Posts Tagged ‘Add new tag’

There’s gold in them old veins….

26 August, 2008

I have often spoken of “molecular archeology” in my lectures, and of the possibility of identifying past epidemic / pandemic strains of human flu in particular, by looking at which viruses are recognised by antibodies from people who lived through the epidemics.

A new paper in Nature ups the stakes in this game considerably: a team led by one James E Crowe Jr describes how 32 survivors of the 1918 Spanish Flu pandemic – born in or before 1915 – were “mined” for antibodies, and seven donors additionally were shown to have circulating B cells which secreted antibodies which bound the 1918 H1N1 virus haemagglutinin (HA).  The team isolated 5 monoclonal antibodies from these subjects, and showed that these potently neutralised the infectivity of the virus and bound the HA of a 1930 swine virus, but did not cross-react with the HAs of more recent human  H1-containing viruses.

Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors : Abstract : Nature via kwout

 This achievement is undoubtedly a tour de force of modern molecular immunology – but is it useful?

Well, one very obvious fact is that people can obviously maintain significant levels of humoral immunity to viruses that infected them – in the words of the authors – “…well into the tenth decade of life.”  This is good news indeed for vaccinees who received vaccines for viruses which do not change much, like measles, mumps and poliomyelitis viruses.  However, given that influenza virus even of one H and N type can change so as to be unrecognisable in just a few years – the MAbs they generated did not react to any great extent with presumptively H1N1 human isolates from 1943, 1947, 1977 and 1999 – this is only of any use if the original virus were to be re-introduced somehow.

There was an intriguing statement in the paper which may shed some light on a long-running controversy as to the origin of the 1977 H1N1 pandemic, when the virus reappeared in humans for the first time since the early 1950s – allegedly as a result of an escape from a Soviet biowarfare lab.

The 1F1 antibody bound and neutralized the 1977 virus, albeit to a lesser degree than either the 1918 or the Sw/30 viruses … and to a minimal degree the 1943 virus”.

Ye-e-e-sssss…strange, that.  So the 1977 virus was antigenically more similar to 1930s era viruses than to one from 1943??

The proposed use of the findings also elicit biowar scenarios: for example, the fact that passive immunisation of people with antibodies to a particular virus can help them get over infection with it is purely academic for MAb to the 1918 virus – or is it?

I hope it is.

H5N1 flu: The End is still in sight

15 July, 2008

While the much-dreaded Big One – a major flu pandemic – still seems to be holding off, I am pleased to see that the latest edition of Nature has devoted an editorial and other commentary space to pandemic flu in general, and H5N1 flu in particular.

The Nature issue of 10th July 2008 – which has Ebola virus glycoprotein on the cover, about which, more later – has as its lead editorial title, “The long war against flu“.  The header goes on:

“That the H5N1 strain of bird flu has not yet caused a pandemic is no cause for complacency. Preparations for the inevitable must be redoubled to mitigate the potential devastation.”

My feelings entirely, and especially for the developing world – shared with you here and here, in MicrobiologyBytes, and here, in your own ViroBlogy.  It is all too easy to easy to fall into a state of complacency, or even H5N1 pandemic fatigue: however, this is really dangerous, especially for planners.  The editorial goes on:

“Five years after the deadly H5N1 avian influenza virus exploded into a global epidemic in birds, it has infected more than 300 people. Happily, it has not yet evolved into a strain that can transmit easily between humans — an event that would trigger a pandemic that could kill tens of millions. But as long as H5N1 continues to be present in animals, that risk persists. And with so many other flu strains out in the world, all constantly evolving, a flu pandemic is inevitable.”


“…improved control measures, especially for H5N1 itself, and public-health infrastructure are our frontline defences against a pandemic. Unfortunately, the overall control picture is bleak. Thailand, Vietnam and China have notched up successes in curbing outbreaks in birds, which is key to minimizing the chance that the virus can pass to humans. But South Korea had its worst outbreak ever in April, and the disease has become endemic in Indonesia, Bangladesh, Vietnam and Egypt. Eradication now seems impossible, and the task of containing the virus has become chronic and costly.”

Which sets the stage for Commentaries in the same issue: in “Ready for Avian Flu“, Tadataka Yamada et al. offer up “…a roadmap for heading off a global avian influenza catastrophe“.  They discuss how the WHO has made plans for stockpiling H5N1 vaccines, and that major vaccine manufacturers have offered to contribute – but also that the necessary allocation plan and ethics framework still need to be worked out.  They discuss how adjuvanting flu vaccines can reduce the dose by up to to four times, and how this together with dedicating the existing manufacturing framework – capable of some 500 million doses of trivalent vaccine a year  – to single-valency production, could allow some 6 billion doses a year to be produced.

Which, of course, would neatly cover the world’s population.  This sounds wonderful – but ignores the fact that H5N1 viruses are notoriously difficult to produce via conventional egg-based methods, which is what provides the bulk of the present manufacturing capacity….  Still, they also point out that adjuvanted, non-matched vaccines can still cross-protect against strains that have undergone seven or so years of genetic drift, meaning that stockpiled H5N1 vaccines could still be relevant in several years time.

They state the following:

“In the next 18 months we [Bill & Melinda Gates Foundation, the Pasteur Institute and the Wellcome Trust] will develop, maintain and disseminate a central inventory of funded research activities that are relevant to human influenza to ensure that stakeholders are well-informed. We will also coordinate roadmapping exercises to identify knowledge gaps. These will assist funders and researchers in establishing research-funding priorities, with specific focus on vaccines, drug therapies and epidemiology/population science (for example, diagnostics, surveillance, transmission and modelling). The Bill & Melinda Gates Foundation and the Wellcome Trust will collaborate to fund these activities.”

And how much developing country input will there be into this?  Distressingly little, probably, given the propensity of these funds to at best give money to developed country groups to work with developing country folk, but at least the roadmap addresses issues that are relevant to the whole world community.  Like intellectual property concerns, coordination of stockpiling and distribution, fair distribution, funding…and surveillance, the forgotten and possibly most important factor in determining if a flu outbreak is getting out of hand.  

Apropos of which, another commentary in the same issue – “The contents of the syringe“, by Steven Salzberg – notes that the influenza vaccine failed this northern hemisphere winter, and that future success relies on sharing data more widely and making the virus strain selection process more transparent.  Salzburg says:

“The WHO met on 11–13 February this year to decide on the strains to be included in the vaccine for the 2008–09 season. As usual, the meeting was closed to all but invited participants, who this year included members of the WHO influenza surveillance network, representatives of national drug regulatory agencies, and influenza vaccine manufacturers. The experts involved chose to replace the H3N2 strain with a more recent isolate, from 2007, which should be a better match to the circulating viruses next season. Neither the WHO nor the CDC publishes the evidence used to support their decision [my emphasis]. That evidence includes hemagglutinin inhibition tests of hundreds of isolates, genome sequences of some isolates and data on the ease with which the isolates can be grown in eggs.”

“The process of choosing flu-vaccine strains needs to be much more open. Other scientists, such as those in evolutionary biology with expertise in sequence analysis, could meaningfully contribute to the selection. At present, external scientists cannot review the data that went into the decision, nor can they suggest other types of data that might improve it.”

Whoops…so those who would safeguard us, feel no need to tell us what is going on??  Salzburg has some suggestions:

“The leaders of the influenza community, especially the WHO and the CDC, should create policies — for sharing data and isolates — that are more open, and should insist that their own scientists follow those policies. When these leading organizations set an example, the rest of the community will follow.”

“Of course, preparing vaccine in cell culture could reduce some of the pressures put on that dark room of vaccine predictors. The current system, in which most of the world’s vaccine supply is grown in chicken eggs, is an antiquated, inefficient method requiring six months or more to ramp up production, which in turn means that the vaccine strains must be chosen far in advance of each flu season. More crucially it sometimes prevents the use of the optimal strain, as it did in 2007. And, if the next pandemic is an avian-influenza strain such as H5N1, then it could easily sweep through the chicken farms that we rely on to produce eggs for vaccines. [me again]”

 He goes on to extol the benefits of sharing sequence information in particular, so as to enable rational, evidence-based choice of flu strains for vaccines – and the use of non-egg-based cell culture methods for vaccine production, and how these should allow far quicker development of flu vaccines.

All of this is very cogent and timeous.  However, it begs the question, previously raised in ViroBlogy, as to how production will be increased to take care of everyone who may be affected.

I still think plants are the answer…!  I note the plant-based flu vaccine group paper that I blogged on previously in this forum has a sequel: this is a better paper all around, and points up the need to explore this sort of production system for this kind of virus.

But I digress – so let me do so thoroughly.  The Nature issue also has a news item on the Eppendorf Song, a new piece of viral advertising with a boy band extolling the virtues of a multipettor.  Not a patch on the Biorad PCR Song, guys – but nice to see some popular culture making its way into science equipment advertising!

So there IS light at the end of the tunnel

1 April, 2008

After the shock of the second failure of an HIV-1 vaccine in Phase III trials recently – detailed to some extent here – we were surely due some relief.

And it is here: William Borkowsky and team have just published in AIDS and Human Retroviruses a paper which describes what amounts to successful “autologous immunisation” of a paediatric HIV-infected cohort by a series of progressively longer treatment interruptions, or drug holidays. 

The children, who ranged in age from 4 to 19, were all on HAART or highly active anti-retroviral drug therapy, and all had initially undetectable viral loads.  The subjects in the experimental arm of the trial were given a series of drug holidays of progressively increasing length over up to 17 cycles of treatment in some cases.  In the words of the authors:

“Increased HIV-specific immune responses and decreased HIV RNA were seen in those children who have had >10 cycles of antiretroviral discontinuations of increasing durations acting as autologous virus vaccinations. Other studies may have failed due to an insufficient number of exposures to HIV; most of the studies had fewer than six drug interruptions.”

This is a quite momentous finding: given that it is known that increased CD8+ T-cell responses to Gag proteins of HIV are correlated with decreased viral load in infected patients, this means that many times-repeated exposures of immunocompetent people to live virus seems to successfully elicit suitable immunity and reduce viral load, just as a vaccine could be wished to do.

But in all the vaccine trials, and in previous treatment interruption trials, no more than 4 vaccinations or 6 drug interruptions were performed – which may mean, given the lack of persistence of T-cell as compared to antibody responses, that simply too few treatments have been given in the past.

So is the solution to dose people considerably more often in prophylactic vaccine trials aimed at protecting against HIV infection? 

And possibly with subunit vaccines (such as our recent offering…B-) or killed whole-virus vaccines instead of “genetic vaccines” such as the DNA and virus-vectored HIV gene vaccines which have been so popular up to now?

We need to explore these possibilities – and to explore them soon.  There is a lot riding on the outcome….