Lethal Pandemic Research Articles

Introduction

Introduction

The effect of growth temperature on the nanoscale biochemical surface properties of Yersinia pestis.

Yersinia pestis, the causative agent of plague, has been responsible for several recurrent, lethal pandemics in history. Currently, it is an important pathogen to study owing to its virulence, adaptation to different environments during transmission, and potential use in bioterrorism. Here, we report on the changes to Y. pestis surfaces in different external microenvironments, specifically culture temperatures (6, 25, and 37°C). Using nanoscale imaging coupled with functional mapping, we illustrate that changes in the surfaces of the bacterium from a morphological and biochemical standpoint can be analyzed simultaneously using atomic force microscopy. The results from functional mapping, obtained at a single cell level, show that the density of lipopolysaccharide (measured via terminal N-acetylglucosamine) on Y. pestis grown at 37°C is only slightly higher than cells grown at 25°C, but nearly three times higher than cells maintained at 6°C for an extended period of time, thereby demonstrating that adaptations to different environments can be effectively captured using this technique. This nanoscale evaluation provides a new microscopic approach to study nanoscale properties of bacterial pathogens and investigate adaptations to different external environments.

Status of vaccine research and development of vaccines for HIV-1

Human immunodeficiency virus (HIV) is the cause of one of the most lethal pandemics in human history, although in recent years access to highly effective anti-retroviral therapy has provided new hope worldwide. Transmission of HIV by sexual contact, childbirth and injection drug use has been reduced, but 2 million are newly infected each year, and much of the transmission is from people who do not know their status. In addition to known methods, a preventive vaccine is needed to end the pandemic. The extraordinary mutability and genetic diversity of HIV is an enormous challenge, but vaccines are being designed for broad coverage. Computer-aided design of mosaic immunogens, incorporating many epitopes from the entire genome or from conserved regions aim to induce CD8+ T cells to kill virus-infected cells or inhibit virus replication, while trimeric envelope proteins or synthetic mimics aim to induce broadly reactive neutralizing antibodies similar to those cloned from some infected patients. Induction of more potent and durable responses may require new adjuvants or replicating chimeric vectors chimeras that bear HIV genes. Passive or genetic delivery of broadly neutralizing antibodies may provide broad protection and/or lead to insights for vaccine designers. Proof-of-concept trials in non-human primates and in one human efficacy trial have provided scientific clues for a vaccine that could provide broad and durable protection against HIV. The use of vaccines to destroy HIV reservoirs as part of therapy or cure is now also being explored.

The Lipid Mediator Protectin D1 Inhibits Influenza Virus Replication and Improves Severe Influenza

Influenza A viruses are a major cause of mortality. Given the potential for future lethal pandemics, effective drugs are needed for the treatment of severe influenza such as that caused by H5N1 viruses. Using mediator lipidomics and bioactive lipid screen, we report that the omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protectin D1 (PD1) markedly attenuated influenza virus replication via RNA export machinery. Production of PD1 was suppressed during severe influenza and PD1 levels inversely correlated with the pathogenicity of H5N1 viruses. Suppression of PD1 was genetically mapped to 12/15-lipoxygenase activity. Importantly, PD1 treatment improved the survival and pathology of severe influenza in mice, even under conditions where known antiviral drugs fail to protect from death. These results identify the endogenous lipid mediator PD1 as an innate suppressor of influenza virus replication that protects against lethal influenza virus infection.

Protective effects of long pentraxin PTX3 on lung injury in a severe acute respiratory syndrome model in mice

The outbreak of severe acute respiratory syndrome (SARS) in 2003 reinforces the potential of lethal pandemics of respiratory viral infections. The underlying mechanisms of SARS are still largely undefined. Long pentraxin PTX3, a humoral mediator of innate immunity, has been reported to have anti-viral effects. We examined the role of PTX3 in coronavirus murine hepatitis virus strain 1 (MHV-1)-induced acute lung injury, a previously reported animal model for SARS. PTX3-deficient mice (129/SvEv/C57BL6/J) and their wild-type (WT) littermates were intranasally infected MHV-1. These mice were also treated with recombinant PTX3. Effects of PTX3 on viral binding and infectivity were determined in vitro. Cytokine expression, severity of lung injury, leukocyte infiltration and inflammatory responses were examined in vivo. In PTX3 WT mice, MHV-1 induced PTX3 expression in the lung and serum in a time-dependent manner. MHV-1 infection led to acute lung injury with greater severity in PTX3-deficient mice than that in WT mice. PTX3 deficiency enhanced early infiltration of neutrophils and macrophages in the lung. PTX3 bound to MHV-1 and MHV-3 and reduced MHV-1 infectivity in vitro. Administration of recombinant PTX3 significantly accelerated viral clearance in the lung, attenuated MHV-1-induced lung injury, and reduced early neutrophil influx and elevation of inflammatory mediators in the lung. Results from this study indicate a protective role of PTX3 in coronaviral infection-induced acute lung injury.

Triple combinations of neuraminidase inhibitors, statins and fibrates benefit the survival of patients with lethal avian influenza pandemic

The high mortality of highly pathogenic avian influenza A (H5N1) viruses infection in humans gives rise to considerable concern that it might someday cause another lethal pandemic. At present there is no other effective alternative besides the early and enough administration of neuraminidase inhibitors, which may be crucial for the patient management. However, its efficacy is sometimes limited because of the late administration in some patients especially the seriously ill ones and the continual occurrence of oseltamivir resistant A (H5N1) strains. The specific candidate vaccine are still under development and the practical value of passive immunization is hard to be widely applied because of the scarcity of convalescent human plasma, especially in the early stage of a serious and rapidly progressing pandemic. Statins and fibrates, both of which are used in clinical practice, have anti-inflammatory and immunomodulatory effects and other multiple biologic activities. So we hypothesized that the two immunomodulatory agents may exhibit synergistic effects when they were combined to neuraminidase inhibitors to treat the A (H5N1) viruses infections via inhibiting the production of either the early inflammatory mediators (e.g., many cytokine/chemokine) or the late mediator (e.g., High Mobility Group Box Protein 1), even showing the anti-viral activities with the prevention of the development of antiviral resistance. Therefore, the novel triple combinations may be an optimal management to confront the next lethal influenza pandemic on its very beginning.

Address of the president, Lord Rees of Ludlow OM KT PRS, given at The Anniversary Meeting on 30 November 2010

Address of the president, Lord Rees of Ludlow OM KT PRS, given at The Anniversary Meeting on 30 November 2010

Coupling sensitive in vitro and in silico techniques to assess cross-reactive CD4+ T cells against the swine-origin H1N1 influenza virus

The outbreak of the novel swine-origin H1N1 influenza in the spring of 2009 took epidemiologists, immunologists, and vaccinologists by surprise and galvanized a massive worldwide effort to produce millions of vaccine doses to protect against this single virus strain. Of particular concern was the apparent lack of pre-existing antibody capable of eliciting cross-protective immunity against this novel virus, which fueled fears this strain would trigger a particularly far-reaching and lethal pandemic. Given that disease caused by the swine-origin virus was far less severe than expected, we hypothesized cellular immunity to cross-conserved T cell epitopes might have played a significant role in protecting against the pandemic H1N1 in the absence of cross-reactive humoral immunity. In a published study, we used an immunoinformatics approach to predict a number of CD4+ T cell epitopes are conserved between the 2008–2009 seasonal H1N1 vaccine strain and pandemic H1N1 (A/California/04/2009) hemagglutinin proteins. Here, we provide results from biological studies using PBMCs from human donors not exposed to the pandemic virus to demonstrate that pre-existing CD4+ T cells can elicit cross-reactive effector responses against the pandemic H1N1 virus. As well, we show our computational tools were 80–90% accurate in predicting CD4+ T cell epitopes and their HLA-DRB1-dependent response profiles in donors that were chosen at random for HLA haplotype. Combined, these results confirm the power of coupling immunoinformatics to define broadly reactive CD4+ T cell epitopes with highly sensitive in vitro biological assays to verify these in silico predictions as a means to understand human cellular immunity, including cross-protective responses, and to define CD4+ T cell epitopes for potential vaccination efforts against future influenza viruses and other pathogens.

Safety and immunogenicity of an influenza vaccine A/H5N1 (A/Vietnam/1194/2004) when coadministered with a heat-labile enterotoxin (LT) adjuvant patch

Background The use of adjuvants to enhance the immune response to novel pandemic influenza vaccine candidates may overcome the poor immune responses seen in immunologically naïve populations. The confluence of a highly pathogenic H5N1 influenza virus and the widespread absence of pre-existing immunity has driven the search for effective strategies for immunization in the face of a lethal pandemic. The potent adjuvant, heat labile enterotoxin from E. coli (LT), placed over the immunization site in a patch, is a novel adjuvant strategy for immune enhancement, and was evaluated using an H5N1 injectable vaccine. Methods In this observer-blind, placebo-controlled clinical study, 500 healthy adults 18–49 years of age were randomized to receive two intramuscular doses of A/Vietnam/1194/2004 A/H5N1 vaccine (5 μg, 15 μg or 45 μg) or placebo (saline) 21 days apart. For each of the influenza vaccine doses, a 50 μg LT adjuvant patch was applied over the injection site at either the second or both immunizations and the HI responses (titers) were compared to H5N1 vaccine alone. The study's primary endpoint was safety, and secondary immunogenicity endpoints were evaluated using European (CHMP) licensure criteria. Results The vaccine was safe and well tolerated, and subjects generally lacked pre-existing H5N1 immunity. The single-dose injection 45 μg HA/LT patch regimen met all CHMP licensure criteria, including a 73% seroprotection rate compared to 49% seroprotection without a patch. Significant adjuvant effects were seen at all HA doses on Day 21. By contrast, only modest adjuvant effects were observed with the boosting regimen in subjects first primed with H5N1 alone and given the adjuvant patch only on the second immunization. The two-injection/two-patch 45 μg HA regimen achieved significantly higher titers and GMFR compared to injection alone (GMFR 33.1 vs. 16.9, HI 226 vs. 94, p < 0.05) and a 94% seroprotection rate. Conclusions The LT adjuvant patch placed over the injection site was safe, significantly enhanced the immune response to an H5N1 candidate vaccine, and achieved a 73% seroprotection rate after a single dose. The LT adjuvant patch has more modest benefits in recently primed populations similar to other candidate vaccine adjuvants, but a two-dose patch plus injection regimen resulted in robust HI responses.

The Pathology of Influenza Virus Infections

Influenza viruses are significant human respiratory pathogens that cause both seasonal, endemic infections and periodic, unpredictable pandemics. The worst pandemic on record, in 1918, killed approximately 50 million people worldwide. Human infections caused by H5N1 highly pathogenic avian influenza viruses have raised concern about the emergence of another pandemic. The histopathology of fatal influenza virus pneumonias as documented over the past 120 years is reviewed here. Strikingly, the spectrum of pathologic changes described in the 1918 influenza pandemic is not significantly different from the histopathology observed in other less lethal pandemics or even in deaths occurring during seasonal influenza outbreaks.

How did the ancestral HIV-1 group M retrovirus get to Leopoldville from southeastern Cameroon?

In previous papers in this journal, I have described and elaborated a hypothesis for the origin and evolution of a strain of HIV that has produced a lethal pandemic. Here I address the provocative question of how the ancestral HIV-1 group M retrovirus got to Leopoldville (Kinshasa, where the pandemic clearly spawned) from southeastern Cameroon (where the HIV-1 strains all seemed to originate from transfer of SIV(cpz) to humans). Consistent with the phylogenetic history of HIV-1 group M (e.g., by Korber et al.), I place the critical relocation of the ancestral HIV-1 in the timeframe 1920-1927. However, unlike other hypotheses, I believe that the ancestral retrovirus was already well adapted to humans and can be identified as HIV-1 Group M subtype A(pre)-1927. Based on documents from that time period (1920-1928), it can be shown that it was not unusual for native Africans to be brought as far as 500 miles for treatment at the Leopoldville clinic (national borders were no issue because health agencies had mandate to work throughout Cameroon and Congo-Brazzaville). Specifically, sleeping sickness (trypanosomiasis) was one of the diseases of most concern at the Leopoldville clinic; in the period 1926-1928 there was an outbreak of sleeping sickness in Cameroon; and one of the native African children in the pamaquine (plasmoquineTM) study that I believe selected for the major HIV-1 group M subgroups had trypanosomiasis. Thus, this child (or other patients/relatives from Cameroon) could have brought the ancestral HIV-1 group M retrovirus to the Leopoldville laboratory and spread it among the group of children who were undergoing treatment for malaria between February and August 1927. The diagnosis and monitoring of these protozoan diseases (trypanosomiasis and malaria) involved repetitive sampling of blood, which provides many opportunities for spreading the ancestral HIV-1 infection.