After endless toing and froing over whether two studies that demonstrated how bird flu, also known as avian H5N1 influenza, or avian flu, should be published, one of them has appeared in the latest issue of the journal Nature in its entirety. The studies show how the bird flu virus could become transmissible from mammal-to-mammal; as humans are mammals, the same would apply to humans.

This is the end of a marathon debate, mainly between infectious disease experts versus influenza and public health researchers who stressed that not only was publication important, but also vital. To properly develop influenza surveillance and preparedness for a pathogen that could turn into a global, human pandemic, the scientists insisted that publication had to occur.

University of Wisconsin-Madison flu researcher, Yoshihiro Kawaoka, whose study of H5N1 virus transmissibility was at the center of the controversy, said:

“Our study shows that relatively few amino acid mutations are sufficient for a virus with an avian H5 hemagglutinin to acquire the ability to transmit in mammals. This study has significant public health benefits and contributes to our understanding of this important pathogen.

By identifying mutations that facilitate transmission among mammals, those whose job it is to monitor viruses circulating in nature can look for these mutations so measures can be taken to effectively protect human health.”

Other mutations we do not know about which might make the virus mammal-transmissible may be possible, Kawaoka cautions. It is because of this that further research into additional potential mutations are important.

Kawaoka led an international team of researchers for this study. They say it shows that some of the viruses now in circulation in nature only need four mutations to the hemagglutinin protein, which is located on the surface of the virus and makes it possible for it to bind to host cells, and then to become a vastly more dangerous threat to human health.

Some viruses, which currently circulate in poultry flocks in Egypt and Southeast Asia, already appear to have a subset of the mutations that were identified by the Wisconsin group – this fact alone underlines the importance of science-based surveillance, Kawaoka explained.

In this latest Nature article, the Wisconsin scientists describe a bird flu/human flu hybrid virus that was modified in the lab; the virus has the capacity to become transmissible in an animal model for human infection with just a few mutations.

Flu viruses that naturally exist in the environment are forever changing as they circulate – they exchange genes with other flu viruses. There is a chance that one day they swap genes in such a way that they become human-transmissible – the chances of this happening are much bigger than a great many experts believe, says Kawaoka.

Kawaoka said:

“H5N1 viruses remain a significant threat for humans as a potential pandemic flu strain. We have found that relatively few mutations enable this virus to transmit in mammals. These same mutations have the potential to occur in nature.”

At least 600 humans have been infected with the H5N1 viruses since 2003. The majority of infections have occurred in Asia. Over 50% of infected people did not survive.

Humans can become infected after close contact with poultry. However, an infected human extremely rarely can infect another human – this fact has led many scientists and health experts to believe that H5N1, although deadly, is not really a pandemic threat.

The NIAID (United States National Institute of Allergy and Infectious Disease), in a Blue Ribbon Panel report (2006) decided that research on virus transmission from animal reservoirs should be a priority. The World Health Organization (WHO) came to the same conclusion in its 2009 Public Health Research Agenda.

Kawaoka’s study results demonstrated that the experimental mutant virus could be controlled with current medical countermeasures. The H5N1 vaccine proved effective, as well as the antiviral oseltamivir (Tamiflu).

A virus depends on its ability to get into and appropriate host cells, so that new virus particles can be made, which then infect other cells and spread to other hosts. The flu virus, however, generally comes from a few animals, such as pigs or poultry, before infecting humans – they have to adapt by changing their surface topography to match those of a new host species.

Hemagglutinin is a protein that exists on the surface of the flu virus – it helps the virus access host cells. It uses a globular head (bulb-shaped structure) to bind to host cells when infection occurs. The amino acids in the hemagglutinin protein are similar to the combination sequence that opens a safe – if they do not have the right combination, they cannot enter a host cell and cause infection.

Flu viruses are expert shape-shifters; they have to be in order to adapt to new animal hosts. Viruses in general, including flu viruses readily swap genetic information and mutate to acquire features that make them even more infectious.

Kawaoka says:

“It is hard to predict. The additional mutations may emerge as the virus continues to circulate. Should surveillance activities identify flu strains accumulating additional key mutations, these emerging viruses should then be priority candidates for vaccine development and antiviral evaluation.”

Kawaoka’s team discovered how the H5N1 virus transmits – its mechanism was identified. They said that their discovery should help in the development of countermeasures. They explained that their findings also add to the fundamental knowledge on flu virus transmission.

The authors explained that their studies will help public authorities and governments in many parts of the world understand why the mass culling of poultry flocks is sometimes necessary when dangerous bird flu virus mutations are identified, despite the huge economic hardship that results.

Ferrets were used in the new study, because these animals generate small droplets when they are infected with flu and sneeze and cough – the droplets carry the virus from animal-to-animal, demonstrating transmissibility. There are many cellular similarities between the ferret’s and human’s respiratory tract.

The NSABB (National Science Advisory Board for Biosecurity), which advises the NIH (National Institutes of Health), last year recommended removing sensitive data from Kawaoka laboratory’s report. The panel recommended that the same be done with a Dutch study. The Panel wanted the methodologies used to make the virus transmissible removed from the report, as well as the mutations required to make the virus mammal-transmissible. This month they changed their recommendation.

Kawaoka’s lab had engineered a low virulence virus. The hybrid virus was created by building the H5N1 hemagglutinin gene into the pandemic H1N1 flu virus. The H5-H1N1 hybrid was less virulent than pandemic H1N1 virus.

Written by Christian Nordqvist