Breakthroughs Blog: Vaccines

The US Food and Drug Administration (FDA) approved the first 3D-printed drug last week, paving the way for the technology to be used to customize medical care to individual patients. 3D printing is a manufacturing process that involves using a computer to create an object one layer at a time. In the case of the recently approved Spritam—a treatment for epilepsy—the printing allowed for greater control over formulation of the drugs, resulting in the creation of the first 1,000 milligram tablets that remain easily dissolvable despite their large size. The use of 3D printers could ultimately enable hospitals to produce their own medicines, adjusting the dose for individual patients. Meanwhile, at the University College London School of Pharmacy, researchers are exploring the possibility of using 3D printing to create uniquely shaped drugs. Drugs are absorbed at different rates depending on the surface area and volume of the tablet, and by adjusting the shape of a tablet (i.e., creating a pyramid or doughnut shaped pill) the rate at which a drug’s active ingredients are released could be manipulated. Leaders at the FDA and the US Department of Health and Human Services propose mechanisms and protocol to expedite drug development in public health emergencies in The New England Journal of Medicine, stating “if we are to act on lessons learned [from the Ebola outbreak] there is no time to waste.” The authors note that limited research capacity delayed the testing of experimental treatments, calling for efforts to strengthen clinical trial infrastructure globally. The outbreak also prompted debate about research ethics in emergency settings (i.e., whether it was ethical to administer untested therapies and the ethics of using placebos in an outbreak). Consequently, the authors recommend that processes for ethical review of studies in outbreaks be streamlined. Finally, the authors stress the need for coordination between health and regulatory authorities, researchers, and product developers. In the Ebola outbreak, the US government partnered with West African governments, academic institutions in both regions, and product developers at every stage. Clinical trials of different therapies were conducted concurrently, allowing partners to have a single, shared control group. The authors note that to facilitate collaboration for rapid drug development in outbreaks, there is a need to establish “model agreements” regarding data management and intellectual property rights. BiondVax Pharmaceuticals announced last week that those vaccinated with an experimental flu vaccine in 2012 had stronger immune responses to strands of influenza that didn’t even exist three years ago. The vaccine was developed to provide broad protection against different strands of influenza, in contrast to the seasonal flu vaccine which protects against the three to four strands of influenza predicted to be the most virulent that year. In 2012, the vaccine (M-001) was tested in phase II clinical trials in which 90 participants—all aged 65 or older—received the vaccine and 30 served as the control group. The vaccine successfully triggered an immune response, including the development of antibodies against several different strains of influenza. Earlier this year, BiondVax exposed blood plasma collected from participants in the 2012 trial to a strain of influenza that did not exist in 2012, and discovered protective antibodies against the strain in 50 percent of the plasma samples from those that received the vaccine, compared to just 10 percent of the samples from those in the control group. As BiondVax’s President Ron Babecoff explains, the vaccine “provides a safety net by broadening the immunogenicity [immune response] to existing and future flu strains.” Next, the vaccine will be tested in phase 3 clinical trials. Blood smear revealing Trypanosoma brucei parasites, which cause African sleeping sickness. (Photo: CDC/ Dr. Mae Melvin) A simple innovation—blue cloth and fine netting sprayed with insecticide between two sticks—could wipe out African sleeping sickness in a mere five to six years. African sleeping sickness is transmitted by tsetse flies, which breed along rivers looking for “something that contrasts with the green vegetation,” according to entomologist Steve Torr, “and for some reason they’re especially attracted to bright blue.” The flies are attracted to the blue cloth and the insecticide kills them within three minutes. The contraption is currently being tested in northern Uganda, where more than 17,000 have been installed over 1,500 square miles; in less than two years, the population of tsetse flies has been reduced by 90 percent. Only 1 in 1,000 flies carry the parasite, and the flies only reproduce once every nine days—whereas mosquitoes lay hundreds of eggs each day—bringing Torr’s team to the estimate of five to six years to both reduce the tsetse population, and eliminate the parasite from the remaining population.

Sabin Vaccine Institute—a member of GHTC—and Texas Children’s Hospital Center for Vaccine Development received a US$1.8 million grant to expedite the research and development of the first therapeutic vaccine for Chagas disease, which is currently undergoing preclinical research by the same team. Chagas is caused by the parasite Trypanosoma cruzi, which attacks and feeds on human tissue, resulting in heart or digestive disorders in nearly one-third of those infected. The disease is endemic throughout Latin America and in recent years has moved into the United States. The grant comes from the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, which works to improve the quality of life in southern Texas, where investigators estimate there are anywhere from tens to hundreds of thousands of Chagas cases in humans. The Critical Path Institute (C-Path)—a nonprofit that facilitates cross-sector partnerships to expedite drug development and regulatory approval—has formed a Pre-Launch Consortium tasked with establishing and operating a Global Pediatric Clinical Trials Network. The Consortium will be comprised of representatives from academia, the public and private sectors, the pharmaceutical industry, foundations, and child health advocacy groups and will determine the structure and leadership of the Network, which will be nonprofit and independent from C-Path. The Network is intended to be a resource, providing technical expertise and using its global infrastructure to advance the development and approval of pediatric treatments across diseases and conditions, phases of trials, and types of studies. The Network’s resources will be available to all product developers, both for- and not-for-profit. Photo: CDC Dr. Rebecca Richards-Kortum and Dr. Maria Oden, professors of Bioengineering at Rice University, are working to create a “Nursery of the Future” to save the lives of babies born prematurely in low-resource settings. Prematurity is the leading cause of death for children under five years old. In hospitals in high-income countries, expensive computer monitors are used to alert staff when a baby stops breathing, so that they can wake the infant and trigger him or her to keep breathing. As a low-cost, innovative alternative, the team has successfully tested a band that wraps around an infant’s belly and vibrates—using motors similar to those in cell phones—when the baby stops breathing, waking it directly. Next, Richards-Kortum and Oden want to develop low-cost alternatives for infant warmers, oxygen concentrators, and serum bilirubin tests—all expensive equipment used in hospitals in high-income countries. Their eventual goal is to create an entire nursery that costs less than US$10,000. A new study suggests that “leaky” vaccines, which decrease the severity of an infection rather than prevent it entirely, could lead to the evolution of more virulent pathogens. The basic premise is that when a pathogen is able to survive in a vaccinated person, it grows stronger, and the vaccinated person can then become an asymptomatic carrier of the more deadly version of the pathogen. The study, led by Dr. Andrew Read, a professor of Biology and Entomology and Pennsylvania State University, applied the theory to Marek’s disease, a poultry disease against which farmers regularly vaccinate their chickens. Read’s team demonstrated that, when infected with different strains of Marek’s disease virus, vaccinated chickens were effective carriers, and that those infected with highly virulent strains were able to spread the disease to a greater number of unvaccinated chickens. Read believes that “we are entering the era of leaky vaccines in humans,” as researchers develop partially effective vaccines for complicated viruses such as malaria or HIV and AIDS. However, vaccine researcher Dr. Adrian Hill of Oxford University argues that the theory is plausible but unlikely, referring to Marek’s disease as “the only example of this happening” and noting that the development of natural immunity in a population could have the same effect.

Later this year, French pharmaceutical company Sanofi plans to launch a vaccine for dengue fever, the first on the market for an infection for which nearly half of the world’s population is at risk. Sanofi has spent more than US$1.5 billion over 20 years on the research and development (R&D) of this dengue vaccine and expects it to be not only lifesaving, but also highly profitable. Dengue fever is endemic in a number of low- and middle-income countries in Asia and Latin America and is spreading into high-income countries in southern Europe as well as Japan and the United States. In preparation for the launch, Sanofi has invested more than $300 million in a manufacturing facility for the vaccine with the capacity to produce 100 million vaccines each year. Pharmaceutical companies Takeda, Merck & Co., Inc., and GlaxoSmithKline are also developing vaccines for dengue fever, and Takeda’s candidate could be on the market by 2020. The US Food and Drug Administration (FDA) granted a Breakthrough Therapy Designation to pharmaceutical company Bristol-Myers Squibb for its HIV treatment BMS-663068, based on the results of phase 2 clinical trials. The designation expedites FDA review in order to accelerate the availability of drugs for serious or life-threatening conditions and in cases where preliminary evidence suggests that the new product would offer significant advantages over current treatments. BMS-663068 is the first antiretroviral drug that actually prevents the HIV virus from attaching to and entering human immune cells. The designation is limited to use of the drug for “treatment-experienced” HIV patients who are developing resistance to other antiretroviral treatments. A new study suggests that the appearance of a pill can impact a patient’s perception of its efficacy. The study asked more than 100 participants each from the United States, China, and Colombia to rate images of pills on anticipated bitterness, ability to fight off headaches, and how hard it is to swallow, based solely on the shape and color of the pill. Across all three countries, participants perceived white pills as the most effective, and diamond-shaped pills—in contrast to round or oval pills—as the most difficult to swallow. A majority of US participants considered green pills to be the least effective and believed that red pills would lead to greater mental alertness. Past research has also suggested that a pill’s appearance can impact use; a study from 2014 indicates that when generic manufacturers change the shape or color of a pill, nearly one-third of patients will stop using the medication. On Monday, July 20, the Center for Global Development published The White House and the World, a report with concrete policy recommendations for the next US president on everything from energy and climate to migration and trade. The report notes that the United States often serves as the “first responder” in outbreaks and is a leader in global health, but calls for clear leadership—including the appointment of a global health coordinator—and pathways for coordination across US agencies. The report highlights the needs for reform at major multilateral organizations such as the World Health Organization and suggests that the United States should spearhead reform efforts and use those platforms to advance US priorities. The report identifies ways for the United States to provide technical assistance—through an office of Global Health Trade, Economics, and Knowledge Exchange—with partners in low- and middle-income countries, ultimately calling for a shift from the “aid-based status quo” and positioning the United States as a “forward-looking and strategic investor” in global health. The Guardian took an in-depth look at the status of antimicrobial R&D, including antibiotic drug discovery, alternative treatments for drug-resistant bacteria, and improved diagnostics. In the 1950s through the 1970s, researchers were discovering around twelve new antibiotics each year just by examining soil samples and identifying compounds—generated by the one percent of micro-organisms that can grow in normal laboratory settings—that could fight off bacteria. A new device known as iChip allows scientists to cultivate microbes while still in soil, enabling them to work with the other 99 percent of micro-organisms. Researchers at Northeastern University have identified 25 potential compounds using iChip, including one that demonstrates promise against drug-resistant tuberculosis and that the team believes could be available for use in humans within five years. According to Dr. Kim Lewis, the project’s lead researcher, “the rule of thumb is you need 50 promising leads for one drug, [so] we will keep searching for more.” Dr. Matt Cooper, a professor of chemistry at the University of Queensland, is also searching for new antimicrobial compounds. Earlier this year, he established the Community for Open Antimicrobial Drug Discovery, which will collect thousands of chemicals and test them for antibiotic potential. While Lewis and Cooper search for new compounds, others look for alternative or supplemental treatments for drug-resistant bacteria. The London-based biotech company Helperby Therapeutics has developed a “resistance breaker,” which Chief Scientific Officer Anthony Coates describes as “punching holes in the membrane of bacteria” to enhance the ability of existing antibiotics to combat the bacteria. David Livermore, a professor of medical microbiology at the University of East Anglia, is calling for rapid diagnostics to improve the diagnosis and treatment of drug-resistant infections. Livermore compares the current use of antibiotics to “carpet bombing in the second world war,” killing off all bacteria in patients, including protective bacteria in the human gut, and leaving a vacuum in which harmful bacteria can develop resistance. Because antibiotics are cheap and used by patients for a short amount of time, however, large pharmaceutical companies can be hesitant to invest in their R&D. As Cooper explains, the “low-hanging fruit[s]” have been discovered, and government investment is now needed to return to the “golden era” of antibiotic drug discovery.

An experimental, aerosol vaccine completely prevented infection from Ebola in monkeys, and will be tested in human clinical trials shortly. The vaccine was tested on twelve monkeys, with four each receiving one and two doses, two receiving a liquefied version of the vaccine, and a control group comprised of the remaining two monkeys. Four weeks after vaccination, all 12 monkeys received a massive dose of the virus, 1,000 times the fatal amount. While the two unvaccinated monkeys became ill, all ten of the vaccinated monkeys remained healthy, and the researchers found no trace of the virus in their blood. Aerosol vaccines are easy to administer and do not require a trained health professional, and thus are ideal for use in an outbreak or a country without a robust health workforce. Earlier this year, Apple Inc. launched ResearchKit, an open source software framework to facilitate the collection of health information in clinical trials, and soon two major pharmaceutical companies—GlaxoSmithKline and Purdue Pharma—may be utilizing the software. The software makes it easy for researchers to create their own iPhone applications to connect with participants in clinical trials and is already being used by academic institutions and nonprofits for data collection. Not only can these applications survey participants, but they can measure hand tremors in patients with Parkinson’s disease, physical activity in relation to cardiovascular disease, and geographic locations that exacerbate the symptoms of asthma. The software provides researchers more frequent access to a greater number of participants. Researchers are also looking into connecting other devices to the software, for example, asthma inhalers that transmit data via Bluetooth. While smartphones, and in particular iPhones, are less prevalent in low- and middle-income countries, the software could be used by health professionals or researchers for data collection. Already, smartphones are being used to perform eye exams in Kenya, pasteurize milk for breast milk banks in South Africa, and could soon be used to detect infection with Loa loa filariasis in Africa. Photo: CDC/ Dr. Mae Melvin Researchers at the Duke-NUS Graduate Medical School in Singapore have discovered an antibody—a protein in the immune system that identifies and combats specific pathogens—against one of the four viruses that causes dengue fever. The team, led by Shee-Mei Lok, a professor of Emerging Infectious Diseases at the university, first identified the specific part of the virus that triggers the production of antibodies in mice and believes that a vaccine comprised of just that part of the virus could provide protection from infection. Lok hopes to create a cocktail treatment against dengue fever using antibodies against each of the four types, and the team is continuing their research to identify an antibody against DENV-4, the one virus responsible for dengue fever for which there is not a known antibody. Bats are the natural reservoir, or host, for more than 65 viruses, bacteria, and other pathogens that infect humans, including Ebola, rabies, and the coronaviruses responsible for SARS and MERS. A team of researchers surveyed 1,270 people in rural Ghana, shedding light on the interactions between bats and humans and consequently, how these diseases are transmitted to humans. Two-thirds of respondents reported physical contact with bats, with 37 percent having been bitten, scratched, or exposed to the urine of bats. While only 17 percent of Ghanaians reported interacting with bats at work or at home, nearly half regularly visit bat caves.