Research Roundup: priority review vouchers, diagnosing drug resistance, and oral and universal flu vaccines

In this guest post, Lindsay McKenna, TB/HIV project officer at GHTC member Treatment Action Group (TAG), writes about a newly released report examining advancements in tuberculosis (TB) research and development (R&D). TAG’s 2015 Pipeline Report looks at advances in diagnostics, treatment, and prevention that offer hope for those engaged in the global fight against TB. The report, which also covers HIV and hepatitis C, highlights scientific potential while recognizing that the realization of innovations in the pipeline is conditional on our ability to mobilize political will, resources, and collaboration. Indeed, the direction of TB R&D is positive relative only to decades of stagnation, which has resulted in lengthy therapy, a lack of options for treating children, cumbersome diagnostics, and a vaccine of waning efficacy. Improved tools are therefore not only possible, but urgently needed. This article highlights key findings from the report and its recommendations for researchers, funders, regulators, and advocates to ensure continued and accelerated progress. The TB treatment pipeline: moving beyond “making the most of what we’ve got” TB treatment researchers are making progress, though it is slow. There are few new TB drug candidates and limited funding to develop them. A number of advances to shorten preventive therapy for TB and evaluate the possibility of preventing multidrug-resistant TB (MDR-TB) offer potential for markedly improving TB prevention, though they raise questions about implementation strategies. For active TB disease, studies to determine the best drug combinations, dosing, and strategies to shorten treatment are ongoing and may answer long-standing questions. TRUNCATE-TB, a bold new design to shorten treatment for drug-susceptible TB, will attempt to bring TB treatment for most cases down from six to just two months. Trials to test new drugs in better combinations are at varying stages of development and, although results are still years away, offer the prospect of improved treatment for MDR-TB. CDC research studying drug-resistance. Photo: CDC/ Hsi Liu, Ph.D., MBA While R&D is advancing for existing—and a few late-stage—TB drugs, the small number of new early-stage compounds, the lack of diversity in the TB drug pipeline (i.e., only six compounds from three drug classes), and the slow pace at which they are progressing is worrisome. Furthermore, access to new TB drugs and those used off-label for TB treatment remains a challenge for researchers, programs, and patients, slowing scientific advancements and their impact on those in need of them. To ensure the development and availability of improved treatments for TB, the 2015 Pipeline Report calls for increased funding for TB R&D, wise investments of this funding, early planning for access to new treatments, and improved regulatory systems to facilitate adoption of innovations once developed. Momentum in the pediatric TB treatment pipeline Pediatric formulations of TB drugs are urgently needed. Photo: PATH/Gabe Bienczycki Inadequacies in TB treatment are magnified for children, and major data gaps on TB treatment in children persist. However, research currently planned and underway aims to optimize treatment with existing drugs and inform the use of new treatments for children with TB. A movement toward including children at an earlier point in TB drug research may also help shorten the time between adult and pediatric approvals and improve access in the future. Studies underway will evaluate preventive therapy in children exposed to MDR-TB and whether it is possible to shorten treatment for less severe forms of TB and TB meningitis in children. Appropriately dosed pediatric formulations of first-line TB drugs are approaching market introduction, but those for second-line and new drugs are farther behind. Much work remains to study regimens and new drugs in children and to develop missing pediatric formulations. The 2015 Pipeline Report recommends earlier and expedited investigation of new drugs in children, in which both developers and stringent regulatory authorities play an important role. The report also urges the immediate advancement of guidelines for and development of pediatric formulations of second-line drugs. Increased investments in pediatric TB R&D will facilitate all of these important steps. The TB diagnostics pipeline We urgently need new diagnostic tests for TB. Fortunately, we now have a clearer-than-ever picture of what types of tests are most essential: a more effective but low-tech test to replace smear microscopy in detecting TB, a rapid drug-susceptibility test to guide treatment, a biomarker test, and a triage test. Yet the pipeline for TB diagnostic tools remains stagnant, with several products in line but little high-quality evidence being generated towards an effective, accessible, point-of-care test. Eiken TB-LAMP (loop-mediated isothermal amplification) and Alere Determine LAM (urine lipoarabinomannan lateral flow test) underwent World Health Organization (WHO) expert review and are awaiting decision. WHO review is expected soon for Hain Lifescience MTBDRsl, a test to detect resistance to fluoroquinolones and injectable agents. Results were published for several molecular diagnostic and drug-susceptibility test candidates, including Xpert MTB/RIF Ultra, a platform that claims improved sensitivity and ability to detect isoniazid resistance. However, appropriate field evaluations and more evidence is required in order for any tests in the pipeline to be considered for WHO expert review and to inform national TB program policies. To improve detection of TB, the 2015 Pipeline Report recommends that we invest in TB R&D and diagnostics research, including for new biomarker-based triage/point-of-care tests, and integrate TB diagnostics research into ongoing treatment studies. The report also argues that access to validated new tests and to drug susceptibility testing should be universal, and linkages to treatment ensured. Countries and donors must prepare for the launch of next-generation tests while eliminating the current use of inaccurate and misleading tests. As with drugs, regulatory capacity to oversee TB diagnostics research needs improvement. The TB vaccines pipeline: a new path to the same destination? A researcher conducting a vaccine clinical trial. Photo: AERAS Attention and resources for TB vaccine R&D are moving away from late-stage clinical trials and back to basic discovery and preclinical science. Motivating this welcome shift is emerging evidence that encourages a reexamination of the assumptions that have guided the last ten years of TB vaccine research. Candidates in the current TB vaccines pipeline only contain a few of the vast number (4,500) of targetable antigens and focus on stimulating just one of the many parts of the immune system. The shift “to the left” of the development pipeline will allow exploration of more vaccine concepts and help to de-risk vaccine development. The report highlights progress in basic science and preclinical development, including the pursuit of biomarkers of protective immunity to TB infection or disease, the application of radiology to study immune activity against mycobacterium TB and to better understand host-pathogen interactions, and vaccine design concepts to trigger robust cell-mediated immunity. The development of a more efficacious vaccine with longer-lasting immunity will require us to: increase funding and support for basic science and create opportunities for immunology work in clinical trials; establish meaningful partnerships with civil society organizations and TB-affected communities; and be guided by principles of equity while preparing for access to future vaccines.

A new paper-based diagnostic can test for Ebola, dengue, and yellow fever in just ten minutes without running water, electricity, lab equipment, or highly-trained personnel. “We purposely designed it to be very simple not only to assemble but also to use and to read out,” says lead developer Dr. Kimberly Hamad-Schifferli, a Massachusetts Institutes of Technology professor. Initial symptoms for these three hemorrhagic fevers are nonspecific, making them hard to diagnose, and existing diagnostic methods—while more accurate—are impractical for low-resource settings. This paper-based diagnostic currently costs US$20, although Hamad-Schifferli believes it could be manufactured for even less. The test uses red, orange, and green nanoparticles to test for Ebola, yellow fever, and dengue respectively, and just by identifying the colors that appear on the strip, a diagnosis can be made. Photo: PATH/Gabe Bienczycki An experimental vaccine against Middle East Respiratory Syndrome (MERS) will be tested on humans later this year in clinical trials run by Inovio Pharmaceuticals and GeneOne Life Science. The vaccine, which was developed by researchers at the University of Pennsylvania in partnership with Inovio, the US and Canadian governments, and the Universities of Washington and South Florida, will be the first against MERS to advance to human clinical trials. The team took a novel approach to developing the vaccine, using an artificially engineered DNA sequence, rather than material from the MERS virus itself. The DNA prompts the recipient’s immune system to produce a protein that is unique to the MERS virus, which in turn triggers the production of protective proteins—known as antibodies—that detect that unique MERS protein and attack it. The vaccine successfully induced the production of these protective proteins in mice, monkeys, and camels, and as it does not contain any live viral material; it’s anticipated to be safer than traditional vaccines. Gilead Sciences Inc., a California-based biotechnology company, is aiming to cure HIV and AIDS and hepatitis B and one candidate—GS-9620—has shown promise in combatting both infections in animal studies. “Gilead is the leader in HIV,” according to Andrew Cheng, executive vice president of Clinical Research and Development Operations at Gilead Sciences, and he’s got a point: 80 percent of new HIV and AIDS patients start treatment using a Gilead product. Their expertise in antivirals expands beyond HIV and AIDS; the company has doubled its sales over the past two years, due to the market introduction of Sovaldi and Harvoni—drugs that cure Hepatitis C in 90 percent of patients. Existing treatments for HIV and AIDS prevent active, HIV-infected cells from reproducing, however, inactive cells are able to escape detection, effectively hiding from the immune system. GS-9620 is one of several drug candidates that uses a method known as “shock and kill” to wake the latent, infected cells, enabling the immune system to identify and attack them. The treatment successfully triggered viral activity in monkeys and is now being tested in humans. The treatment has also been tested in woodchucks infected with Hepatitis B, and within a month, the virus was completely undetectable. Researchers at the University of Pennsylvania and the University of Ulm in Germany have discovered a molecule that attacks both HIV-infected cells and a protein in semen that enhances the infectivity of the HIV virus. The molecule—CLR01—latches onto viral membranes, known as viral envelopes, but passes over cell membranes. This suggests that the molecule is unlikely to have any major side effects and that it might be successful in combatting other sexually transmitted viruses. The tweezer-shaped molecule also targets and suppresses molecules in the semen that attach to the HIV virus and help it bind to human immune cells, ultimately making the virus 10,000 times more virulent. CLR01 has been successfully tested in zebrafish and mice and will next be tested for safety in efficacy in nonhuman primates. According to the researchers, mass producing CLR01 is relatively simple, making it a microbicide candidate.