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Global efforts against flu evolving in the face of continuing threat

Current vaccines are quite good but they offer no protection against novel pandemic strains of the flu. Jason Rogers

Influenza is never off the news agenda for long. If it’s not the flu season (and it always is in one hemisphere) and the attendant calls for vaccinations, it’s news about vaccines causing problems or new ones that will imbue immunity to all variants and mutations of the virus.

In this first of a two-part series on influenza and the future of vaccines for it, Peter Doherty discusses how these viruses mutate and how we monitor them to create effective vaccines.

Read Part 2: Search for the elusive universal flu vaccine

Human influenza vaccines usually contain three components designed to protect against two different influenza A viruses (H1N1 and H3N2) and one influenza B virus. Influenza B viruses are only known to infect pigs and seals, while A viruses of various types infect everything from whales to cats and seagulls to dogs.

All three vaccine components are subject to what’s called “antigenic drift”, that is, they throw off escape mutants that are no longer destroyed by blood-borne antibodies.

These mutants then emerge as novel variants of the virus that transmit throughout a susceptible population. This susceptible pool includes those given the previous vaccine that stimulated the (formerly) protective antibody response.

This is a classical case of Darwinian evolution at work, though I don’t know if the anti-evolution creationists claim lethal viruses like influenza and HIV as part of their fantasy world.

Seasonal and pandemic flu

“Seasonal” influenza viruses tend to emerge every year or two and spread rapidly around the world. But, no matter how severe they may be, we don’t call these occurrences pandemics.

By definition, a “pandemic” influenza virus shows evidence of more than just incremental change.

Seasonal variants of the H3N2 “Hong Kong” flu have been circulating in humans since 1968, while the current H1N1 seasonal strain is the H1N1 “swine flu” that caused the 2009 pandemic. Each initially arose by a completely different process, called reassortment, to embody what we call an “antigenic shift”.

The basis of this shift lies in the influenza virus’ RNA genome being organized in eight different segments. If a single cell in, say, the respiratory tract of a human or a pig happens to become infected with two different influenza A viruses, they can simply “re-package” to give rise to a new virus that has bits from each parent virus.

The Hong Kong flu, for instance, is thought to have become a human pathogen when an H3N8 duck virus and the H2N2 Asian flu that had been circulating globally since 1957 got together in the lung of a person or a pig to provide the new H3N2 pandemic virus that soon displaced the seasonal strain.

This opportunistic re-packaging is why novel influenza A viruses tend to emerge from warm, wet environments where “traditional” agricultural practices bring water birds, pigs and humans into close proximity.

Craig Cloutier

What (probably) happened in 2008 is that two swine H1N1 variants (North American and Eurasian) reassorted in the lung of a Mexican pig to create a novel virus that could spread readily between people. Humans can catch influenza from pigs, and vice versa.

Current vaccines

All influenza vaccines currently in use in Australia are made by growing viruses to a high concentration in either hen’s eggs with embryos or in tissue culture.

These concentrations of viruses are then cleaned up to remove impurities and viral components that may be unduly reactogenic (likely to cause fever).

Any infectious virus is killed (inactivated) by treatment with chemicals such as formaldehyde or betapropiolactone. The balance between reactogenicity and immunogenicity (giving a good antibody response) is fairly fine.

Some countries in the Northern Hemisphere also use “attenuated”, live vaccines that grow only in the nose and give a more “natural” immunity.

This is essentially the same as the difference between the killed (Salk) and attenuated-live (Sabin) polio (poliomyelitis) vaccines. The Sabin vaccine is never used in a situation where it’s thought that poliovirus is close to eradication (so a mutation back to virulence can’t emerge).

Killed influenza-virus vaccines give good antibody responses that, at least in young, healthy people, protects well.

Global flu watch

What’s happening globally with influenza is monitored very closely by a global network of five world reference centers (including one in Melbourne), working with a much larger number of national laboratories.

New variants are rapidly sequenced to see where mutational changes have occurred, and there’s a constant and open interchange of information.

This effort is coordinated by the World Health Organisation (WHO) in Geneva and culminates in two annual meetings (one for the North and one for the South) where the decision is made about which strains of the influenza A and B viruses should be used to make the “seasonal” vaccines for the coming year.

Generally (though not always) they get it right. But any prediction in science is probabilistic, and influenza can behave in unexpected ways. So there are several problems with this approach.

The first is that, while the correlation between annual influenza vaccination and longevity is strong, these vaccines work sub-optimally in the elderly.

And the second is that vaccines generally have to be made afresh each year to deal with novel, seasonal variants, and the WHO “best guess” isn’t always 100% perfect.

Diego Cupolo

The final problem is that these vaccines provide no protection at all against a novel pandemic strain.

It took six months before any vaccine against the 2009 “swine” H1N1 was in people’s arms. By that time, the virus had spread globally and the first peak of infection was already past.

Fortunately, even though this virus was incredibly transmissible, it wasn’t too virulent. But we could have had a catastrophe if, for example, something like a novel H5N1 “bird flu” variant had jumped into humans.

These “high pathogenicity” H5N1 viruses are currently evolving very rapidly in bird populations, and a recent experiment (done under very high security conditions) in the Netherlands showed that only five mutational changes are required to enable transmission between ferrets.

Ferrets are generally considered to be the optimal model for people, and the first human influenza virus isolate ever was recovered (in 1933) by ferret inoculation.

The problem for us is that, first off, we have to keep making new influenza vaccines specific for “antigenically shifted”, seasonal variants and that any resistance to infection with a newly “shifted” pandemic strain is minimal to none.

What we need are novel flu vaccines to stimulate cross-reactive immune responses that provide much broader protection. And there are some new, and intriguing possibilities. While some media claims may go a bit beyond present reality, progress is being made.

Read Part 2: Search for the elusive universal flu vaccine

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