Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

October 30th, 2009

Eradicating malaria?

Of the tools that are available or envisioned, only a highly efficacious, long-lasting vaccine would provide the degree and duration of transmission-blocking needed to achieve the simultaneous protection applied across a whole population at contiguous risk that is required to reduce and maintain R0 < 1 for that entire area

Plowe, C., Alonso, P., & Hoffman, S. (2009). The Potential Role of Vaccines in the Elimination of Falciparum Malaria and the Eventual Eradication of Malaria The Journal of Infectious Diseases DOI: 10.1086/646613


… taking Bill and Melinda Gates’ challenge to heart and considering it seriously, we have come to the conclusion that eradication just might be possible, but only if a new set of tools are developed that focus on reducing the effectiveness of the mosquito vector. … Could a vaccine alone eradicate malaria? … A vaccine used in combination with antimalaria drugs and vector control could be quite effective in reducing the disease burden. However, eradication is a different story. We would argue that, in addition to vaccines, antimalarial drugs, and presently available vector control methods, eradication will require special tools that we have yet to develop.

Miller, L., & Pierce, S. (2009). Perspective on Malaria Eradication: Is Eradication Possible without Modifying the Mosquito? The Journal of Infectious Diseases DOI: 10.1086/646612

Further reading
Malaria eradication: The smallpox precedent
Malaria vaccination – a victim of its own (feeble) success
Malaria eradication?
October 28th, 2009

On designing malaria vaccines

Our deepening knowledge of the immune evasion mechanisms of malaria is revealing the parasite’s ability to orchestrate the human immune response. … It would thus seem futile to test novel antigens or vaccine platforms without first incorporating features designed to circumvent parasite immune evasion strategies. … The prominent feature of a successful vaccine targeting chronic infectious agents such as malaria may therefore not be the antigens it includes, but rather the strategy used to free the immune system from its shackles.

Casares, S., & Richie, T. (2009). Immune evasion by malaria parasites: a challenge for vaccine development Current Opinion in Immunology, 21 (3), 321-330 DOI: 10.1016/j.coi.2009.05.015

August 7th, 2009

Antibodies are OK, really

Broadly neutralizing anti-HIV antibody
Broadly neutralizing anti-HIV antibody
in contact with HIV gp120

My research is focused on T cell responses to viruses, so I don’t tend to talk about antibodies all that much here. For that matter, I personally don’t find antibodies very interesting, research-wise. But I don’t want to dis antibodies as clinical entities, and a few recent papers emphasize how useful they can be. (See also my previous post, Antibody-based vaccines)

Very brief background: Antibodies (also known as immunoglobulins) and T cells are the two branches of the adaptive immune response. The adaptive immune response, invented by sharks1 is capable of a broad, flexible, and long-lasting response to pathogens, contrasting to the relatively narrow and inflexible innate immune response. The T cell response involves cells as the effectors; the antibody response involves (surprise!) antibodies, which are simple proteins, usually soluble — that is, floating freely around in the blood or in various bodily secretions. Antibodies can neutralize pathogens in various ways, almost all of which require the antibody to physically bind to the pathogen. That means that the target on the pathogen has to be exposed (on the outside of the pathogen) where the antibody can see it. It also requires the target on the pathogen to be moderately constant; if antibodies target a particular molecule on a pathogen, and that molecule changes later on, then the pathogen is potentially invisible to the antibody.

Almost all vaccines work mainly through antibodies. Antibodies are relatively easy to induce in a relatively predictable way, whereas even today it’s harder to consistently and reliably induce a protective T cell response to a pathogen. Dead pathogens can induce antibodies, but not T cells (without a lot of jiggering); even pieces of pathogens — subunit vaccines — can induce strong antibody responses; so you can have a big safety factor built in to antibody-based vaccines.

So if antibodies worked for polio and measles and pertussis and so many other highly-effective vaccines, why is there any interest at all in T-cell based vaccines? Simply put, it’s because we’ve already nailed the easy targets for vaccines, and the ones that are left are hard because in general antibody-based vaccines haven’t worked well against them. The 800-pound gorillas out there are malaria and HIV, and antibody-based vaccines against malaria and HIV (and a universal influenza vaccine, the other 800-pound gorilla) simply haven’t been effective. The conclusion has been that effective vaccines against these guys will require T cells.

Anti-lysozyme antibody contacting lysozyme
Anti-lysozyme antibody contacting lysozyme

But that’s not necessarily so. Some papers I’ve run across recently demonstrate that antibodies are more versatile and effective than I usually give them credit for. First, there the observation2 that antibodies actually can protect against HIV. The key seems to be driving constant production of the antibody — in one case,3 via gene therapy rather than conventional immunization. This points to a solution to one of the major problems facing anti-HIV antibodies, but not the second: the constant mutation and variation of HIV surface proteins means that antibodies are usually limited to targeting a very limited number of HIV strains — there’s little cross-protection between strains, in other words. But there’s also some encouraging work on that front, with the identification of broadly cross-reactively neutralizing antibodies. 4 I’ve had questions about how you’d make use of such an antibody — constructing a vaccine that could reliably drive production of this precise antibody would be difficult — but the gene therapy approach would circumvent that problem altogether, so it might kill two birds with one stone.

Malaria vaccines have been under development for decades and none have worked very well. The ones in clinical trials (I’ve talked about them here and here) offer maybe 50% protection — a hell of a lot better than nothing, but as vaccines go pretty awful. A complementary approach to preventing disease in malaria-exposed people — the aim of these sorts of vaccines — would be to reduce spread of the parasite from one infected person to another individual; if this worked, then the disease frequency would, hopefully, drop. 5 I was impressed to see a paper6 describing an antibody-based approach to blocking malaria transmission. The key here seems to be a fairly simple approach (simple in concept, not in practice) of optimizing production of the vaccine target.

As we all know, influenza vaccines have to be tweaked every year, because the vaccines only protect against the very specific strains within the vaccine itself.  (See also this post and this one.)  The problem is similar to HIV — influenza virus surface proteins are highly variable, and antibodies against one strain don’t cross-react against different strains. There’s a lot of interest in develop T-cell-based vaccines with a broader cross-reactivity, but in the meantime there’s some evidence that it might be possible to do something similar using antibodies. There are several papers showing broadly cross-reactive antibodies — for example:

Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. 7

Again, there are technical difficulties — how to drive an immune response against such a precise target, given that it doesn’t arise with any significant frequency in natural infections or with conventional vaccines — but just knowing that the potential is there, is intriguing.

Does this mean we should abandon T-cell approaches and return to tried-and-true antibodies?  I don’t think so; most likely the most effective immunity will be a combination of antibodies and T cells, as happens in natural infections, and in each of these cases the work is extremely preliminary.  But on the other hand, we shouldn’t lose track of the antibodies (boring though they are) in the rush to T cells.

  1. And, in quite a different form, by lampreys and hagfish[]
  2. Reviewed in Haigwood, N., & Hirsch, V. (2009). Blocking and tackling HIV Nature Medicine, 15 (8), 841-842 DOI: 10.1038/nm0809-841[]
  3. Johnson, P., Schnepp, B., Zhang, J., Connell, M., Greene, S., Yuste, E., Desrosiers, R., & Reed Clark, K. (2009). Vector-mediated gene transfer engenders long-lived neutralizing activity and protection against SIV infection in monkeys Nature Medicine, 15 (8), 901-906 DOI: 10.1038/nm.1967[]
  4. For example, see this paper and references therein: JULIEN, J., BRYSON, S., NIEVA, J., & PAI, E. (2008). Structural Details of HIV-1 Recognition by the Broadly Neutralizing Monoclonal Antibody 2F5: Epitope Conformation, Antigen-Recognition Loop Mobility, and Anion-Binding Site Journal of Molecular Biology, 384 (2), 377-392 DOI: 10.1016/j.jmb.2008.09.024 []
  5. I think this has been modeled in a paper I saw a while ago, but I don’t remember the details of the model.[]
  6. Chowdhury, D., Angov, E., Kariuki, T., & Kumar, N. (2009). A Potent Malaria Transmission Blocking Vaccine Based on Codon Harmonized Full Length Pfs48/45 Expressed in Escherichia coli PLoS ONE, 4 (7) DOI: 10.1371/journal.pone.0006352[]
  7. Throsby, M., van den Brink, E., Jongeneelen, M., Poon, L., Alard, P., Cornelissen, L., Bakker, A., Cox, F., van Deventer, E., Guan, Y., Cinatl, J., Meulen, J., Lasters, I., Carsetti, R., Peiris, M., de Kruif, J., & Goudsmit, J. (2008). Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells PLoS ONE, 3 (12) DOI: 10.1371/journal.pone.0003942[]
July 2nd, 2009

Simple, obvious, and wrong answers

Macrophage and mycobacterium
Macrophage phagocytosing mycobacteria

Sometimes the simple, obvious answer is right, and sometimes it’s completely backwards.

Tuberculosis was a terrifying, ubiquitous killer in the 19th century, but is relatively rare today (at least, in developed countries). The reason for the drop in Tb deaths isn’t entirely clear; it started with social factors probably including accidental or deliberate isolation of Tb patients, antibiotic treatment also knocked the disease back, and in some areas the vaccine (known as BCG) made a difference as well.

BCG is one of the oldest vaccines still in wide use; it was developed in the 1920s when a strain of Mycobacterium bovis (tuberculosis of cattle, contagious to humans) spontaneously lost virulence in culture. This avirulent strain of the bacterium was sent around the world and cultured independently, resulting in many distinct vaccine strains in different places and times. These strains are not only distinct genetically, but also phenotypically — they look different in culture, or grow differently, or whatever.

Over time, the vaccine has changed functionally, as well. Very early on the vaccine abruptly became even less virulent. More gradually, it seems that BCG has also become less effective; it’s no longer is able to protect against pulmonary Tb (although it’s still protective against other forms of the disease). Why is this?

At first glance this seems unsurprising. The bacterium has been grown in culture — outside of any animal host — for nearly 100 years. It’s had no selection to maintain its ability to grow in animals, or to avoid their immune responses, so of course it’s going to lose its ability to grow in animals.

But a recent paper1 suggests that exactly the opposite happened. Whether randomly, or because of some unexpected type of selection, the BCG strain has actually amplified an immune evasion function. This modern variant of the vaccine strain isn’t simply passively failing to induce an immune response; it’s actively suppressing the immune response.

Specifically, the authors argue that normal (wild, virulent) Mycobacterium secretes antioxidants as an immune evasion mechanism; that modern BCG also secretes lots of antioxidants; and that this is related to genomic duplications in some BCG strains:

Some BCG daughter strains exhibit genomic duplication of sigH, trxC (thioredoxin), trxB2 (thioredoxin reductase), whiB1, whiB7, and lpdA (Rv3303c) as well as increased expression of genes encoding other antioxidants including SodA, thiol peroxidase, alkylhydroperoxidases C and D, and other members of the whiB family of thioredoxin-like protein disulfide reductases.1

Further reading
Tb family trees
Conspicuous consumption
Life & Death, pre-vaccination

MycobacteriaIn other words, the long-term culture of BCG has yielded variants that are less immunogenic, because they are more actively suppressing the immune response. If their reasoning is correct, then reducing the antioxidant secretion from BCG should increase its immunogenicity. They took a BCG strain and deleted the duplicated antioxidant gene sigH (as well as the overexpressed SodA), and sure enough, the deleted version was more immunogenic and more protective in mice. “By reducing antioxidant activity and secretion in BCG to yield 3dBCG, we unmasked immune responses during vaccination with 3dBCG that were suppressed by the parent BCG vaccine.1

As a possible explanation, they note that their deletion variant also grows more slowly in culture than the “wild-type” BCG, and especially under certain culture conditions, and that this has led, coincidentally, to the reduced immunogenicity:

The practice of growing BCG aerobically with detergents to prevent clumping may have increased oxidant stress to cell wall structures and selected for increased antioxidant production. Then with each transfer the bacilli making more antioxidants represented a slightly greater proportion of the culture until they became dominant. In vivo, these mutations caused the vaccine to become less potent in activating host immunity. In effect, we believe that as BCG evolved it yielded daughter strains with an increased capacity for suppressing host immune responses. 1

If this turns out to be generally true, then there’s a relatively straightforward handle for converting BCG back into a more effective, and safer, vaccine; whereas if the reduced immunogenicity was because of over-attenuation, it’s not so simple — you’d be trying to make a vaccine more virulent, which is a tricky tightrope to walk.

Incidentally, I frequently complain about the terrible, terrible quality of press releases about scientific advances  (and therefore the terrible quality of much “science reporting”, which is basically regurgitating the terrible press releases) so I want to give props to the person at Vanderbilt University Medical Center who put together the release for this paper — it’s a clear, simple, interesting, and as far as I can tell accurate account of the finding, background, and observation.  It can be done well — I wish it was done this well more often.

  1. Sadagopal, S., Braunstein, M., Hager, C., Wei, J., Daniel, A., Bochan, M., Crozier, I., Smith, N., Gates, H., Barnett, L., Van Kaer, L., Price, J., Blackwell, T., Kalams, S., & Kernodle, D. (2009). Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG PLoS ONE, 4 (5) DOI: 10.1371/journal.pone.0005531[][][][]
June 26th, 2009

On vaccine design

Thus, not unlike the solutions to global warming or dependence on foreign oil, the proper immunization for rapidly evolving viruses cannot be a single T cell vaccine but instead must combine many different modalities that, like the ‘cooperative arms’ of the immune system, work in a complementary way to counter several steps of a pathogen’s life cycle.

–Margulies DH (2009) Antigen-processing and presentation pathways select antigenic HIV peptides in the fight against viral evolution. Nat Immunol 10:566–568. doi:10.1038/ni0609-566

(referring to
Tenzer S, Wee E, Burgevin A, Stewart-Jones G, Friis L, Lamberth K, Chang CH, Harndahl M, Weimershaus M, Gerstoft J et al. (2009) Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance. Nat Immunol 10:636–646. doi:10.1038/ni.1728 )

June 19th, 2009

Tb family trees

BCG (Max Planck)
Macrophage engulfing Bacillus Calmette-Guérin

The oldest vaccine, as everyone knows, is the smallpox vaccine. 1 Another  old vaccine (though not in the same class as smallpox vaccine) is the tuberculosis vaccine, Bacillus Calmette-Guérin (BCG), developed in 1921.

There’s all kinds of interesting stuff about BCG. It’s a live vaccine, meaning that the vaccine is live Mycobacterium bovis (the bovine tuberculosis bacterium). Albert Calmette and his assistant/colleague Camille Guérin, at the Institut Pasteur, repeatedly passaged a virulent isolate of M. bovis on a particular type of medium, noticed that some colonies looked different, and determined that these were less virulent for lab animals; after further passages, they announced that the variant was “inoffensif” in humans,2 and by the late 1920s BCG was being used around the world as a vaccine against tuberculosis. Overall, it’s probably around 50% effective as a vaccine, with geographical location accounting for most of the variability. 3 That’s very low as vaccine efficacy goes, and it means that vaccination is really only useful where there’s lots of disease, not so much where there’s a moderate incidence; which pretty much matches how BCG has been used worldwide.  On the other hand, the vaccine seems to be pretty innocuous, with a low complication rate.

BCG Genealogy
BCG genealogy 4

This much, I was more or less aware of,5 but there’s much more to the story than that, as I’ve recently learned. 4,6 One fascinating question is, exactly what is the vaccine? This is an old vaccine, it was never homogenous (that is, it was basically a crude culture consisting of a wide range of minor variants around a central genome), and it’s been passaged independently all over the world for 85 years. There’s no such thing as “the” BCG any more; there are dozens of different BCGs, some of which can be traced directly back to the original Pasteur stock, others of which have bounced around and been sub-cultured from sub-cultures. There are at least 6 widely-used vaccine strains of BCG,7 not to mention older strains,  trial strains, and so on; and most of them behave differently in more or less subtle ways.  (See the genealogy of some of the more prominent strains, to the right.)  Even the “same” strains have clearly changed over time; for example, somewhere between 1926 and 1934, the Pasteur strain of BCG became drastically less virulent:8

Watson also stated that the strains he had received from Calmette between 1924 and 1927 were potentially virulent for animals, whereas the BCG strains he received and tested between 1929 and 1932 were no longer virulent.9

We don’t have the original BCG strain any more, let alone the virulent M. bovis isolate from which it was derived, but some of the history can be inferred from genome analysis. Unsurprisingly, the different sub-strains have slight variants in their DNA sequences:

These results are best understood from an evolutionary perspective and indicate that BCG has continued to change with in-vitro passage. All BCG strains are lacking deletion region 1, a genetic deletion that may correspond with the altered morphotype observed by Calmette and Guérin. Subsequently, strains obtained before 1926 and maintained on different continents have the 2-IS6110/mpt64+ genotype, which was likely the genetic composition of early BCG. … With such documented genetic change it would be surprising if there has not been phenotypic change over 1173 passages in-vitro, a notion supported in numerous reports describing ongoing attenuation after 1921. … In conclusion, we have demonstrated that through DNA fingerprinting, it is possible to verify the micro-evolution of attenuated Mycobacterium bovis over about one thousand passages. 4

So: We have an old, widely-used vaccine strain, that has a long history of variation. (This is similar, by the way, to smallpox vaccine — vaccinia virus was also widely distributed and showed extensive variation in its characteristics.) The BCG strains used today have all been more or less selected — either deliberately, or empirically — to be safe and effective vaccines; they’ve also been selected for a wide range of other factors (stability, ease of processing, rapid growth, and so on), some of which we know about, some of which we don’t.

Could strain variability account for the wild variation in tested vaccine efficacy? Well. historically, perhaps not — different strains of BCG haven’t correlated with the differences in efficacy that have been seen, most of which (as I said) follow geography.

But I’ll leave you with this: It seems that the BCG vaccines used today are generally less effective than they were back in the 1920s.10 Could that be linked to some of these genomic variations?

In early clinical studies, the live tuberculosis vaccine Mycobacterium bovis BCG exhibited 80% protective efficacy against pulmonary tuberculosis (TB). Although BCG still exhibits reliable protection against TB meningitis and miliary TB in early childhood it has become less reliable in protecting against pulmonary TB.11

  1. Even if we take into account the mysterious shift from cowpox to vaccinia virus as the vaccine strain[]
  2. A. Calmette and C. Guérin, Nouvelles recherches expérimentales sur la vaccination des bovidés contre la tuberculose. Ann. Inst. Pasteur. 34 (1920), pp. 553–560.[]
  3. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta-analysis of the published literature.
    JAMA. 1994 Mar 2;271(9):698-702
    Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, Mosteller F.[]
  4. Behr, M. (1999). A historical and molecular phylogeny of BCG strains Vaccine, 17 (7-8), 915-922 DOI: 10.1016/S0264-410X(98)00277-1[][][]
  5. As I’ve pointed out before, I’m not a bacteriologist, so I mainly picked up this much by osmosis[]
  6. Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree.
    Tubercle and Lung Disease(1999) 79(4), 243–250
    T. Oettinger, M. Jørgensen, A. Ladefoged, K. Hasløv, P. Andersen[]
  7. Connaught, Danish, Glaxo, Moreau, Pasteur, and Tokyo[]
  8. Watson E A. Studies on bacillus Calmette-Guérin (BCG) and vaccination against tuberculosis. Can J Med Res 1933;9:128.[]
  9. Development of the Mycobacterium bovis BCG vaccine: review of the historical and biochemical evidence for a genealogical tree.
    T. Oettinger, M. Jørgensen, A. Ladefoged, K. Hasløv, P. Andersen
    Tubercle and Lung Disease(1999) 79(4), 243–250  []
  10. Correlation between BCG genomics and protective efficacy.
    Scand J Infect Dis. 2001;33(4):249-52.
    Behr MA


    Has BCG attenuated to impotence?
    Marcel A. Behr1 & Peter M. Small
    Nature 389, 133-134 (11 September 1997) doi:10.1038/38151[]

  11. Reducing the Activity and Secretion of Microbial Antioxidants Enhances the Immunogenicity of BCG
    Sadagopal et al
    PLoS ONE 4(5): e5531. doi:10.1371/journal.pone.0005531[]
June 15th, 2009

Conspicuous consumption

CTuberculosis and the Grim Reaper
Tuberculosis and the Grim Reaper

A while ago I made the point that many of the biggest killers of 19th-century London were almost unknown today, because of vaccination (“hooping cough”, measles, smallpox) and sanitation (typhus, cholera) (see “Life & Death, pre-vaccination“).

I have a small confession to make: I kind of rigged that chart, because I wanted to avoid a complicated story that I didn’t know much about.  I still don’t know much about it, but I’ll share my ignorance with you, dear readers, because it’s a fascinating story and because it hooks up with something else I want to talk about, maybe later this week.

The “rigging” was pretty minor.  If you look at the table I took the mortality info from (from the Journal of the Statistical Society of Landon, Vol. XII, 1850)  you’ll see the infectious causes that I listed, neatly clustered together at the bottom.  In 1847, mortality from these diseases looked something like this:

Mortality in London, 1847

What’s missing?  The biggest killer of them all;1 it’s not included in this section because before 1882,2  they didn’t know tuberculosis (“consumption”) is an infectious disease.

Here’s what happens when we include “tubercular diseases” in the same chart — watch the scale!

Mortality in London, 1847

In developed countries most of us don’t think about tuberculosis much, but in the 19th century it was everywhere.  The poor — crowded and malnourished — were at the most risk, but consumption spared no one.  Rich and poor, merchant or noble or laborer, everyone had friends and family who died of consumption.

What happened to it?  Why did Tb go from causing 20% of all deaths, to only infecting 0.01% of the population (and killing a far smaller fraction)?  Unlike the other infectious diseases, vaccination and sanitation can only explain a part of that.  The death rate of Tb was already dropping drastically well before 1882, when Koch showed that it was infectious:3

Trends in Tb mortality

From “Pulmonary Tuberculosis
Maurice Fishberg (Lea and Febiger, Philadelphia, 1922)

So although antibiotics and, to some extent, vaccination were to help push Tb to obscurity in the 20th century, the disease was already, very slowly, fading before that.  (Tb rates had exploded in the 18th century, as urbanization crowded the poor together.  It wasn’t for many years that cities became self-sustaining and didn’t reply on immigration.)

Consumption (19th-century physician)
From “Passages from the diary of a late physician
Samuel Warren (Baudry’s European Library, 1838)

Why was Tb becoming less common? Well, this is the part I don’t actually understand very well, but according to Arthur Newsholme4 in 19085 this was indirectly because of the Poor Law of 1834 (Wikipedia on Poor Laws).  The Poor Laws were very, very primitive versions of welfare; the 1834 Act brought about a system of workhouses, where the desperately poor — and they had to be utterly desperate — were fed (barely) and housed (kind of ) and generally abused.  The point being, the poorest of the poor were kept in these workhouses; because the Tb sufferers, who couldn’t work normally, tended to be the poorest of the poor, they were housed in the workhouses and essentially quarantined.  After Koch demonstrated that Tb is contagious, in 1882, quarantine became a deliberate policy6 and rates dropped still more; and when antibiotics were introduced in the 1940s, rates of Tb dropped still more.

So although I said the biggest killers of the 19th century have been almost eliminated by sanitation and vaccination, that’s not really true of tuberculosis.  Antibiotics broke the back of the disease, but it was already being controlled to a large extent by social factors and then by medical opinion — one of the few cases where formal medicine actually had an influence on these diseases.

  1. Well, “Diseases of the lungs and other Organs of respiration” killed more people, but that’s not a single disease[]
  2. Koch, R. 1882. Die Aetiologie der Tuberculose. Berl. Klin. Wchnschr., xix: 221-230.[]
  3. And it wasn’t for years after that that an effective treatment or vaccine was available[]
  4. The Prevention of Tuberculosis, by Sir Arthur Newsholme.
    Methuen, 1908 []
  5. Supported by others since, e.g.  Wilson, L. (2004). Commentary: Medicine, population, and tuberculosis International Journal of Epidemiology, 34 (3), 521-524 DOI: 10.1093/ije/dyh196[]
  6. I believe Sir Arthur Newsholme was important in instituting this in Britain[]
April 27th, 2009

On immunology and malaria

Malaria life cycle
Life cycle of Plasmodium falciparum

“In this article we have attempted to make the case that we may not know enough about malaria to make an effective vaccine. If we agree that the development of a malaria vaccine would profit from a better understanding of the basic immunology of the human response to malaria, we then need to ask the following question: have we engaged a sufficient number of immunologists to address the problem? At the moment, probably not. Relative to the magnitude of the global disease burden imposed by malaria, there are only a small number of scientists with the training and expertise in the human immune system who are committed to working at the molecular interface of the parasite and the immune system.”

Pierce, S., & Miller, L. (2009). World Malaria Day 2009: What Malaria Knows about the Immune System That Immunologists Still Do Not The Journal of Immunology, 182 (9), 5171-5177 DOI: 10.4049/jimmunol.0804153

April 15th, 2009

Malaria vaccination – a victim of its own (feeble) success

Malaria parasites in mosquito midgut
Malaria parasites in mosquito midgut

A followup study 1 of the most successful malaria vaccine to date is not very impressive:

In cohort 2, adjusted efficacy of the RTS,S/AS02A candidate malaria vaccine against first or only clinical malaria episodes in Mozambican children aged 1 to 4 years was of 35.4% during the first six months of follow up (ATP cohort), decreasing to 9.0% in the subsequent 12 months. 1

(My emphasis)  In  the earlier clinical trial, this vaccine had been moderately effective, 2 something like 35-65% efficacy — pretty feeble, but better than other malaria vaccines.  And in one subset of children, the protection seemed to last reasonably well, remaining roughly constant for 21 months. 3   But in this second group of vaccinated children, the protection dropped like a rock.  Why?

The most likely difference is that children in the second (poor long-term protection) group were treated for malaria.  That means the first group was constantly re-exposed to malaria parasites, which acted as a vaccine booster.  The second group didn’t get that booster effect, and their immunity dropped.  (The first group was also in a higher-risk area, again meaning they were more likely to be re-exposed to the parasite.)

Children in cohort 1 were probably exposed to low-density parasitaemias for a longer time than children in cohort 2, in which the development of this enhanced asexual-stage immune response may have been impaired. We propose this may explain a waning of the vaccine-specific protective response in cohort 2. 1

Does this mean the vaccine is useless?  Not at all.  In high-risk areas this can clearly reduce disease.  But equally clearly, this isn’t likely to be helpful for eradicating malaria, because the more successful this vaccine is at reducing malaria, the less effective it will become.

  1. Guinovart, C., Aponte, J., Sacarlal, J., Aide, P., Leach, A., Bassat, Q., Macete, E., Dobaño, C., Lievens, M., Loucq, C., Ballou, W., Cohen, J., & Alonso, P. (2009). Insights into Long-Lasting Protection Induced by RTS,S/AS02A Malaria Vaccine: Further Results from a Phase IIb Trial in Mozambican Children PLoS ONE, 4 (4) DOI: 10.1371/journal.pone.0005165[][][]
  2. Abdulla, S., Oberholzer, R., Juma, O., Kubhoja, S., Machera, F., Membi, C., Omari, S., Urassa, A., Mshinda, H., Jumanne, A., Salim, N., Shomari, M., Aebi, T., Schellenberg, D. M., Carter, T., Villafana, T., Demoitie, M. A., Dubois, M. C., Leach, A., Lievens, M., Vekemans, J., Cohen, J., Ballou, W. R., and Tanner, M. (2008). Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. doi:10.1056/NEJMoa0807773

    Bejon, P., Lusingu, J., Olotu, A., Leach, A., Lievens, M., Vekemans, J., Mshamu, S., Lang, T., Gould, J., Dubois, M. C., Demoitie, M. A., Stallaert, J. F., Vansadia, P., Carter, T., Njuguna, P., Awuondo, K. O., Malabeja, A., Abdul, O., Gesase, S., Mturi, N., Drakeley, C. J., Savarese, B., Villafana, T., Ballou, W. R., Cohen, J., Riley, E. M., Lemnge, M. M., Marsh, K., and von Seidlein, L. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. doi:10.1056/NEJMoa0807381[]

  3. Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, et al. (2005) Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial. Lancet 366: 2012–2018[]
March 31st, 2009

Baffling vaccine quiz

It’s a busy day today as I submit a grant application, so here’s a quick quiz.  Based on the following charts, can anyone guess the years in which vaccination against measles, mumps, and rubella was introduced to the US? Click for larger versions, should you need it.

Measles cases and deaths

Mumps cases

Rubella cases

Pretty tricky, eh?