Breakthroughs Blog: Research Roundup

Until very recently, no new class of antibiotics had been discovered in nearly 30 years. However, as antimicrobial resistance spreads, there is an urgent need for new antibiotics, particularly those that can treat infections resistant to existing drugs. In article in Health Affairs, Allan Coukell, senior director for health programs at the Pew Charitable Trusts, is calling on Congress to pass the Promise for Antibiotics and Therapeutics for Health (PATH) Act, which would permit the US Food and Drug Administration (FDA) to approve new antibiotics for use in limited patient populations with modified clinical trial requirements that would be determined by the agency itself. There is little financial incentive for antibiotic R&D as they are prescribed for short periods of time and as there is much competition among antibiotics. Conducting clinical trials, particularly for drug-resistant infections, is challenging: not only are these infections rare, but many patients are disqualified from participation due to compromised immune systems or pre-existing conditions. Additionally, the dearth of rapid tests results in many patients starting antibiotic regimens before being diagnosed with a drug-resistant infection. The PATH Act has passed the Senate Health, Education, Labor and Pensions Committee and was included in the 21st Century Cures Act, which passed the House of Representatives last year. Pharmaceutical company GlaxoSmithKline (GSK) announced that it will not file patents for its products in least developed and low-income countries, enabling manufacturers to produce and distribute generic versions of their medicines in 50 countries with a combined population of nearly 1 billion people. In lower middle income countries, GSK will continue to file patents but will offer ten-year licenses to generic manufacturers for a small royalty. GSK is also exploring innovative ways to increase access to its new and future cancer drugs through voluntary licensing via the Medicines Patent Pool, a United Nations–backed initiative that partners with patent holders and generic manufacturers to facilitate access to medicines. The Pool was founded in 2010, exclusively for HIV and AIDS drug patents, but has since been expanded to include tuberculosis and hepatitis C. The HIV virus mutates rapidly, and thus, standard approaches to vaccine development have not been successful. Rather, researchers have been testing and adapting antibodies—proteins targeting a specific pathogen—from patients, searching for the rare broadly neutralizing antibodies which are effective against manifold strains of the virus. Scientists at The Scripps Research Institute (TSRI) have now characterized the first “teenage” broadly neutralizing antibody, an immature version of the molecule, not yet effective against the HIV virus. The molecule was discovered by the Chinese Center for Disease Control and Prevention (China CDC). The team at China CDC collected blood samples from hundreds of HIV-positive patients, identifying those with the most effective anti-HIV antibodies. The patients were then monitored for five years, enabling the researchers to observe antibody development. Previously, scientists believed that broadly neutralizing antibodies matured over 10–15 years, however, from its teenage stage, this potent antibody developed rapidly in just 2 years. The researchers hope this discovery could inform HIV vaccine research and development by providing insight into how to prompt the human immune system to rapidly produce effective broadly neutralizing antibodies.

One-third of the world’s population—more than 2 billion people—has latent tuberculosis (TB) and each year, 9.6 million people develop active TB. However, a team of scientists have identified 16 genes, referred to as a “risk signature,” that can predict which cases are most likely to progress to active TB. In two studies enrolling more than 10,000 participants across South Africa and Gambia, researchers collected and analyzed blood samples to detect the presence of the risk signature. The genes predicted cases of active TB with sensitive and specificity rates of 66.1 percent and 80.6 percent: in other words, two-thirds of the patients with the genetic risk signature developed active TB during the study, compared to only one-fifth of those without the risk signature. TB is the world’s leading infectious disease killer, resulting in 1.5 million deaths in 2014. However, the study suggests that this risk signature could be used to predict cases of active TB up to 18 months in advance, and treating latent TB can reduce the risk of developing the disease by 90 percent. A new tool to easily insert intrauterine devices (IUDs)—long-acting contraceptive devices that can remain in the uterus for up to twelve years—could make the devices more accessible in low-resource settings. IUDs contain either copper, which is toxic to sperm, or hormones that preclude the release of eggs from the ovaries. The devices are safe and more than 99 percent effective, however, they can be difficult to insert. However, a new IUD inserter could make the contraceptive devices much more accessible, particularly for postpartum woman. The inserter was developed by Population Services International, in partnership with Stanford Program for International Reproductive Education and Services and Pregna International Ltd., costs just US$1, and is longer and sturdier than existing tools. In a trial enrolling 80 women in India each of whom had given birth just hours before, 90 percent of health workers reported that the IUD was easy to place with the new inserter and more than 90 percent of women felt no increase in pain during the procedure. Improved inserters could have a significant impact in settings without ultrasound technology—used to confirm the placement of the IUD—or with limited ability to sterilize equipment. Next Billion took an in-depth look at existing vaccines to prevent and treat cancer, emphasizing their need in low-resource settings, where cancer testing and treatment are often inaccessible and prohibitively expensive. Rather than targeting pathogens, these vaccines train the immune system to attack cancerous cells. There are currently preventative vaccines available against strains of human papillomavirus (HPV) and hepatitis B virus that cause cervical and liver cancer, respectively, and other vaccines available and under development can prevent the spread or relapse of bladder, prostrate, and lung cancer. Cervical cancer results in more deaths among women in low- and middle-income countries than any other type of cancer. Fortunately, HPV vaccines prevent against several strains of the virus, including the two responsible for 70 percent of cases. Liver cancer ranks second in cancer mortality worldwide, however, many cases could be averted with increased access to hepatitis B vaccines. Individuals infected with hepatitis B are 100 times more likely to develop liver cancer. Lung cancer is the leading cause of death from cancer worldwide, and non-small cell lung cancer (NSCLC) accounts for 85 percent of cases. However, researchers in Cuba are developing a therapeutic vaccine against NSCLC, which has extended survival rates for patients by 68 percent in phase 3 trials. Additionally, the TB vaccine is used to fight bladder cancer and the vaccine Sipuleucel-T is used against advanced prostate cancer.

A new study out of the Washington University School of Medicine in St. Louis, Missouri, revealed a proliferation of antibiotic-resistant bacteria in the gastrointestinal tracts of premature infants. The team collected fecal samples from 84 babies born premature and identified nearly 800 genes that enable bacteria to develop resistance to 16 different antibiotics. Preterm infants are more susceptible to infection and nearly all are given antibiotics preemptively for at least the first few days of life. However, this practice could have unintended consequences; high bacterial diversity in the gut protects against infection from harmful bacteria, and the study indicated that preterm infants have one-tenth the number of bacteria species found in babies born full term. The team used a novel technique to identify genes that can confer drug resistance, resulting in the discovery of hundreds of genes not previously associated with antibiotic resistance. Further, the findings suggest that administering one antibiotic can result in a growth in resistance to other antibiotics. However, breastfeeding and aging appeared to have a positive impact on the infants’ gut, resulting in increased bacterial diversity. A novel, low-cost technique can diagnose tuberculosis (TB) in 25 minutes using just a urine sample. Standard TB tests require X-rays and/or mucus samples, which are harder to acquire than urine samples, particularly in low-resource settings. In a study of more than 2,500 patients across four countries in sub-Saharan Africa, use of the test reduced TB deaths in HIV and AIDS patients by four percent, as improved detection enabled patients to start treatment early. In Africa alone, 300,000 HIV and AIDS patients die of TB annually, and thus, this diagnostic technique could save thousands of lives each year. The new tool costs US$2.66 per test, whereas the leading TB test costs $10 and requires a $17,000 machine to read the results. Last week, US government representatives met with scientists and public health officials to discuss a White House ban, instated 18 months ago, on research that makes viruses more dangerous than natural strains. Within the scientific community, many argue that such research can be done safely, and that the potential scientific and public health benefits are significant, whereas others contend that the benefits are overstated and the risk is too high. The officials met to discuss the establishment of a high-level committee which would review proposals for such studies, weighing the potential benefits and risks, evaluating the security of the laboratory facilities, and determining whether the results could be achieved through less risky research. Prior to the meeting, Dr. Inglesby—CEO of the UPMC Center for Health Security—along with Drs. Lipsitch and Relman of Harvard University and Stanford University, proposed policy options for conducting such research safely. The recommendations include: requiring a high-level official to approval such research (i.e., the director of the National Institutes of Health), defining “red lines” for research that would prompt additional safety reviews, limiting such research to select labs with the highest level of security, or requiring the purchase of insurance policies for such research.

Photo: PATH/Map Photo Agency Gilead Sciences, a California-based biopharmaceutical company, has received US Food and Drug Administration (FDA) approval for Odefsey®, a complete, single-pill regimen for HIV and AIDS. Odefsey® contains tenofovir alafenamide (TAF), a modified version of the antiviral tenofovir, used to treat HIV and AIDS and hepatitis B. TAF is highly effective at entering HIV cells, and thus can be administered in doses a mere ten percent of that required for tenofovir-based medicines. Gilead also recently received a positive opinion from the European Medicines Agency (EMA) on Descovy, another TAF-based treatment. The EMA’s recommendation will be evaluated by the European Commission, which can grant regulatory approval for the 28 European Union member states. Prior to the 2014 Ebola outbreak, the experimental therapy ZMapp had only been tested in non-human primates. The therapy, which is comprised of three antibodies against the virus, is particularly difficult to manufacture, and thus only seven patients received ZMapp during the outbreak. Now, results of the first human clinical trial of ZMapp affirms that the treatment could be an important tool in fighting Ebola. The randomized control trial was conducted by the US National Institute of Allergy and Infectious Diseases (NIAID) in partnership with the governments of Guinea, Liberia, and Sierra Leone. As the spread of Ebola slowed, so too did new cases, and thus the partners could only enroll 72 patients, one-third of the 200 for which they had planned. In the study, all patients received supportive care, including provision of fluids and electrolytes, and half of patients received three doses of ZMapp. Patients receiving ZMapp recovered much faster, in terms of symptoms and presence of the virus in the blood, and the fatality rate was lower for ZMapp recipients: 22 versus 37 percent. Despite the small trial size, NIAID Director Dr. Tony Fauci is optimistic that the FDA will “favorably consider” the results, in light of the dearth of approved Ebola treatments and positive animal study results, in which the drug was 100 percent effective. A team of Google engineers is working with the United Nations Children’s Fund (UNICEF) to develop a platform to track and predict the spread of Zika, a mosquito-borne virus linked to birth defects that was recently declared a Public Health Emergency in Latin America. The platform uses data such as weather and travel patterns to anticipate communities at-risk for Zika, and will be adaptable for use in other outbreaks. Google is also providing a US$1 million grant to UNICEF for mosquito control and behavior change efforts, with the goal of reaching 200 million people throughout the Americas. The company is also working to ensure that helpful, accurate information is readily available to all using the search engine, adding detailed information in 16 languages on Zika prevention and symptoms as well as government public health alerts.