Why do flu vaccines have to be given every year and still provide less-than-complete protection?
As we face into another flu season, Dr John B Carrigan takes a timely look at the possibility of bringing a universal flu vaccine to the market
Over the course of the swine flu pandemic in 2009 and early 2010, the Health Service Executive distributed 1.78 million doses of vaccine to HSE vaccine-clinics and GPs. Over 1.2 million doses were used and the remainder are being held in a central cold-chain store.
Approximately 25 per cent of the population have been vaccinated, with between 50-60 per cent of those belonging to medically at-risk groups. Over 60 per cent of the under fives have also been vaccinated.
The HSE’s official position is to continue to store some pandemic vaccine stock in the HSE National Cold Chain Service, so that additional supply will be available in case it is required for use later this year. This is considered to be a safe policy, as a return of swine flu is a real danger in the eyes of many experts.
Yet many of our European neighbours feel that they have an oversupply issue and have been in protracted negotiations to stem the problem.
The Dutch Government announced recently that GlaxoSmithKline has agreed to reduce a contract for the supply of H1N1 flu vaccines to the Netherlands, cutting the order by 30 per cent and saving €21 million. France is pursuing a similar strategy.
The Dutch Government has also decided to sell the leftover vaccines to other countries, entering into agreements to sell a total of 257,000 doses to Estonia, Macedonia, Suriname and Lithuania. Although it will discuss possible sales with other countries, the Netherlands said it does not expect to sell large amounts of doses.
All of this comes against a background where seasonal flu still kills a large number of people each year.
If there is one thing that the outbreak of the H1N1 virus and the subsequent handling of the situation has taught us, it is that we cannot continue with the current policy of trying to keep up with the latest outbreak year on year, as well as having to second-guess the likely implications.
Universal vaccine
This all brings into sharper focus the need for a real solution to the problem and whether the answer lies in the much-talked-about concept of the universal flu vaccine. But just why is it that two shots of measles vaccine given during childhood protect a person for life and four shots of polio vaccine do the same, but flu shots must be received every year? And why do flu vaccines still provide less-than-complete protection?
The answer lies not just in the very structure of the flu virus, but in particular that area we have been targeting since vaccination against flu first became possible in the 1940s, when the US military developed the first approved inactivated vaccines for influenza, which were used in the Second World War. (The first seasonal influenza vaccine in the United States became available in 1945.)
A protein on the surface of the influenza virus called haemagglutinin (HA) has led to immunisation with influenza HA vaccines that can induce the production of virus neutralising antibodies. The protein is charged with the responsibility of recognition and fusion with the host target cells.
There are 16 known subtypes of HA proteins. Influenza A viruses can include any of them. The HA proteins fall into two groups, Group 1 and Group 2, depending on structure. Group 1 has ten of the known HA subtypes and Group 2 has the remaining six. Such is the importance of haemagglutinin that it partly determines the name of the flu, i.e. H5N1 has HA5.
Incidentally, the ‘N’ comes from neuraminidase, a protein that is expressed on the surface of the host cell that can promote the release and spread of the virus.
Mutable protein
The problem with haemagglutinin is that this lollipop-shaped protein, the head of which is largely targeted for immune response, is actually highly mutable. That is, the predominant target of neutralising antibodies accumulates mutations from one year to the next – a process called antigenic drift.
In some years, this random process yields a virus variant that escapes from the antibodies we have already developed for earlier strains. While it has not escaped the medical/scientific world’s attention, attempts to develop immunobodies recognising other, more stable, virus proteins has proven very difficult.
However a shift in thinking occurred quite recently after an announcement by Dana-Farber Cancer Institute. It identified a small family of human monoclonal antibodies that can neutralise an unprecedented range of influenza A viruses, including the bird flu virus (H5N1), previous pandemic viruses (such as the 1918 Spanish flu, which killed an estimated 50 million people – about 3 per cent of the world’s population) and some seasonal flu viruses.
This work was carried out by the Harvard Medical School, in Boston, Massachusetts; in the Burnham Institute for Medical Research in La Jolla, California; and in the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia. Results were published in Nature Structural & Molecular Biology.
Probably the most interesting part of the work that Marasco and colleagues did on this study was to describe the detailed atomic structure of a section of the flu virus to which the monoclonal antibodies they produced bound. This is in a hidden part of the virus, located in the ‘neck’, below the ‘head’ of the haemagglutinin protein.
Another important discovery was that once the antibodies bound to this part of the viral protein, they could not change shape, which prevented them from fusing properly to the cell – and allowing entrance to the host cells to cause infection. This was the key to the neutralising power of these antibodies.
Antibodies
Marasco’s work was quite elegant. At first, the team worked on avian flu viruses. By scanning billions of monoclonal antibodies produced by bacteriophages (viruses that infect bacteria), they found a number of them that could function against the four main strains of H5N1 bird flu virus. Subsequently, these specially selected antibodies were tested in both cell cultures and mice and were successful in neutralising other known influenza type A viruses in these organisms.
The monoclonal antibodies that Marasco and colleagues found neutralised all testable viruses that contained the ten Group 1 HA proteins, including the H1 virus that caused the 1918 Spanish flu and the H5 bird flu types, but they did not work against any of the viruses containing the Group 2 HAs, which are structurally slightly different.
Upon closer examination of one of these monoclonal antibodies bound to the H5N1 virus, it was revealed that an arm of the antibody reaches into a pocket in the neck of the HA protein. It is this that stops the virus changing shape and being able to fuse with the membrane of a host cell.
Marasco and colleagues then looked at more than 6,000 other genetic sequences of the 16 Group 1 and Group 2 subtypes and found that within a group, the pockets were similar, but the groups were quite different to each other. They speculated that the pockets are genetically stable because they are an ‘evolutionary constraint’ that enables the virus to fuse with the cell and as such, they are simply not as open to being mutagenically altered as the more prominent lollipop head.
Dr Robert Liddington, Professor and Director of the Infectious and Inflammatory Disease Center at Burnham, puts it rather succinctly: “The stem [neck] region of haemagglutinin is highly conserved, because it undergoes a dramatic conformational change to allow entry of viral RNA into the host cell. It’s very difficult to get a mutation that doesn’t destroy that function, which explains why we aren’t seeing escape mutants and why these antibodies neutralise such a variety of strains of influenza.”
Antigens into vaccines
So why not just use this antigen to make a flu vaccine? That might very well be possible, but people like Ruben Donis, PhD, Chief of the CDC’s Molecular Virology and Vaccines Branch, think we are about three to five years away from such a development. The primary difficulty is likely to be that separating the neck portion of the lollipop is a lot harder than it sounds.
The antigen has to be exactly the right shape, and the true three-dimensional shape of the HA antigen is more like three lollipops stuck together in just the right way. Even if this is achievable, Donis warns that a vaccine may not be better than a treatment. “These antibodies pave the way for the generation of a different kind of universal flu vaccine,” he stated at the news conference to announce Marascos’s results last year.
“People tend to emphasise vaccines as the ‘Holy Grail’ of flu, as it were. These antiviral antibodies are very effective, and can be very effective in a pandemic setting – they just need to be used judiciously,” said Dr Robert Liddington. “These antivirals are ready to go and should be effective just as they are, as soon as they get through Food and Drug Administration approval and are stockpiled in large enough amounts in metropolitan areas where an outbreak might begin.”
In spite of Dr Liddington’s protests, the general view of antibodies themselves as medicine is that they are expensive to manufacture and time-consuming to infuse into patients.
References
- ‘Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses.’ Sui et al. Nature Structural & Molecular Biology 16, 265-273 (2009)
- ‘Research and development of universal influenza vaccines.’ Du L, Zhou Y, Jiang S. Microbes Infect. 2010 Apr;12(4):280-6
- ‘1918 influenza: the mother of all pandemics.’ Taubenberger JK, Morens DM. Emerg Infect Dis. 2006 Jan
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