Search for the elusive universal flu vaccine

All vaccines rely on generating an immune response that persists but our understanding of immune memory has some way to go. James Gathany/CDC

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 part of a short series on influenza and the future of vaccines for it, Peter Doherty discusses how flu vaccines are made and assesses the possibility of a universal vaccine.

Read Part 1: Global efforts against flu evolving in the face of continuing threat

The human family is at constant risk from novel, pandemic influenza A viruses, so it’s not surprising that there’s increasing interest in developing some form of “universal” influenza vaccine.

We currently have a big NHMRC Program Grant, with six separate Melbourne laboratories working towards that goal. And this is only one of a number of efforts worldwide to create a vaccine that will protect against all influenza viruses.

But the science of vaccine creation is complex, technical and incomplete and the road to a universal flu vaccine is long.

All vaccination depends, of course, on generating a specific immune response that then persists to give long-term protection, but our basic understanding of this immune memory has a way to go.

So what’s being done now with respect to developing influenza vaccines that can protect against a range of influenza viruses (cross-reactive vaccines)?

Antibody-based vaccines

One approach that’s being tried by a major US group is to make a universal flu vaccine based on an understanding of protein structure (the kind of studies done with the synchrotron).

The idea is to focus the antibody response on a part of the surface (on the virus) hemagglutinin (H) protein common to all variants rather than, as normally occurs, to the highly mutable “head” region that changes in successive, “seasonal” flu strains.

Other efforts are directed towards generating protective antibodies directed at M2e, a very stable, virus-coded ion channel protein that’s also found (though at low abundance) on the outer surface of the virus particle.

Peter Doherty

There are also promising results using new chemicals (adjuvants) that promote a stronger, and more cross-reactive antibody response but these require rigorous safety testing.

Recruiting killer cells

Another strategy is to prime a different component of the immune response, the memory CD8+ (or “killer”) T cells. Specific receptors on these circulating white blood cells are targeted to small segments of viral protein (peptides) that find their way to the surface of infected cells bound in the tip of our own transplantation, or “self” major histocompatibility complex (MHC) molecules.

These extraordinarily variable MHC proteins are the structures recognized as “foreign” (non-self) when a kidney, for example, is transplanted from one person to another. Adding a “non-self” virus peptide makes any infected cell that expresses this new “altered self” MHC molecule seem as alien as a transplant from an unrelated person.

We found more than 30 years ago back that these CD8+ “killer” T cells are much more cross-reactive (destroy cells infected with a range of related viruses) than antibodies when it comes to recognizing influenza virus-infected cells.

If we establish CD8+ T cell memory to one influenza A virus (either by prior infection with a cross-reactive strain or by using some special vaccine), then the next time this individual is infected with a quite different flu virus, she will still recover more quickly.

But, unlike a situation where the “best-fit” antibody is immediately available in the body to respond to infection, the time taken to achieve that transition from “resting memory” to “active killer” status in an immune person means that primed CD8+ T cells don’t provide instantaneous, “sterile” protection. There’s always a lag phase.

Influenza A viruses replicate incredibly quickly and, even in someone who has good T cell memory, the pathogen will grow to a high concentration in the lung before the “killers” become available to do their job and clean out the source of further infection.

The problem of individuality

Virus-specific CD8+ T cell memory isn’t induced effectively by the standard, inactivated flu vaccines. It is primed by “attenuated”, live-virus vaccines, though such limited infections may not give a very good immune response. These live-virus vaccines are also not currently licensed for use in Australia, or suitable for the very young and the elderly.

Peter Doherty

But turning instead to some type of non-living vaccine runs into problems because the variability of the MHC proteins that CD8+ T cells recognise also applies to the viral peptides that bind to these diverse MHC molecules.

What’s more, every human being has three relevant MHC gene loci, meaning that each of us has six different MHC genes (three from each parent) and, while some MHC types are shared between large numbers of people (such as HLA-A2 in Caucasians), no two people are ever likely to be the same.

That’s why, for example, it can be so hard to find even a partial match for a kidney or heart/lung transplant. This problem is generally solved by a life-long need for the organ recipient to take immunosuppressive drugs.

Impending universal vaccine?

A recent claim that there’ll soon be a universal influenza vaccine requiring one shot in a lifetime is, I believe, based on the use of a polytope (a number of different peptides stitched together) to promote broad spectrum CD8+ T cell memory.

I have my doubts that this will really do the job. We tried that approach years ago without any great success and, even if someone has now have made a much better product, it’s clear that human T cell memory wanes with time and boosting will be needed.

And whenever we’ve looked experimentally at the protective value of primed T cell memory, it’s promoted the more rapid elimination of relatively mild influenza strains, but anything that is highly virulent will simply “blast through” and remain potentially lethal.

Still, if we could combine these two approaches (cross-reactive antibodies and T cells) to develop a partially protective vaccine (allows some infection but minimizes morbidity/mortality), such a product would be of real value in, for example, the face of challenge with a novel, pandemic influenza strain.

It could be stockpiled for emergencies, or used regularly to minimize the consequences of “seasonal” influenza.

U.S. Navy

Also, a vaccine that provides a measure of protection while allowing some virus growth has the advantage that cross-reactive responses (both antibodies and T cells) would be boosted regularly as new “seasonal” variants emerge.

Apart from developing and testing such a universal, partially protective vaccine in the laboratory, the challenge would to convince both regulatory authorities and vaccine manufacturers that this is a good strategy. And that’s why most activity is still based in academic institutions.

The promise of technology

It’s also possible to envisage a completely different scenario. Advances in molecular technology and vaccine production protocols may, in the not too distant future, allow manufacturers to produce a specific vaccine against a newly emerged influenza A virus both very rapidly and in massive quantities.

A lot of progress is also being made in developing better therapeutics, both drugs and cross-reactive monoclonal antibodies, that could be used as preventives or treatments in the face of a major pandemic.

Vaccines are much less expensive than chemicals (drugs), and infinitely cheaper than monoclonals, but both can be produced in bulk ahead of time as a strategic reserve.

However this pans out when the next bad influenza comes along, it is extremely gratifying for those of us in the infectious disease area to see the recent re-emergence of vaccine research and development as a very dynamic and innovative field of endeavor.

Science protects humanity, and vaccines (along with public health measures and therapeutics) are a big part of that story.

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