implementation of bedaquiline.30 Between March 2013 and March 2015, 1 percent of all DR TB patients on treatment received the bedaquiline regimen (200/24,688 patients)
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Ndjeka described these results as encouraging and catalytic for continued improvement.31 Bringing Innovation to the Development of New Transformative Tuberculosis Regimens Presented by David Hermann, Bill & Melinda Gates Foundation Hermann highlighted progress toward a shorter, simpler, safer pan-TB regimen -- that is, a regimen for treating multiple forms of TB. He highlighted the R&D activities for TB over the past decade that are spurring progress toward a shorter, simpler, safer pan-TB regimen, which included the first approvals for several new TB drugs -- bedaquiline, delamanid, and pretomanid -- in a number of years.
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From page 103... ...
Furthermore, quantitative translational modeling could be used. Continuing to establish connections between nonclinical tools, pharmacometrics modeling, and success in the clinic, as described by Nahid earlier from the experience with TBTC Study 31/A5349, would be beneficial.
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Innovation in Mycobacterium Tuberculosis Antimicrobial Discovery Innovation is currently taking place in the area of Mycobacterium tuberculosis antimicrobial discovery, Hermann noted. For instance, clustered, regularly interspaced short palindromic repeats -- known as CRISPR -- interference was used as a platform to aid in lead target generation (Bosch et al., 2021)
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Hermann remarked that these collaborations drive the portfolio forward, and that data sharing is fundamental to this effort. Therefore, the Bill & Melinda Gates Foundation has embedded a basic tenet of data sharing in their investments that applies across organizations within a collaboration and across collaborations.
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Economic Analysis of Novel Tuberculosis Treatment Regimens Presented by Anna Vassall, London School of Hygiene & Tropical Medicine Vassall explored the value of conducting context-specific economic analyses of novel TB treatment regimens to inform future program design and investment. She explained that in the TB field, the conventional approach adopted by researchers is to perform economic analyses after positive trial results -- such as those from TBTC Study 31/A5349, described by Nahid -- with the aims of disseminating the results and convincing policy makers that the regimen is not only clinically effective, but also cost-effective, to promote funding and uptake.
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From page 107... ...
. Inclusion of Tuberculosis Treatment in National Benefits Packages As an example of how new TB treatment regimens can fit within national benefits packages, Vassall described cost-effectiveness analyses conducted in Ethiopia and Pakistan to inform which interventions would be included in their essential health packages.
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In a limited fiscal space, there is a trade-off between including a greater number of TB interventions in benefits packages regardless of their cost-effectiveness -- and consequently achieving low coverage of all of them -- versus including a smaller number of only the most cost-effective interventions and achieving full coverage. Economic Assessment of Shortened Tuberculosis Treatment Regimens Most analyses examining noninferior DS TB and DR TB regimens have found shortened regimens to be either cost saving or highly cost-effective at prices of around $1 to $5 per day compared to standard of care, said Vassall.36 A caveat is that these analyses typically presume that DR TB treatment is fully financed, yet it is unclear whether even shorter regimens for DR TB would fit within the available fiscal space in many countries.
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From page 109... ...
The experience in South Africa also demonstrates that guideline adherence -- or the extent to which treatment is observed by health care workers -- will determine the amount of treatment cost savings. Pricing for a Future Universal Drug Regimen Vassall and colleagues have looked ahead to 2030 to examine the pricing and value of a shortened universal drug regimen for TB when it eventually comes to market.37 They considered the effect of changes in the size of the future fiscal space, the uptake of health technology assessments, and implementation of national strategic plans in the current planning and TB programs to estimate the potential revenues that would occur when those drugs were introduced.
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Strategies for Using Economic Analyses of New Tuberculosis Regimens Vassall highlighted several strategies for using economic analyses of new TB regimens to inform program design and garner investment in TB treatments and care. Cost-effectiveness analyses have long been used informally in this area, but formal cost-effective evidence is increasingly required.
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He also presented an overview of a standardized monitoring and evaluation framework developed by USAID to help track a country's progress in ending the TB epidemic. Improving Individual Lives Through Better Tuberculosis Care: Clinical Vignettes Tessera presented two clinical vignettes drawn from his early days of clinical practice to explore the profound personal consequences of improving TB care.
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For people with TB, the effect of the disease could be mitigated and their lives could be profoundly changed by good-quality prevention, early detection, shorter regimens, and stronger systems of care. The advancements and innovations in TB care to date are promising, said Tessera, adding "We still have a long way to go." Performance-Based Monitoring and Evaluation Framework Data issues represent major barriers to improving systems for TB treatment and care, said Tessera.
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A benefit is that using the framework does not require any substantial investment in collecting additional data; the available data are simply repackaged and used to monitor programs and inform decision making. Core Indicators The framework includes 10 core indicators (see Box 4-3)
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Contact investigation coverage 7. TB treatment success rate 8.
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Framing Tuberculosis as a Global Health Emergency Presented by Richard Chaisson, Johns Hopkins University School of Medicine Chaisson's presentation focused on the need to frame TB as a global health emergency. He noted that WHO declared TB a global public health emergency in 1993 (Nakajima, 1993)
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A twofold approach can be used to address regulatory issues hampering TB innovation, Chaisson stated. First, more investment is needed in regulatory and research ethics and administrative aspects of clinical research and clinical trials to ensure that requirements do not stifle innovative research.
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Advances in TB diagnosis, treatment, and prevention that will translate into progress in TB elimination could be pursued as an emergency. He stated that unless TB is treated as a global health emergency, advances in the development of tools to end TB will continue to be very slow, and unacceptably high rates of disease, suffering, and death will continue.
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From page 118... ...
Prior efforts include marketing XDR TB as "Ebola with wings" and connecting TB with HIV in the President's Emergency Plan for AIDS Relief. Monique Mansoura, executive director for Global Health and Biotechnology at the MITRE Corporation, commented that coronavirus vaccine development was de-prioritized for 17 years.
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Nahid remarked that some people question the value of data sharing in relation to the amount of effort it requires. He shared a recent experience in pooling the data from four fluoroquinolone-substitution trials.
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At the same time, the good should not be killed in search of the perfect, he emphasized, noting that a vaccine antigen that provides up to and beyond 50 percent protection can advance the goal of disease elimination. Cassell noted that Moderna announced that they will manufacture mRNA vaccines for HIV.
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Although TB is not a major problem in Korea, the country is committed to addressing it and has invested heavily in the company. In fact, Korea has two state-of-the-art facilities: the recombinant vaccine technology center and a center for BCG vaccine funded in part by the Green Cross.
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In addition, the IMPAc-TB study funded by the National Institute of Allergy and Infectious Diseases is examining immunological aspects of TB in a collaborative way that has not before been attempted. She emphasized that a vaccine that provides 50 percent protection can substantially curb the TB epidemic, and therefore technologies for these products should be advanced.
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