Breakthroughs Blog: Vaccines

Each year, a new flu vaccine is developed, containing proteins from three to four strains of influenza. These proteins train the immune system to recognize different versions of the virus, enabling a rapid response in the case of infection. For the past eight years, the same strain of H1N1 (swine flu) has been included in flu vaccines globally, however, the World Health Organization has recommended this strain be replaced with a more recent version of the ever-changing virus. Normally, flu vaccines prompt the greatest immune response in healthy adults, however, since 2013, their efficacy has been decreasing in adults aged 30 to 60. The theory? Many of these adults were first exposed to H1N1 between 1977 and 1985, and the strains circulating at that time shared one critical component with those circulating between 2009 and 2013. Consequently, those who had been exposed to H1N1 between 1977 and 1985 responded to the flu vaccine as if it were a booster shot. Rather than producing entirely new antibodies tailored to the new version of the virus, their immune systems ramped up production of the existing antibodies tailored to the old version. In 2013, the virus mutated further, losing the component it shared with older strains, and thus, adults who experienced the booster shot phenomenon were no longer protected by the vaccine. Fortunately, experts have identified a new version of the virus, retrieved from a patient in Michigan, which should provide broader protection against H1N1 for future flu vaccines. A recent study out of South Africa suggests that one in ten children who are infected with HIV have no immune response to the virus and consequently experience none of the symptoms associated with HIV and AIDS. The researchers analyzed blood samples from 170 children who are HIV positive and have not received treatment, but nonetheless have not developed AIDS. The samples confirmed high volumes of the virus in the blood, and the lack of either an immune response or symptoms demonstrates, “HIV disease is not so much to do with HIV, but with the immune response to it,” according to Dr. Philip Goulder, an author of the study. This response—or lack thereof—has also been reported in more than 40 nonhuman primate species, but has not been seen in adults, who often have more aggressive immune reactions to pathogens. While limited, existing research indicates that some children with this protective attribute develop AIDS as they age, while others continue to display no symptoms. However, treatment may still be needed to prevent further transmission of the virus. SciDev.Net took an in-depth look at the European & Developing Countries Clinical Trials Partnership (EDCTP) and how its second iteration (EDCTP2) could be a catalyst for increased investments in health research and development (R&D) by African governments. EDCTP was launched in 2003 and ran through 2014, during which time it invested US$425 million into 254 collaborations between African and European scientists. The Partnership funded phase 2 and 3 clinical trials for HIV and AIDS, malaria, and tuberculosis. In 2014, EDCTP2 was established, expanding the scope to cover phase 1 and phase 4 (postmarketing surveillance) and to include other neglected infectious diseases. In just two years, EDCTP2 has mobilized nearly US$115 million. The role of the African member countries has been elevated in the second iteration—they have voting rights in the EDCTP General Assembly and have each pledged EUR€200,000 (US$224,000) to the Partnership.

This weekend, Kenya became the first country to roll out the world’s first and only pediatric tuberculosis (TB) medicines. TB infects one million children each year, resulting in 140,000 deaths, and yet, children have historically been treated with crushed up pills in estimated doses. The new formulations, which were developed by TB Alliance, are not only appropriately dosed for kids, but they are fruit-flavored and dissolvable—making them much more kid-friendly than a handful of bitter pills that must be swallowed. Kids must remain on treatment for six months, and the improved dose, flavor, and delivery are expected to have a significant impact on adherence to the regimen, preventing the development of drug-resistant strains. An additional 17 countries have placed orders and plan to introduce the medicines in the coming months. Vaccines and drugs could soon be manufactured on-the-go with the use of a portable, handheld kit developed by researchers at Harvard University. The kit contains all the ingredients needed to produce biologics (medical products derived from biological, rather than chemical sources): both the DNA that triggers the production of proteins to fight disease and the proteins that synthesize the final product. The DNA and proteins are freeze-dried into pellets, making them easy to store and transport, and with just the addition of water, the vaccine or therapy is ready to use. The team put the kit to work, successfully producing four different biologics, however, the vaccine candidate had to be purified before use. More research and testing is needed, and it could be more than a decade before such a system would be safe and appropriate for use in low-resource settings. Diarrheal diseases are a leading cause of death among children under five, and a new study suggests that 89 percent of cases are caused by pathogens. Further, 78 percent of cases are caused by just six pathogens, including rotavirus, Shigella, enterotoxigenic Escherichia coli (ETEC), Cryptosporidium, Campylobacter, and adenovirus. The researchers analyzed stool samples from more than 10,000 children under five, half of whom had diarrhea, to determine the leading causes of childhood diarrhea. Of the six, there is currently only a vaccine against rotavirus, however, GHTC member PATH is currently developing vaccines against Shigella and ETEC. Scientists are exploring whether the powerful antimicrobials created by certain species of ants could be used to fight infection in humans. Over the past 15 million years, more than 200 ant species have evolved to farm fungi—a symbiotic relationship in which the ants collect plants, feed them to fungi, and in turn, the ants feed off of the fungi. However, some ant species are vulnerable to hostile fungi that attack the ants’ nests and farmed fungi and have consequently adapted to fight off pathogens. These species cultivate bacteria—which appear as white patches along the ants’ bodies—that produce antibacterial and antifungal compounds. So far, the results have been encouraging: 1 in every 15 of these antimicrobial agents have proved promising in the lab, compared to just one in a million of those discovered through soil sampling.

The US National Institutes of Health (NIH) announced the Antimicrobial Resistance Diagnostic Challenge last week, a competition which will award US$20 million for the development of rapid, point-of-care diagnostics to combat antimicrobial resistance. The competition will be funded by NIH's National Institute of Allergy and Infectious Diseases and the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, while the US Centers for Disease Control and Prevention and the US Food and Drug Administration will provide scientific and regulatory expertise. Eligible diagnostics are those that either test for drug-resistant bacteria or differentiate between viral and bacterial infections, critical tools to reduce ineffective and unnecessary antibiotic prescriptions. The recently launched Coalition for Epidemic Preparedness Innovations (CEPI) will fund early stage human clinical trials and stockpile vaccine candidates for the viruses most likely to cause the next major epidemic. CEPI will collaborate with product developers and the World Health Organization (WHO) to facilitate regulatory review of vaccine candidates and to ensure that large scale clinical trials can be rapidly rolled out in the case of an outbreak. Eligible vaccine candidates will target viruses identified by the WHO as the greatest threats, including Crimean Congo hemorrhagic fever, Ebola and Marburg, Lassa fever, Rift Valley fever, Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS), and Nipah virus. The coalition was formed by the governments of India and Norway, philanthropic organizations the Wellcome Trust and the Bill & Melinda Gates Foundation, and the World Economic Forum and will be housed at the Norwegian Institute for Public Health in Oslo. The International Vaccine Institute (IVI) is partnering with Xiamen Innovax Biotech Co., Ltd. (Innovax) to expand access to the world’s first and only vaccine against Hepatitis E—a viral disease that causes 20 million infections and results in 70,000 deaths and 3,000 stillbirths each year. The vaccine, Hecolin®, was developed by Innovax and is only licensed for use in China. The Gates Foundation will support an assessment of the vaccine to determine its eligibility for WHO prequalification—a process that evaluates the safety, efficacy, and quality of a specific health tool produced by a specific manufacturer and that enables the product to be purchased by United Nations agencies. Hecolin® offered complete protection against hepatitis E in a phase 3 clinical trial with more than 100,000 participants. Pharmaceutical company Takeda has initiated a phase 3 clinical trial of its vaccine candidate against dengue fever, a mosquito-borne infection caused by four closely related viruses. Last year, pharmaceutical company Sanofi launched the world’s first dengue vaccine, however, new research suggests that the vaccine could actually increase the severity of infections in children who have never been exposed to dengue. This is due to antibody-dependent enhancement, in which protective antibodies against a virus (in this case, one strain of dengue virus) can actually help related viruses (the other three strains of dengue virus) attack human cells. Consequently, the antibodies produced by children receiving the vaccine could actually exacerbate the symptoms of future infections. In phase 1 and 2 trials, Takeda’s vaccine candidate appeared to be safe and resulted in the production of antibodies against all four strains of the virus. For its phase 3 trial, Takeda plans to enroll 20,000 children in dengue-endemic nations in Latin America and Asia. The trial will evaluate safety and efficacy against all four strains of dengue and in children with and without prior exposure to the virus.

Penicillin, the world’s first antibiotic, works by targeting certain proteins—appropriately named penicillin-binding proteins (PBPs)—that play a critical role in building and maintaining the bacterial cell wall. Now, scientists at Harvard Medical School have identified another class of proteins which play a similar role and could be a target for the next generation of antibiotics. The road to discovery started in 2003, when it was determined that certain bacteria could grow without PBPs. In their absence, the proteins responsible for maintaining cell wall shape, elongation, division, and spore formation (SEDS proteins) continued to function normally, enabling the bacteria to thrive. SEDS proteins are found in more types of bacteria than PBPs, and consequently a treatment targeting SEDS proteins could have even broader application than penicillin. On February 22, the Obama Administration requested US$1.9 billion in emergency funding for the Zika response, and 181 days later, Congress has yet to approve it. Consequently, the Department of Health and Human Services (HHS) has shifted $81 million from other programs to support Zika vaccine research and development—$34 million of which will go to the National Institutes of Health (NIH) and $47 million of which will be allocated to the Biomedical Advanced Research and Development Authority (BARDA). Earlier this year, HHS repurposed $589 million in funding from the Ebola response to combat Zika, however, that funding will run out by the end of this month. The NIH will use its funding for human clinical trials of its leading Zika vaccine candidate, however, the agency will need an additional $196 million for additional trials and to advance a second and third candidate. BARDA’s funding will enable the agency to secure contracts and establish partnerships for Zika vaccine development, however, an additional $342 million will be required to continue its work. New research suggests that infection with the Plasmodium parasite, which causes malaria, could reduce the severity of Ebola infection. A team of scientists at the US National Institute of Allergy and Infectious Diseases has examined 1,868 blood samples from an Ebola treatment unit in Liberia—1,182 of which tested positive for Ebola—concluding that patients co-infected with malaria were 20 percent more likely to survive. These results held true even when controlling for the patient’s age and viral load. Viral load actually correlated with survival rates: those with the highest levels of Plasmodium had an 83 percent survival rate, compared to 46 percent of those only infected with Ebola. At the treatment center, all patients were provided with antimalarials, and consequently, treatment for malaria was not responsible for survival rates. While the reason for this trend remains a mystery, Drs. Emmie de Wit and Kyle Rosenke—the study’s lead scientists—suspect that an existing malaria infection expedites the immune response to Ebola, consequently increasing survival rates.