Breakthroughs Blog: Vaccines

Photo: National Institute of Allergy and Infectious Diseases (NIAID) Researchers at Tulane University successfully tested an experimental aerosol tuberculosis (TB) vaccine in monkeys, demonstrating that the candidate was more effective in protecting against infection than BCG—the only TB vaccine on the market. To create the vaccine, the researchers genetically modified the TB bacterium, removing a gene that plays a key role in infection. The vaccine was then administered to seven monkeys, while another seven each received either an aerosol version of BCG or no vaccine. After eight weeks, the monkeys were exposed to TB at a lethal level. The experimental vaccine not only was more protective than BCG, but it also induced a stronger immune response in the lungs, which is thought to be key to preventing infection. A new formulation and coating for existing HIV and AIDS medicines could significantly decrease the frequency with which the drugs must be taken. Researchers at the University of Nebraska Medical Center used a process called nanoformulation, which involves modifying drugs at the most basic level (i.e., atomic or molecular level) in order to convert them into nanoparticle crystals. In this experiment, the antiretroviral medicine crystals were coated with fat and protein, allowing them to last much longer in the body. In the lab, the drug proved to be effective in combatting HIV and AIDS. The team hopes its findings could eventually lead to the development of an HIV and AIDS treatment that could be administered once or twice per year, rather than daily. Resistance to the leading antimalarial—artemisinin—was first reported in Cambodia in 2008, and a new study in Nature Communications suggests that the drug-resistant parasite has the ability to infect African mosquito species. A team of researchers at the US National Institute of Allergy and Infectious Disease infected two Asian and one African mosquito species with the drug-resistant malaria parasite, and all three species proved to be susceptible. Furthermore, the African species were no less vulnerable to infection, which came as quite a surprise as the species have evolved independently for more than 30 million years. Health officials from the United States and Saudi Arabia are considering a collaboration for the development of a vaccine against Middle East Respiratory Syndrome (MERS), which has infected more than 1,500 people across 27 countries. There are currently a number of MERS vaccines in development and several have yielded promising results in animal studies. The Saudi Ministry of Health has US$70 million available for the project; however, the proposed role of the US government remains unknown.

In this guest post, Dr. Jayasree K. Iyer—Chief Scientific Officer at the Access to Medicine Foundation—writes about the findings from their newest study, which examines the current state of the vaccine pipeline and how large pharmaceutical companies are considering access to these products. Vaccine manufacturers play a critical role in innovating new vaccines and making existing vaccines more suitable for use in developing countries. Apart from developing effective, appropriate vaccines, manufacturers work with relevant stakeholders to ensure that access to these vaccines is ramped up upon market introduction, addressing issues like supply and affordability. Vaccines are the cornerstone of disease prevention: mass immunization has led to the eradication of smallpox, and between 2000 and 2010, it helped cut the global childhood mortality rate in half. Yet many people cannot access full immunization, especially with newer vaccines. Recent attempts to boost immunization coverage (e.g., of the relatively new pneumococcal and rotavirus vaccines) shows that immunization coverage and access can be increased when good vaccines, committed funding, and strong global partnerships come together. The vaccine R&D challenge The challenge with vaccine development and access is twofold: the need for new vaccines for diseases where there are no vaccines on the market (e.g., for HIV and AIDS, malaria, and for almost all neglected tropical diseases (NTDs)) and the need for vaccines that are more suitable for use in the developing world (e.g., thermostable vaccines, oral, more effective vaccines and combination vaccines). The research and development (R&D) pipeline for vaccines is primarily driven by the vaccine industry, product development partnerships (PDPs)—such as the PATH Malaria Vaccine Initiative (MVI) and Sabin Vaccine Institute—and other research institutes. With the recent outbreak of Ebola, it is clear that vaccine innovators play a crucial role in the development of safe, quality, effective vaccines, and that R&D must be stimulated by donors and regulators, as well as by market forces. Tracking vaccine development The Access to Medicine Foundation has been tracking the development and deployment of medicines and vaccines for use in developing countries since 2008. Our almost ten years of research into the world’s 20 largest research-based pharmaceutical companies has given rise to special insight into the opportunities for addressing specific challenges. These insights can be used to inform the work of other pharmaceutical companies, as well as governments, investors, donors, and market shapers. Our research prompted us to embark on the first Access to Vaccines Index (due early in 2017). While talking with vaccine stakeholders and defining appropriate, robust metrics and analysis scopes for this new access-analysis tool, we also published a preliminary report on vaccine R&D, which offers a baseline on industry efforts in this area. Data from the 2014 Access to Medicine Index was used to report on (a) the R&D pipeline for high burden vaccines and (b) the use of mechanisms that ensure rapid access and uptake of vaccines upon market approval (termed “access provisions”). Promise in the pipeline The study highlights and confirms that the vaccine R&D pipeline covers the highest burden diseases. There appears to be relatively promising candidate vaccines emerging for diseases where no vaccine yet exists on the market (e.g., for malaria and dengue). However the pipeline for these types of vaccines remains relatively empty. Considering the large development costs associated with vaccine development and the high attrition rate of vaccine R&D projects, there is little promise that other new high-need vaccines products will enter the market in the coming years. Persistent R&D gaps remain Considering the large development costs attributed with vaccine development and the high attrition rate of projects in the pipeline, there may be few vaccines entering the market in the coming years from industry. There may be other projects under development by research institutes, PDPs, and biotech companies and by other smaller vaccine manufacturers. However, without significant investment (which many of the stakeholders may not have access to), chances of successful products reaching the market remain limited. And with so many global priorities competing for investments, product development is almost certain to take a strong hit. Interestingly, the majority of vaccines in the pipeline are aimed at adapting or improving existing vaccines (e.g., to improve their efficacy or give longer-lasting immunization or to develop combination vaccines), or creating the next generations of existing vaccines. Many of these projects target leading causes of child death including diarrheal disease and pneumonia. This is important, as coverage, adherence, and acceptance is also improved with these types of products. Accelerating access to suitable new vaccines Having a vaccine on the market that meets a health need and is suitable for LMICs does not automatically resolve access issues. Photo: PATH/Aaron Joel Santos To drive strategic R&D decisions that meet public health needs, particularly for low- and middle-income countries, the World Health Organization develops Preferred Product Characteristics (PPC)– recommendations for priority indications, target groups, possible immunization strategies, and desired clinical data, as well as ensuring that vaccine presentation and packaging is suitable for low-resource settings (such as remote populations, or where infrastructure is weak). Together these PPCs and presentation and packaging recommendations form an essential part of vaccine developers’ Target Product Profiles (TPPs). Companies can use these TPPs to assist in defining target product characteristics, such as dosage, target price, target population, and route of administration. Just having a vaccine in the pipeline or even on the market that meets a priority need and is suitable for use in a low- and middle-income country will not automatically solve the world’s access problems. Companies and other stakeholders have a joint responsibility to ensure that there are mechanisms in place to ensure the vaccine’s quick roll-out, thus ramping up coverage of vaccines upon market introduction. Companies are expected to continuously innovate through R&D towards the goals defined in the TPP, and ensure that access provisions are aligned with the needs and intended reach of vital products. Big pharma actions to drive access In our vaccine R&D study, we found that companies have used at least one access provision in 17 percent of the vaccine projects in the pipeline. Out of 70 projects analyzed, 42 are nearing the end of the pipeline, yet only 8 projects have provisions in place for driving access once they hit the market. It is not clear whether access provisions are truly lacking, or whether low transparency accounts for this gap. A close look at the usage of the provisions revealed examples such as tiered pricing strategies aimed at ensuring affordability, the use of local manufacturing capacity based in a developing country to reduce cost and ensure local supply, the use of advanced market commitments, commitments for discounted prices, and commitments to manufacture large volumes at the point of market entry. The systematic application of access provisions will help ensure that successful vaccine candidates are suitable for use in the countries that need them most and align with the needs outlined in the PPCs and TPPs. This could help ensure uptake, acceptance, and coverage is ramped up upon market entry and ultimately more lives are saved. While we indeed need clear incentives for companies to invest in vaccine pipelines, they are encouraged to consider and put in place access provisions as early as phase II clinical stages to develop vaccine candidates with poor, rural, and isolated populations in mind.

Dr. Robert Gallo co-discovered the HIV virus and subsequently led the development of the first HIV and AIDS blood test. Now, his team at the University of Maryland School of Medicine is initiating human clinical trials of an experimental HIV and AIDS vaccine that aims to prevent the virus from attaching to immune cells. The HIV virus uses a protein on its surface—gp120—to bind onto one part of human immune cells—the CD4 receptor—and then subsequently bind onto a second part of the cell—CCR5. This vaccine candidate interrupts this process by preventing the HIV virus from attaching to CCR5, therefore disrupting the process of infection. While many vaccines target specific viral strains, this candidate is intended to neutralize all strains of the HIV-1 virus. The first phase of the trial will enroll 60 healthy, adult volunteers to determine the vaccine’s safety and to ascertain if it successfully triggers an immune response. A 23-year-old engineer has developed an inflatable incubator that is designed to be easy to transport, use, and maintain, which could dramatically reduce deaths of premature babies in refugee camps. Developer Briton James Roberts has created electronic and functional prototypes which indicate that the incubator, known as MOM, will provide the required warm, stable, and sterile environment. Roberts designed the product with Syrian refugee camps in mind, as an estimated three-fourths of premature infant deaths in camps could be prevented with proper incubation. The incubator can be collapsed (see Figure 1) to fit in care packages commonly distributed in refugee camps and while it does require electricity, it can run off of a car battery or solar power. Roberts recently won two cash prizes to support product development and manufacturing but is continuing to fundraise to support the costly process of regulatory approval for medical devices. Roberts believes the product could be ready for market by 2018. Photo: CDC/ Dr. Scott Smith The US Department of Defense (DoD) and National Institutes of Health (NIH) have both supported the research and development (R&D) of drugs and vaccines for Ebola since the early 2000s. In both agencies, budget constraints halted progress despite promising clinical trials. In 2004, a researcher at army installation Fort Detrick was exposed to Ebola, prompting the DoD to partner with pharmaceutical company Sarepta Therapeutics to rapidly develop an experimental treatment for Ebola. The treatment was given emergency approval by the US Food and Drug Administration (FDA), but the researcher did not become infected and the treatment remained unused. In 2010, the DoD awarded Sarepta a US$291 million contract to continue its work. Sarepta’s drug demonstrated 60 to 80 percent efficacy in clinical trials with primates and proved safe for use in phase 1 human clinical trials. In September 2012, the FDA granted Sarepta’s drug fast-track status—to expedite its regulatory review—but just one month later, the DoD discontinued the project, in light of looming budget cuts that seemed inevitable due to congressional gridlock. In mid-2014, after the onset of the Ebola epidemic in West Africa, Sarepta CEO Chris Garabedian approached the DoD about the possibility of continuing their work, however, the agency chose to fund products that were not as far along as Sarepta’s. While the DoD has since reconsidered—inviting Sarepta to apply for funding for phase II trials—Sarepta declined, and under new leadership, has terminated their Ebola R&D. The US Department of Agriculture (USDA) has contracted two veterinary pharmaceutical companies—Harrisvaccines and Ceva Santé Animale—to manufacture, store, and ship vaccines to prevent the strain of avian influenza which caused an outbreak and consequent shortage of eggs and turkey in the United States earlier this year. The contract requires the companies to store the vaccines for up to five years, regularly testing them for quality assurance, and will ship them within ten days to anywhere in the United States if requested by the USDA National Veterinary Stockpile. To improve clarity and expediency of communication—for which the agency was criticized by veterinary, poultry, and egg groups during this year’s outbreak—the USDA has also worked with Iowa State University to translate avian influenza–related biosecurity materials for Spanish-speaking farm workers.

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.”