Kat Kelley

Photo: CDC/ Melissa Dankel A new study conducted by the Malaria Genomic Epidemiology Network (MalariaGEN)—a community of researchers across malaria-endemic regions—reveals a formerly unknown genetic variations that make people less susceptible to malaria. The team collected over 20,000 samples from across sub-Saharan Africa, and have identified a genetic variation that provides 33 percent protection against malaria (although the rate varies across populations) as well as dozens of additional genes that appear to have some connection to natural resistance to the disease. The location of these genetic mutations in the human genome is near a region unusually similar to the chimpanzee genome, which suggests that these mutations could have developed millions of years ago. According to the study’s lead author Dominic Kwiatkowski, a process known as balancing selection might have occurred: “[the mutations] would be maintained at a sort of intermediate frequency”—common but not ubiquitous—“implying that it had both beneficial and deleterious effects.” Furthermore, this phenomenon has been observed with sickle cell trait, a gene mutation well known for providing partial protection against malaria, but that can cause a serious blood disorder when two copies of the mutation are present.   A new report from the Access to Medicine Foundation evaluates the vaccine pipelines of 20 major pharmaceutical companies, calling on these leaders in vaccine development to address the gaps in vaccine research and development (R&D) and take steps to ensure that their products will ultimately be accessible and affordable in low- and middle-income countries. The report identifies 70 vaccine candidates against 13 high-burden diseases, noting that nearly half are being developed by just three companies: GlaxoSmithKline, Novartis, and Sanofi. Of the 70 candidates, 16 target diseases for which there are currently no approved vaccines, including dengue fever, HIV and AIDS, malaria, tuberculosis, leishmaniasis, and Chagas disease. Nearly half of the candidates are for lower-respiratory infections (19 candidates), including pneumonia and influenza, or diarrheal diseases (14 candidates). There are currently access provisions—plans to ensure access to the final product—for only 12 of the candidates. Starting October 15, the US Food and Drug Administration (FDA) will have the ability to destroy   drugs sent to the US by mail if they are denied admission into the country. The FDA blocks the importation of drugs that are incorrectly labeled, not approved for use in the United States, or that appear to be counterfeit, including those that do not have the active ingredient, that have inadequate or excessive amounts of the active ingredient, or that contain the wrong, or even harmful, ingredients. Currently, the FDA returns these refused packages to the sender, and not only does this allow the sender to make another attempt, but it’s not uncommon for the same exact parcel to be sent right back to the United States “with the sticker indicating prior refusal by FDA still attached and visible.”

The US Department of Health and Human Services (HHS) is partnering with New York–based Regeneron Pharmaceuticals, Inc. for the development of an Ebola treatment. The treatment, developed by Regeneron, is comprised of three monoclonal antibodies that help the human immune system identify and bind to the Ebola virus, and thus prevent the virus from entering human cells and reproducing. Through the Biomedical Advanced Research and Development Authority, HHS will contribute up to US$38 million over two years, which will support both the advanced development of the treatment, as well as manufacturing enough doses of the treatment to be used in clinical trials. Swiss pharmaceutical company Novartis announced a new program last week to expand access to 15 of its medicines by offering them to health care providers in low- and middle-income countries for just $1 per drug per month. The program will initially be launched in Kenya, Ethiopia, and Vietnam, but could be expanded to as many as 30 countries. The 15 medicines included in the Novartis Access portfolio treat chronic diseases including cardiovascular and respiratory illnesses, diabetes, and breast cancer. Novartis will partner with governments and nongovernmental organizations to implement the program. Photo credit: CDC/ Melissa Dankel Researchers at Stanford University may have discovered a way to combat Clostridium difficile (C. diff)—a deadly bacteria that affects the intestines—without using antibiotics. C. diff’s virulence relies on a specific toxin—Toxin B—it releases that is responsible for the diarrhea, abdominal pain, and damage to the intestinal wall associated with the bacteria. While broad-spectrum antibiotics combat C. diff and other bacteria by attacking all bacteria—including safe, healthy bacteria—this new approach uses a molecule called ebselen that targets and deactivates Toxin B. The team at Stanford gave mice multiple rounds of antibiotics followed by a multidrug-resistant strand of C. diff; in other words, they made the mice particularly susceptible to infection and then introduced a particularly virulent bacteria. However, the use of ebselen to treat the infection almost completely protected the mice from symptoms. Ebselen is currently being tested for use in humans to treat other conditions, and initial results suggest that it is safe and well-tolerated. The US Food and Drug Administration (FDA) gives breakthrough designation to drugs that treat serious conditions and that have the potential to be significantly better than anything on the market. The FDA expedites the development and review of drugs deemed to be breakthroughs, but the designation is not a guarantee of safety, efficacy, or ultimate approval of the drug. However, a new study suggests that use of the word “breakthrough” could give patients “unwarranted confidence […] which could prevent them from making a fully informed decision about whether to take the drug or not,” according to the study’s coauthor Tamar Krishnamurti. The team recruited 600 online participants, each of whom were given one of five descriptions of a drug that has received breakthrough designation. The first description included just the facts, while the second and third described the drug as “promising” and “breakthrough,” respectively. The fourth and fifth clarified that continued approval of the drug depended on the results of additional clinical trials. In the subsequent survey, participants who read that the drug was “promising” or “breakthrough” were more than twice as likely to describe the drug as very or completely effective. While nearly a third of those who read the “breakthrough” description falsely considered the drug’s efficacy to be proven, compared to only 10 to 16 percent of participants who read the clarification regarding continued approval. All participants were then asked to read two descriptions of the same drug and identify which they would take. Ninety percent of respondents chose the description that used the word “breakthrough.”

Photo: CDC/ Hsi Liu, Ph.D., MBA; James Gathany The US Department of Health and Human Services (HHS) announced last week a partnership with pharmaceutical company AstraZeneca for the research and development (R&D) of antibiotics. Through its Biomedical Advanced Research and Development Authority (BARDA), HHS will invest an initial US$50 million and up to $170 million into the project over five years. BARDA and AstraZeneca will meet annually to update their portfolio of drug candidates, determining which projects to initiate, continue, or terminate. The first project will be the advanced development and, ideally, regulatory approval of a treatment comprised of two existing antibiotics—Aztreonam and Avibactam—which is currently undergoing phase 2 clinical trials. The partners will also test new and existing antibiotics for use against diseases considered to be leading bioterrorism threats. Last Tuesday, US President Barack Obama nominated Dr. Robert Califf to lead the US Food and Drug Administration (FDA), where he has been serving as deputy commissioner for medical products and tobacco since January. Califf is a cardiologist and researcher, and previously served as the director of the Duke Translational Medicine Institute—which advances R&D by facilitating cross-sector partnerships—and as founding director of the Duke Clinical Research Institute. If confirmed by the Senate, Califf will succeed Dr. Stephen Ostroff who has served as acting commissioner since former Commissioner Dr. Margaret Hamburg announced her resignation in February. After joining the FDA in January, Califf announced that streamlining the clinical trial process would be a major focus during his tenure. A new analysis in the Guttmacher Policy Review calls for increased US investment in multipurpose prevention technologies (MPTs)—products that protect against multiple risks, including unintended pregnancy, HIV and AIDS, and other sexually transmitted infections (STIs). There is currently only one MPT in phase 3 clinical trials—a female condom that prevents pregnancy, HIV and AIDS, and four STIs—as well as nine in phase 1 trials, and thirteen in preclinical development. Among these MPTs are female condoms and vaginal rings, gels, films, nanofibers, and tablets. As MPTs are primarily intended for use in low-resource settings, private-sector interest has remained low. Additional, non-financial barriers to MPT R&D include scientific and regulatory hurdles: most MPTs have two or more active ingredients, and could thus be subject to review by as many as three divisions within the FDA. The report notes that the US government is already the biggest funder of MPT R&D, accounting for 89 percent of the $6.5 million invested in MPTs in 2013. New Delhi, India, is currently experiencing the worst outbreak of dengue fever it has seen since 2010, with nearly 1,900 confirmed cases this year. All four of the known strains of dengue virus are present in India, however, new evidence from the All India Institute of Medical Science (AIIMS) suggests that a fifth, previously undetected strain of the dengue virus, may be partially to blame for the severity of this year’s outbreak. Recovery from dengue fever provides lifetime immunity against the specific strain, however, the introduction of a new strain would leave the entire population vulnerable. AIIMS recorded the potential new strain after testing an initial fifty samples from recent dengue patients and is working with the Indian Ministry of Health and Family Welfare to collect and test more samples before coming to a conclusion.

A new study suggests that with basic training, individuals can learn to accurately and safely test themselves for HIV and AIDS. Nearly 17,000 adult and adolescent citizens of urban Malawi were provided with testing kits, and within a year, more than three-fourths had self-tested. Across sub-Saharan Africa, only one-fourth of adults have recently been tested for HIV and AIDS, and only half of people living with HIV and AIDS know their status. The research team conducted repeat HIV and AIDS tests on 1,649 participants, and in 99.4 percent of cases, the results of self-testing proved accurate. The results also suggest that HIV and AIDS self-testing is culturally acceptable in urban Malawi and that pre- and post-test counselling was adequate, as no testing-related partner violence or suicides were reported. As the stigma surrounding HIV and AIDS remains a significant barrier to both testing and treatment, HIV and AIDS self-testing could be a game changer in curbing the epidemic. Photo: CDC/ James Stewart Researchers at the University of Queensland in Australia and the University of California, Berkeley have identified a protein—nonstructural protein 1 (NS1)—that may be the key to the dengue virus’ virulence. The virus infects nearly 400 million people each year, resulting in 22,000 deaths, primarily from fluid loss and damage to the blood vessels. The discovery dates back to the early 2000s, when a study in Thailand revealed a correlation between NS1 levels and the severity of the disease in patients. Further research demonstrated that NS1 attaches itself to another molecule which enables it to bind to blood vessel walls; NS1 also prompts the immune system to produce cytokines—proteins that weaken the blood vessels. Essentially, NS1 causes the immune system to react as it does to bacterial infections. These findings could pave the way for both a vaccine and a treatment against dengue fever. The team at Berkeley has demonstrated that NS1 could be used in a dengue vaccine, as the immune system readily detects NS1, rather than the dengue virus itself. In mice, NS1 provided protection against all four strains of the dengue virus, at rates of 60 to 100 percent efficacy. Furthermore, Dr. Paul Young of the University of Queensland believes that a drug for sepsis that is currently in clinical trials could be an effective treatment for dengue. The Drugs for Neglected Diseases initiative (DNDi) has completed phase I human clinical trials for SCYX-7158 (AN5568), a drug candidate with the “potential of becoming the first ever, oral-only, single-dose treatment” for human African trypanosomiasis (sleeping sickness), according to DNDi’s Dr. Antoine Tarral. The compound was identified by Anacor Pharmaceuticals, Inc. as part of DNDi’s lead optimization program, through which partners screened compounds from Anacor’s chemical library to identify those that combat sleeping sickness in a laboratory setting. The candidate was tested for safety and tolerability, as well as its effect on and interaction with the body, in 128 healthy volunteers. Due to the trials’ successful results, DNDi and partners will initiate phase 2 and 3 studies in 2016 in the Democratic Republic of the Congo. The leading treatment for sleeping sickness—also developed by DNDi—requires injections, and consequently skilled personnel; prior to the 2009 introduction of this therapy, the best option was an arsenic-based drug with extreme side effects.

Pharmaceutical company AbbVie is paying United Therapeutics US$350 million for its priority review voucher (PRV)—which expedites the US Food and Drug Administration’s (FDA) review of a product by four months—and EP Vantage speculates on their motive. The FDA awards PRVs to pharmaceutical companies that receive FDA approval for drugs to treat neglected tropical diseases (NTDs) or rare pediatric diseases. The PRVs provide an incentive for companies to invest in research and development for these diseases. To date, six PRVs have been awarded—three each for NTD and rare pediatric disease treatments—and four have been sold. The PRVs have been sold at increasing prices, with the previous three purchased for $67, $125, and $245 million. While AbbVie has seven products currently in phase 3 clinical trials, EP Vantage argues that the PRV will likely be saved for use with filgotinib—a treatment for rheumatoid arthritis (RA)—which is currently in phase 2 trials and on track for a 2018 market introduction. For chronic conditions such as RA, patients are hesitant to switch medications, meaning an earlier launch can have an impact on sales for years. However, a number of new RA drugs are expected to reach the market before filgotinib: Eli Lilly's baricitinib could be launched as early as 2016, and as the US patent for AbbVie’s blockbuster RA drug Humira expires in late 2016, filgotinib could face competition from generic or biosimilar versions of Humira as well. Researchers at the University of California, Santa Barbara (UCSB) are proposing a novel approach for identifying drug-resistant bacteria, challenging the standard method that has been used for more than 70 years. Normally, doctors collect biological samples from sick patients, and the sample is placed on petri dishes filled with a medium known as Müller-Hinton agar, on which nearly any bacteria in the sample will readily grow. They can test the bacteria’s drug-resistance by monitoring how it grows or subsides when exposed to different antibiotics. Patients are then prescribed an antibiotic that caused the bacteria to subside on the petri dish. However, the chosen antibiotic is sometimes unable to fight off the infection in the body, despite its demonstrated ability to combat it in the lab. In these cases, the bacteria can develop resistance to new drugs, making it even harder to treat. Led by Dr. Michael Mahan, the team at UCSB used a less common medium, LPM, which mirrors the conditions within human cell (i.e., it is much more acidic and is low in phosphate and magnesium) and discovered that bacteria may be more sensitive or more resistant to different antibiotic compounds in different settings. According to Mahan, the use of a medium such as LPM could enable doctors to more accurately predict how a patient will react to a certain antibiotic. Furthermore, their findings could lead to the identification of new antibiotic compounds. According to Mahan, there are “millions of chemical compounds that were excluded as antibiotics…but they were never tested since standard [Müller-Hinton agar] petri plates ruled them out.” Photo: PATH/Aaron Joel Santos NBC News reports on three recently released studies that show progress toward the development of an oral flu vaccine and a universal flu vaccine. Biotech company Vaxart, Inc. recently completed early phase 1 clinical trials of an experimental oral flu vaccine, which proved to be both safe and effective. These results have prompted the production of antibodies that are “strongly associated with protection in humans” in three-fourths of participants, according to flu vaccine expert Dr. John Treanor. An injectable vaccine goes straight to the bloodstream and is rapidly detected by the immune system; however, Vaxart had to “come up with a different way of getting the flu gene into the intestines and have the immune system recognize the flu gene as foreign,” according to Vaxart Founder and Chief Scientific Officer Sean Tucker. Meanwhile, teams of researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and Scripps Research Institute have been working on universal flu vaccine candidates. There are several different types of influenza strains that affect humans, including H1 and H3 strains of influenza A as well as influenza B strains. Seasonal flu vaccines protect against three to four strains, based on which are predicted to be most virulent that year, and they train the immune system to detect and attack the virus’ hemagglutinin protein, which is uniquely shaped for each strain. Both NIAID’s and Scripps’ universal flu vaccine candidates use the stem of hemagglutinin, which looks the same for, and should grant protection against, all H1 and H5 (avian influenza) strains. Both candidates have proved safe and effective in mice.

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.