Breakthroughs Blog: Vaccines

Schistosomiasis, the second most common parasitic disease, infects more than 240 million people each year, and can result in liver failure, bladder cancer, and even death. Schistosomiasis is treated using the antiparasitic drug Praziquantel, however, resistance to the drug has been reported in Kenya and Uganda. Despite its efficacy, the mechanism of action of Praziquantel remains a mystery; scientists don’t understand how it combats schistosomiasis. By comparing the genomes of parasites that are sensitive and resistant to the drug, researchers at the Texas Biomedical Research Institute and the University of Texas have identified genes that are associated with resistance, and have received a US$3.5 million grant from the US National Institutes of Health to further examine the individual genes and mutations that confer resistance. The team will collect parasite eggs from patients in Kenya and Uganda before and after treatment with Praziquantel; the eggs from patients who are cured and those that remain infected will be classified as sensitive and resistant to the drug, respectively. They will then sequence the parasites’ genomes, honing in on the genes and mutations linked to resistance, with the goal of better understanding how resistance develops. This information is critical to developing drugs that are effective against Praziquantel-resistance parasites and diagnostics that can detect resistance. Researchers at the All India Institute of Medical Sciences (AIIMS) have completed successful animal trials of an oral vaccine against hepatitis B using a nanotechnology platform that could be adapted for other viruses. Oral vaccines are challenging to develop, as the key components are often degraded in the stomach before they can be absorbed through the intestines. However, they offer significant advantages: they don’t require needles and consequently there’s no risk of blood contamination, many don’t need to be kept cold, and they often spread more thoroughly throughout the immune system. The existing vaccine against hepatitis B is injectable and requires three to four doses, whereas the vaccine under development at AIIMS could be potent enough to require just a single dose. The team used nanoparticles to house the antigen—the part of the vaccine that triggers an immune response—and covered the nanoparticles in a protective surface that can survive the stomach. The vaccine will next be tested in human clinical trials, which the team hopes to complete by 2021. The World Health Organization (WHO) is proposing new guidelines for yellow fever vaccination in emergencies, as alarming outbreaks in Angola, Uganda, and Peru intensify due to a limited global supply. Clinical trials suggest that the vaccine is effective at much smaller doses, and the WHO is expected to recommend that member states use just one fifth of the standard dose. However, the studies were conducted exclusively in adults, raising concerns that the fractional dose might not be enough to protect children. It’s also unclear if the smaller dose would provide lifelong immunity, and the WHO’s proposal will likely recommend a booster to be administered at a later time. Once complete, the proposal will be submitted to the WHO’s Strategic Advisory Group of Experts on Immunization for review, and if approved, will be implemented if the outbreak reaches emergency levels.

Last Wednesday, researchers from the Washington University School of Medicine, the University of São Paulo, and the Chinese Academy of Sciences offered new insights into the impact of the Zika virus on fetal brain development in mice, publishing their findings in Cell, Nature, and Cell Stem Cell, respectively. The first two studies sought to successfully infect pregnant mice with Zika—a feat in itself as mice don’t often fall ill after infection with the virus. Consequently, the team at Washington University used a genetically modified mouse with a weakened immune system as well as a mouse whose immune system was weakened by an antibody, while researchers at the University of São Paulo used a particularly high dose. The team at Washington University detected placental insufficiency in the infected mice—which limits blood flow to the fetus—and the team at University of São Paulo reported intrauterine growth restriction, a condition restricting the growth of the fetus. When the virus reached the fetal brains, both teams witnessed a thinning of brain tissue and cell death. The concentration of the virus in the brain was limited, which inhibited further research on how Zika behaves once in the brain. The team at the Chinese Academy of Sciences, however, injected the virus directly into the brains of fetal mice, and they determined that the virus targets neural progenitor cells and causes the fetal brain to shrink. Silk has been used in developing heat-stable vaccines and drugs, and now, researchers at Tufts University have demonstrated that silk can be used to maintain blood samples in low-resource settings. Blood-based diagnostics are only effective if certain proteins, which indicate either the presence of a pathogen or the immune system’s response to it, are preserved, however, heat and humidity can directly damage the proteins or cause enzymes in the blood to attack the proteins. Labs prefer that blood samples are refrigerated, although they can also be dried on special filter paper that can withstand heat but which often doesn’t hold enough blood for analysis. The team at Tufts created a silk-based powder and solution, combined it with blood samples, and allowed it to dry. The samples were then stored at high temperatures (72 to 113ºF) and remained viable for 84 days. GHTC member the International Vaccine Institute (IVI) announced last week that a single dose of the oral cholera vaccine Shanchol, currently administered in two-dose regimens, provides protection against the disease. The two-dose regimen provides 65 percent protection against cholera for at least five years, while the single dose demonstrated 40 percent protection against the disease for at least six months. While the two-dose regimen is preferred, the single dose could be appropriate for epidemics or in settings where the two-dose vaccine schedule is impractical. The study enrolled 204,700 individuals residing in the urban slums of Mirpur in Dhaka, Bangladesh, where cholera is endemic. In addition to reducing cases by 40 percent, the vaccine resulted in a 63 percent decrease in cases of severely dehydrating cholera.

There is a safe, affordable, single-dose vaccine that protects against yellow fever for 99 percent of those vaccinated, yet a recent outbreak of the disease has resulted in nearly 2,000 cases and killed 258 in Angola. Yellow fever is endemic in 44 countries, including Angola, and the global demand for the vaccine surpasses availability by 42 percent. Additionally, the cost of the vaccine has increased 30 percent annually. The vaccine is currently produced by four manufacturers, and its production is complicated, requiring embryos in chicken eggs. A vaccine with an inactivated version of the virus, which would be much easier to manufacture, has successfully completed phase 1 clinical trials, however, it has not yet been commercialized. As the World Health Organization is leading negotiations to divert yellow fever vaccines from routine immunization programs to Angola, the existing vaccine could also be delivered in smaller quantities to more people: just one-fifth of the standard dose has proven to be effective against the virus. A team of American and German scientists have demonstrated that an injection with potent anti-HIV antibodies can protect against the virus in monkeys for nearly six months. The researchers used four different antibodies that have proven to be effective against various HIV strains and administered one type each to four different groups of monkeys. The monkeys were then exposed to the virus on a weekly basis. On average, the monkeys were protected for 12 to 14 weeks, although some were protected for up to 23 weeks. Previous studies have shown that antibodies can provide short-term protection against HIV in monkeys, however, in most studies, the monkeys were exposed to the virus in one high-dose shot. In reality, most infections in humans develop gradually as a result of repeated, low-dose exposures, and thus, this study sought to emulate standard human transmission. Currently, the first-ever clinical trial of a single antibody is being tested in individuals at high-risk for HIV infection, however, it’s expected that a cocktail of these potent antibodies would be even more effective at preventing infection.  New research out of Florida Gulf Coast University indicates that previous infection with dengue virus could exacerbate symptoms from the Zika virus. This phenomenon—antibody-dependent enhancement, in which the presence of protective antibodies against one disease increases vulnerability to another—has been reported among different strains of dengue virus. The team at Florida Gulf Coast University confirmed that in cell cultures, the presence of antibodies against dengue intensified Zika infection, however the research also suggests that a single vaccine candidate could be effective against both diseases. These findings, coupled with the shared Aedes aegypti mosquito vector, indicate that the spread of Zika in dengue-endemic regions could be more virulent than expected. 

This post is part of the #MarketsMatter expert blog series. Read the full series here. The size, strength, and stability of markets dictate how health product developers set priorities and fund research and development (R&D); a 1 percent increase in the potential market size for a drug category leads to a 6 percent increase in the number of medicines introduced in the US market.[i] However, relying on market forces alone to drive health R&D leads to staggering disparities in funding and real-world impact. Today, only 1 to 2 percent of all global investment in health R&D targets neglected diseases, which kill more than 6 million people each year and disproportionately affect low- and middle-income countries (LMICs).US Navy Lt. Kimberly Edgel, left, and Christian Baldeviano examine a positive malaria blood smear at Naval Medical Research Unit (NAMRU) 6 in Callao, Peru. When existing market forces alone fall short in ensuring availability of and access to lifesaving health tools, a range of interventions are needed to alter the market and ultimately change the behavior of its actors. Incentives and innovative financing mechanisms are interventions that have proven effective in accelerating R&D and delivering lifesaving vaccines, drugs, diagnostics, and other health tools to those who need them most. Incentives such as advance market commitments (AMCs), volume guarantees, milestone prizes, and priority review vouchers reward developers who conduct neglected disease R&D or guarantee a market for a health product, ensuring that developers are able to recoup the costs of R&D. Innovative financing mechanisms, including mix-method financing, cross-sector partnerships, pooled funding, and competitions directly subsidize and consequently catalyze R&D. These platforms and partnerships are already accelerating R&D and promoting access to new innovations. AMCs—agreements by procurers to purchase a specified quantity of a new product at a predetermined price, effectively securing a market for product developers—have moved from innovative idea to reality over the past decade. In 2007, Gavi, the Vaccine Alliance launched an AMC for pneumococcal vaccines, raising US$1.5 billion from six public and philanthropic donors to purchase a future vaccine. While there were already two late-stage candidates in the pipeline that met the AMC’s criteria, the commitment created competition and encouraged GlaxoSmithKline (GSK) and Pfizer to adapt the vaccine candidates for low-resource settings. The AMC also stimulated demand; the vaccine has been introduced in more than 50 LMICs, and both GSK and Pfizer scaled up manufacturing to meet the demand, reporting that these decisions were influenced by the existence of the AMC. Earlier this year, Gavi initiated a similar agreement, signing an advance purchase commitment with Merck, providing $5 million toward the development of an Ebola vaccine. Merck guaranteed that the product would be submitted for licensure by the end of 2017, and 300,000 doses would be made available by May 2016 for use in either a future outbreak or clinical trial. Not only has Ebola historically affected LMICs, but the disease typically emerges in short-term outbreaks, and thus, the market is limited and unstable. This agreement will ensure that a stockpile of vaccines are ready to be deployed during the next outbreak and signals to vaccine developers and manufacturers that cross-sector partnerships can offer a market for emerging and reemerging infectious diseases. While incentive mechanisms can expedite product development and access to new health tools by creating market demand and new financial incentives, innovative financing mechanisms that directly fund R&D remain critical and have played a tremendous role in bolstering the neglected disease pipeline. The pipeline has grown from 365 products in 2012 to 485 tools today, three-fourths of which are being developed by public-private partnerships, including product development partnerships, which facilitate collaboration across the public, private, and philanthropic sectors, bringing in new resources and diverse expertise. Other innovative financing mechanisms include pooled funds, such as the Global Health Innovative Technology (GHIT) Fund, which is financed by the Japanese government, seven Japanese pharmaceutical companies, and the Bill & Melinda Gates Foundation. The GHIT Fund has brought new investors and resources to the table and is currently supporting nearly 50 drug, vaccine, and diagnostic candidates. Alternately, Grand Challenge programs offer a platform for open innovation, identifying and financing promising ideas to address health and development challenges. Through its Grand Challenges series, the US Agency for International Development has elicited 7,400 ideas and has supported 224 of them, leveraging $125 million in new funding to match the agency’s investment of $76 million. Markets for neglected disease products are often perceived as insufficient to warrant investments in R&D, and thus, we can’t rely on existing market forces alone to determine R&D funding and priorities. An enabling policy environment, cross-sector partnerships, and innovative financing mechanisms have a critical role to play in galvanizing greater industry engagement and addressing the market failures that inhibit neglected diseases R&D.The Global Health Technologies Coalition (GHTC) works to save and improve lives by encouraging the research and development of essential health technologies. We are a coalition of more than 25 nonprofit organizations advancing policies to accelerate the creation of new drugs, vaccines, diagnostics, and other health tools that bring healthy lives within reach for all people. GHTC is housed at PATH and funded in part by the Bill & Melinda Gates Foundation. Learn more at www.ghtcoalition.org. [i] According to the authors of this study, the correlation between market size and new drugs entering the market likely applies beyond the US market, but this data is not readily available. However, the US market has a disproportionate impact on R&D funding and priorities, as it constitutes an estimated 40 percent of the global market. For more information, see the study, published in The Quarterly Journal of Economics, here.