Mystery Rays from Outer Space

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

August 26th, 2010

“How quickly we forget the ravages of disease”

City Health Detroit 1920
In 1920 there was an outbreak of smallpox in Detroit (see the map below). Of the 133 cases with known history, only two had been vaccinated in the previous 10 years — three others had been vaccinated 12, 60, and 80 (!) years previously; the remainder were unvaccinated. The Detroit Department of Health had this commentary (my emphasis):

Using Knowledge

How quickly we forget the ravages of disease! In the autumn of 1918 the world was visited by the worst plague of recent times — influenza. Probably 1 per cent of the population of the globe was swept away by this scourge. People raved and bewailed at their helplessness. There was no known preventative. We know that crowding aided this disease, but as a reliable preventive against influenza, telling a person to avoid crowds in a congested city has about as much effect as telling a fly to keep out of baby’s cup of milk.

In 1920 influenza returned and exacted further toll of lives. The previous epidemic had not produced an antidote nor a preventative of influenza. The bacteriologists have not been idle. They have worked industriously trying to discover the true cause of the disease and a means of immunizing against it. It is not to their discredit that their efforts have not met with success.

Smallpox is another matter. Jenner, an English physician, proved beyond a shadow of a doubt that material from a pox pustule in a cow when added to the scarified skin of human beings gave them immunity against smallpox. This was in 1796. Vaccination soon became universal.

Boston’s experience is interesting. In 1721 out of a population of 11,000 there were 5,989 cases of smallpox and 850 deaths. In 1730 in a population of 15,000 there were 4,000 cases and 509 deaths. After vaccination had been introduced the disease practically disappeared. From 1811 to 1830 there were but 14 cases. Smallpox has disappeared where compulsory vaccination is in effect.

We do not know how to immunize against influenza.

We do know how to immunize against smallpox.

Shall we utilize this knowledge or not? If not why continue to search for an influenza panacea? If it is not to be used, once discovered, why waste time and effort to discover it? 1

See also earlier posts:

Smallpox in Detroit - map, 1920

  1. City Health. Monthly Bulletin, Detroit Department of Health.  May 1920. Vol. III, No. 8[]
August 17th, 2010

Pigs (and their viruses) fly

Type II PRRSV An emerging disease that I just missed directly seeing emerge is PRRS.

PRRS is “porcine reproductive and respiratory syndrome”, which pretty much sums up the disease. It’s caused by — you’ll never guess — Porcine reproductive and respiratory syndrome virus (PRRSV), an arterivirus that emerged in 1987. That was the year I left large animal veterinary practice, so I never had a chance to deal with PRRS clinically.

Twenty-three years may not seem like all that long a time, but if you’re an RNA virus that’s a lot of generation times and a whole lot of time for mutations and evolution, and PRRS viruses are an evolutionarily mess. 1 There are North American type PRRSV viruses and European type viruses, there are mysterious clusters of related viruses, there are clusters of related diseases, there are thousands of sequences, and it’s just kind of baffling what’s gone on with the whole schtick.

A new paper2 has tried to sort out part of the mess by analyzing some 8624 North American-type PRRSV sequences, from nearly a dozen countries, and working out evolutionary relationships between them all. 3 (The focus on the North American series — the Type II PRRSV — is because this group seems to be a more common source of disease; although the European strains are far from rare themselves.)

There were a couple of interesting points that parallel some other viruses:

1. Feral vaccines. It’s already known, or at least strongly suspected, that some of the modified-live PRRSV vaccines have started to go feral on a small scale (not nearly as dramatically as the vaccinia virus I mentioned a while ago), and that’s supported by this genetic analysis:

In the vaccine-associated sublineage phylogenies (data not shown), there were a number of well-supported small clusters that might reflect the small-scale transmission of the vaccine viruses in the field … 2

As well as vaccinia, there are other live vaccines that are known to spread into the population. The sort of limited transmission that seems to be showing up here is more typical of this sort of thing than are the vaccinia instances I talked about before.

2. The amazing flying pigs. Even though this is just one of the two major sub-groups of PRRSV and it’s less than 25 years since it emerged, they came up with nine fairly distinct lineages of the virus (see the figure to the right). As you’d expect the lineages speak to the history of the virus — which is to a large extent the history of the pigs that carried the virus.4

This version of the virus probably started out in North America (though how it got there … ?) and then got introduced into other countries on several independent occasions. Two of these introductions were in the late 1980s, shortly after the North American emergence. Aside from that there’s evidence of a bunch of smaller introductions:

… lineage 1 had several Thai sequences clustered with early Canadian sequences … ; lineage 8 contained highly pathogenic Chinese strains and their relatives … ; and lineages 8 and 9 had several Italian isolates which were distributed separately along the phylogeny …, indicating independent introductions of PRRSV from the United States to Italy. 2

They were even able to identify smaller-scale travel patterns, between individual states in the USA:

Iowa plays a central role because its viruses were introduced recurrently to all nine other states (Fig. 5B). The remaining states were not just receiving sites. Their local strains also were transmitted to other states repeatedly, but within a narrower range. … Our phylogeographic analyses reveal, for the first time, an interstate PRRSV traffic network in the United States. … The result also indicates that long-distance spread is a frequent process for PRRSV … 2

This is a reminiscent of the history of the pandemic H1N1 influenza virus, when it was still in swine. (Remember that pandemic H1N1 is genetically  a mixture of a North American swine influenza strain and a Eurasian strain.)  There’s a large national and global traffic in pigs, and even though most countries are reasonably careful in the way they handle incoming pigs it’s not a guarantee against virus introduction. I’m not singling out pigs, either — other kinds of livestock also are global travellers, and obviously so are humans.  But it’s a reminder that it isn’t just humans and their viruses that can quickly travel and spread around the globe.

  1. More correctly, our understanding of their evolution is a mess. The viruses are doing just fine.[]
  2. Shi, M., Lam, T., Hon, C., Murtaugh, M., Davies, P., Hui, R., Li, J., Wong, L., Yip, C., Jiang, J., & Leung, F. (2010). Phylogeny-Based Evolutionary, Demographical, and Geographical Dissection of North American Type 2 Porcine Reproductive and Respiratory Syndrome Viruses Journal of Virology, 84 (17), 8700-8711 DOI: 10.1128/JVI.02551-09[][][][]
  3. That’s a lot of viruses, but the sampling is heavily biased to a limited number of places, especially the USA [and especially a few regions within the USA] so it’s probably an underestimate, and maybe a severe underestimate, of the global diversity.

    I didn’t know, by the way, that there’s a PRRSV Database:[]

  4. Or of the pig’s fluids. I think that especially in the early days of the emergence, the virus was spread by the boar semen used for artificial insemination.[]
August 5th, 2010

The good old days, revisited

As a general remark, the Measles were mild, while on the contrary, the Mumps were almost invariably severe, and frequently attended with metastasis to the testicles. Some cases of the latter were attended with enormous swelling and high inflammatory excitement, requiring the lancet and other antiphlogistic remedies. … As a local application to the scrotum none appeared to afford so much relief, as wheat bran wet with a solution of acetate of lead in vinegar — or with vinegar alone — applied by means of a bandage around the hips, in such a manner as to support the testicle — as its own weight, without such support, was of itself tormenting.

“Bad symptoms – a quick pulse – a difficulty in purring – a hoarse mew – decidedly mumps. Recipe some mouse tail soup”

–III. Measles and Mumps in Combination
Western Journal of the Medical & Physical Sciences, Vol. 7 (1834)
Printed and Published Quarterly, at the Chronicle Office, by E. Deming
Cincinnati, Ohio

During the past winter at Camp Lee we have been afforded a rare opportunity of studying mumps in adults. Nine cases of cerebral complications in frank cases of mumps have been encountered and have been made the subject of a special report by Lieut. R.L. Haden, who has had the supervision of the Contagious Disease Service.

These cases were characterized by the occurrence, during an attack of mumps, of increased temperature, headache, vomiting, and frequently evidence of cerebral disturbance, as stupor, delirium, etc.

By Tasker Howard
The American Journal of the Medical Sciences, Vol. CLVIII, pp. 685-689 (1919)
Lea and Ferbiger, Philadelphia and New York

As a military problem, mumps frequently occurs in men between 21 and 31 years. In the soldier and sailor the infection is dreaded because it is disabling and unmanageable. In 1918 there were 5,756 cases of mumps among 18,000 men at Camp Wheeler, an incidence of 32 per cent. … Orchitis is a frequent and painful complication and when both testicles are involved may cause sterility. Other complications are: great prostration; a tendency to develop mania, or wild delirium, or a comatose state resembling uremia; meningism, mastitis, otitis media, tonsillitis, and pneumonia also occur.

Preventive Medicine and Hygiene, 4th Edition
Milton J. Roseneau
D. Appleton & Company, New York & London, 1921

In an article in this issue of the Journal, Kutty et al [8] assist us in our understanding of the true levels of immunity against mumps in the United States. … As the study demonstrated, the calculated seroprevalence of antibodies to mumps virus in 6–49-year-old Americans is only ~90%, which is below the estimated 92% needed for mumps control (ie, herd immunity).

Quinlisk, M. (2010). Mumps Control Today. The Journal of Infectious Diseases DOI: 10.1086/655395

June 17th, 2010

Dendritic cells that don’t prime

Langerhans cells in the skin
Dendritic cells in the skin (Langerhans cells) form a dense network of “sentinels” that act as first line of defense of the immune system.1

There’s a lot of interest in using dendritic cells as vaccines these days.  A paper in PLoS One2 offers a cautionary note.

Dendritic cells (DC) are the main cell type that drive T cells from their normal naive state to an active state.  In the naive state, a T cell can recognize its target, but doesn’t do anything about it; in the active state, the T cell does something, ranging from spreading inflammation to killing infected cells, and so on.  The DC is needed to bridge these states.  DC do many things, but at the simplest level they connect  the presence of an antigen (a T cell target, in this case) with the presence of something dangerous or abnormal — a pathogen, or tissue damage.

There are some conditions where we’d like an immune response, where DC don’t detect one or the other of their components (i.e. antigen or danger).  For example, there may be a situation that we know is dangerous, but where there’s  little evidence of “danger” for the DC.  A vaccine, for example, doesn’t want to deliver a huge amount of tissue damage, but we’d still like to get a strong response to an antigen.  For a natural situation, cancers are often ignored by the immune system even though there may be lots of cancer antigens, and one reason (of many) for this ignorance is that the DC may not perceive a lot of danger in the context of the cancer.

So why not take the DC out of the system, alarm them with some danger information in the test tube, load them up with antigen, and then return them to the body? That’s called a dendritic cell vaccine, and there’s fairly intense interest in the approach.

There’s been some success using this approach, but perhaps less than you’d expect from the biology as we understand it.

Several clinical trials conducted over the past decade have demonstrated that DC vaccines can prime and boost antigen-specific CD8+ T cells in humans. However, their clinical efficacy remains to be definitively demonstrated [6], [19], [20], [21]. The lack of success has been variously attributed to several factors: administration of relatively low cell numbers of DCs, suboptimal route of administration, improper antigen dose, poor choice of antigenic targets, unsuitable maturation state of DCs, and inappropriate frequency of injections. However, understanding exactly which of these concerns represent true problems may be difficult because little is known regarding the fate and function of ex vivo generated DCs after they have been injected 2

Dendritic cell

Yewdall et al asked what happens to DC after they’re given this course and returned to the patient (mice, in this case).  Their surprising conclusion is that the DC don’t work to prime T cells directly.  Instead, they have to hand off their antigens to other cells in the body that have never left:

Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. … This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs. 2

As always in science, a single paper needs to be confirmed by others, so we won’t get too distressed until we see if other groups replicate this, and if it’s a universal truth or something specific to the particular system these authors were looking at.  (And, of course, this doesn’t trump actual evidence of efficacy for DC vaccines.) My own suspicion is that the work is accurate but limited, and there’s something about this particular system which prevented the transferred DC from being good primers; but as I say, I’d like to see some followup from another group.

  1. Tolerogenic dendritic cells and regulatory T cells: A two-way relationship. (2007) Karsten Mahnke, Theron S. Johnson, Sabine Ring and Alexander H. Enk. J of Derm Sci 46:159-167 doi:10.1016/j.jdermsci.2007.03.002 []
  2. Yewdall, A., Drutman, S., Jinwala, F., Bahjat, K., & Bhardwaj, N. (2010). CD8+ T Cell Priming by Dendritic Cell Vaccines Requires Antigen Transfer to Endogenous Antigen Presenting Cells PLoS ONE, 5 (6) DOI: 10.1371/journal.pone.0011144[][][]
May 20th, 2010

Cross-protection and flu vaccines

Gran'pop has a touch of the fluWe know that we need to make new vaccines against influenza each year, because new flu strains arise and spread each year and the previous year’s vaccines don’t give protection against the new strains.  Of course, there’s intense research toward developing cross-protective vaccines.  Ideally, flu vaccines would work like measles vaccines — get a shot as a child, be protected throughout life. That may not be a practical goal, but it’s a theoretical target.  More practically, even being able to vaccinate every five years or so would be a big step forward.    It’s clearly not going to be easy, though.  Natural infections don’t particularly offer a lot of cross-protection, and it’s hard1 to get vaccines that induce a stronger immune response than the natural infection.

The pandemic H1N1 influenza last year was an interesting test ground to see how much, if any, cross-protection seasonal influenza vaccines gave.  Unfortunately the results have been pretty confusing, with different studies finding some cross-protection, no cross-protection, or even some increased risk.

The increased risk thing has been hashed out quite extensively already, so if you follow flu stories much you’ve undoubtedly already seen it. This is from the Canadian study2 that found  that people vaccinated against flu in previous years –that is, against different flu strains — were somewhat more likely to get severe flu.

Influenza gargleNo one understands that finding, I think.  (The article itself is open-source, and there’s an excellent commentary on it3 here that’s also open-source, so check it out yourself.)  No one has been able to find any concrete problem with the study, other than its general nature — observational rather than randomized case/control.   But it’s clearly an outlier: Other studies looking at the same thing either find no effect either way, or a modest protective effect.

The latest in the series is a US Army study4 (open source, you can read it yourself) that finds a moderate protective effect of previous flu vaccinations against the pandemic H1N1 (pH1N1):

Our data also suggests that prior receipt of TIV [trivalent inactivated vaccine: IY] or LAIV [live attenuated influenza vaccine: IY] induces an association of protection against pH1N1-associated illness. This may reflect “priming” of the humoral immune system with influenza vaccine as demonstrated in immunologically-naïve children. … Additional findings from our study support the notion that vaccination with seasonal influenza vaccines in the preceding four years (2004–08) also conferred a certain degree of protective immunological memory relevant to the new viral strain. … Thus, it is reasonable to think that CMI [cell-mediated immunity: IY] plays a significant role and that cross-protective CMI to pH1N1 virus may actually exist in individuals who have been frequently immunized and/or exposed to seasonal influenza. 4

You always need to be a little cautious extrapolating army findings like this to the rest of the population. Military populations tend to be more crowded, more stressed, younger, fitter, and more homogeneous than the rest of the population. The vaccination rate among the service members in this study, for example, was much higher than in the general population.  There are a number of other possible sources of confusion that the authors carefully list. And of course, this is again an observational study, not a randomized prospective one.

But in the big picture, it (and similar studies) really do suggest that some cross-protection is possible in a natural population.  That’s really encouraging, because it shows there’s at least a foundation to build on for broadly cross-reactive vaccines.

  1. Though not impossible[]
  2. Skowronski, D., De Serres, G., Crowcroft, N., Janjua, N., Boulianne, N., Hottes, T., Rosella, L., Dickinson, J., Gilca, R., Sethi, P., Ouhoummane, N., Willison, D., Rouleau, I., Petric, M., Fonseca, K., Drews, S., Rebbapragada, A., Charest, H., Hamelin, M., Boivin, G., Gardy, J., Li, Y., Kwindt, T., Patrick, D., Brunham, R., & , . (2010). Association between the 2008–09 Seasonal Influenza Vaccine and Pandemic H1N1 Illness during Spring–Summer 2009: Four Observational Studies from Canada PLoS Medicine, 7 (4) DOI: 10.1371/journal.pmed.1000258[]
  3. Viboud, C., & Simonsen, L. (2010). Does Seasonal Influenza Vaccination Increase the Risk of Illness with the 2009 A/H1N1 Pandemic Virus? PLoS Medicine, 7 (4) DOI: 10.1371/journal.pmed.1000259[]
  4. Johns, M., Eick, A., Blazes, D., Lee, S., Perdue, C., Lipnick, R., Vest, K., Russell, K., DeFraites, R., & Sanchez, J. (2010). Seasonal Influenza Vaccine and Protection against Pandemic (H1N1) 2009-Associated Illness among US Military Personnel PLoS ONE, 5 (5) DOI: 10.1371/journal.pone.0010722[][]
April 22nd, 2010

Modeling disease and epidemics

Blyuss & Kyrychko, Fig. 5
Fig. 5.  Boundary of the Hopf bifurcation of the endemic steady state … 1

I don’t pretend to be a mathematician or to understand the more complex disease models that are out there, but I do think modeling is an essential way of understanding how to effectively deal with diseases.  A recent paper1 looks at epidemic diseases and seems to reach some interesting conclusions (though I will cheerfully admit that I don’t even remotely understand this paper, which is heavily mathematical).

The authors have built on models of infectious disease that incorporate immunity to the disease, and incorporated the assumption that immunity to the disease can wane over time, as opposed2 to the simpler, but less realistic, assumption that the immunity is either on or off.  I don’t think they are the first to do this, and I don’t understand any of the details of how their techniques differ from other models,3 but what I think they’re saying is that temporary immunity can lead to disruption of a simple, constant level of infection, and can actually drive periodic epidemics:

[W]hen the temporary immunity period is within a certain range, there will be periodic outbreaks of epidemic, and the disease will not be eradicated from the population. … The main feature is that temporary immunity leads to a possible destabilization of endemic steady state, and an interesting open question is what effects would vaccination have on the dynamics of an epidemic in such situation. 1

(My emphasis)  If I’m understanding this correctly, it leads to the possibility that where vaccines lead to relatively short-term immunity compared to the natural infection,4 it’s conceivable that vaccination could actually shift the disease from a steady state to an epidemic mode.  Obviously, if this can happen, it would be nice to be able to predict it.

Offhand, I can’t think of any examples where this might have happened in real life.  The most notorious epidemics, like influenza and norovirus, both tend to have fairly short-term immunity to start with. Something like Marek’s Disease of chickens would be an interesting case study, but the logistics of the poultry agribusiness is going to have a bigger impact than the vaccine (I would think).  The chicken-pox vaccine is the best example I can think of for a vaccine with relatively short-term immunity where the disease was endemic before the vaccine, and we’re not seeing any sign, that I know of, that chicken-pox is entering an epidemic situation.

The more relevant situation, I think, is for the natural epidemics.  As I say, both influenza and norovirus are well known for short-term immunity from natural infection, so maybe this is a factor there.  On the other hand, measles, which is spectacularly epidemic, has pretty long-term immunity from both the vaccine and the natural disease, and I don’t see any sign that the vaccine changed the personality of measles epidemics qualitatively (though of course, quantitatively the epidemics are much smaller now).

On the other other hand, of course it’s entirely possible that I completely misunderstand this paper, so if someone has a better grasp than I do please feel free to correct me.

  1. Blyuss, K., & Kyrychko, Y. (2009). Stability and Bifurcations in an Epidemic Model with Varying Immunity Period Bulletin of Mathematical Biology, 72 (2), 490-505 DOI: 10.1007/s11538-009-9458-y[][][]
  2. I think[]
  3. “For numerical bifurcation analysis of system with weak and strong kernels, we use a Matlab package traceDDE, which is based on pseudo-spectral differentiation and allows one to find characteristic roots and stability charts for linear autonomous systems of delay differential equations … “[]
  4. This is true for some vaccines, though not all[]
April 20th, 2010

Rotavirus vaccine and herd immunity

Rotaviruses are one of the most common causes of gastroenteritis in children.  A new rotavirus vaccine was introduced a few years ago; what impact has it had on disease?

This study confirms on a national scale that the 2008 rotavirus season among children aged <5 years was dramatically reduced compared to pre-RV5 seasons.  …  Based on the observed decrease during the 2008 season, we estimated that ~55,000 acute gastroenteritis hospitalizations were prevented during the 2008 rotavirus season in the United States. A decrease of this magnitude would translate into the elimination of 1 in every 20 hospitalizations among US children aged <5 years.1

(My emphasis)

Here’s what that looks like:

Rotavirus vaccine vs. gastroenteritis

Monthly acute gastroenteritis and rotavirus-confirmed hospitalization rates.  The rotavirus vaccine was introduced in 2006; in 2007 about 3% of children were completely vaccinated; in 2008 about 33% were vaccinated 1

Interestingly, the reduction in gastroenteritis wasn’t only in vaccinated children:

In 2008, acute gastroenteritis hospitalization rates decreased for all children aged <5 years, including those who were either too young or too old to be eligible for RV5 vaccination. …These findings … raise the possibility that vaccination of a proportion of the population could be conferring indirect benefits (ie, herd immunity) to nonvaccinated individuals through reduced viral transmission in the community1

(My emphasis, again)

Assuming this continues to hold up (and similar studies2 have found similar large reductions) it’s a striking example of herd immunity.

(Added later: The vaccine this paper looked at was RotaTeq.  This is not the vaccine that was recently found to be contaminated with porcine circovirus genomic fragments; that was the other rotavirus vaccine, Rotarix.)3

(Second update: RotaTeq apparently also is contaminated with porcine circovirus genomic fragments.)

  1. Curns, A., Steiner, C., Barrett, M., Hunter, K., Wilson, E., & Parashar, U. (2010). Reduction in Acute Gastroenteritis Hospitalizations among US Children After Introduction of Rotavirus Vaccine: Analysis of Hospital Discharge Data from 18 US States The Journal of Infectious Diseases DOI: 10.1086/652403[][][]
  2. For references see
    Weinberg, G., & Szilagyi, P. (2010). Vaccine Epidemiology: Efficacy, Effectiveness, and the Translational Research Roadmap The Journal of Infectious Diseases DOI: 10.1086/652404[]
  3. I haven’t talked about the Rotarix withdrawal because I think it’s been widely and very well covered on other blogs.  (I have 536 papers in my list of things I want to talk about here some time, so I usually don’t bother blogging about findings other places cover in detail.)  Vincent Racaniello at the Virology Blog has his usual high-quality commentary on it here.  He also made an important point on his podcast, This Week In Virology (either number 75 or number 77, I don’t remember which), which I don’t see explicitly on the post: The circovirus-containing vaccine went through all the safety trials, and no problems were seen.

    Obviously circovirus genomes aren’t supposed to be in the vaccine and they’ve got to go.  But (1) we don’t know if the genomes are infectious, or just fragments; (2) there’s no evidence, in spite of centuries of exposure to porcine circovirus, that it has any effects in humans; (3) the vaccines were shown to be safe, at least in the short term.

    On a larger scale, we’re entering a new era of analysis.  I suspect more of this sort of contamination will turn up as the sensitivity of our screening techniques improve, much like chemical detection: As we improve chemical detection to the parts-per-billion and parts-per-trillion level there needs to be better understanding of safety levels. Is this true for biologics? There are good arguments that there may be no safe level for some biologics, and any detection should lead to withdrawal, but on the other hand there clearly is a safe level for other biologics.  Human poop is loaded with vast amounts of viruses of peppers, for example; now that we know that should we regulate pepper mottle virus?

    I don’t have answers, which is why I relegate this to a footnote, albeit a long a rambling footnote.[]

March 19th, 2010

Measles week, Part V: What about the vaccine?

Measles infecting brain cell
Measles infection in a brain cell nucleus

Having gone through Parts I, II, III, and IV of Measles week, let’s finish up by asking what this means for measles vaccine.

We know that measles death rates dropped spectacularly well before the vaccine was introduced in 1963 (the first version; a more effective version was released later). We know, too, that this reduction in deaths was solely because of case-fatality rates — measles was just as common in 1955 as it was in 1910, almost every child got it, the difference was that in 1950 fewer than 1 in a thousand cases died, whereas in 1910 somewhere between 1% and 30% of the cases1 died — over a hundred times higher.

Measles deaths (and case-fatality rates) more or less plateaued in the 1950s.  After vaccination was introduced, measles cases dropped by maybe 90% (see the chart below), and measles deaths dropped along with the case number.

Measles week
Part I: Introduction
Part II: Emerging disease
Part III: Not the answers
Part IV: Some of the answers
Part V: What about the vaccine?

First question– would deaths have continued to plummet if there was was no vaccine? I’ve seen people trying to extrapolate the drop outward with a simple trendline, but that doesn’t make sense — it assumes that it’s a single, linear trend.  That’s clearly not the case. By 1953-ish, a decade before the vaccine was introduced, measles death rates had pretty much flattened out, both in England and in the USA. (Check out charts in Part I, and here.) Case-fatality rates in England hovered at just about 0.02% from 1953 on. (They plateaued at a slightly higher rate in the US, about 0.09%.)

One in ten

In fact, we see very similar case-fatality rates in modern-day measles epidemics in the first world, as in the 1950s:

  • In England, measles cases over the past 30 years have had a just a tick more than 0.02% case-fatality rates.
  • In Switzerland from 2006-2009, 1 death in 4000 cases, 0.025%;2
  • The numbers are confusing in the Italian outbreak of 2002-2003, with different death numbers and estimated cases being offered in different papers,3 and with no clear case number of diagnosed measles.  (“Although notification is statutory, measles cases are often not reported.4 ) Hard numbers give a death rate of 0.2% (ten times higher than the 1950s), but that’s based on a clearly-incomplete case number; soft numbers — estimated cases, which are not comparable to the other stories here — give lower case-fatality rates.
  • European cases in 2006-2007, a 0.05% death rate in a few thousand cases — a little worse than England in the 1950s.5

So in the industrialized world, measles death rates are just about as low as we can get; without the vaccine, the  numbers of deaths wouldn’t have dropped any further after 1955 or so.

But secondly, death isn’t the only problem associated with measles. The estimated complication rate in Italy (2002-2003) and in Switzerland (2006-2009) was about 10% of cases, and this is very typical of measles today.:

It is well known that measles infection can cause serious complications and between 1.4% and 19.0% of measles cases that occur in industrialized countries require hospitalization … 6

Even if you don’t die, the disease is not trivial.

A large number of pneumonia and encephalitis cases were identified. The latter should be underscored, since long term sequelae of measles encephalitis are reported to occur in 20–30% of cases; this implies that between 28 to 41 of the 138 encephalitis cases may have subsequently developed permanent disabilities. 7

Measles cases & deaths in the US around vaccination
Vaccination & measles in the US: Case and deaths (inset) of measles before and after vaccination

Before vaccination, there were roughly 300,000 – 400,000 cases of measles per year in England; vaccination reduced the case number by about 90%. (See the chart of US measles numbers to the left – click for a larger version. I don’t think I need to show where the vaccine was introduced.)  Without even adjusting for the increase in population since then, and using the modern, industrialized-nation data for various complications and deaths, we can see that without vaccination for measles England8 would be seeing (at least) an extra:

  • 75 deaths per year (mainly in infants)
  • 500 cases of encephalitis
  • 10,000 cases of pneumonia
  • 50,000 hospitalizations
  Vaccinating the poor / Drawn by Sol Ettinge, Jun. 1872
Vaccinating the poor. By Sol Ettinge, Jr.
Harper’s Weekly, March 16, 1872

One other interesting thing about measles and measles vaccine.  A couple of years ago, talking about smallpox eradication, I summarized some of the reasons that it was possible to eradicate smallpox as a natural disease. Smallpox:

  • Has no animal host. If you can eradicate the disease in humans, it won’t re-emerge from a mouse, or monkey, or bat reservoir — compare to yellow fever, for example.
  • Has no persistent phase. Smallpox either kills people, or they recover completely and eliminate the virus. In either case, if there are no clinical cases over a reasonable period, then you can be confident that there is no more virus.
  • Induces long-term immunity in survivors.
  • Was a fearful enough disease that the political will to eradicate it lasted through the campaign. Smallpox vaccination continued throughout civil wars and other upheavals.
  • Has a highly effective vaccine that confers long-lasting immunity.

Aside from the political will, all these things are also true for measles.  Technically, measles could be eradicated as effectively as was smallpox, and the World Health Organization has considered setting eradication as a goal.  But without the political will, it’s not going to happen; instead of eradication, the WHO is working toward “sustainable measles mortality reduction” (the WHO document [PDF forumat] is here).

  1. Yes, a huge range, just as is seen in third-world measles epidemics today[]
  2. Richard JL, Masserey Spicher V (2009) Large measles epidemic in Switzerland from 2006 to 2009: consequences for the elimination of measles in Europe. Euro Surveill 14[]
  3. Ciofi Degli Atti ML, Filia A, Massari M, Pizzuti R, Nicoletti L, D’Argenzio A , de Campora E, Marchi A, Lombardo A, Salmaso S (2006) Assessment of measles incidence, measles-related complications and hospitalisations during an outbreak in a southern Italian region. Vaccine 24:1332–1338.
    Filia, A., Brenna, A., Pana, A., Cavallaro, G. M., Massari, M., and Ciofi degli Atti, M. L. (2007). Health burden and economic impact of measles-related hospitalizations in Italy in 2002-2003. BMC Public Health 7, 169.[]
  4. Ciofi Degli Atti ML, Filia A, Massari M, Pizzuti R, Nicoletti L, D’Argenzio A, de Campora E, Marchi A, Lombardo A, Salmaso S (2006) Assessment of measles incidence, measles-related complications and hospitalisations during an outbreak in a southern Italian region. Vaccine 24:1332–1338.[]
  5. MUSCAT, M., BANG, H., WOHLFAHRT, J., GLISMANN, S., & MOLBAK, K. (2009). Measles in Europe: an epidemiological assessment The Lancet, 373 (9661), 383-389 DOI: 10.1016/S0140-6736(08)61849-8[]
  6. Filia, A., Brenna, A., Panà, A., Maggio Cavallaro, G., Massari, M., & Ciofi degli Atti, M. (2007). Health burden and economic impact of measles-related hospitalizations in Italy in 2002–2003 BMC Public Health, 7 (1) DOI: 10.1186/1471-2458-7-169[]
  7. Filia, A., Brenna, A., Panà, A., Maggio Cavallaro, G., Massari, M., & Ciofi degli Atti, M. (2007). Health burden and economic impact of measles-related hospitalizations in Italy in 2002–2003 BMC Public Health, 7 (1) DOI: 10.1186/1471-2458-7-169[]
  8. I have the English data at hand, which is why I’m using it rather than the US numbers[]
February 10th, 2010

A scarifying story

God of Smallpox
Sopona, the Yoruba god of smallpox

A while ago I listed a number of reasons why smallpox was eradicated, whereas other diseases haven’t been (yet). One of the reasons was that the vaccine against smallpox1 is so effective. Vaccinia immunization induces immunity for an extraordinarily long time — memory immune responses have been shown for up to 60 years after vaccination.

So why is vaccinia such an effective vaccine? Part of it is that vaccinia is a live virus: It replicates after you’re inoculated (so there’s lots of antigen there), and it stimulates the innate immune response (which is geared toward detection of live viruses, among other things). (The yellow fever vaccine is another live virus vaccine that’s also famous for inducing long-term immunity.) Vaccinia is also a large virus that has a lot of antigens available, so that there are lots of different modes of immunity triggered. That is, both B cell (antibody-based) immunity, and broad T cell-based immunity, are likely to be present and to have lots of different targets.

A recent paper2 suggests that the route of vaccination is also important. Unlike most vaccines, which are given by intramuscular (e.g. influenza vaccine) or subcutaneous (e.g. yellow fever) injection, or orally (the live polio vaccine), vaccinia is delivered by scarification — scraping the most superficial layers of the skin. I don’t think this was the result of deliberate comparisons — scarification was the traditional method, and it was easy and convenient. Before 1967:

A scratch about 5 mm long was made in the skin with a needle, a lancet or a small knife and the vaccine suspension was rubbed into the site. A single cut or cross cuts were made, in 1 , 2 or 4 different sites. This was essentially the same method as had been used for variolation in Europe during the latter part of the 18th century. ((Smallpox and its Eradication (Chapter 7). F. Fenner, D. A. Henderson, I. Arita, Z. JeZek, I. D. Ladnyi. World Health Organization, Geneva, 1988))

Later, a bifurcated needle was used:

Experiments soon showed that the multiple puncture method, in which the bifurcated needle was held at right angles to the skin, which was then punctured several times with the prongs, was very efficient and very easy even for an illiterate vaccinator to learn. It became the standard method of vaccination throughout the world. 3

Scarification was a simple and convenient way to deliver the vaccine.  It turns out that scarification isn’t just a convenience, it’s the most effective way to get immunity:

VACV immunization via s.s. [skin scarification], but not conventional injection routes, is essential for the generation of superior T cell–mediated immune responses that provide complete protection against subsequent challenges.2

Langerhans cells J Dermatol Sci
Langerhans cells in the skin4

This includes protection against respiratory-spread disease, not just skin infection. My first thought was that this is probably simply because the vaccinia virus replicates better in the skin than by intramuscular injection, but the improved immunogenicity is also seen with a non-replicating version of vaccinia, “MVA”. 5

My next thought is that Langerhans cells are probably part of the reason. Langerhans cells (see the figure to the right) are a subset of dendritic cells, probably extremely good at triggering immunity, that form a dense network under the skin, and probably act very efficiently at filtering skin-delivered antigen and delivering it to the immune system.

Also, the fact that the skin is damaged in the process evokes Polly Matzinger’s “danger” concept of immune stimulation.

At any rate, something, even if we don’t know exactly what, about scarification leads to better immunity, at least for vaccinia virus. That’s useful to know. Having said that, I’m not quite sure why this paper appeared in Nature Medicine, a very high-impact journal — the mechanism wasn’t shown at all clearly, and this isn’t the first time that the general observation has been made:

This study strongly indicated that, although less reactogenic, vaccinia vaccine administered im [intramuscularly] at a dose of 105 pfu fails to induce an immune response comparable to that elicited by standard scarification. 6

Even more broadly, the skin inoculation concept has been shown to lead to high immunogenicity in other systems; for example, it was shown a couple of years ago that yellow fever vaccine is more immunogenic when delivered intradermally than when given by its conventional subcutaneous route:

Intradermal administration of one fifth of the amount of yellow fever vaccine administered subcutaneously results in protective seroimmunity in all volunteers. 7

BIfurcated needle
Bifurcated needle used for smallpox vaccination

(I do have to add that apparently scarification — which is much easier than intradermal injection — does not work for yellow fever, based on some experiments in the 1950s.8 I haven’t read those papers myself, though. I’d be interested to see if the bifurcated needles used in the late 1960s and on for vaccinia might be more effective for the yellow fever vaccine.)

Anyway, seeing this in at least two instances9 makes it seem possible that it’s a general effect. If skin administration enhances immunogenicity, perhaps this is a way of extending limited vaccine stocks in an emergency.

  1. That is, vaccinia virus[]
  2. Liu, L., Zhong, Q., Tian, T., Dubin, K., Athale, S., & Kupper, T. (2010). Epidermal injury and infection during poxvirus immunization is crucial for the generation of highly protective T cell–mediated immunity Nature Medicine, 16 (2), 224-227 DOI: 10.1038/nm.2078[][]
  3. Smallpox and its Eradication (Chapter 11).  F. Fenner, D. A. Henderson, I. Arita, Z. JeZek, I. D. Ladnyi.  World Health Organization, Geneva, 1988[]
  4. MAHNKE, K., JOHNSON, T., RING, S., & ENK, A. (2007). Tolerogenic dendritic cells and regulatory T cells: A two-way relationship Journal of Dermatological Science, 46 (3), 159-167 DOI: 10.1016/j.jdermsci.2007.03.002[]
  5. At any rate, it’s claimed to be non-replicating, but I don’t remember seeing it formally shown that MVA doesn’t replicate, even temporarily, in the skin. Anyone know if this has been tested?[]
  6. Immunologic Responses to Vaccinia Vaccines Administered by Different Parenteral Routes Author(s): David J. McClain, Shannon Harrison, Curtis L. Yeager, John Cruz, Francis A. Ennis, Paul Gibbs, Michael S. Wright, Peter L. Summers, James D. Arthur, Jess A. Graham Source: The Journal of Infectious Diseases, Vol. 175, No. 4 (Apr., 1997), pp. 756-763[]
  7. Roukens, A., Vossen, A., Bredenbeek, P., van Dissel, J., & Visser, L. (2008). Intradermally Administered Yellow Fever Vaccine at Reduced Dose Induces a Protective Immune Response: A Randomized Controlled Non-Inferiority Trial PLoS ONE, 3 (4) DOI: 10.1371/journal.pone.0001993[]
  8. Ann Trop Med Parasitol. 1953 Dec;47(4):381-93.  Vaccination by scarification with 17D yellow fever vaccine prepared at Yaba, Lagos, Nigeria.CANNON DA, DEWHURST F.

    Am J Hyg. 1952 Jan;55(1):140-53.  A preliminary evaluation of the immunizing power of chick-embryo 17 D yellow fever vaccine inoculated by scarification.DICK GW.[]

  9. And I’m pretty sure I’ve seen at least one other example, but I’m blanking on the details[]
December 9th, 2009

Are flu vaccines effective in the elderly?

Influenza vaccine

There’s been a fair bit of discussion online about the new study in the British Medical Journal1  throwing doubt on Tamiflu’s effectiveness against influenza.  (If you haven’t already seen this, see the Avian Flu Diary for an excellent summary of the situation, and an update here.2 Also see the CDC’s recommendations for antivirals here.)

There’s a new paper3 that takes a similar skeptical look at the effectiveness of influenza vaccines in the elderly (I emphasize, the question is how well the vaccines work in the elderly; as far as I know there’s general agreement that the flu vaccines work reasonably well in younger people and children).  It’s long been agreed that flu vaccines don’t work as well in elderly people as they do in the young.  This is a real concern, because it’s also generally agreed that seasonal influenza takes its greatest toll on people over 65 years or so. 4

However, while it’s been agreed that flu vaccines don’t work as well in the elderly, this new paper suggests the situation is even worse than we thought; and in fact the vaccine may hardly work at all (in the elderly!).  The authors argue that the apparent benefits of vaccination, as previously detected, aren’t real; they’re the result of bias in vaccination.  That is, it’s not the people who are vaccinated don’t die of flu; rather, people who aren’t going to die of flu, are the ones who get vaccinated. Correlation is not causation:

Because persons who are most likely to die are less likely to receive the vaccine, vaccination appears to be associated with a much lower chance of dying; thus, the “effectiveness” of the vaccine is in great part due to the selection of healthier individuals for vaccination, rather than due to true effectiveness of the vaccine.3

They offer a number of possible reasons for this bias — perhaps the most frail people don’t get to vaccine clinics; perhaps doctors try harder to have their most energetic patients vaccinated; perhaps those people on the verge of death don’t want further intervention.  I don’t have the statistical chops to critique their analysis in detail, but from what I do follow it seems well supported.  I’d like to see more work on this, because it obviously has huge, huge implications for vaccination policy and vaccination research.

We hope this knowledge will stimulate research into better vaccines for elderly patients (perhaps by use of higher doses or adjuvants) and will lend more weight to the importance of vaccinating schoolchildren to prevent disease in the rest of the population.3

Even if this suggestion eventually doesn’t hold up, it’s a really important message: Always be skeptical.

By the way, I and my family got the H1N1 vaccine last night (even though I read this article last week some time), so I’m walking the walk as well as talking the talk.

  1. Jefferson, T., Jones, M., Doshi, P., & Del Mar, C. (2009). Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis BMJ, 339 (dec07 2) DOI: 10.1136/bmj.b5106
    Also see the editorial:
    Godlee, F., & Clarke, M. (2009). Why don’t we have all the evidence on oseltamivir? BMJ, 339 (dec08 3) DOI: 10.1136/bmj.b5351[]
  2. And if you’re not reading AFD already, why aren’t you?[]
  3. Baxter, R., Lee, J., & Fireman, B. (2009). Evidence of Bias in Studies of Influenza Vaccine Effectiveness in Elderly Patients The Journal of Infectious Diseases DOI: 10.1086/649568[][][]
  4. The biggest difference between this H1N1 pandemic influenza this year and seasonal flu is in the age groups at risk.  Normally, seasonal influenza causes death almost entirely in the older people.  This year, older people are relatively, though not absolutely, not being killed by influenza, while younger people are.  So while it’s true that the mortality rate due to the new swine-origin influenza virus isn’t really higher than usual, and may even be lower, that mortality is clustered in an unfamiliar group — young people, and children, who normally are at essentially no risk of flu-caused death.[]