Selected NIAID Research Advances of 2016
Message from the Director
The National Institute of Allergy and Infectious Diseases (NIAID) conducts and supports research to better understand, treat, and prevent infectious, immunologic, and allergic diseases.
This slideshow highlights scientific advances made by NIAID researchers and NIAID-funded scientists in the United States and abroad during fiscal year 2016. Some advances brought us closer to vaccines and treatments for HIV/AIDS, Zika, influenza, and other infectious diseases of global importance. Other developments offered new insights into allergic and autoimmune diseases, and immune responses to infection. Together, these advances illustrate how public investment in biomedical research drives scientific progress and benefits human health.
For more than 60 years, NIAID research has led to new therapies, vaccines, diagnostic tests, and other technologies that have improved the health of millions of people in the United States and around the world. Through our sustained commitment to basic and clinical research, we will continue to address global health challenges for years to come.
Anthony S. Fauci, M.D., Director, National Institute of Allergy and Infectious Diseases, National Institutes of Health
Preventing and Treating Zika Virus Infection
Multiple countries in the Americas, the Pacific, and Southeast Asia are experiencing active transmission of the mosquito-borne Zika virus. Most people who become infected with Zika virus experience either no symptoms or only mild illness for up to a week. However, infection during pregnancy can lead to severe birth defects. Currently, there are no vaccines or specific therapies to prevent or treat Zika virus disease.
Development of a vaccine to prevent Zika virus infection is a major NIAID research focus. In 2016, NIAID researchers found that two experimental vaccines protected monkeys against Zika infection after two doses. Both vaccines are now being evaluated in clinical studies in humans.
NIAID-supported research also has advanced understanding of immune responses to Zika virus. NIAID-funded scientists found that Zika virus infection confers protection against future infection in monkeys, suggesting that a vaccine that mimics natural immunity to Zika virus may be protective. They also found that the virus lingers in the bodies of pregnant monkeys for a prolonged time, and they are continuing to study the potential effects of this persistent infection.
Another group of NIAID-supported researchers identified in Zika-infected mice two antibodies that neutralized diverse Zika virus strains. Mice given these antibodies as a preventive treatment developed lower blood levels of Zika virus and did not develop clinical signs of infection. The researchers also developed atomic-level structural images of the antibodies bound to a Zika virus protein, information that may aid vaccine development.
Papers: K. Dowd et al. Rapid development of a DNA vaccine for Zika virus. Science DOI: 10.1126/science.aai9137
D Dudley et al. A rhesus macaque model of Asian-lineage Zika virus infection. Nature Communications DOI: 10.1038/ncomms12204
H Zhao et al. Structural basis of Zika virus specific antibody protection. Cell DOI: 10.1016/j.cell.2016.07.020
Zika virus (red) isolated from a microcephaly case in Brazil.
Preventing Peanut Allergy
Peanut allergy is a growing public health problem. Results from the landmark NIAID-funded Learning Early About Peanut Allergy (LEAP) clinical trial reported in 2015 showed that introducing peanut-containing foods to infants deemed at high risk for developing peanut allergy was safe and led to an 81 percent relative reduction in development of peanut allergy by age 5. The infants participating in LEAP were high risk because they already had severe eczema, egg allergy, or both.
In 2016, researchers reported results from the LEAP-On study, an extension of LEAP that showed that the benefits of regularly consuming peanut-containing foods early in life to prevent the development of peanut allergy persist even after stopping peanut consumption for one year. In LEAP-On, all LEAP participants—both peanut consumers and peanut avoiders—were instructed to avoid peanut completely for one year. At age 6, following the avoidance period, children underwent an oral food challenge with peanut.
The clinical benefit seen in the peanut-consumer group persisted through this phase of the study, demonstrating that peanut tolerance achieved through early and regular peanut consumption is robust and durable.
Paper: G du Toit et al. Effect of avoidance on peanut allergy after early peanut consumption. New England Journal of Medicine DOI: 10.1056/NEJMoa1514209
A jar of peanut butter.
Understanding How Powerful Anti-HIV Antibodies Evolve
A minority of people living with HIV naturally produce broadly neutralizing antibodies (bNAbs) that target multiple, diverse HIV strains. HIV bNAbs undergo a complex development and maturation process before achieving their mature, HIV-fighting form. Understanding how bNAbs develop and evolve promises to aid HIV vaccine development efforts.
In 2016, NIAID-supported researchers reported that people with HIV infection who produce bNAbs have different immunological profiles than those who do not produce bNAbs. By comparing blood samples from people with high bNAb levels with those from people with few or no bNAbs, the researchers identified specific immune cell subsets and functions that correlated with high levels of bNAbs. Defining how to safely replicate these attributes in HIV-uninfected vaccine recipients may lead to improved experimental vaccines to protect against HIV.
In a separate study, NIAID-supported researchers and colleagues from NIAID’s Vaccine Research Center analyzed blood samples collected over time from a single individual living with HIV. They monitored the evolution of a particular bNAb from acute to chronic HIV infection. Furthermore, they found that development of this bNAb had affected development of a separate type of bNAb, which neutralizes HIV in a different manner. This analysis revealed critical features in the bNAb development process that could be exploited by vaccination strategies to elicit the immune systems of uninfected people to produce bNAbs against HIV.
Papers: M Moody et al. Immune perturbations in HIV-1-infected individuals who make broadly reactive neutralizing antibodies. Science Immunology DOI: 10.1126/sciimmunol.aag0851
M Bonsignori et al. Maturation pathway from germline to broad HIV-1 neutralizer of a CD4-mimic antibody. Cell DOI: 10.1016/j.cell.2016.02.022
Blood bags used to study HIV infection
Using Antibody Infusions to Prevent and Treat HIV Infection
Scientists are exploring broadly neutralizing antibodies (bNAbs) that target multiple, diverse HIV strains as potential tools for HIV prevention and treatment.
In 2016, NIAID scientists and colleagues reported that a single antibody infusion can protect monkeys against infection with SHIV, an HIV-like virus. The scientists gave a single infusion of one of four individual HIV bNAbs—VRC01, 3BNC117, 10-1074, or a modified version of VRC01—to four groups of monkeys, then exposed the animals weekly to low doses of SHIV. In all cases, the bNAb infusion delayed the acquisition of SHIV, with the longest period of protection lasting 23 weeks.
In a separate study in humans, scientists at NIAID’s Vaccine Research Center found that a single infusion of VRC01 can suppress the level of HIV in the blood of infected people who are not taking antiretroviral therapy (ART). The study involved 23 people living with HIV, eight of whom were not taking ART. In six of these eight people, VRC01 infusions reduced viral load (the amount of HIV in blood) more than 10-fold. The antibody did not appear to have an effect in people taking ART, in whom the virus was already suppressed.
Several ongoing NIAID-supported studies, including the AMP studies assessing whether VRC01 can safely prevent HIV infection in people, promise to further elucidate the potential role of HIV bNAbs in preventing or treating HIV infection.
Papers: R Gautam et al. A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges. Nature DOI: 10.1038/nature17677
RM Lynch, E Boritz et al. Virologic effects of broadly neutralizing antibody VRC01 administration during chronic HIV-1 infection. Science Translational Medicine DOI: 10.1126/scitranslmed.aad5752
Model of the VRC01 broadly neutralizing antibody.
Improving Influenza Vaccines
Currently, influenza vaccines must be updated annually to target the viruses predicted to circulate in a given year. Recent work conducted and supported by NIAID has increased understanding of factors that may affect flu vaccine effectiveness, providing valuable information for the development of new and improved vaccines.
Seasonal flu vaccines aim to elicit antibodies against the influenza protein hemagglutinin (HA). Higher levels of anti-HA antibodies have long been associated with greater protection against influenza infection. After exposing healthy volunteers to 2009 H1N1 influenza virus under carefully controlled conditions, NIAID scientists observed that antibodies against a different viral protein—neuraminidase—were the better predictor of protection against flu infection and severity of illness. The researchers suggest that the role of neuraminidase antigens should be considered for development of future influenza vaccine platforms.
In another study, NIAID-funded scientists evaluated immune responses to 2009 H1N1 influenza virus and found that people with low levels of preexisting H1N1-specific antibodies generated neutralizing antibodies targeting the stalk region of HA, which changes little between different influenza strains. Those with higher levels of preexisting antibodies generated antibodies targeting the highly variable head region of HA. The investigators also noted that preexisting anti-head antibodies prevented clear access to the stalk by anti-stalk antibodies. These data suggest that considering immune history will be critical in the design of a universal flu vaccine that targets a wide variety of influenza strains.
Papers: MJ Memoli et al. Evaluation of antihemagglutinin and antineuraminidase antibodies as correlates of protection in an influenza A/H1N1 virus healthy human challenge model. mBio DOI: 10.1128/mBio.00417-16
SF Andrews et al. Immune history profoundly affects broadly protective B cell responses to influenza. Science Translational Medicine DOI: 10.1126/scitranslmed.aad0522
A woman receives the seasonal influenza vaccine.
Advancing HIV Vaccine Design
Scientists are working to develop HIV vaccine regimens that stimulate the immune systems of uninfected people to produce broadly neutralizing antibodies (bNAbs) that target multiple, diverse HIV strains. In 2016, research conducted and supported by NIAID helped advance toward this goal.
A team led by scientists at NIAID’s Vaccine Research Center discovered a new vulnerable site on HIV called the fusion peptide and a bNAb that binds to the fusion peptide, stopping the virus from infecting a cell. The researchers isolated a powerful bNAb, named VRC34.01, from the blood of an HIV-infected person. Further experiments allowed them to characterize in atomic-level detail how VRC34.01 attaches to the HIV fusion peptide and revealed that VRC34.01 stops the virus from infecting a cell by binding to a key cell-surface molecule. The researchers now are working to create a vaccine designed to elicit antibodies similar to VRC34.01.
Antibodies are produced by immune B cells, which start off as precursor cells and mature to produce specific antibodies. NIAID-funded researchers have studied precursor cells that mature to produce a specific HIV bNAb known as VRC01 and have found that almost everybody has these bNAb-precursor B cells. The researchers precisely engineered a protein called eOD-GT8 that they show can bind to these precursor cells, demonstrating that this protein has the potential to induce these precursors to develop into HIV bNAb-producing cells. The findings support further exploration of eOD-GT8 as a potential vaccine candidate.
Papers: R Kong et al. Fusion peptide of HIV-1 as a site of vulnerability to neutralizing antibody. Science DOI: 10.1126/science.aae0474
JG Jardine, DW Kulp, C Havenar-Daughton, A Sarkar et al. HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science DOI: 10.1126/science.aad9195
Model of VRC34.01 (green and yellow) bound to the fusion peptide (red) on a spike on HIV’s surface (gray).
Assessing Islet Transplantation to Treat Type 1 Diabetes
People with type 1 diabetes who have impaired awareness of hypoglycemia—an inability to sense low blood sugar levels—are at high risk of experiencing dangerous drops in blood sugar (known as severe hypoglycemia) that can lead to seizures, loss of consciousness, and death. Some experience these problems despite expert medical management of their diabetes.
In 2016, researchers from the NIH-funded Clinical Islet Transplantation Consortium reported results from a clinical trial showing the benefits of transplantation of pancreatic islets (cell clusters that contain insulin-producing cells) for people with type 1 diabetes complicated by severe hypoglycemia despite expert medical treatment. The 48 participants each received at least one transplant of pancreatic islets prepared from deceased donors using a standardized manufacturing protocol.
One year after transplantation, 88 percent of participants were free of severe hypoglycemic events, had near-normal control of blood sugar levels, and had restored hypoglycemic awareness. After two years, 71 percent of participants met these criteria. Side effects included bleeding at the time of transplant and modest reductions in kidney function, most likely a result of taking immune-suppressing drugs to prevent rejection of the donor islets.
The researchers are continuing to follow the participants to evaluate the durability of the benefits of islet transplantation and the long-term risks of chronic immunosuppression.
Paper: BJ Herring, WR Clarke, ND Bridges, TL Eggerman et al. Phase 3 trial of transplantation of human islets in type 1 diabetes complicated by severe hypoglycemia. Diabetes Care DOI: 10.2337/dc15-1988
The pancreas contains clusters of cells called islets. Beta cells within the islets make insulin and release it into the blood.
Developing Treatments for Ebola Virus Disease
There are currently no licensed treatments for Ebola virus infection, which caused more than 11,000 deaths during the 2014-2015 outbreak in West Africa. The experimental treatment ZMapp, a cocktail of three anti-Ebola antibodies derived from Ebola-immunized mice, has shown some promise in clinical studies.
Scientists from NIAID’s Vaccine Research Center and colleagues aimed to identify human antibodies against Ebola virus that could be used in a simplified treatment approach. The researchers identified and isolated anti-Ebola antibodies from the blood of a survivor of the 1995 Ebola outbreak in Kikwit, Democratic Republic of the Congo. In the laboratory, two of the antibodies, named mAb100 and mAb114, neutralized both older and more recent variants of Ebola virus and induced killing of Ebola-infected cells.
Next, the scientists tested the antibodies in animal studies. Investigators administered a lethal dose of Ebola virus to four monkeys, waited five days, and then treated three of the animals with daily intravenous injections of mAb114 for three days. The untreated control animal showed indicators of Ebola virus disease and died on day nine. The treated group survived and remained free of Ebola symptoms.
The finding suggests that simplified therapeutic regimens with these antibodies could confer protection against Ebola virus disease in people infected with the virus, even several days after exposure.
Paper: D Corti, J Misasi et al. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science DOI: 10.1126/science.aad5224
Ebola virus particles (green).
Evaluating the Potential of a Vaccine against Dengue Virus
Dengue fever, prevalent throughout the tropics and subtropics, is caused by any of four related dengue viruses—called serotypes—that are spread by Aedes mosquitoes. Although the majority of people who become infected with dengue virus develop mild or no symptoms, the infection can cause serious illness. In dengue-endemic areas, many adults have experienced infection in the past, and this high degree of pre-existing immunity makes it difficult to assess the effectiveness of dengue vaccine candidates.
NIAID researchers designed a human challenge model in which volunteers are exposed to an infectious dengue virus under carefully controlled conditions to evaluate the TV003 dengue vaccine candidate developed by NIAID scientists. TV003 comprises live, weakened strains of each of the four dengue virus serotypes.
Six months after administration of a single dose of TV003 or a placebo, volunteers at two clinical research sites in the United States were exposed to a modified dengue-2 virus strain that causes viremia—virus in the blood—and a dengue rash. All 21 volunteers who received TV003 were protected from infection (viremia and rash), while all 20 placebo recipients experienced full infection.
The results informed the decision by officials in Brazil to advance TV003 into a large clinical trial. In addition, the findings suggest that the modified dengue-2 strain used in this challenge study, as well as a recently developed modified dengue-3 strain, may be useful tools for evaluating future dengue vaccine candidates before initiating clinical trials in areas where the virus is endemic.
Paper: BD Kirkpatrick, SS Whitehead et al. The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a human challenge model. Science Translational Medicine DOI: 10.1126/scitranslmed.aaf1517
Adult Aedes aegypti mosquito, which can spread dengue virus.
Advancing Toward a Malaria Vaccine
While substantial progress has been made to control and eliminate malaria, it continues to be a major global health problem. A malaria vaccine that provides long-term protection would help eliminate transmission and reduce deaths from malaria. With support from NIAID, the biotechnology firm Sanaria developed the experimental PfSPZ vaccine, which is composed of live but weakened sporozoites (the early developmental form) of the malaria-causing Plasmodium falciparum parasite.
In 2016, NIAID researchers and collaborators reported findings from an early-stage clinical trial showing that the PfSPZ vaccine protected a small number of healthy adults in the United States who had never had malaria from infection for more than one year after immunization.
The researchers assessed how vaccine dosage, regimen, and route of administration affected protection. Collectively, the data showed that four intravenous infusions with the PfSPZ vaccine provided malaria protection for 59 weeks in 55 percent of people. In those people, the vaccine appeared to confer sterile protection, meaning the individuals would be protected against disease and could not further transmit malaria. Participants tolerated the vaccinations well, and there were no serious side effects attributed to vaccination.
Based on the favorable safety profile observed in this study, scientists are testing higher doses of PfSPZ in larger clinical trials to see if even greater long-term protection can be achieved against different P. falciparum strains.
Paper: AS Ishizuka et al. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nature Medicine DOI: 10.1038/nm.4110
Malaria-infected red blood cell.
Understanding How Infections Compromise Long-Term Immunity
Although scientists have long thought that infections may initiate the development of chronic inflammatory diseases, direct evidence supporting this idea has been lacking. Recent NIAID-led research in mice indicates that a single gut infection can create long-lasting immunological damage. Furthermore, the naturally occurring bacteria in the gut, or microbiota, may help maintain immune imbalance despite clearance of the initial infection.
The scientists infected mice with Yersinia pseudotuberculosis, a foodborne bacterium that also infects people. While some mice recovered normally, others exhibited long-term abnormalities in the gut, including enlarged lymph nodes and chronic inflammation. The inflammation was associated with leakage of certain immune cells out of the lymphatic vessels that bridge the gut to the lymph nodes and into the surrounding fatty tissue. Due to this leakage, immune cells could not communicate properly, leading to defective immunity.
The abnormalities persisted despite clearance of Y. pseudotuberculosis, leading the researchers to suspect that the microbiota might play a role in maintaining the harmful immune changes triggered by the infection. Mice treated with antibiotics to clear the microbiota had reduced inflammation, suggesting that targeting defined commensal microbes may be a strategy to restore immune balance.
The findings provide a framework for future work to better understand the etiology of chronic inflammatory diseases. In addition, they may help explain why orally administered vaccines tend to be less effective in developing countries, where persistent gut infections may contribute to the remodeling of gut immunity.
Paper: DM da Fonseca, TW Hand, et al. Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity. Cell DOI: 10.1016/j.cell.2015.08.030
Immune cells (colored) are measured in the fatty tissue around the gut. Compared to mice that recovered normally after infection with Y. pseudotuberculosis (left), mice that did not recover normally (right) had leakage of immune cells into the fat.
Understanding the Earliest Immune Responses to HIV
A better understanding of the immune responses to HIV during the period between initial mucosal exposure to the virus and the point at which it becomes detectable in the blood would help inform development of strategies to prevent HIV infection. However, these very early responses are difficult if not impossible to study in people with HIV.
NIAID-funded researchers vaginally exposed 44 monkeys to SIV, the monkey equivalent of HIV, and then analyzed the animals in detail during the first few days after viral exposure. To ensure that the animals would become infected, researchers exposed them to a high dose of SIV. The scientists found that SIV disseminates rapidly through the body, with viral RNA present in at least one tissue outside the reproductive tract in most monkeys analyzed one day after vaginal exposure.
The researchers also observed early host responses that suppress antiviral immunity, thus promoting viral replication. Vaginal transmission of virus induced two early responses in the monkeys that seemed to benefit the virus more than the host. Increasing amounts of viral RNA correlated with rising amounts of a host protein that suppresses non-specific antiviral immunity. The scientists also detected activation of a cell-signaling pathway that correlated with lower levels of antiviral T-cell responses and higher levels of SIV replication.
The findings suggest that the window of opportunity to contain or eliminate HIV at its mucosal port of entry is more limited than researchers previously had thought. Scientists may apply these insights to the continued development of vaccines, microbicides, and drugs to prevent HIV infection.
Paper: DH Barouch et al. Rapid inflammasome activation following mucosal SIV infection of rhesus monkeys. Cell DOI: 10.1016/j.cell.2016.03.021
An HIV-infected immune cell.
Identifying Genetic Signatures Associated With Viral Infections
Respiratory viral infections pose a major threat to global health. Current antiviral drugs target specific viruses, such as influenza, and these drugs may be of limited use due to the development of drug-resistant strains. An alternative strategy to antiviral drug development involves identifying factors in the human host that are necessary for viral replication or virulence.
Working toward this goal, NIAID-supported researchers analyzed genetic data from 18 publicly available datasets to identify host factors necessary for susceptibility or resistance to respiratory infection. They identified a common host genetic signature consistent across different respiratory viral infections that allowed them to distinguish people with viral infections from healthy individuals and those with bacterial infections. By analyzing the genetic signatures, researchers also could detect virally infected people prior to the onset of symptoms.
In addition, the scientists identified an influenza-specific signature that could distinguish people infected with influenza virus from those with bacterial and other respiratory viral infections. The influenza-specific signature was also able to distinguish between influenza vaccine responders and non-responders, suggesting its potential use as a marker of successful vaccination.
Although additional studies are needed, the results have potential applications for the diagnosis of viral infections and also may serve as a starting point to identify host factor targets for development of broad-spectrum antiviral drugs.
Paper: M Andres-Terre et al. Integrated, multi-cohort analysis identifies conserved transcriptional signatures across multiple respiratory viruses. Immunity DOI: 10.1016/j.immuni.2015.11.003
H1N1 influenza virus particles.
Understanding How Bacteria and Fungi in the Gut Shape Allergy, Asthma Risk
The microbes that naturally colonize the digestive tract of very young infants may affect their risk of developing childhood allergies and asthma. In 2016, NIAID-funded scientists identified several patterns of microbial communities in the stool of infants aged 16 to 137 days old. Every pattern of organisms potentially results in a different metabolic environment in the gut based on what the organisms produce as they grow.
One particular pattern of microbes in these infants appeared to influence immune cell populations and promote the development of allergy and asthma. Newborns at highest risk for allergies and asthma had a lower abundance of certain bacteria and increased abundance of specific fungi compared to those at lower risk.
Taking a step further, the scientists identified a relationship between a set of metabolites resulting from the growth of this particular pattern of organisms and the risk for allergy. When the researchers exposed immune cells from healthy adults to sterile metabolite mixtures from the stool of high-risk newborns, the proportion of allergy-promoting immune cells increased, while the proportion of cells that protect against allergy decreased. Exposing the healthy immune cells to one metabolite called 12,13-DiHOME, which was present in higher amounts in the stool of the infants who were more likely to develop allergies or asthma, caused a similar decrease in allergy-protective cells.
Although more research is needed, the findings may help advance development of early-life interventions to prevent allergies and allergic diseases.
Paper: KE Fujimura et al. Neonatal gut microbiota associates with childhood multi-sensitized atopy and T-cell differentiation. Nature Medicine DOI: 10.1038/nm.4176