immunopaedia.org.za: Breaking News

Elimination of self-reactive T Cells in the thymus: A timeline for negative selection

Fri, 24 May 2013 08:42:00 +0200

T cells bearing autoreactive T cell antigen receptors are typically eliminated via thymocyte apoptosis and removed by thymic phagocytes during development in the thymus, in order to protect against autoimmunity. This process is known as negative selection. However, the sequence of events that occur in vivo, and the relationship between thymocyte death and phagocytic clearance, are unknown. This study therefore examined a synchronized population of developing thymocyte undergoing negative selection within three-dimensional living thymic tissue. However in spite of this synchronized early response, individual thymocytes then undergo a delayed and asynchronous entry into apoptosis somewhere between 2 and 12 hours later. Using time-lapse two-photon imaging, the study then showed that thymocyte death and the clearance of the dead cells actually occurs at the same time, with thymocytes already engulfed by a macrophage before the cell death-related changes in chromatin and membrane permeability are evident. Thus providing a timeline of the major events during negative selection, and suggesting close coupling between thymocyte death and clearance by macrophages. Link to article

Dupilumab in persistent asthma with elevated eosinophils

Thu, 23 May 2013 09:01:00 +0200

This week drug makers Sanofi and Regeneron announced results from their Phase 2a study of the asthma drug Dupilumab, for the treatment of patients with moderate-to-severe allergic asthma. Dupilumab is an investigational monoclonal antibody targeting the alpha subunit of the interleukin 4 receptor (IL-4R alpha), which modulates signaling of both IL-4 and IL-13, drivers of Th2 (Type 2 helper T cell) immune response. The proof-of-concept study enrolled 104 patients with moderate-to-severe, persistent asthma that was not well controlled with inhaled glucocorticosteroids (ICS) and long-acting beta agonist (LABA) therapy, and who had elevated eosinophils in blood or sputum. The primary objective of the trial was to assess the effect of dupilumab, dosed subcutaneously, once a week for twelve weeks. Study participants were divided into treatment and placebo groups of 52 in each group. All patients received ICS and LABA, with the treatment group receiving dupilumab and the placebo group given subcutaneous placebo. The LABA was withdrawn at week four and the ICS was tapered to withdrawal between weeks six and nine. Patients were treated for 12 weeks or until they experienced a protocol-defined asthma exacerbation, the primary endpoint of the study. Results found that 23 patients (44.2%) receiving placebo experienced an asthma exacerbation compared to three patients (5.8%) receiving dupilumab, resulting in an 87% reduction in the incidence of asthma exacerbations for the dupilumab arm. Clinically meaningful and statistically significant improvements were also observed for lung function and forced expiratory volume over one second (FEV1). Adverse events were generally non-specific and of mild-to-moderate intensity. In conclusion the study indicated a potential role for IL-4/IL-13 blockade in a subpopulation of patients with persistent asthma. However the study was only for 12 weeks, indicating the need for longer studies to confirm these observations. Link to article

Discovering naturally processed antigenic determinants that confer protective T cell immunity

Wed, 22 May 2013 08:53:00 +0200

Understanding vaccine-mediated correlates of immunity is critical for the design of novel pathogen-free vaccines against diseases caused by complex pathogens such as HIV, malaria and TB. CD8+ T cells (TCD8) confer protective immunity against these infectious diseases, thereby suggesting that microbial TCD8 determinants are promising vaccine targets. However current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection, key information for the rational design of TCD8-targeted vaccines. This study therefore used a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV). VACV consists of about 200 proteins making it an ideal model for studying TCD8 responses to pathogens with complex proteomes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a partially overlapping or variegated manner. Many of these determinants were also recognized by HLA class I–transgenic mouse immune TCD8, which were then able to elicit protective TCD8 immunity against lethal intranasal VACV infection. Of note, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Therefore showing that this strategy in which fundamental insights into T cell epitope processing and presentation were used to define targets of protective TCD8 immunity may provide general application for future vaccine research. Link to article

Peripheral B cell tolerance defects observed in patients with multiple sclerosis

Tue, 21 May 2013 09:22:00 +0200

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system caused by an autoimmune response in genetically susceptible individuals. Although T cells are considered to be the main effectors recent studies have highlighted the important contribution of B cells in disease progression. This role of B cells, although not well understood, has been demonstrated in MS by the clinical benefits achieved with anti-CD20 (rituximab) therapy–mediated peripheral B cell depletion. In order to better understand B cell involvement it is known that developing autoreactive B cells in healthy individuals are removed at 2 discrete points. The first being a central B cell tolerance checkpoint in the bone marrow, from where the vast majority of B cell clones expressing polyreactive antibodies are removed. While the second checkpoint is peripheral and counterselects autoreactive new emigrant B cells before they enter the mature naive B cell compartment. Both central and peripheral B cell tolerance checkpoints are defective in untreated patients with active rheumatoid arthritis (RA) or type 1 diabetes, while in the case of MS this study found that only the peripheral, but not the central, B cell tolerance checkpoint is defective.The study was also able to show that anti-CD20 therapy which has efficacy with MS also had some efficacy in the treatment of RA and to a lesser extent type 1 diabetes, thus further suggesting that the deletion of autoreactive B cell clones may either prevent or delay autoimmune manifestations. Link to article

IL-21 restricts virus-driven Treg cell expansion

Mon, 20 May 2013 08:47:00 +0200

T cell exhaustion represents a state of T cell dysfunction that is associated with viral infections and certain cancers. The immunological mechanisms leading to this outcome, following chronic infections, is not well understood. This study therefore works to explain two major findings thought to contribute to T cell exhaustion during viral infection. The first shows that a persistence-inducing virus triggers massive proliferation of Foxp3⁺ regulatory T (Treg) cells giving Treg cells the potential to promote T cell exhaustion and chronic infection. Secondly they identified IL-21 as a key host factor for antagonising this virus-driven expansion of the Treg population in a cell intrinsic manner independent of IL-2. Thus, in addition to its known pre-dominant direct positive effects on antiviral T cells, IL-21 can also alleviate the suppressive activity of Treg cells. Together, these results suggest that enhanced Treg cell responses are a mechanism of immune evasion that could be therapeutically targeted with IL-21. Link to article

H7N9 and novel Coronavirus

Fri, 17 May 2013 09:53:00 +0200

The Center for Disease Control (CDC) has reported two new deadly virus’s the Coronavirus (NCoV) originating in the Middle East and the H7N9 virus originating in China. The coronavirus outbreak in the Middle East has 38 confirmed cases and 20 deaths, over the last 2 months. With two of these cases identified in France, one from travel to the gulf and one from transmission on the patient’s return. The CDC has now confirmed that NCoV is transmitted from person to person, as was seen with SARS a virus from the same family responsible for hundreds of deaths in 2003. However, the difference is that with NCoV, the spread occurs following close contact for long periods of time with no evidence that the virus is able to sustain general transmission in communities. As of yet researchers have been unable to determine the source of the virus. While the H7N9 virus, which was first detected in March, has been isolated in more than 130 cases with 35 deaths over the last two months. However there is no evidence the H7N9 virus can be transmitted from person to person and has instead been shown to occur following contact with infected poultry or contaminated environments. Studies on disease transmission, vaccines, and anti-viral medication for treatment are currently underway. Link to article

TRAIL+ T cells suppress GVHD and augment antitumor activity

Thu, 16 May 2013 09:20:00 +0200

Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved over the years, successful treatment remains limited by disease relapse and graft-versus-host-disease (GVHD). Furthermore current strategies to suppress GVHD often end up compromising graft-versus-tumor (GVT) responses due to impairment of T cell function. In a previous study it was shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allo-HSCT. Therefore to model a donor-derived cellular therapy, this study genetically engineered T cells to overexpress TRAIL followed by adoptively transferring donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. The results showed that that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD as well as enhancing in vitro and in vivo antilymphoma GVT responses. While human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and chronic lymphocytic leukemia (CLL) cells. Thus indicating that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD. Link to article

Genital shedding of HIV and human herpes virus in men on ARVs

Wed, 15 May 2013 09:03:00 +0200

Antiretrovirals (ARVs) suppress HIV replication in the blood and semen of most HIV-positive men, substantially reducing the risk of sexual transmission. However, genital shedding of HIV can still occur in the presence of antiretroviral therapy with case reports showing HIV transmission occurring despite suppressed viral load in blood plasma. One of the reasons for this may be untreated sexually transmitted infections (STIs) whereby local inflammation may be causing an increase in the risk of transmission. Additionally, research in ARV naïve HIV positive men has shown that some human herpes viruses including CMV and EBV, can increase viral load in semen. To better understand this researchers from UCLA designed a study to investigate the relationship between STIs, seven herpes viruses and shedding of HIV in semen. The study cohort included 114 HIV infected men on ARTs with blood plasma HIV <500 copies/ml, of which 88% had viral loads below 50 copies/ml. Asymptomatic participants were screened for bacterial STIs and non-specific genital inflammation. Levels of HIV and seven human herpesviruses were then measured by real-time (RT)-PCR in seminal plasma. The results found that HIV was detected in the semen of 10% of the participants, with the greater percentage being found in those participants who had a detectable blood plasma viral load (50-500 copies/ml). While one of the herpes virus was detected in the semen of 63% of participants. Of these CMV was detected in the genital tract of 49% of participants and EBV in 31% of participants. They further found that high-level shedding of CMV was also a predictor of genital shedding of HIV in semen showing that CMV was present in 64% of participants with detectable HIV in semen, compared to 24% without. Detectable EBV was also shown to have a significant association with genital shedding of HIV. Of note was that urethral STIs did not increase the risk of shedding HIV in semen. The study thus concludes that the association between isolated HIV shedding and high-level CMV replication and EBV replication in the genital tract suggests that the presence of these viruses is a potential risk for HIV transmission. Link to article

Cancer outcome predicted by peptide-MHC affinity

Tue, 14 May 2013 08:51:00 +0200

A major challenge that faces cancer survivors is the possibility of experiencing relapse following an initial response to therapy. It is not clearly understood why this happens other then that the type of treatment the patient receives plays some role. Researchers from the University of Chicago therefore conducted murine studies to investigate tumor relapse following successful adoptive T cell therapy. The study mice were initially injected with a fibrosarcoma cell line that expressed one of a series of defined peptide antigens. Once tumors were established, the mice were then treated with T cells specific for that antigen. In vitro results showed T cells killing tumor cells independent of the peptide's affinity for binding to major histocompatibility complex (MHC). While the in vivo results showed that only the mice able to bind to MHC with high affinity remained cancer-free. Those with affinities less than 10nM experienced relapse, indicating that less efficient cross-presentation of peptide antigens by stromal cells surrounding the tumor was less protective. Thus, strong interactions between peptide antigens and MHC may prevent relapse by promoting robust T cell responses that target both the tumor and the surrounding tissue. Link to article

NIH scientists have a tool for identifying broadly neutralizing antibodies

Mon, 13 May 2013 10:02:00 +0200

Scientists from NIH have developed a new tool to identify broadly neutralizing antibodies (bNAbs), the antibodies capable of preventing infection by the majority of HIV strains. Until now, the methods available to examine these antibodies have been laborious, yielding only small amounts of information as to how HIV bNAbs develop and attack the virus. Now with this new tool, scientist are able to precisely determine the HIV bNAbs present in a particular blood sample by analyzing the neutralized HIV strains found there. The process is called neutralization fingerprinting, which uses a mathematical algorithm to examine the large body of data on HIV bNAbs that has been generated in recent years. The neutralization fingerprint of an HIV antibody is a measurement of which virus strains it can block and with what intensity. Antibodies that target the same portion of the virus tend to have similar fingerprints. Blood samples contain mixtures of antibodies, so the new algorithm calculates the specific types of HIV bNAbs present and the proportion of each by comparing the blood’s neutralization data with the fingerprints of known HIV bNAbs. This approach is particularly useful as it is fast and requires only small samples of blood. The researchers believe that not only could this method help with HIV vaccine development but the underlying approach could also be applied to the study of human responses to other pathogens, such as influenza and hepatitis C viruses. Link to article

DRAM represents a mechanism of self-defense during host/pathogen interactions in HIV

Fri, 10 May 2013 09:07:00 +0200

The intracellular organelles lysosomes have a major function of digesting macromolecules and regulating autophagy. In the context of host-pathogen interactions, productive viral infections are associated with lysosome membrane permeabilization (LMP) and programmed cell death (PCD). At a molecular level, the tumor suppressor protein 53 or p53, a key player in the detection of DNA damage, also acts as a sensor of pathogen replication. Activation of p53 results in “cell suicide” in order to limit viral infection. This study now presents evidence that damage-regulated autophagy modulator (DRAM), a p53 target gene, regulates both LMP and PCD of HIV-infected CD4 T cells, and shows for the first time that when this gene is silenced there is a resulting increase in HIV viral infection. The authors conclude that although it is to the advantage of the pathogens to preserve their hosts and thus facilitate their multiplication and dissemination, hosts in turn have developed altruistic cellular processes to defend themselves, thereby limiting the spread of the infectious agent in multicellular organisms. In this case the DRAM protein represents a mechanism of self-defense, inducing elimination of infected cells through LMP. Link to article

Mechanism for regulation of bacterial innate immune evasion and virulence

Thu, 09 May 2013 08:39:00 +0200

The CRISPR-Cas (clustered regularly interspaced palindromic repeats/CRISPR-associated) system, which is found in many bacteria, is known as an adaptive defense against the invasion of foreign DNA. The bacteria are able to capture fragments of plasmids and phages and incorporate them into one or more CRIPSR loci. These sequences are then transcribed and cleaved into short CRISPR (cr)RNAs, which, when bound by a Cas nuclease complex, are used to target the invading nucleic acid for destruction. Based on this researchers believe that there is most likely a link between bacterial virulence and the CRISPR system. This study shows that in the intracellular parasite Francisella novicida, CRISPR-Cas is required for evasion of the host's innate immune system. They found that the F. novicida CRISPR locus encodes a small CRISPR/Cas-associated RNA (scaRNA) complementarity to both a trans-acting crRNA (tracrRNA) and its own lipoprotein gene. The scaRNA, together with the tracrRNA and Cas9 nuclease were able to repress expression of the F. novicida lipoprotein during host infection and avoid detection by one of the host's pathogen pattern recognition receptors, thus evading the host's innate immune response. The study therefore concludes that CRISPR-Cas regulation plays a role in bacterial virulence. Link to article

Pacifier cleaning practices and allergy development

Wed, 08 May 2013 08:56:00 +0200

The adult oral cavity contains a complex mixture of more than 600 aerobic and anaerobic bacteria. Infants may be exposed to parents’ oral microbes, transferred in saliva via kissing or if the parent puts the infant’s feeding spoon or pacifier (dummy/soother) into their own mouth before giving it back to the infant. To determine whether this early exposure to oral microbes is protective against allergy development, this study was conducted to examine if the mode by which parents clean their infant’s pacifier affects the risk of allergy development in the infant. The study consisted of a cohort of 184 infants, of which 80% had at least one parent with known allergies, who were examined for clinical allergy and sensitization to airborne and food allergens at 18 and 36 months of age and at anytime symptoms occurred. Pacifier use and pacifier cleaning practices were recorded during interviews with the parents when the children were 6 months old. The oral microbiota of the infants was characterized by analysis of saliva samples collected at 4 months of age. Results from the study found that children who’s pacifiers were “cleaned” by their parents saliva were less likely to have asthma, eczema and sensitization at 18 months of age, than children whose parents did not use this cleaning technique. In addition the study found that protection against eczema remained at age 36 months although these same results were not noted for asthma. They also noted that the salivary microbiota differed between children whose parents cleaned their pacifier by sucking and children whose parents did not use this practice. Although the study is inconclusive the authors recommend the practice of parental sucking of their infant’s pacifier as it does no harm and may in fact reduce the risk of allergy development. Link to article

A mechanism for targeted regulation of interferon regulatory factors 4 and 8

Tue, 07 May 2013 08:24:00 +0200

Interferon regulatory factor (IRF) consists of various subtypes, each with their own function in the context of pathogen response, signal transduction, cell proliferation and hematopoietic development. Included in this group are IRF4 and IRF8 that are transcription factors and critical mediators of B-cell development. IRF4 is an oncoprotein with anti-apoptotic properties, enhanced expression of which is often associated with multiple myeloma and adult T-cell lymphomas. While IRF8 functions as a regulator of apoptosis and tumor suppressor in many hematopoietic malignancies. Epstein-Barr virus (EBV), one of the first characterized human tumor viruses is linked to a broad spectrum of B-cell malignancies. One of the essential antigens, EBV encoded nuclear antigen 3C (EBNA3C), plays a critical role in EBV-induced B-cell transformation. This study demonstrates that EBNA3C forms a molecular complex with IRF4 and IRF8 specifically through its N-terminal domain and shows that IRF4 is stabilized by EBNA3C, resulting in downregulation of IRF8 through proteasome-mediated degradation and subsequent inhibition of its tumor suppressive activity. Moreover, si-RNA-mediated inhibition of IRF4 showed a substantial reduction in EBV transformed B-cell proliferation, and also enhanced their sensitivity to DNA-damage induced apoptosis. Thereby providing novel insights into the contribution of EBNA3C to EBV-mediated B-cell transformation through regulation of IRF4 and IRF8 and an additional molecular link to our knowledge of the mechanisms by which EBV dysregulates cellular activities. Link to article

Quantitative and qualitative differences found in response to influenza and pneumococcal vaccines

Mon, 06 May 2013 08:22:00 +0200

Although vaccinations have successfully provided prevention of many diseases the question remains why some vaccines work and others fail. Researchers from Baylor, Texas have worked to answer this question by characterizing the immune response induced in people given either the trivalent seasonal influenza vaccine or the pneumococcal vaccine, both of which induce a protective antibody response. Gene expression profiling combined with functional assays at multiple time points after vaccination revealed that the two vaccines take different routes early, despite a similar ability to induce protective antibodies. The early response to the influenza vaccine was characterized by the induction of an antiviral and, to a lesser extent, inflammatory gene response. In contrast, the pneumococcal vaccine elicited a predominately inflammatory gene response. However within one week following vaccination, a developing antibody response was apparent in all vaccines. Link to article

Lung tumor NF-kB signaling promotes T cell–mediated immune surveillance

Fri, 03 May 2013 09:18:00 +0200

Despite being a leading cause of cancer, the 5-year survival rate in lung cancer has remained essentially unchanged, indicating the need for effective therapies. While targeted therapies against driver oncoproteins have shown considerable promise, very little is available for mutant tumors and tumors without known driver mutations. Therefore one of the new modalities being tested is immunotherapy. T cell presence in tumors is typically associated with immune surveillance and improved patient survival, making blockade of negative regulators of T cell function an attractive approach. One of the frequently activated pathways in cancer is the NF-kB transcription factor pathway, that plays a crucial role in regulating inflammatory and immune responses as well as in regulating cell proliferation and cell survival. NF-?B is constitutively activated in many cancers and known to directly promote tumor growth and enhance tumor-associated inflammation, leading to increased angiogenesis and metastasis. This study investigated the role of cancer cell NF-kB activity in T cell–mediated antitumor responses. In tumors rendered immunogenic by model antigen expression or following administration of antitumor vaccines, it was found that high NF-kB activity leads to tumor rejection and/or growth suppression in mice. To investigate NF-kB function in human lung tumors, the study identified a gene expression signature in human lung adenocarcinoma cell lines that was associated with NF-?B activity level. In patient tumor samples, overall lung tumor NF-kB activity was strongly associated with T cell infiltration but not with cancer cell proliferation. These findings in both murine and human lung cancer therefore indicate that a crucial and previously unappreciated function of tumor NF-kB is to promote T cell–mediated immune surveillance responses. Link to article

Effector proteins promote progression of primary pneumonic plague

Thu, 02 May 2013 09:05:00 +0200

Yersinia pestis is the causative organism of plague, which leads to inflammation, necrosis and rapid bacterial growth resulting in acute lung congestion and death. In order to cause infection the bacteria needs to overcome the immune system. This study therefore looked at the mechanism whereby Y.pestis manipulates innate immune responses by controlling host cell death. The bacterial type III secretion system (T3SS) is a mechanism that injects effector proteins into host cells, which then combine their activities enabling them to establish infection. Y.pestis requires the presence of these effector proteins to evade the innate immune system during infection by controlling apoptosis and pyroptosis. This study showed that Yersinia induces apoptosis of macrophages through two distinct mechanisms, each through the activity of the well-characterized T3SS effector YopJ, yet regulated in an opposing manner through the activity of a second effector protein YopK. In a murine pneumonic plague model, the study found evidence that YopK regulates apoptosis of macrophages during the early stage of infection, leading to uncontrolled inflammation and disease. In contrast, the absence of YopK-regulated apoptosis allowed recruitment of lymphocytes and CCR2⁺ immune cells which led to bacterial clearance and resolution of inflammation. Together the data suggest that Yersinia YopK modulates apoptosis of immune cells to control the inflammatory response during infection. Link to article

Phase II b Aviator trial for HCV demonstrates sustained viral response

Tue, 30 Apr 2013 08:49:00 +0200

News from the International Liver Congress^® (ILC) in Amsterdam shows encouraging results from AbbVie's phase IIb AVIATOR study. This study was designed to compare six different interferon-free combinations of direct-acting antivirals (DAAs) for the treatment of hepatitis C virus (HCV) infection among treatment naïve patients and in patients who had previously failed treatment with pegylated interferon and ribavirin (null responders). With the aim of selecting future interferon-free combination regimens for testing in larger phase III studies. The investigation was able to demonstrate high sustained viral response (SVR) rates against genotype 1 HCV, across patient types. Data showed greater than 90% SVR were achieved in both treatment naïve patients and in null responders. In addition, similar high SVR rates observed after 12 and 24 weeks of treatment in the Phase IIb trial reinforced the adequacy of the 12-week treatment duration for the investigational interferon-free, triple DAA combination currently being studied in Phase III clinical trials. AbbVie's clinical development program aims to improve virologic cure rates, including in patients who have historically been harder to treat with current therapies. While further studies are required to confirm these findings, the high viral response rates and the safety profile seen in the Aviator study have been encouraging. Link to article

Sterol regulatory element–binding proteins essential for T cell expansion and adaptive immunity

Mon, 29 Apr 2013 09:00:00 +0200

When cytotoxic CD8⁺ T cells recognize and respond to an infection, they undergo clonal expansion. This is a very energy demanding process which requires lipid biosynthesis, followed by metabolic reprogramming for glycolysis to meet these needs. However, the signals that mediate metabolic reprogramming remain poorly defined. This study conducted by researchers from UCLA demonstrates an essential role for sterol regulatory element–binding proteins (SREBPs) in the acquisition of effector-cell metabolism. They showed that the expression of SREBPs is up-regulated in response to T cell activation and is required for the induction of a lipid synthesis program. Using murine studies they found that CD8⁺ T cells from mice with a T cell–specific deficiency in SREBPs exhibited poor blastogenesis and proliferation upon activation, altered lipid homeostasis, and did not undergo the typical activation-induced metabolic reprogramming. They were further able to demonstrate that impaired responses of SREBP-deficient mice to infection with lymphocytic choriomeningitis virus underscored the physiological relevance of this pathway. Link to article

HIV vaccine trial, HVTN 505, stopped

Fri, 26 Apr 2013 08:43:00 +0200

Today, the National Institute of Allergy and Infectious Diseases (NIAID) has announced that there will be no further immunization injections in the phase IIb HVTN 505 clinical trial of an investigational HIV vaccine regimen. The trial that began in 2009 was testing an investigational prime-boost vaccine regimen developed by NIAID’s Vaccine Research Center. The study was designed to determine whether the vaccine regimen could prevent HIV infection and/or reduce the amount of virus in the blood of vaccine recipients who became infected with HIV. The decision today came from an independent data and safety monitoring board (DSMB) which found during a scheduled interim review that the vaccine regimen did not prevent HIV infection nor reduce viral load among vaccine recipients who became infected with HIV. The regimen involved a series of three immunizations over the course of eight weeks, beginning with a DNA-based vaccine designed to prime the immune system. The DNA priming vaccine contained genetic material expressing antigens representing proteins from both the surface and internal structures of HIV. Immunizations with the priming vaccine were followed by a single injection at week 24 with a recombinant vaccine based on a weakened adenovirus type 5 (Ad 5). The adenovirus was used as a vector of genetic material expressing a matching set of HIV antigens. Structures from all three major HIV clades, or subtypes, were included. The investigational vaccines themselves could not cause HIV infection as neither contained live or weakened versions of HIV. It should be noted that there was a non-statistically significant increase in HIV acquisition among volunteers in the investigational vaccine group compared to those in the placebo group. It is not clear why this occurred and further analysis is needed to draw any firm conclusions. NIAID will therefore amend the study protocol to allow for closer, extended follow up of the vaccine recipients. Detailed scientific findings will be made publicly available as soon as possible. Link to article