What a decade it has been in global immunisation! In a very quick gallop through what I see as the main trends, I want to try and embed our effort in immunising the world’s children in the larger context of what I see as a bit of a new breeze blowing through the overall development aid field.
I will begin by talking about the July 2005 summit, the day after the London bombings, when the G8 group of nations committed themselves to a new global imperative: get rid of extreme poverty in the world, especially in Africa. What is really needed here is a new Marshall Plan, a really big commitment by the North to work with the South to get a new deal going.
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It is very interesting to ponder the words of US Secretary of State George Marshall when he was describing his Marshall Plan, because what he said is so applicable today, 60 years later:
Our policy is directed not against any country or doctrine but against hunger, poverty, desperation and chaos. There’s no doubt in my mind that the whole world hangs in the balance.
I think it was a lovely little catchphrase that Bono and Bob Geldof coined when they said, ‘Make Poverty History.’ As Jeffrey Sachs so often reminds us, the grinding poverty that afflicts one-sixth of the world’s population, where there really is no hope, is a scandal.
Health comes so centrally into this situation, because it is important from a humanitarian point of view, it is important from an educational point of view – a sick kid can’t learn – and it is important from an economic point of view. So a kind of a virtuous circle unites health, education and economic growth.
The Commission on Macroeconomics and Health that Gro Harlem Brundtland initiated some seven or eight years ago came to the conclusion that 41 life-saving interventions, which would cost $40 per person per year, would save 8 million lives per year, and the economic benefit – the economic benefit, forget the humanitarian benefit – would be $6 for every dollar spent.
Here we have Jeffrey Sachs’ words:
There is absolutely no excuse for us to live on a planet where, at 10 cents per $100, millions of lives could be saved every year. It’s hard to understand why we kill people [in wars] but absolutely unthinkable how we let millions of people die when we stand by without understanding what is in our own interest and moral obligation.
(Jeffrey D Sachs, Earth Institute, Columbia University, 2003.)
I took some figures from the Web a few days ago. The world GDP last year was US$51 trillion. So Sachs’ 10 cents per $100 would raise US$51 billion extra. That is, roughly speaking, what you need for the health deal that the Commission spoke about.
In the US alone, health expenditure is US$2.2 trillion. And world health expenditure is US$5 trillion, so the US$50 billion that we need is exactly 1 per cent. Cut 1 per cent off the health budgets of the world, and you have got what Jeffrey Sachs wants.
Of course you are going to have to have priorities. Within health I think the aid priorities should still be infectious diseases as number 1, with nutrition, especially micronutrients, hugely important. Essentially, with the exception of emergencies and war and so forth, there is no calorie malnutrition in the world. There is protein malnutrition, and there certainly is malnutrition with respect to iron, iodine and vitamin A. That needs to be fixed.
Antenatal and obstetric care is hugely important, as is birth control, birth spacing, and so is the looming epidemic of obesity and diabetes.
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The big thing that I want to say is that progress is possible. It is a few months now since UNICEF announced that, for the first time ever, deaths in children under five fell below 10 million. It was 13 million in 1990; in 2006, 9.7 million. And of course you won’t be surprised to read that Sub-Saharan Africa and South Asia account for the majority of those deaths. Nor will you be surprised to read that the infectious diseases which to a significant degree this conference has been about are enormously important killers – the pneumococcus, 1.8 million deaths; the diarrhoeal diseases together, 1.6 million. (Those are not all in children, but total deaths.)
I am extremely heartened to think that for the first time we are beginning to address these problems with real money. What has convinced me that all of the ambitions that Julian Lob-Levyt spoke about yesterday are possible is that since the world finally did face the terrible problem of HIV/AIDS, in two particular funds, for the first time we are talking billions, not millions. I don’t know whether many of you, like me, have spent endless, endless hours on various World Health Organisation committees – I am sure you have. You would know how hard it is for WHO to scratch around and find a few million dollars for a new program. But now we are talking about billions.
Let’s consider the Global Fund to fight AIDS, TB and malaria. In the first five years of the program, $8.4 billion has been pledged to 136 countries; 770,000 patients are on HAART (highly active anti-retroviral therapy), starting from nothing a decade ago in the developing countries; 9.4 million people have been given HIV testing and counselling; 2 million people have been on TB chemotherapy; 18 million insecticide-impregnated bednets have been distributed – a wonderful best buy, a simple expedient that has halved the mortality from Falciparum malaria – and 23 million malaria treatments have been given.
Well, if you thought that the Global Fund is off to a pretty good start, watch George W Bush! Did any of you think I would be giving a bit of praise to George Bush?
PEPFAR, the President’s Emergency Plan for AIDS Relief, has been a really generous program. It is going to be $5.8 billion this year: $4.2 billion goes to HAART for 15 focus countries, putting the money into where the US authorities believe the most good can be done; some funds recycle through the Global Fund; some funds go to malaria control.
Between these two funds, the Global Fund and PEPFAR, 2 million people will be treated this year for AIDS – as I said before, from none a decade ago. And the goal for both the G8 and the UN, enunciated by them, is to have 100 per cent coverage of AIDS patients by 2010.
We are going to have a lot of ‘glass half empty, glass half full’ types of discussions today. Seven million people need treatment, so 2 million, in a way, isn’t really all that many. But looked at another way, it is a hell of a lot better than none. And these funds are starting to flow via regular aid programs.
We have had a bit of a discussion about TB: 2 billion people infected, 9 million new cases per year, 2 million deaths per year. The directly observed therapy short-term works reasonably well – it is a good program, but it doesn’t help everyone – and of course resistance to the first-line drugs (multi-drug resistance, MDR) is a major, major problem.
A looming, not yet – fortunately – an extremely common problem is the extreme drug resistance (XDR), where you are not resistant just to the cheap drugs but to the expensive ones as well. That has got to be watched extremely carefully. About 3 per cent of the new cases fall into that camp now.
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None of this stuff is easy. I have put up this one slide about polio, because we have been on the polio eradication jag for a long time – that wonderful collaboration between Rotary International and WHO. And look, we’re doing well. Up to today, in this year, there have been only 132 cases in India and 46 in Nigeria. (The other two countries in which polio has never been eradicated are Afghanistan and Pakistan.) However, those numbers are not lower than they were last year. There is clearly a very big problem in eradicating polio among the poorest of the poor, in the slummest of the slums and so forth.
On the other hand, the good news is that in 22 of the 27 countries that unwisely stopped their immunisation because the disease had been certified as having been eliminated, we got on top of the problem pretty quickly. So there are only five importation countries where the polio virus is circulating.
I have flashed up the Somalia one because that is one hell of a tough country and yet Somalia, through heavy volunteer labour, has had its last case just a year ago. It is now polio free.
Margaret Chan, the Director-General of WHO, believes that we have got to go on with it, that there is a big investment there now. That investment is costing $400 million a year, and if we stop trying to do it, it will go back so very quickly. So she says that finishing the job of polio eradication is a best buy.
You would all know the figures about malaria: at least 300 million attacks per year, probably more; at least 1 million deaths, probably closer to 2 million; the resistance to the drugs and the Anopheles resistance to insecticides; and, as I mentioned, 18 million insecticide-treated bednets.
I want to mention very briefly a program that Graham Mitchell and I have been pretty involved in, called Medicines for Malaria. This is again a public-private partnership, involving quite a few of the pharmaceutical companies, who are offering up their libraries of drugs for screening. Out of that have come 11 hopeful candidate new malarial drugs – five of them are artemisinine derivatives – and these are now in early clinical trial. So that is a good news story.
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We have spent a lot of time here on acute respiratory diseases and meningitis. And what a success these conjugate vaccines have been, a fantastic success. But they are expensive, and how far the companies will be able to go with their tiered pricing to bring these prices down we have yet to find out.
Therefore, I believe a lot of importance attaches to the field of genome mining, to find one or more common protein vaccines in respect of the pneumococcus.
The Haemophilus influenzae B and Neisseria meningitidis C have equally been very, very good vaccines, and the Hib is certainly beginning to be deployed in the Third World. And I will say a few words later about Mening A, because that is an extraordinarily interesting story.
We still have a residual problem with Mening B, where you would all know that the carbohydrate is a sialic acid and therefore there is tolerance, and therefore breaking that tolerance would be dangerous. We don’t have a vaccine here yet. Genome mining looks as though it is going to solve that problem, and Novartis are pressing ahead with a trivalent, acellular vaccine that at the moment looks pretty good.
Non-typable Haemophilus is another problem.
To turn to diarrhoeal diseases: well, there is good news and there is bad news. You heard a lot about this from John Clemens yesterday. Two rotavirus vaccines have been registered, more are in the pipeline. Rotavirus is an important disease, with 600,000 deaths per year, a surprising number of deaths.
I think Shigella is a big problem, because really we have some very promising antigens from pre-clinical research, but relatively speaking we have very little clinical research. Just quite recently the Gates Foundation charged PATH (Program for Appropriate Technology in Health), a small non-governmental organisation based in Seattle, with trying to revitalise this area through a sizeable grant for Shigella and for enterotoxigenic E. coli (ETEC). So we are going to, hopefully, get some very good funding flows and have people like John come and solve these problems for us.
You heard from John about the cholera; he didn’t have a chance to say much about the typhoid. I think the frustration here is that very good vaccines exist but they are not being used enough. I think the work that John has done to get the cholera vaccine widely accepted in certain countries is hugely important work.
With the typhoid, I guess all of us would be pretty bullish about the Vi carbohydrate linked to a protein carrier as a very viable and excellent way of moving forward. And there are some good candidates for ETEC as well.
We have heard a lot about vaccines which prevent the viral causes of cancer. Here I would have to say that Marc Kane has done an outstanding job in getting the Gates Foundation and GAVI to put hepatitis B right at the top of his list of new vaccines to be deployed – often against the initial wishes or the initial feelings of the health ministers of the affected countries, because it is not as widely known as it should be what a villain hepatitis B really is, with its capacity to cause cirrhosis and liver cancer.
Hepatitis C I think has been slower than it needs to be. Again we know the right antigens, we probably need a T cell based vaccine here. There is some progress.
You have heard about the HPV and the two equally brilliant vaccines that we have in the clinic, and they will be being picked up, hopefully, by GAVI in the not too distant future. And you would realise, from the 70 per cent that we are covering now with the HPV 16 and 18, that we need more serotypes. That should be fairly straightforward R&D, but still it has got to be done and it will be expensive, and it has got to be trialled. I am looking forward to progress here.
I actually think that the lack of progress clinically with Helicobacter pylori is very reprehensible. We have proof of principle. In fact, the first proof of principle was obtained at CSL by Chris Doidge that we can have both a prophylactic and a therapeutic vaccine, in his case in a not particularly good model. But we know that Chiron have a beagle dog model where both prophylactic and therapeutic vaccines have been trialled and are looking good – a straightforward multivalent acellular vaccine, nothing fancy about it – and no-one seems to be wanting to make the investment for very large-scale clinical trials.
These diseases are very important, and gastric cancer, much of it associated with Helicobacter pylori, kills about a million people a year.
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You can take your pick of which other vaccine you want to put on the list. I have put up on this slide just a very short list, to tell you of progress in all of these areas and difficulties when we ask ourselves how many of those will be able to be universally deployed, both for cost reasons and because there is starting to be just a little bit of maternal resistance to the many needle pricks.
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Well, I too thought I wanted to spend a few slides talking about the GAVI Alliance, because I think some of these statistics are quite stunning: 36.8 million extra children have received the standard six vaccines as a result of GAVI, and 176 million children have received any or all of hepatitis B, Hib and yellow fever vaccines. I am enormously impressed with the measles results, with a 60 per cent reduction in measles deaths, aiming for 90 per cent by 2010 – that probably won’t happen, but it could easily by the time of the Millennium Development Goals, 2015. And all of that has added up to 2.9 million deaths prevented.
Julian Lob-Levyt told you yesterday that Bill Gates, re his $1.5 billion donation to the GAVI Alliance, termed this his best investment ever. I actually think that is pretty moving. To think that the world’s richest man, whose investment was Microsoft, says this is a better investment than Microsoft – there should be a lot of people pay heed to that call.
But, as we discussed yesterday, the glass is ‘half full’ but it is half or even three-quarters empty! We have still got 28 million children each year who are not being immunised with the common vaccines; we still have 2.5 million vaccine-preventable deaths each year; and we need at least $10 billion to $15 billion extra over the next 10 years.
So I thought I would go into a tiny bit more detail than Julian was able to do, on the International Finance Facility–Immunisation (IFFIm).
You might think this is ‘funny money’, but in point of fact it is difficult to get governments to commit money off their budgets this year. There is always some good reason for postponing it. The International Finance Facility–Immunisation gets over that. Bonds are issued through the international capital markets guaranteeing large, immediately available sums, and then these are redeemed, as Julian showed you, by legally binding pledges over a number of years – up to 20 or 30 years – from the same governments as the donor countries that could have given you the money straightforwardly but don’t.
So, on 14 November 2006, IFFIm placed US$1 billion of five-year bonds at 5.2 per cent interest rate, just a little bit above the bond rate in the United States. And, whereas many of the investors were central banks and superannuation funds as you might have thought, there were quite a few ‘mums and dads’ investors – there is private sector interest in this area.
Over the next 10 years, IFFIm plans to raise US$4 billion for the GAVI Alliance. (The next tranche, as Julian told you, is coming this year.) The donor countries are France, Italy, Norway, South Africa, Spain, Sweden and the UK. There are some pretty noteworthy omissions there.
The Advanced Market Commitments for Vaccines is, in a way, an even more ambitious scheme. The idea of this is that it is a new mechanism for development and then subsidised purchase of priority vaccines, including ones not yet invented.
The pneumococcus was chosen last year as the first target, because it kills 1.6 million people annually and this is really low-hanging fruit, because all you really have to do is get the same conjugate vaccine that works very well as a Prevnar® to have chiefly the strains that are circulating in the Third World. That should be very do-able. But it is the first example of new money being made available for a vaccine which actually doesn’t yet exist, and to have the guarantee that if the companies come up with the vaccine, it will be purchased.
US$1.5 billion has been pledged, with Italy and the United Kingdom as the chief drivers of this new idea. And, as I said before, the Advanced Market Commitments will fund research, support development and provide funds for a sustainable supply, and they have to negotiate a reasonable price.
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I said I would mention African meningitis. This is very, very important for me, for one simple reason: that a Third World manufacturer was finally chosen by WHO and PATH as the person contracted to deliver this vaccine. The epidemic of meningitis in the so-called meningitis belt of Africa, where about 350 million people are involved, is important not really just because of the number of people it kills – the case fatality rate is about 10 per cent – but because when the epidemic is on it paralyses the health services of the nation concerned. People fear Mening almost more than they fear anything else. You know, it can be from healthy person to death in 24 hours, quite easily. And we actually even fear it here in Australia, don’t we? It is a horrible disease.
The Serum Institute of India was chosen, and two contract research organisations have to help with the technology transfer. The thing is now on track, because a sizeable, almost phase 1½ trial in Mali and The Gambia showed that with the conjugate manufactured in India the kids make 20 times more antibody than with the unconjugated, old-fashioned carbohydrate vaccine.
The Dell Foundation is going to fund a large demonstration study, where all the kids and all the young adults in Burkina Faso are going to be immunised. So again it is work somewhat similar to what John Clemens has persuaded me is very important – to actually do a demonstration study, as part of your research, to show that this thing can work. And that, if it works, I feel sure will unlock the $400 million that will then be needed to immunise the 350 million people in the 20 other countries of the meningitis belt.
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I have to confess to you that I have the greatest admiration for the US Department of Defense and for GlaxoSmithKline, to have hung in there with Ruth Nussenzweig’s sporozoite style vaccine – they call it RTS,S – with the special adjuvant that you will be hearing about in a moment. Not only has it been safe and immunogenic in children aged 3 to 5, as you will hear, but more recently it has been shown to be safe and immunogenic in infants. So the possibility of delivering this vaccine as part of the DPT platform looks very good.
Yes, one would like higher-percentage efficacy, and yes, one would like a longer duration of protection. But in a very dark area this has been a good news story over the last couple of years.
Blood stage antigens have been difficult, they have been very disappointing, broadly speaking. But the famous AMA-1 developed by Robin Anders in Graham Mitchell’s lab is looking good, and there are two AMA-1 phase 1 clinical trials ongoing.
And then let’s pause for a second to consider what an extraordinary thing Steve Hoffman has been able to persuade the Gates Foundation to support. This is the idea of actually using living mosquito salivary glands as the factory for sporozoites, which are then irradiated – and we know that irradiated sporozoites work, from challenge trials, 90 per cent effective in human volunteers, duration at least four years. And this will be entering clinical trials in 2008.
It is a bit crazy but it’s brave. And if it works, I think the next step will be Stefan Kappe’s work using genetically attenuated sporozoites, rather than frying the thing to death with irradiation, which is not a very modern thing to do.
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Tuberculosis we have talked about a lot. Again the Gates steps in and supports the Aeras Tuberculosis Vaccine Foundation – this is Jerry Sadoff, and this is in a sense trying to have a global overview of tuberculosis vaccines and supporting a lot of investigators in a lot of countries.
You heard that these strategies include new BCG strains with genes for selected soluble antigens inserted – there are about 20 viable antigens here – as well as novel recombinant proteins with novel adjuvants, and also prime-boost regimens using adenovirus 35, which should avoid the Ad5 problem that the Merck AIDS vaccine ran into with pre-existing immunity in the humans. The adenovirus 35 doesn’t infect humans, and there should be no pre-existing antibodies.
You can take your pick of the antigens. From my reading of the literature, probably the most promising include ESAT6, antigen 85B, TB 10.4 and HSP90.
Six phase 1 studies have started or are just about to start under Aeras support. Jerry hopes to have two phase 3 clinical trials by late 2010. I have mentioned here the work of Peter Andersen, from Sweden, not so much in respect of the Ag85B and the TB 10.4 but because the IC31 antigen from Austria, from a little company called Intercell, does genuinely look to be the goods. And one will wait and see what those trials bring forward.
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As to HIV/AIDS, you can’t complain about there not being enough money in the AIDS vaccine search. The total world effort now is about $800 million per year, and I think that the best thing that has happened in AIDS, with IAVI (International AIDS Vaccine Initiative) as the ones that pointed the way early on, the first ones to actually think along these lines, is to have coordination and collaboration – to have the whole world working together rather than in competition, one with another.
This comes in a variety of flavours. We have the Gates Collaboration for AIDS Vaccine Discovery, very strongly funded. We have the NIH Vaccine Research Center (intramural) and the Centers for HIV/AIDS Vaccine Immunology (an extramural program). We have IAVI, based in New York. We have a strong effort in Europe, under Euro Vacc. And, would you believe, little South Africa has a very credible program called the South African AIDS Vaccine Initiative.
Because all of these forces want to work together, we now have Alan Bernstein, the distinguished Canadian scientist and health administrator, running GHAVE, the global HIV/AIDS vaccine enterprise, the duty of which is communication, knowledge management and policy development, keeping all of these partners working as a consolidated whole.
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I wouldn’t want to tell you that the early clinical work has been incredibly promising. As you all would know, it has not. There are about 30 candidates in early clinical trials. Some of them are finished and robust, others are still at a very early stage.
Really, there have recently been, after the VaxGen fiasco (if I can term it such), only two candidates in efficacy trials: the Sanofi-Pasteur canarypox vector with HIV inserts and boosted with the VaxGen straight protein – there is a large trial going on in Thailand – and, as you heard, the recently stopped Merck trial, using the adenovirus serotype 5 with gag, pol and nef expressed, which was stopped on 21 September 2007 because it had a triple strike against it. Not only did it clearly fail to prevent infection, but also it failed to lower the set point, that level that the virus achieves during the latent period, which is a very important prognostic marker: a lowered set point would mean longer disease-free duration of life. But, in a sense most worryingly of all – not by an overwhelming statistical amount but by quite a clear-cut amount – the people who had pre-existing antibody to Ad5 got AIDS more frequently than placebo controls.
Now, we have to have a post hoc ergo propter hoc style argument here – there might have been confounding variables between those two groups. But if in fact it is true that pre-existing immunity to the vector sets you up for some kind of inflammatory situation after the vaccine which makes it more likely that you get AIDS, that would be a truly terrible thing.
I can well remember when Ian Gust took on the job of running AIDS policy for Australia. Ian was a lot less cautious than his predecessor in that role, and I can remember a totally brilliant lecture that he gave, talking about risks. He said, ‘Well, I reckon the risk of contracting AIDS, if it is male to female transmission, is about 100 to 1 for each intercourse.’ So, one time in 100 you catch it. He had very little evidence for this, but it made a very good story. And in point of fact, what might be happening here is that this pre-immunisation with something that you are already immune to – so there will be immune complexes, there will be inflammation – raised it from one in 100 to one in 25 or 30. That of course needs a lot more research.
But I tell you what, it has put a very sober kind of overhang in the global HIV vaccine story.
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I won’t labour my last slide. There is a lot of promise still: mimicking the trimeric envelope structure, which we haven’t been able to do yet; stabilising or mimicking the intermediate (cross-linked envelope CD4) transition state just prior to the virus engaging the co-receptor – there has been some interesting work on gp120-CD4 complexes, or analogues thereof; mimotopes of those epitopes to which broadly neutralising monoclonal antibodies bind; new adjuvants, new prime-boost regimens; and much theoretical work about how clinical trials could be shortened by looking for what reduces the set point of virus load.
Well, ladies and gentlemen, is the glass half empty or is the glass half full? I don’t know the answer to that question, but I am really enormously encouraged that there is no way in the world that I could have given this talk a decade ago. And a decade is a relatively short term in human history. Go forth, all of you who are doing the real work. Keep up the good work.
Discussion
Graham Mitchell (Chair): Thank you very much, Gus, for a masterly global sweep of an entire field, as we have come to expect in this particular conference – a great update of what is actually happening out there: that arithmetic we have all grown up with, of the impact of these neglected diseases. I think one of many messages I took away, Gus, is that we are getting the same sort of arithmetic in respect of now genuine money to address these issues. And, as you say, it is a completely different landscape from 10 years ago.
Question: Gus, thanks for that. That was really inspiring. The question I had was based on IFFIm. We have just been subject to the subprime crisis, and the market is so fickle, and all of a sudden you are putting out bonds to get lots of money for immunisation. What happens if we have a major crash and there is a funding vacuum?
Gus Nossal: As far as I know, this IFFIm – which is actually a company, a British-based entity – has, as it were, completely tied up the countries concerned, so that the pledges for the countries to redeem the bonds are legally binding. In other words, if Norway defaulted on its obligation to commit to its share, there would be a civil action against the government of Norway.
How watertight is that, and what happens if there is a global subprime crisis? What happens if there is a 1929–31 style depression? Of course I can’t answer that question.
It is, in a way, ‘funny money’. There have been articles published, strongly criticising IFFIm, and there are people who don’t think it is a good idea at all. But, unfortunately, I have just seen too many examples of governments in the flush of some big meeting promising to do things, but when the actual time comes to pony up the money, there is some very good reason for not doing it. It is a way of circumventing that.
Question: A very important part of the polio eradication program is the acute flaccid paralysis surveillance network. I wondered if there are plans for that well-established network to be redeployed for something else – or, at the very least, to keep surveilling for AFP once polio is declared eradicated.
Gus Nossal: Well, in headier days, when we thought this job might be done by about 2005, there was a great deal of talk about using that existing and very important labour force that is doing the surveilling at country and regional and district level, for a measles eradication campaign. In measles we have a brilliant vaccine; it has got one defect, that it won’t work in the presence of maternal antibody – fundamentally, it won’t work before nine months of age. So we have got that gap between four or five months and nine months. That is the one drawback of the measles vaccine that we have got, and WHO is doing a lot of work on the idea of an inhalable measles vaccine to circumvent that.
I guess what has really happened is that this polio is proving so much more recalcitrant than people had hoped, that people just aren’t talking about measles eradication any more. There is another little sleeper about the polio job being done: who is going to give the vitamin A? At the moment, the vitamin A for 2 cents is being given with these big campaigns through National Immunisation Days or Sub-National Immunisation Days – a fabulous investment. That is going to have to be done some other way.
But I agree with you that the very significant volunteer, and professional, labour force that is involved in that surveillance is a public good and must be preserved.
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