Developing a Needle-Free Flu Vaccine
Decades of NIAID-funded research helped create FluMist, the first nasal spray vaccine for influenza approved by the Food and Drug Administration. The vaccine, manufactured by MedImmune, contains live but weakened influenza viruses that are cold-adapted, meaning that they reproduce only in cooler temperatures found in the nose and upper respiratory tract. Because the viruses cannot replicate at normal body temperature, they do not cause illness, but they do prepare the immune system for any future flu encounters.
Researchers at the University of Michigan established the cold-adapted viruses for use in the vaccine in 1967. During the 1970s, NIAID funded scientists within and outside the Institute to study and further develop the cold-adapted flu strains to the point where they could enter large-scale human testing. In 1995, NIAID partnered with a pharmaceutical company to begin evaluating the vaccine in clinical trials, many of which were conducted by the NIAID-supported Vaccine and Treatment Evaluation Units. FluMist first received Food and Drug Administration approval in 2003.
Today, the vaccine is recommended for healthy, non-pregnant individuals aged 2 to 49 years. It provides a welcome alternative for those who want their seasonal flu shot without the needle. In September 2009, another version of FluMist was approved to protect the same population from 2009 H1N1 influenza.
Nurse administers FluMist vaccine to a patient.
Credit: MedImmune
Enhancing HIV Vaccine Design
HIV mutates rapidly, leading to changes in its surface molecules that allow the virus to evade antibodies produced by the immune system. NIAID researchers have helped advance the design of a potential HIV vaccine by studying broadly neutralizing antibodies (bnAbs) that neutralize many HIV strains. Only about 20 percent of HIV-infected people naturally produce bnAbs, and usually they do so too late after infection for the bnAbs to be helpful.
In 2010, scientists at NIAID’s Vaccine Research Center (VRC) identified two bnAbs in the blood of an HIV-positive person that neutralize more than 90 percent of known HIV strains. Researchers have since found similar antibodies in almost a dozen HIV-infected people. This class of bnAbs binds to one of the few parts of the HIV surface that remains similar across HIV variants—the CD4 binding site, which helps the virus attach to cells. In 2012, VRC researchers identified a potent bnAb that targets a different vulnerable site on the virus’ surface.
Although these findings are encouraging, scientists still face the challenge of developing a vaccine that can elicit bnAbs. These antibodies undergo an unusually complex development and maturation process and typically gain potency against HIV after the virus has established infection. In 2013, NIAID-funded researchers at Duke University tracked in a patient the evolution of HIV and a bnAb called CH103. Although CH103 does not offer protection against as many strains of HIV as the bnAbs identified by the VRC researchers, it undergoes a much less complicated development process, which could make it easier to elicit with a vaccine.
Atomic structure of the antibody CH103 binding to the gp120 region of HIV.
Credit: NIAID
Preventing Mother-to-Child HIV Transmission
NIAID research on mother-to-child transmission (MTCT) of HIV has paved the way for new health interventions that have saved lives in the United States and abroad. In 1994, a landmark study co-sponsored by NIAID demonstrated that the drug AZT, given to HIV-infected women who had little or no prior antiretroviral therapy, reduced the risk of MTCT by two-thirds. This and other findings since then have helped reduce perinatal HIV infections in the United States by more than 90 percent, according to the Centers for Disease Control and Prevention.
In 1999, an NIAID-funded study in Uganda made a breakthrough that offered fresh hope to developing countries hit hardest by HIV and AIDS. Researchers found that two oral doses of the inexpensive drug nevirapine—one given to HIV-infected mothers at the onset of labor and another to their infants soon after birth—reduced MTCT by half when compared with a similar course of AZT. Subsequent clinical trials, including some funded by NIAID, showed that antiretroviral drugs also can reduce the risk of MTCT through breast milk. These and other studies have led to World Health Organization recommendations that can help prevent MTCT while allowing women in resource-limited settings to breastfeed their infants safely.
NIAID continues its commitment to research on reducing MTCT worldwide. In 2010, it helped launch the PROMISE study, a multinational clinical trial comparing different antiretroviral treatment regimens in hopes of finding the safest and most effective approaches to preventing MTCT. The study aims to enroll nearly 8,000 women and 6,000 infants from more than 15 countries.
African mother carrying child.
Credit: iStockphoto
Developing the World’s First Licensed Hepatitis A Vaccine
NIAID scientists played a crucial role in the development of Havrix, the world’s first licensed hepatitis A vaccine. Hepatitis A is an infectious disease of the liver caused by the hepatitis A virus (HAV). In 1973, NIAID researchers first identified HAV in fecal samples from infected human volunteers. In subsequent studies, they isolated and cultivated the HAV strain, called HM175, used to create the vaccine. They also developed methods to weaken and inactivate HM175 so it would trigger immune responses without causing disease, and tested HM175’s protective effect in animal models.
In 1988, SmithKlineBeecham (now called GlaxoSmithKline [GSK]) partnered with NIAID to develop HM175 as a candidate vaccine. GSK researchers conducted large clinical trials to determine its safety and effectiveness. NIAID, the Centers for Disease Control and Prevention (CDC), and the U.S. Army also were significantly involved in development of the vaccine, which received regulatory approval in Europe in 1991 and in the United States in 1995.
Today, Havrix helps prevent HAV infection in military personnel and travelers destined for areas where the virus is common. In the United States, hepatitis A vaccination is recommended for all children over the age of 1 and for high-risk groups such as men who have sex with men. According to the CDC, the rate of new hepatitis A infections in the United States declined by more than 92 percent between 1995 and 2008.
Hepatitis A vaccination is recommended for travelers destined for areas where hepatitis A virus is common.
Credit: iStockphoto
Helping Inner-city Children Breathe Easier
Asthma affects approximately 25 million people in the United States. It is the most common chronic condition among children and disproportionately affects children in poor urban communities. In 1991, NIAID launched its first multicenter initiative focused on inner-city asthma. Since then, NIAID has funded four similar initiatives.
These programs have significantly increased the understanding of key risk factors for asthma and evaluated a range of educational, behavioral, and environmental interventions. For example, research has shown that customized programs aimed at decreasing exposure to household allergens, such as dust mites, cockroaches, and rodents, can reduce asthma symptoms and the need for emergency room care or hospitalization. The Centers for Disease Control and Prevention now recommend such home-based interventions to improve the quality of life of inner-city children with asthma.
Today, studies supported by these initiatives seek to further understand the immune mechanisms at play in asthma and to explore ways of modifying the immune system to prevent or treat the disease, especially in vulnerable inner-city populations. The researchers involved in these studies also aim to develop more effective and longer lasting allergen immunotherapies, treatments in which patients receive gradually increasing amounts of allergens to build up their tolerance to them.
Girl half way down a slide, with playmate close behind.
Credit: iStockphoto
Inventing Effective Mosquito Repellants
Basic research conducted by NIAID-funded scientists led to the development of Kite Patch, a small sticker that renders humans undetectable by mosquitoes for up to two days. The sticker, which is worn on clothing, may offer an effective, nontoxic alternative to topical insect repellants. Kite Patch could help prevent the spread of malaria, dengue fever, and other mosquito-borne diseases.
Mosquitoes track humans by detecting exhaled carbon dioxide. Building off of previous work with fruit flies, NIAID-funded researchers in 2011 identified odor molecules that mask a mosquito’s carbon-dioxide-sensing ability. One type of molecule blocks the carbon dioxide receptor in the mosquito’s olfactory system. A second type of molecule strongly activates the mosquito’s carbon dioxide sensors over a long period of time. This sustained activation confuses the mosquito, and the insect is unable to locate the source of exhaled carbon dioxide.
Olfactor Laboratories licensed the technology, expanded the research, and incorporated into Kite Patch a set of compounds that activate or block the mosquito carbon dioxide receptor. Kite Patch has successfully deterred mosquitoes from humans in laboratory settings, and the company plans to begin field testing in Uganda in 2014.
NIAID continues to fund research to develop other new insect repellants. In 2013, researchers identified four compounds that elicit in mosquitoes a similar avoidance response to the one triggered by DEET, the commonly used but toxic insect repellent.
An Anopheles stephensi mosquito obtains a blood meal.
Credit: CDC
Understanding and Treating Fungal Infections
Fungal infections have emerged as a growing health threat, especially in people whose immune systems have been weakened by HIV or other causes. Cryptococcosis, caused by the ubiquitous fungus Cryptococcus neoformans, rarely affects people with healthy immune systems but is the most common fungal disease in HIV-infected people. If untreated, it can lead to fatal brain infection.
During the 1950s, NIAID researcher Chester Emmons, Ph.D., discovered the environmental source of C. neoformans. The fungus is found throughout the world in soil contaminated with bird excrement. Although only the asexual, yeast-like form of the fungus has been found in infected humans, C. neoformans also can reproduce sexually. Sexual reproduction of C. neoformans, which was first described by NIAID scientist K.J. Kwon-Chung, Ph.D., during the 1970s, forms infectious spores.
In addition to advancing knowledge of C. neoformans biology, NIAID scientists have focused on developing treatments for fungal infections. Much of the early work on the antifungal drug amphotericin B was performed at NIAID. Although effective at treating cryptococcosis, the drug can cause serious side effects, such as kidney damage. In 1979, NIAID scientists found that a combination of amphotericin B and flucytosine is as effective as and less toxic than high-dose amphotericin B.
Nearly two decades later, NIAID-funded scientists reported that amphotericin B plus flucytosine, followed by the antifungal drug fluconazole, substantially decreases the risk of dying from cryptococcosis in patients with AIDS or other immunodeficiencies. Today, this is the standard regimen for cryptococcosis treatment in HIV-positive people and other immunocompromised patients. NIAID continues to conduct and fund studies of potential new treatments for cryptococcosis and other fungal diseases.
Cryptococcus neoformans.
Credit: CDC
Guiding Food Allergy Care Across Medical Specialties
Food allergy is a serious health concern in the United States. Currently, no treatment exists for the disease; it can be managed only by avoiding the allergenic food or by treating symptoms when they arise. These symptoms range from mild to severe and, in some rare cases, can be life-threatening. It is difficult to diagnose food allergy accurately, and non-allergic food reactions, such as food intolerance, often are misclassified as food allergy, resulting in the over-diagnosis of the disease.
In 2010, an NIAID-sponsored expert panel took a major step toward improving the diagnosis and management of patients with food allergy by issuing comprehensive food allergy guidelines. The clinical guidelines establish consistency in terminology and definitions, diagnostic criteria, and management practices for acute and severe food-allergic reactions. They resulted from a two-year collaborative effort in which NIAID worked with 34 professional organizations, federal agencies, and patient advocacy groups.
The guidelines are intended for use by a variety of health care professionals, including specialists in areas such as allergy, pediatrics, family medicine, internal medicine, dermatology, gastroenterology, emergency medicine, and pulmonary and critical care medicine. The ultimate beneficiaries, however, are patients and their families.
Children looking in friend’s lunch bag.
Credit: Getty Images
Improving the Standard of Care for HIV-Infected Infants
Each year, hundreds of thousands of babies around the world are born with HIV. Though their developing immune systems make them more susceptible to rapid HIV disease progression and death, many of these children do not get tested for the virus, get tested too late, or get tested but lack access to life-saving antiretroviral therapy (ART).
In 2005, a study sponsored by NIAID with support from the departments of health of the Western Cape and Gauteng in South Africa, the London-based Medical Research Council, and GlaxoSmithKline set out to determine the best time to start ART in infants. The standard of care at that time was to begin ART in infants when they showed signs of HIV illness or a weakened immune system. The results of the Children with HIV Early Antiretroviral Therapy (CHER) study, announced in 2007 and published the following year, have helped improve this standard.
The CHER study found that testing at-risk infants for HIV and then giving ART immediately to those who test positive dramatically reduces the rates of illness and death. HIV-infected infants were four times less likely to die if given ART immediately after they were diagnosed with HIV, when compared with the standard of care.
This finding helped influence the World Health Organization (WHO) to change its guidelines for treating HIV-infected infants. The guidelines now strongly recommend starting ART in all children under age 2 immediately after they have been diagnosed with HIV, regardless of their health status.
In 2010, a clinical trial funded by NIAID and the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development found that African infants less than 3 years old had better outcomes with an ART regimen based on protease inhibitors than infants given an ART regimen based on nevirapine. The WHO currently is reviewing the results of this and other studies to determine whether to change recommendations about which treatment regimen is best for HIV-infected infants.
Father and child in a village in southern Africa.
Credit: iStockphoto
Helping Prevent Childhood Pneumococcal Infections
Streptococcus pneumoniae is a major bacterial cause of invasive diseases such as pneumonia and meningitis, resulting in approximately 1 million childhood deaths annually. While a pneumococcal vaccine has existed for some time, the original vaccine was not effective in young infants, one of the populations most vulnerable to devastating pneumococcal disease.
Basic research supported by NIH helped establish conjugate vaccines, a novel technology that enables a vaccine to be recognized by an infant’s immune system. During the 1990s, NIAID helped fund the development of a pneumococcal conjugate vaccine that protects against strains of S. pneumoniae commonly found in the United States. The Food and Drug Administration approved this vaccine in 2000.
Before a conjugate vaccine was available, approximately 65,000 cases of invasive pneumococcal disease (IPD) occurred in the United States each year. Seven years after the vaccine was introduced, the overall incidence of IPD among U.S. children decreased by 45 percent, while the incidence of IPD caused by the vaccine-targeted strains fell by 94 percent.
Soon after the conjugate vaccine was developed for use in the United States, NIAID set out to learn if it might work in the developing world, where most IPD deaths occur. NIAID supported development of a conjugate vaccine that combined S. pneumoniae strains commonly found in developing countries. It then joined with the British Medical Research Council, the Gambian government, the World Health Organization, and others to test the vaccine in The Gambia. The vaccine was found to be effective in that setting. Health authorities and other groups are now working with industry to introduce pneumococcal vaccinations in resource-poor nations.
Scanning electron micrograph of Streptococcus pneumoniae.
Credit: CDC/J. Carr
Understanding and Detecting Drug-Resistant Malaria
Since the 1940s, highly effective malaria drugs have reduced deaths from this mosquito-borne parasitic disease. The drug chloroquine was widely used after World War II, but Plasmodium falciparum, the most deadly malaria parasite, quickly developed ways to evade the drug’s effects. Chloroquine-resistant parasites emerged in Southeast Asia in the 1950s and spread into Africa over the next two decades.
In 2000, NIAID scientists discovered that mutations in a single parasite gene cause chloroquine resistance. In collaboration with colleagues in the United States and Mali, Africa, the NIAID researchers developed a molecular marker that can be used to diagnose people infected with chloroquine-resistant malaria parasites and to investigate the origin and worldwide spread of these parasites.
Today, control of P. falciparum malaria mainly depends on artemisinin-based combination therapy, which combines fast-acting artemisinin with longer-lasting drugs. However, parasites resistant to artemisinin are beginning to emerge and spread in Southeast Asia. A better understanding of the molecular mechanism of artemisinin resistance could help researchers design new antimalarial treatments and potentially prolong the usefulness of existing drugs.
In 2013, NIAID scientists, together with French and Cambodian colleagues, developed a new test that detects artemisinin-resistant parasites in malaria-infected people. This test will enable health officials to track the spread of resistance and choose appropriate treatments, as well as help scientists screen new malaria drug candidates in the laboratory.
Boy in Liberia, West Africa.
Credit: iStockphoto
Developing Novel Tuberculosis Drugs
Current tuberculosis (TB) treatment regimens require people to take several antibiotic drugs for at least six months. The difficulty of faithfully completing these treatments has contributed to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the bacterium that causes the disease.
NIAID supports and conducts research to identify new and improved TB drugs, and scientists have uncovered numerous drug candidates during the past two decades. In the late 1990s, NIAID researchers tested more than 60,000 compounds related to the TB drug ethambutol. They identified several compounds that were effective against Mtb in the laboratory and collaborated with the pharmaceutical company Sequella on further drug development. Mouse studies revealed that a compound called SQ109 kills Mtb, including drug-resistant strains, in the animals’ lungs.
Early human clinical studies indicated that SQ109 is safe, and additional clinical trials are underway to evaluate SQ109’s effectiveness. The Food and Drug Administration (FDA) has granted SQ109 Orphan Drug and Fast Track status, which could help accelerate eventual FDA approval.
In 2000, NIAID scientists and collaborators reported the discovery of another potential TB drug, PA-824. In the laboratory, the drug eliminates both actively growing Mtb and a dormant form of the bacterium, suggesting that it might be effective against latent TB infections. Currently, there are no drugs that specifically target latent TB. PA-824 entered clinical trials in 2005, and initial results suggest that it is safe and effective.
NIAID researchers and NIAID-funded scientists also are investigating the anti-TB action of existing drugs. For example, in 2012, results from an NIAID-funded clinical trial indicated that the antibiotic linezolid is effective against extensively drug-resistant TB.
Sputum cultures from tuberculosis patients. Sputum often is used to detect and identify bacteria in the lungs.
Credit: NIAID
Advancing Toward an Effective HIV Vaccine
When the results of the RV144 clinical trial were announced in 2009, it marked the first time that a candidate HIV vaccine strategy had demonstrated some ability to prevent HIV infection. There were 31 percent fewer HIV infections among trial participants who received doses of two investigational HIV vaccines compared to those who received placebo injections. The study, sponsored by the U.S. Army in collaboration with NIAID, Sanofi Pasteur, and Global Solutions for Infectious Diseases, enrolled more than 16,000 adult men and women in Thailand.
Since the RV144 trial, researchers have sought to understand and build on the findings. For example, they found that, among participants who received the experimental vaccines, those who produced high levels of antibodies that bind to specific parts of HIV’s outer shell after vaccination were less likely to become infected with HIV than those who did not.
In 2012, NIAID researchers and collaborators suggested that these vaccine-induced antibody responses block certain HIV variants from establishing infection. By examining HIV genetic sequences from 110 HIV-infected RV144 volunteers, the researchers identified two genetic signatures in the Env V2 region of HIV’s outer shell that contributed to the vaccine’s effectiveness. The researchers estimated that the vaccine was 80 percent effective against HIV variants containing both signatures.
These and other findings will help scientists modify the vaccine regimen to increase its level of protection against HIV. Studies also are underway to determine whether additional doses can increase the vaccine’s effectiveness.
An HIV-infected T cell.
Credit: NIAID
Pursuing a Universal Flu Vaccine
Seasonal flu vaccines are designed to be effective against a select few strains of currently circulating influenza viruses. Like natural exposure to the virus, the seasonal vaccine elicits antibodies that bind to the head region of the lollipop-shaped viral protein hemagglutinin (HA), preventing the virus from entering and infecting cells. The HA head frequently undergoes genetic changes as flu viruses evolve, making the antibodies produced against one strain ineffective against another. Researchers at NIAID and elsewhere are helping advance the development of a universal flu vaccine—one that stimulates an immune response that can neutralize multiple influenza strains.
NIAID scientists showed in 2010 that a two-step immunization strategy called prime-boost vaccination triggers production of broadly neutralizing antibodies (bnAbs) in laboratory animals, protecting them from a variety of influenza strains. These bnAbs targeted the stem region of HA, which unlike the head, varies little among flu viruses.
In 2013, NIAID scientists showed how a novel synthetic flu vaccine could protect mice and ferrets against a wide range of flu strains. The scientists fused HA from a 1999 strain of H1N1 flu with ferritin, a protein that naturally forms spherical clusters, to create microscopic nanoparticles. The nanoparticle vaccine protected animals against many H1N1 strains, including a 2007 strain, suggesting that the vaccines might protect against future strains of the flu. Today, NIAID continues to fund research to understand how bnAbs evolve and to develop new protective strategies against rapidly mutating influenza viruses.
H1N1 influenza virus particles. Surface proteins on the virus particles are in black.
Credit: NIAID
Developing Radiation and Nuclear Countermeasures
NIAID research paved the way for the first drug approved by the U.S. Food and Drug Administration (FDA) to treat radiation-induced bone marrow injury following a nuclear disaster. Exposure to high levels of radiation affects many of the body’s cells, including the rapidly dividing cells of the bone marrow. This exposure reduces the number of pathogen-fighting neutrophils and clot-forming platelets in the blood, which can lead to death from infection or excessive bleeding.
In 2013, NIAID-funded researchers reported that the blood-boosting drug filgrastim almost doubles the survival rate in radiation-exposed monkeys. Seventy-nine percent of animals that received filgrastim survived for more than 60 days after radiation exposure, compared to 41 percent of animals that did not receive the drug. Monkeys that received filgrastim also experienced fewer infections than those not given the drug.
Based on these study results, an FDA advisory panel concluded that filgrastim therapy is likely to benefit humans exposed to radiation. Because human studies of the drug’s effectiveness cannot be done ethically, the FDA approved filgrastim as a radiation medical countermeasure under its Animal Rule, a regulation that permits approval of some products based on efficacy testing in animals and safety testing in humans. The approval promises to improve access to filgrastim during a public health emergency.
A red blood cell (left), platelet (center), and white blood cell (right). Radiation can reduce the levels of blood cells, increasing a person’s risk of infection and bleeding.
Credit: National Cancer Institute
Advancing Early, Rapid Diagnosis of River Blindness
The eye and skin infection known as onchocerciasis, or river blindness, affects more than 18 million people worldwide, mostly in rural African communities near streams and rivers. The disease is caused by the parasite Onchocerca volvulus, which is spread through the bite of an infected blackfly. Symptoms of onchocerciasis, which can include severe itching and eye lesions, develop slowly and may not become apparent until years after infection.
Currently, health care workers diagnose onchocerciasis by removing small pieces of skin to look for O. volvulus larvae. However, this technique cannot detect early infections. The lack of a quick and inexpensive test to detect O. volvulus makes it difficult to track new infections and provide timely treatment.
During the early 1990s, NIAID scientists identified Ov16, an O. volvulus protein that is abundant in the early stages of infection. The researchers showed that antibodies against Ov16 can be detected in the blood of infected people up to one year before infection appears in the skin. This simple blood test showed promising results in initial field trials conducted in seven West African villages during late 1999 and early 2000.
In 2013, NIAID investigators licensed the technology to the Program for Appropriate Technology in Health for the development of a rapid, noninvasive, and inexpensive diagnostic test that health care workers in resource-poor settings can use. By enabling early detection and treatment of river blindness, this test promises to aid efforts to eradicate the disease.
An O. volvulus parasite emerges from an infected blackfly.
Credit: Armed Forces Institute of Pathology
Developing Noninvasive Tests to Predict and Diagnose Kidney Rejection
One of the most serious problems facing organ transplant recipients is rejection, when the immune system attacks the transplanted organ as if it were a threat. The current gold standard for diagnosing kidney transplant rejection is the biopsy, in which doctors remove a small piece of kidney tissue to look for rejection-associated damage. Doctors usually perform biopsies when kidney damage is already evident. Although generally considered safe, the procedure carries some risks, such as bleeding and pain. In addition, the small biopsy samples may not accurately reflect the condition of the entire kidney.
One of the goals of the NIAID-sponsored Clinical Trials in Organ Transplantation (CTOT) program is to discover molecules, called biomarkers, that physicians can use to safely and accurately diagnose or predict transplant rejection. In 2013, CTOT investigators reported results from two trials that evaluated urinary biomarkers of kidney transplant rejection. In one study, scientists identified a set of three biomarkers that can accurately detect and predict rejection. In the second study, researchers found that levels of a certain urinary protein can distinguish kidney recipients at low risk of developing kidney rejection from those at high risk.
Although these noninvasive urine tests require further development before they can be used in clinical practice, they offer the possibility of routine monitoring for kidney transplant rejection. This would allow doctors to intervene only when treatment is required and to adjust immunosuppressive medications as needed, leading to more personalized care and better long-term outcomes for kidney transplant recipients.
Scene from the U.S. Transplant Games, a four-day athletic competition among transplant recipients.
Credit: National Kidney Foundation, 2010 U.S. Transplant Games.
Understanding Human Resistance to Malaria
NIAID researchers have played a crucial role in determining what makes some people resistant to malaria. Understanding malaria resistance mechanisms promises to help scientists identify ways to mimic these protective effects using drugs or vaccines.
During the mid-1970s, NIAID researchers found that people who lack a red blood cell protein called the Duffy antigen are resistant to Plasmodium vivax, the most geographically widespread of the five malaria parasites that infect humans. NIAID scientists were the first to show that P. vivax depends on the Duffy antigen for entry into red blood cells (RBCs).
More recently, NIAID research has shed light on other mechanisms of malaria resistance. Certain parasite proteins alter the surfaces of infected RBCs, causing them to stick to blood vessels. NIAID scientists found that RBCs from malaria-infected children with a type of oxygen-carrying hemoglobin called hemoglobin C have lower amounts of a specific parasite protein. This trait impaired the cells’ stickiness and may make African children less prone to deadly cerebral malaria, which is caused by parasite-infected RBCs accumulating in the brain.
A separate NIAID study in Mali, Africa, showed that a deficiency in the enzyme glucose-6-phosphate dehydrogenase confers protection against severe, life-threatening malaria. Continued study of these and other human resistance mechanisms will help scientists understand how malaria parasites cause disease and develop new ways to control malaria.
Red blood cell infected with malaria parasites (blue). Uninfected cells are shown in red.
Credit: NIAID
Using Drugs to Prevent HIV Infections
Pre-exposure prophylaxis, or PrEP, is an HIV prevention strategy in which HIV-negative people at risk for HIV infection take drugs daily to reduce the chance they will become infected. In 2010, the NIAID-funded iPrEx clinical trial found that, among men who have sex with men, those who took Truvada—a combination of the HIV drugs emtricitabine and tenofovir—had a 44 percent lower risk of HIV infection than those taking placebos.
The study found that PrEP was even more effective—reducing the risk of infection up to 73 percent—among participants who closely followed the daily drug regimen. Based on findings from iPrEx and other studies, the Food and Drug Administration approved Truvada for HIV prevention in 2012.
However, results from other studies, including the NIAID-sponsored VOICE study, have been less encouraging. VOICE enrolled more than 5,000 women in Africa assigned to groups receiving tenofovir-containing vaginal gel, tenofovir pills, Truvada, or placebo. Scientists reported in 2013 that rates of new HIV infections were comparable among all the groups. For reasons that are unclear, many of the women did not use their assigned regimen as directed.
NIAID continues to work to identify effective PrEP strategies. A new NIAID-funded clinical trial called NEXT-PrEP will test the ability of the drug maraviroc, alone or in combination with tenofovir and emtricitabine, to prevent HIV infections in men and women who have sex with men. While tenofovir and emtricitabine interfere with viral replication after HIV has infected a cell, maraviroc prevents HIV from entering cells.
Cartoon representation of tenofovir, one of the components of Truvada.
Credit: Wikimedia Commons (User: Damien Persohn)
Protecting Animals from Infectious Diseases
A technology conceived during the 1980s by NIAID researchers is today being used to protect millions of animals from serious infectious diseases. NIAID’s pox-vector technology, licensed in 2006 by animal product company Merial, has been developed into more than 15 different vaccines approved by the U.S. Department of Agriculture to safeguard companion animals, farm animals, and wild animals from diseases that are often fatal, including feline leukemia, rabies, distemper, and avian influenza.
A pox-vectored vaccine uses weakened versions of a poxvirus to deliver modified genetic material from another infectious organism. The vaccine provides just enough viral material to stimulate the immune system, but it does not cause disease in an otherwise healthy animal.
For example, Merial’s Raboral V-RG is an oral pox-vectored vaccine for rabies. It is encased in solid bait, which enables health officials to immunize large numbers of wildlife by airplane or helicopter, or by hand. Local, state, and federal agencies have used oral rabies vaccines such as Raboral in more than 15 states to curtail the geographic expansion of rabies spread by raccoons, the most frequently reported rabid wildlife species.
NIAID pox-vector technology has been used in vaccines to protect companion animals from infectious disease.
Credit: CDC/J. Gathany