The amount of HIV diversity within a single infected individual can exceed the variability generated over the course of a global influenza epidemic, the latter of which results in the need for a new vaccine each year.
–Walker BD, Burton DR (2008) Toward an AIDS vaccine. Science 320:760–764.
(See my previous posts here and here for more explanation.)
The other day I was talking about immune recognition of human endogenous retroviruses (HERVs) in tumors. (HERVs are the husks of ancient retroviruses, now trapped in our genomes. Some of them still express various proteins, either under normal conditions or when stimulated, as in tumors.) One of the reasons this is an interesting finding, is that HERVs may offer a relatively constant antigen, even though the tumors themselves may be highly variable.
There are other, rather obvious, scenarios in which we would like to have a constant antigen in the face of an antigenically-variable disease. For example, HERVs have been proposed to be useful vaccine targets in HIV infection.
One of the many obstacles to overcome in developing a vaccine against HIV is the virus’s rapid mutagenesis. Because of its error-prone replication, HIV can readily escape a lot of immune recognition. Especially when cytotoxic T lymphocytes (CTL) recognize a limited number of antigenic targets, all the virus needs to do to escape immune control is mutate a single amino acid. Usually once the virus does this and escapes immune control, new CTL arise and once again shut down the virus, but only to have new escape variants arise and replicate. Over the multi-year course of an HIV infection, there may be dozens or hundreds of major HIV variants, each escaping temporarily from CTL and destroying T cells during their limited period of freedom.
There are several strategies aimed at reducing the effectiveness of immune escape: targeting multiple HIV antigens, so that the virus would have to simultaneously find many mutations at once; targeting regions in the virus that are so essential that they can’t tolerate mutation; and so on. But wouldn’t it be nice if there was an antigen that wouldn’t change?
HIV and HERVs are distant cousins, both retroviruses, so it seems reasonable that HIV infection might turn on sleeping HERVs. In fact, for nearly 10 years there have been intermittent studies suggesting this might be the case; first based on antibody responses in HIV patients1, and recently with more specific evidence of reactivation of HERVs both in patients2 and in the lab, in infected cells.3
Last fall Douglas Nixon’s group took this to the next step.4 Although the antibody responses1 had suggested that HERVs were immunogenic when turned on by HIV, antibodies aren’t believed to be terrible important in control of HIV; rather, CTL are thought to be critical.5 Nixon’s group showed that in HIV-infected people, there were often functional CTL responses to HERVs; what’s more, the higher the anti-HERV response, the lower the HIV plasma load, implying that the anti-HERV CTL might actually be controlling HIV. (See the figure to the left; click for a larger version.)
As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design.
Let’s go back to a paper6 I mentioned last year, where a group looked at genomic variation linked to disease progression in HIV. They found three genomic regions that were linked to viral set-point; one is an RNA polymerase, one is in the MHC region and affects levels of the MHC class I gene HLA-C, and the third … well, the third is a HERV, called HCP5.
The authors pointed out that HCP5 might not be the actual factor involved, because it might be riding along with HLA-B*5701, an MHC class I allele that’s associated with HIV resistance (and I noted that natural killer ligands MICA and MICB are also close by). Still, they clearly like the idea that HCP5 is itself directly involved. They suggested that it might act by an antisense mechanism or something, but I think it might be very interesting to look at CTL responses to HCP5 proteins.
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| “Human cytomegalovirus infected human endothelial cells” by Joerg Schroeer |
There’s a famous picture in Field’s Virology1 showing how ectromelia (mousepox virus, a model for smallpox) infects a new host, spreads within the mouse, and then is transmitted to a new host. The figure is below2 (click for a larger version). Simplified, ectromelia initially infects the skin through small cuts; it replicates at the site, then spreads through blood and lymph to organs (spleen, liver) where it replicates further. The progeny virus from this replication then spreads again through the blood, this time back to the skin, where it replicates once again (now vastly amplified from the initial infection) to form the classic “pock” lesions, which shed virus that can infect a new victim.
It’s generally accepted that this is a common pattern of pathogenesis for many of the viruses that go systemic; not necessarily all viruses, because certainly some remain localized or only spread through, say, direct contact, but for something that spreads through the entire host, it should be a reasonably accurate model.
Human and mouse cytomegaloviruses certainly spread throughout the entire host, and infect many cell types within the body — endothelial cells, lymphoid cells in the spleen and elsewhere, liver, and probably other tissues as well. However, Ulrich Koszinowski’s group now suggests that in spite of this, it isn’t following the ectromelia pattern; replication within some of the organs (liver) is a dead end, that doesn’t help disseminate the virus. 3
Koszinowski has a habit of constructing very cool systems for analyzing his pet virus; sometimes so fancy that I wonder if he makes them a little baroque just because he can (and I know4 that he has occasionally been bitten by his elaborate systems). Here he used a Cre/lox recombination system, with the flox in the CMV and the Cre in the mouse under cell-specific promoters, so that the virus genome gets modified only when it replicates in the particular organ. Don’t worry about the details, the point is that the virus is tagged as soon as it replicates in a particular organ, so you can look at viruses throughout the whole mouse and identify whether their ancestors ever replicated in one particular organ. You can also work out timing of replication, and a few other things.
The unexpected bottom line is that what happens in the liver, stays in the liver. There is more MCMV in the liver than anywhere else in the body, but it’s a dead end; once it’s in the liver it doesn’t spread to other organs.5 Instead, the relatively small amount of virus that replicates in endothelial cells (and perhaps in the spleen) seems to be a major source for further spread within the body and for transmission.
The results challenge the concept that organs that produce the bulk of infectious virus during acute infection necessarily also play a major role in dissemination.
Surprisingly, to me anyway, even suppression of the adaptive immune system didn’t change this; the virus still hung out in the liver. (The door is still open for innate immune restriction of spread.)
This shows how little we really know about what goes on in authentic viral infections. So much of our understanding of virology is based on tissue culture, but it’s harder than it looks to extrapolate a simple in vitro observation to the complicated interactions within the body, and it’s dangerous to extrapolate from one virus to another.
Why does CMV replicate in the liver if it’s a dead end? Is this simply a matter of indifference to the virus (replicate anywhere you can and hope you’re in the right spot to spread) or is it doing something specific to modulate the host in some way? My bias is that this is something the virus is doing for a reason, but I don’t know what.
My first foray into research, when I started grad school, was to work on a vaccine against bovine adenovirus type 3.1 From a technical viewpoint, it was a great introduction to research; I got to do classical virology, animal work, tissue culture, protein purification, all kinds of immunology, and so on. Still, I ended up unenthusiastic about vaccinology (though not about vaccines, which I regard as one of the most important benefits to civilization in history). The problem was that so much of vaccine research seemed purely empirical, with no solid theory underlying it. The way to design a new vaccine was just to try a whole bunch of different things (sometimes applying rules of thumb) and see what worked.
To some extent that’s still true — there’s a great deal we still don’t understand about the immune system, and predicting how to drive a safe, protective response still has a lot of guesswork to it. 2 At the time, though, the most frustrating aspect of the field for me was adjuvants.
Adjuvants are factors that you include with your antigen, in order to drive a potent immune response. In general, the more pure an antigen is, the worse the immune response to it. Adjuvants allow you to provide a clean, defined antigen, without losing the immunogenicity of the filthy natural antigen.
The problem was that no one knew how adjuvants worked. They just … worked. There were a myriad of choices (for animals; in the US and Canada there’s only one adjuvant, alum, that’s licensed for humans), and they all mostly worked, and sometimes one worked better and sometimes another worked better, or differently; but there was no understanding of how, or why. Sometimes toe of newt was the best choice, and sometimes you were better off with eye of toad, and it depended on the phase of the moon and on which malign vapours were influencing your system.
Had I but known, of course, just about the time I switched out of vaccines and into other aspects of viral immunity, Charlie Janeway was offering up a grand unified theory of adjuvants3 which has for the most part proven triumphantly true. (I talked about it here.) He suggested that the immune system normally initiates a response when it recognizes conserved features of pathogens, and that adjuvants work because they mimic these conserved pathogen-associated molecular patterns. (Polly Matzinger also proposed a related model, in which immune responses start because cells are damaged — the danger hypothesis.) Since then, many of the pathogen-associated patterns have been identified, and many of the pattern receptors have been identified; adjuvants are no longer magic, they’re science.
Well, all except for one: Alum, the most important one of all (because it’s the main adjuvant used for human vaccines). We had no real idea how that works, because it looks nothing like any plausible pathogen pattern.
A paper in J Exp Med4 now argues that alum’s adjuvant activity comes from uric acid. As it happens, this is less related to Janeway’s hypothesis, and is closer to Matzinger’s. Uric acid is released by dying or damaged cells, and is a powerful natural adjuvant5 — it’s an indicator to the immune system that cells are being damaged in the vicinity, meaning that there is “danger” nearby.
I’m not entirely convinced that this is the whole, or even the main, story. The implication is that alum acts by damaging cells. The authors say that “alum has been shown to induce a considerable degree of necrosis”. That may be true with the intraperitoneal injection model they used, but alum-adjuvanted vaccines in people are more often given intramuscularly, and I don’t know that alum is all that nasty in that context.6 After all, the reason alum is approved for use in humans is that it is so innocuous. And simple experience says that while vaccines sting, you don’t expect any kind of large-scale necrosis in your injected arm afterward — no more than you’d get from a modest bruise, which isn’t enough to trigger the kind of adjuvant effects we see with alum. Perhaps there is a small release of uric acid effect, and alum somehow amplifies the effect (perhaps by facilitating uric acid crystallization, which is essential for its adjuvant activity). Or perhaps uricase is important in intraperitoneal inject, but is less so in more clinically-relevant injections. I don’t know.
Still, it’s nice to see that adjuvant activities, nowadays, can actually be tested within well-defined theoretical contexts. That’s just a huge advance since the days when I had to play with them.
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| Normal mouse spleen: B cells (red), CTL (green), dendritic cells (blue) |
We know that HIV can be controlled by an appropriate immune response. Cytotoxic T lymphocytes (CTL) are capable of very effectively suppressing HIV; in fact, in a standard HIV infection, the virus typically spends most of its early phase being controlled by a T cell response. In most people, unfortunately, the control is temporary; since HIV replication is sloppy, the virus throws off mutants at regular intervals, and eventually one of the mutants will be invisible to the dominant CTL response. That mutant replicates rapidly (probably damaging the immune response as it does so) until a new CTL response brings that virus under control, only for other variants to arise again.
Some people are apparently able to hold the virus under control for very long periods — the long-term non-progressor HIV patients. Some of these people seem to have T cell responses against part of the virus that has very precise sequence requirements; if the virus mutates away from CTL recognition, the virus is crippled and can’t replicate effectively. Other people seem to have a broad T cell response, one that recognizes several parts of the virus at once. The odds of successfully mutating all of the targeted areas simultaneously are exponentially lower than of mutating a single region.
Obviously, either of these are states that vaccine designers want as outcomes. That’s not all that easy. People are variable, and there don’t seem to be general rules that you can use to force an immune response to the target of one’s choice. 1 Wouldn’t it be nice if there was a way of bypassing the whole messy immunization step, and just moving straight on to the desired finale of CTL specific for the target of one’s choice?
A paper in the March ‘08 issue of Journal of Virology2 does just that.
When you induce T cell-mediated immunity, whether through a vaccine or a real infection, what you’re actually doing is expanding a pool of T cells whose receptor recognizes your special antigen. There are a huge number of potential T cell receptors (TcRs); under normal conditions, any particular antigenic target might have only 20 or 100 T cells that can recognize it, scattered among the millions of T cells with irrelevant specificities. Once a T cell finds its antigen, though,3 that T cell clone divided and expands enormously, as much as 100,000 times. The next time that antigen rides through town, it finds hundreds of sheriffs awaiting it, not just one or two.
If the TcR is all you need for specific recognition, can you bypass the whole annoying specific recognition and expansion step? Why not take the TcR from a previous clone, that you already know is useful (perhaps one from another individual altogether) and swap it into generic, non-specific T cells? In fact, that’s been done in a number of cases, and it actually seems to work.4
Joseph et al. tried this with a TcR specific for a HIV antigen. They swapped this known TcR into ordinary generic T cells from a normal blood donor, and turned those boring old plain T cells into CTL that specifically killed HIV-infected cells.
OK, their system is very artificial, involving transformed target lines and a Rube Goldbergesque mouse system to test “in vivo activity”, so it’s not really possible to draw any conclusions about clinical potential. In an actual infection, you’d presumably want to do this with multiple TcRs simultaneously, to target many HIV antigens at once and reduce the risk of immune escape (otherwise, just putting in one chimeric TcR is not different from getting a strong CTL response to HIV — which we know is not sufficient in the long run). I don’t think we know what would happen in that situation; would there be competition between the different TcRs to the point that most would be outcompeted and swamped, ending up with a de facto single target after all? 5
Another question I have is whether the original TcRs might cause mischief — if the T cell has two TcRs, stimulation through one might lead to reactivity with the other, and if the other, original, TcR happens to react with a self antigen you might get the mother of all autoimmune diseases. So my guess is that this is mostly a cute idea that will never go anywhere (for HIV; I think it has much more potential in tumor treatment).
Still, it really is a neat concept, and I hope some of my questions get addressed.
I’ve observed before that the common belief that viruses evolve toward avirulence is not particularly true. It’s more accurate to say that viruses evolve toward improved transmission. Some viruses are better transmitted if they let their host survive longer, but other viruses have to be virulent in order to spread. The former may evolve toward reduced (though not necessarily loss of) virulence, but the latter would “want” to maintain stable virulence.
What about increasing viral virulence? What could drive that?
There’s at least one fairly well-documented example of that. The increase in virulence is probably because of a change in the virus’s environment that forces the virus to become more virulent in order to continue to transmit efficiently. Ironically, the environmental change is vaccination.
As far as I know — I want to put this up front, to forestall the vaccine loons — there’s no instance where this has happened with a vaccine used for humans. 1 I’m talking about a chicken vaccine, for Marek’s Disease.
Marek’s Disease Virus (MDV) is an extraordinarily interesting virus. It’s a herpesvirus of chickens; it causes, among other symptoms, tumors. MDV was a relatively minor problem when chicken farming was a backyard industry. When very large, intensive commercial chicken farms arose, the virus was able to sweep through flocks and cause truly enormous losses. The first Marek’s Disease vaccine, introduced in the 1960s, reduced losses by some 99%. (Incidentally, this was the first vaccine ever to prevent cancer.)
But the 99% protection rate didn’t last long. Losses began to creep up once again, as more virulent viruses arose. New vaccines have been introduced a couple times; each time losses dropped, but then once again new and increasingly-virulent viruses arose. Marek’s Disease viruses isolated today are far more virulent than the relatively benign viruses of the 1960s and early 1970s; the original vaccine is essentially useless against them.
The figure at right2 (click for a larger version) shows the virulence of virus strains isolated over a ten-year period — although there’s a lot of variability, there’s a pretty clear upward trend. (This chart — and all the others I could find — only shows changes relatively late in the story, skipping the interesting periods in the 1970s and early 1980s when the first changes in virulence were noted. I think this is a technical issue of having the appropriate strains available for comparison. However, see: Increased virulence of Marek’s disease virus field isolates. Witter RL. Avian Dis. 1997 Jan-Mar;41(1):149-63. doi:10.1016/j.tvjl.2004.05.009 for a more detailed analysis of MDV strain virulence over the years.)
This evolution is actually very reminiscent of the myxoma/rabbit co-evolution story I’ve talked about, here and here. Australian rabbits have evolved to become much more resistant to myxoma virus than their European cousins. In this case, MDV is more analogous to the rabbits than to myxoma — evolving mechanisms to persist and replicate in the face of a lethal challenge (for the rabbits, myxoma virus; for Marek’s Disease virus, the vaccine-derived immunity).
Before rabbits could evolve resistance, there had to be some survivors of myxoma infection. In that case, myxoma virus itself evolved to become somewhat less virulent (70-90% lethal, instead of 98%). In the Marek’s Disease story, a key factor is that the vaccines all suck3 in their ability to actually prevent infection; they prevent the disease, but viruses can still infect vaccinated birds, although the virus replicates slower (which reduces transmission).
This is a recipe for virulence. Viruses in general evolve toward improved transmission. The MDV vaccine reduces, but doesn’t eliminate, transmission. Increasing replication in the face of the vaccine increases transmission. Increasing viral replication also increases viral virulence.4
This probably isn’t the whole story (there’s some evidence that the virus was already evolving toward increased virulence even before the vaccine was introduced — perhaps related to changes in its environment brought about by factory farming), and the mechanisms underlying the changes in virulence are not known, but the solution would seem to be clear: Develop a Marek’s Disease vaccine that will induce sterilizing immunity, as do most vaccines used against human viruses. That way, there’s no survivor virus that can act as a seed for evolution of virulence.
Unfortunately, of course, herpesviruses like MDV are notoriously difficult to vaccinate against. There’s still no commercial vaccine against herpes simplex virus, in spite of decades of research. Feline herpesvirus vaccine, which is universally used among pet cats, is like Marek’s in that it prevents symptoms but doesn’t prevent infection. (There is an effective vaccine against varicella-zoster virus [chicken pox] which does seem to effectively prevent infection — an exception to the rules.) So the chicken world is forced to stick with the non-sterilizing vaccines, even though “MD vaccines also appear to have a malign influence on the continued evolution of the pathogen itself.” 2
Viruses replicate inside cells, which shields them from some components of the immune system. In particular, antibodies can’t penetrate inside a cell1 to bind to a virus there, so antibodies are not much use for eliminating a viral infection.2 For some viruses that have to exit the cell to spread to a new target cell, antibody may help limit spread, but many viruses can spread directly from one cell to its neighbor without ever being exposed to antibodies. So once a virus has entered a host’s cells, you probably want mostly cell-mediated immune responses, such as T helper cells and cytotoxic T lymphocytes, to get rid of the virus.
That’s for eliminating viral infections. What antibodies are often extremely good at is blocking infections—stopping the virus from ever getting a foothold. A virus that enters your body has to be exposed to extracellular components at least briefly before it can burrow into its protective cell. During that phase the virus is vulnerable to antibody-mediated inhibition. Antibodies therefore may be relatively unhelpful for getting rid of an ongoing infection, but they can be very good at protecting against new infections.
Not surprisingly, then, most3 antiviral vaccines depend on inducing a strong and specific antibody response. That also means you can often get away with killed virus vaccines like the Salk polio vaccine, or even subunit vaccines like Hepatitis B vaccine; these are very poor at inducing cytotoxic T lymphocyte (CTL) responses, but they don’t have to. Killed vaccines are, in principle, intrinsically safer than the attenuated viruses, or even vector-based recombinant vaccines.
So why is there so much interest in developing vaccines that stimulate CTL? Why are so many groups working on vector-based vaccines or attenuating viruses? One reason is that these vaccines are (again, in principle) intrinsically more immunogenic than killed vaccines. If you can give one dose of vaccine, and then have your antigens stick around for a couple of weeks, or even amplify themselves as they replicate in situ, then you may not need to give a second (booster) dose of the vaccine. That’s a moderate advantage in the first world, and potentially a huge advantage in the third world, where you may only have one chance to visit your patients.
Another reason is that to a large extent we’ve already nailed the simple problems. If a killed vaccine can protect against a major pathogen, we probably already have that vaccine up and running. We’re left with those virus diseases that, for one reason or another, are not easily prevented by antibody-type responses, and so cellular CTL-type responses are the most promising next step.
What keeps a virus from being blocked by antibodies? There are a number of reasons, but the most obvious is that the virus offers a moving target to antibodies. HIV is probably the most famous example of this approach. The HIV surface is dominated by glycoproteins that are enormously variable; an antibody that blocks one particular HIV strain does nothing against a different strain. Hepatitis C virus (HCV) is another virus with highly variable surface proteins. Malaria, a parasite rather than a virus, has enough room in its genome to take this strategy even further. As well as using strain variation, individual parasites can dynamically change their surface proteins, stepping methodically through some 60 variants.4
Surface antigens in these pathogens have probably evolved to be variable; there’s been selective pressure for a pathogen to be different from the majority, since that way they’re less likely to infect an immune host.5 Internal antigens—those that are not exposed to antibodies—tend to be more highly conserved. Internal antigens aren’t exposed to antibodies, but they’re perfectly good targets for CTL. This is one reason for the interest in developing vaccines that induce good CTL responses.
There’s another approach, though. We have a lot of experience with antibody-based vaccines. It would be nice if there was a way to use them against HIV and HCV. Are there sections of the virus surface that are not variable? If so, then designing a vaccine that raises antibodies against these regions might be effective against many different strains. That’s been a hot topic for quite a while, and in fact there have been some steps forward on this front for HIV.6 More recently, in the latest issue of Nature Medicine7 there’s an article suggesting that some antibodies may be able to neutralize many hepatitis C strains.
The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable.
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| Tametomo’s force driving away the gods of smallpox. Yoshitoshi Taiso, 1890 |
Following up to my last post , about the Gates Foundation’s call to eradicate malaria, I thought I would talk about historical experience with eradication of infectious diseases. Here is the list of diseases that have been eradicated throughout all of recorded history:
I’ll pause so you can write that down.
OK, there are a couple of other diseases that are, hopefully, on their way to eradication (notably poliovirus), and there are a bunch of others whose incidence has been spectacularly reduced through vaccination (such as measles, diphtheria, and rubella),1 sanitation (such as guinea worm), and even antibiotics (leprosy). But only smallpox has been eradicated. 2
Why was smallpox eradicated, where four other global eradication campaigns3 failed? What was special about smallpox and its vaccine? What are the factors that allowed this disease to be reduced from millions of cases per year, to none? And, most to the point, what aspects of smallpox eradication are applicable to malaria?
In fact, most of the special aspects of smallpox that allowed it to be eradicated are not particularly true for malaria. Smallpox …
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| Vaccinating the poor. Sol Ettinge, Jr., 1872 |
And the smallpox vaccine (vaccinia virus) is also exceptional in that it …
The smallpox vaccine is also exceptional in its frequency and severity of adverse effects. I think that for no disease today would the risks of smallpox vaccine be tolerated — back to the fourth point above, that smallpox was such a terrible disease that people were willing to take the risks of vaccination. 4
There were also a vast number of technical and logistic components that, I think, are mostly applicable to any eradication program (for example, the cost per dose of a vaccine is much less if the vaccine can be prepared in large, multi-dose vials; but that means you need to use the vial up all at once, which means in turn organizing large numbers of vaccination on a single day; and that in turn implies an efficient communication network and so on), and which I won’t talk about here. There’s a fascinating review in Henderson, D. A. (1987). Principles and lessons from the smallpox eradication programme. Bull World Health Organ, 65(4), 535-546. if you want to learn more.
“A much greater change — not apparent but real — was produced by the introduction of vaccination in 1798. It was computed, that, in 1795, when the population of the British Isles was 15,000,000, the deaths produced by the small-pox amounted to 36,000, or nearly 11 per cent. of the whole annual mortality. Now, since not more than one case in 330 terminates fatally under the cow-pox system, either directly by the primary infection, or from the other diseases supervening; the whole of the young persons destroyed by the small-pox might be considered as saved, were vaccination universal, and always properly performed. This is not precisely the case, but one or one and a half per cent. will cover the deficiencies; and we therefore conclude, that vaccination has diminished the annual mortality fully nine per cent. After we had arrived at this conclusion by the process described, we found it confirmed by the authority of Mr Milne, who estimates, in a note to one of his tables, that the mortality of 1 in 40 would be diminished to 1 in 43-45, by exterminating the small-pox. Now this is almost precisely 9 per cent.”
Combe, George. 1847. The Constitution of Man and Its Relation to External Objects. Edinburgh: Maclachlan, Stewart, & Co., Longman & Co.; Simpkin, Marshall, & Co., W. S. Orr & Co., London, James M’Glashan, Dublin.It’s important to point out that eradication of a disease is possible when not all of these factors are matched — poliovirus, which is almost eradicated (and could have been eradicated altogether with a bit more political help) is different in several ways. But it does offer a checklist for known success. How does malaria match up?
Not so well, actually. Malaria …
Since there are no effective malaria vaccines as yet, we can’t very well compare them to the smallpox vaccine. I don’t know enough about the irradiated vaccine that will enter trials next year, but the “RTS,S/AS02D” vaccine in phase I/II trials5 requires multiple doses and apparently offers relatively low protection — certainly better than nothing, if this holds true through phase III trials, but it’s hard to imagine that it’s sufficient for eradication.
So vaccines are probably going to be an important component of malaria eradication (if it happens) but the nature of the disease means that they’re not likely to be sufficient. Melinda Gates said in her eradication speech that “This is a long-term goal; it will not come soon,” and she focused on four “intervention points”:
To eradicate malaria, you have to end transmission — and there are multiple points where you can intervene. Reduce the number of infected mosquitoes. Keep mosquitoes from biting people. Keep people who are bitten from getting infected. Keep people who are infected from transmitting malaria back to mosquitoes.
Vaccines are good candidates to help with the last two points, and may help with the first. But overall, this is a more complex problem than smallpox. Nevertheless, smallpox eradication has plenty of lessons for malaria, as well.
I’m marking final exams for the grad immunology class I teach, so I don’t have a lot of time to blog. But I do want to point to a really amazing, ambitious, and potentially world-changing initiative that doesn’t seem to have got the attention it deserves in the blog-world. A couple of months ago, Melinda Gates made a speech in which she said:
Bill and I believe that these advances in science and medicine, your promising research, and the rising concern of people around the world represent an historic opportunity not just to treat malaria or to control it-but to chart a long-term course to eradicate it.
I don’t need to give figures, I think, on what a devastating disease malaria is. The WHO fact sheet is filled with dismal stats (”A child dies of malaria every 30 seconds.“) And I’ve previously blogged about the track record of malaria vaccines, which have been encouraging but unsuccessful for forty years. Gates’ proposal really is (as she herself says) audacious, but I think she presents three excellent reasons for aiming for eradication:
Is it possible? I have no idea, myself. It’s been tried before (the poster at the top is from 1958) without success, and we are certainly a long, long way away from that aim at the moment. I do think it’s a worthy goal. And there are some new glimmers of hope. A Lancet article1 that came out about the same time as Gates’ talk shows that a new malaria vaccine is safe and at least moderately effective.
Is “moderately effective” good enough? We don’t really know yet how effective the vaccine is; this study (which wasn’t designed to test effectiveness per se) found around a 65% level of protection — low for a vaccine in general; high for a malaria vaccine. A commentary on the paper in the same issue of Lancet2 says that “Some experts have predicted that the effect of the introduction of a partly protective vaccine will be reduction in morbidity and mortality in the first years of life, with negligible effect on transmission.” If so, then this is more a step toward control than eradication.
Still, it’s a step, and if in fact vaccination can reduce malaria at all then it’s a very promising step. Other vaccines are on their way, and the experience with this one will help in developing more and more effective approaches. As Epstein’s commentary3 says, “The next 5-10 years will probably be the most exciting in the long journey to bring a malaria vaccine to the developing world.“
