Flu (Influenza [2]) Recent Scientific Findings

Study Yields Hybrid Flu Strains That Cause Severe Disease
NIAID-supported researchers at the University of Wisconsin, Madison have found that when H5N1 avian influenza reassorts (combines) with a seasonal flu strain, the results can be a highly pathogenic (causing severe disease) avian influenza. Led by Dr. Yoshihiro Kawaoka, the team used reverse genetics to generate 254 combinations of reassortant viruses between a low-pathogenic avian H5N1 virus and a human seasonal H3N2 virus. The study found that 22 viruses were more pathogenic for mice than the original H5N1 virus and 3 viruses caused extremely severe disease. The findings underscore the critical need for virus genetic surveillance and the importance of monitoring influenza strains in wild birds, animals and people.

Li C, Hatta M, Nidom CA, et al. Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence. Proc Natl Acad Sci 2010 Feb 22; early online edition

Combination Drugs a Potential Treatment for Influenza
The threat of serious disease requiring hospitalization caused by the emerging pandemic influenza A (H1N1) virus is a concern and underscores the need for new effective antivirals. One potentially effective therapeutic approach is to use drugs in combination. It is possible that administering two drugs in combination, compared to each drug alone, could reduce signs of disease and death. Moreover, treatment options for seasonal and pandemic influenza strains are becoming increasingly limited due to the rise in antiviral resistance, reinforcing the need for new therapeutic alternatives.

NIAID-supported scientists at Utah State University recently conducted a combination drug study in mouse models to test the effectiveness of using osteltamivir (Tamiflu) and T-705 together. Tamiflu is an FDA-licensed antiviral and T-705 is a compound in late-stage drug development. The two antivirals were selected because they act on different viral targets, so would not work in competition. They may, in fact, have complementary modes of action.

In this study, suboptimal doses (or doses that when given alone do not prevent death) of the two antivirals were combined and administered to mice infected with influenza. Survival in the combination-treated groups was compared with survival levels in groups of mice given a suboptimal dose of just one of the antivirals. Enhanced survival with the combinations was shown against three different influenza virus strains: H1N1, H3N2 and H5N1 influenza. Results of the study suggest that a combination of the two antivirals may be a viable strategy for treatment of human influenza infections.

Smee, DF et al. Effects of Combinations of Favipiravir (T-705) and Oseltamivir on Influenza A (H1N1, H3N2, and H5N1) Virus Infections in Mice. Antimicrob Agents Chemother. 2009 Nov 9. [Epub ahead of print]

Researchers Find Immune System of Healthy Adults May Be Better Prepared Than Expected to Fight 2009 H1N1 Influenza Virus
A study team led by the La Jolla Institute for Allergy and Immunology, which included a researcher at UT Southwestern, looked at molecular similarities between the 2009 H1N1 influenza virus and other strains of seasonal H1N1 virus that have been circulating in the population since 1988. Their findings suggest that healthy individuals may have immune memory that recognizes the 2009 H1N1 strain and therefore can mount some measure of an immune attack.

The researchers studied epitopes – molecular structures known to be recognized by the immune system − on 2009 H1N1 influenza and seasonal H1N1 viruses. Analysis of scientific data input into the NIAID-supported Immune Epitope Database and Analysis Resource, found that some viral epitopes are identical in both the 2009 and seasonal H1N1 viral strains.

Viral epitopes are recognized by immune cells called B and T cells: B cells make antibodies that can bind to viruses, blocking infection, and T cells help to eliminate virus-infected cells. This study showed that epitopes that could be recognized by two subsets of T cells, called CD4 and CD8 T cells, are 41 percent and 69 percent identical, respectively. Subsequent experiments using blood samples taken from healthy adults suggested that this level of T-cell epitope conservation may provide some protection and lessen flu severity in healthy adults infected with the 2009 H1N1 influenza virus.

J Greenbaum et al. Pre-existing immunity against swine-origin H1N1 influenza viruses in the general human populace. Proceedings of National Academy of Sciences. DOI: 10.1073/PNAS.0911580106 (2009).

Visit the Immune Epitope Database and Analysis Resource.

Researchers Find 2009 H1N1 Influenza Virus Spreads Rapidly But Generally Causes Mild Illness in Ferrets
Investigators studied how easily the 2009 H1N1 influenza virus spread and how severely ill it made a community of ferrets, which are known to be a good model for estimating how influenza disease spreads in humans. Their findings are in agreement with observations of human infections, which indicate that the 2009 H1N1 viruses cause generally mild disease but also spread between individuals relatively effectively.

In this study, a swine-origin 2009 A/H1N1 virus isolated in the Netherlands was introduced to the ferrets. Researchers compared the effects of this virus to a strain of seasonal influenza and found that the 2009 H1N1 virus was more pathogenic, meaning that it replicated and spread throughout the respiratory tract more efficiently than the seasonal flu. In addition, the scientists found that virus shedding, or the expelling of the virus from the body, was more abundant in the upper respiratory tract of the 2009 H1N1-infected ferrets than those with seasonal flu. Subsequently, the 2009 H1N1 strain was also found to spread efficiently between ferrets through aerosol or respiratory droplets. Despite these characteristics, the 2009 H1N1 virus did not cause any mortality in the ferret model, whereas highly pathogenic influenza viruses (like avian H5 and H7 subtypes and the 1918 Spanish influenza virus) often prove fatal for ferrets.

Munster, VJ, et. al. Pathogenesis and transmission of swine-origin 2009 A/H1N1 influenza virus in ferrets. Science. 325: 481-483.

Researchers Examine 2009 H1N1 Influenza Protection, Severity and Treatment


Investigators at the University of Wisconsin–Madison, led by Dr. Yoshihiro Kawaoka and supported by the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS), found that infection with human H1N1 viruses that are antigenically related to viruses circulating in 1918 confers neutralizing antibody activity against the currently circulating 2009 novel H1N1. These findings suggest that people alive during the 1918 influenza pandemic have the most protection against the current 2009 H1N1 influenza virus because of their prior exposure.

The researchers also conducted a detailed study of the 2009 H1N1 influenza virus in pigs, mice, ferrets, and non-human primates. This study showed that in all but the pigs, lung infections were more severe than would be expected from average seasonal influenza viruses.

Finally, the team confirmed that some commercially available antiviral drugs, including oseltamivir (Tamiflu) and zanamivir (Relenza), are effective against the new H1N1 pandemic virus in human cells grown in the lab.

Itoh Y et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature. 2009 Jul 13.

NIAID Funded Researchers Find H1N1 Influenza Was Transmitted to Humans Several Months Before Recognition of the Outbreak
A team of researchers at Hong Kong University conducted an evolutionary analysis on the currently circulating 2009 novel H1N1 influenza virus to determine its origins and early developments. Led by Dr. Gavin Smith and supported by the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS), researchers found that the virus was derived from several viruses circulating in swine, and that the initial transmission to humans occurred several months before recognition of the outbreak.

A phylogenetic estimate of the gaps in genetic surveillance suggested a long period of unsampled ancestry before the outbreak, implying that the reassortment of swine lineages may have occurred years before the disease emerged in humans. These findings highlight the need for systematic surveillance of influenza in swine, and provide evidence that the mixing of new genetic elements in swine can result in the emergence of viruses with pandemic potential in humans.

Smith GJ, et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature. 2009 Jun 25;459(7250):1122-5.

TipDCs—The Necessary Evil of Lethal Influenza Virus Infection
Could the lethality of some influenza viruses actually result from the body’s own immune response? Researchers in this s found that mice with virulent strains of influenza had larger numbers of a specific type of immune cell, TNF-α/inducible nitric oxide synthase producing dendritic cells or tipDCs, than those mice with a less virulent form of the virus. TipDCs are cells specific to the immune response that are produced to fight infection in the lung. Researchers also worked to control the number of tipDCs by reducing or eliminating the number of cells present in the lungs using the immune moderating drug pioglitazone. Decreasing – rather than completely eliminating the tipDCs resulted in decreased mortality and a faster recovery for the infected mice. This research demonstrates the potential for using pioglitazone as a treatment for influenza in the event of pandemic outbreak.

Aldridge, JR, et. al. TNF/iNOS-Producing Dendritic Cells—The Necessary Evil of Lethal Influenza Virus Infection. PNAS. March 9, 2009.

(Published on March 9, 2009)

Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: Implications for pandemic influenza preparedness
This paper concludes that the majority of deaths in the 1918-1919 influenza pandemic likely resulted directly from secondary bacterial pneumonia caused by common upper respiratory-tract bacteria. Less substantial data from the subsequent 1957 and 1968 pandemics are consistent with these findings. If severe pandemic influenza is largely a problem of viral-bacterial co-pathogenesis, pandemic planning needs to go beyond addressing the viral cause alone (e.g., influenza vaccines and antiviral drugs). Prevention, diagnosis, prophylaxis, and treatment of secondary bacterial pneumonia, as well as stockpiling of antibiotics and bacterial vaccines, should also be high priorities for pandemic planning.
Flu (Influenza) Recent Scientific Findings