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I'm examining a dataset of a measles outbreak, and for each patient I have the date of first appearance of symptoms $t_1$, date of appearance of rash $t_2$, and if applicable, date of death $t_d$. According to the literature, patients are infectious for one day before appearance of symptoms, and up to about 4 days from appearance of rash, so the interval of infectiousness is approximately $left[t_1 -1, t_2 + 4 ight]$. After this, most of the time their symptoms gradually abate and they get better.
However, if a patient dies, presumably they remained sick until they died. If $t_d$ is like, 10 or 15 days after $t_2$, are they infectious during all of this period? Or is it reasonable to conclude that they're infectious for the same length of time as everyone else, and the symptoms that kill them are non-infectious complications?
The characteristic rash of measles is itself an immune response, and is a good marker for progression of the immune response. Patients with immunodeficiency can have a much more limited or even absent rash. In most patients, if it's been 4 days since the appearance of the rash, and they have improvement in fever, runny nose, and conjunctivitis, without a productive cough, they probably aren't infectious. If you have that data (fever and mucous membrane inflammation), I'd pay attention to that as well as the time since the appearance of the rash. A sick patient with measles should be kept in respiratory isolation regardless, but if you're looking at modeling disease transmission, you can follow the symptom progression.
As far as death is concerned, there are several pathways. Measles can cause a poorly understood immunosuppression and immune dysregulation, which certainly contributes. The most common cause of death is pneumonia (often secondary pneumonia), but early diarrhea can be a major cause in malnourished children. Otherwise immunosuppressed individuals (e.g., HIV, and primary immunodeficiencies) can develop a fatal measles encephalitis (a brain infection). Some deaths result from a fatal post-infectious autoimmune syndrome.
Some of these individuals are probably still shedding virus (diarrhea, primary measles pnuemonitis or encephalitis), many of them aren't (secondary pneumonia and autoimmune cases).
Many texts focus on vaccination and the current epidemiology of measles in developed countries, but Cecil Medicine has a very good chapter (375) on the clinical manifestations of measles. There is an interesting article in Lancet Infectious Diseases about the US army outbreak in 1917-18 that is a good example of the interaction of measles with other respiratory pathogens.
Measles is a highly contagious virus that lives in the nose and throat mucus of an infected person. It can spread to others through coughing and sneezing.
If other people breathe the contaminated air or touch the infected surface, then touch their eyes, noses, or mouths, they can become infected.
Animals do not get or spread measles.
The virus can live for up to two hours in an airspace.
Measles is one of the most contagious diseases
Measles is so contagious that if one person has it, up to 90% of the people close to that person who are not immune will also become infected.
Infected people can spread measles to others from four days before through four days after the rash appears.
Measles virus can live for up to two hours in an airspace after an infected person leaves an area.
Measles is one of the most contagious diseases of humans, and an important cause of childhood deaths. The global effort to reduce measles mortality aims to achieve routine measles vaccination coverage of at least 90% in every district throughout the world. So far, this effort has resulted in a dramatic decline in deaths from measles . The high vaccination coverages have changed the epidemic pattern from a roughly biennial cycle to an irregular sequence of outbreaks [2–4]. A proper understanding of the size and timing of these outbreaks is a prerequisite for adequate monitoring of a vaccination programme, and essential for assessing the risk of future measles outbreaks.
The size of an outbreak depends on both the fraction of susceptible individuals in the population and on chance events in the transmission process . The fraction of susceptible individuals determines the expected size of an outbreak. Already in 1927, Kermack and McKendrick predicted that there should exist a critical threshold level for the fraction of susceptible individuals below which introduction of infection can only lead to minor outbreaks . This so-called threshold theorem  underlies the concept of herd immunity, and it explains why it is possible to eradicate an infectious agent even without achieving complete vaccine coverage [8,9]. Variability in the size of outbreaks arises due to chance events in the transmission process. This variability becomes very large when the fraction of susceptible individuals is close to the epidemic threshold level [4,10]. When the fraction of susceptible individuals exceeds the threshold level, chance events determine whether a minor or a major outbreak will occur. The probability that the outbreak will be a major one increases with the fraction of susceptible individuals in excess of the threshold [5,11]. In their 1927 paper, Kermack and McKendrick showed that when the proportion of susceptible individuals is only slightly above the threshold level, almost two infections occur per susceptible individual in excess of the threshold level during a major outbreak  this so-called second threshold theorem has been useful in calculating expected outbreak sizes [7,12]. Thus, the epidemic threshold for fraction of susceptible individuals marks a bifurcation in expected infection attack rates from only minor to both minor and major outbreaks, where the infection attack rate during major outbreaks is almost twice the excess fraction of susceptible individuals (Figure 1A).
(A) Expected infection attack rates during measles outbreaks in an idealised homogeneously mixing population.
(B) Expected infection attack rates during measles outbreaks in a population protected by solid herd immunity.
(C) Expected infection attack rates during measles outbreaks in a heterogeneous population consisting of a small community embedded in a larger population. The expectations are calculated for a stochastic “susceptible–exposed–infectious–recovered” (SEIR) model, with measles basic reproduction number R0 = 17 , and ten imported measles cases per year. The population structure is as reported for the Netherlands, where a small community of 300 000 persons with a variable fraction of susceptible individuals exists in a larger population of 15 million persons with a fraction of susceptible individuals of 0.043 .
Dark blue markers correspond to major outbreaks light blue markers correspond to minor outbreaks. The solid gray line indicates the approximation, near the threshold, of the infection attack rate: two infections occur per susceptible individual in excess of the threshold.
Most observational studies on outbreak sizes in highly vaccinated populations have relied on two assumptions: first, the fraction of susceptible individuals is uniform throughout the population, and, second, the fraction of susceptible individuals remains below the epidemic threshold [3,4,13]. If these assumptions are met, the population is protected by solid herd immunity and no major outbreaks can occur. A simple one-to-one relationship exists between the observed infection attack rate and the fraction of susceptible individuals in the population (Figure 1B). This one-to-one relationship makes it possible to derive several epidemic variables of interest from observed outbreak sizes [3,4,10]. For example, countries and regions with elimination strategies for measles have been advised to monitor the average outbreak size as an indicator of “elimination status” : smaller outbreaks are indicative of fewer susceptible individuals in a homogeneous population that is protected by solid herd immunity.
Many countries and regions have a heterogeneous distribution of the fraction of susceptible individuals . This heterogeneity can be due to religious communities that refrain from vaccination (for example, the Amish in the United States of America ) or due to different vaccination programmes (for example, failure to implement additional vaccinations in the São Paulo region of Brazil ). The threshold concept, although often illustrated for an idealised homogeneous population, also applies with a few minor modifications to a heterogeneous population. In a simple heterogeneous population, consisting of a community with many susceptible individuals embedded in a population with few susceptible individuals, one still recognises an epidemic threshold for the average fraction of susceptible individuals in the entire population. And when a major outbreak hits the community with many susceptible individuals, approximately two cases occur per susceptible individual in excess of this population average threshold (Figure 1C). As a consequence, there is no longer a simple one-to-one relationship between the observed infection attack rate and the fraction of susceptible individuals in the population.
To our knowledge, there are no direct observations that show the precise nature of the relation between the fraction of susceptible individuals and infection attack rate during the irregular measles outbreaks that are characteristic for highly vaccinated populations. However, such observations could shed light on how one should interpret observed infection attack rates, and how to assess the risk of future measles outbreaks once endemic transmission has been interrupted. To overcome this deficiency, we have investigated the relation between the fraction of susceptible individuals and the infection attack rate for measles outbreaks over a 28-y period in the Dutch population. The Dutch data are ideally suited for an ecological study of measles outbreaks in a real, heterogeneous population: endemic measles transmission during this period was frequently interrupted in between the measles outbreaks, while the vaccination coverages and birth rates remained almost constant [18,19].
In this study, standardised postal questionnaires were sent to individuals with confirmed or suspected measles. Questionnaires were sent to individuals with suspected measles in the North West England outbreak from 1 st June 2012 and the study was extended throughout England from 2 nd October 2012 to 5 th July 2013 targeting only individuals with confirmed measles.
Individuals with suspected measles were confirmed positive if they were measles immunoglobulin M-positive on saliva or through polymerase chain reaction testing in urine, saliva or a throat swab. A suspected measles case was defined using the following criteria from Vivancos et al. 2012 :
- Clinical presentation: fever and measles-like rash and one or more of the following symptoms: cough, conjunctivitis, coryza, or Koplik's spots.
- Residence/reported from: residence or history of travel to endemic, outbreak or adjacent areas, or being a close contact of a confirmed or probable case of measles.
Individuals in traveller communities with laboratory-confirmed measles were not invited to participate in the study, because Public Health England engages with this community through different protocols and procedures . A member of the traveller community was defined as someone self-identifying as a member of the traveller community or someone living on a traveller site, whether authorised or not authorised.
We excluded individuals with confirmed measles with a reported symptom onset date more than two weeks before case status was confirmed to minimise the time between perceived symptom onset and receiving the first questionnaire.
Unless stated, the analysis that follows is based on individuals with confirmed measles.
The EuroQol EQ-5D-3L is a generic multi-attribute health-state classification system , . HRQoL is assessed in five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is assessed using three levels: no problems, some problems and severe problems, facilitating the evaluation of 243 ( = 3 5 ) different health states. The EuroQol scoring algorithm converts the responses into a health utility specific to the individual's health state. A visual analogue scale (VAS) invites the individual to rate their health state on a scale from 0 – 100, with 0 being the worst health state imaginable and 100 being the best health state imaginable. The National Institute for Health and Clinical Excellence recommends the EuroQol EQ-5D-3L for use in cost-effectiveness analyses in the United Kingdom .
Three age-specific EQ-5D-3L questionnaires were used: the standard EQ-5D-3L for all individuals aged 13 years and older the child-friendly EQ-5D-Y for all individuals aged between 7 – 12 years  and a proxy version of the standard EQ-5D-3L for individuals aged less than 7 years to be completed by the child's parent or guardian. All three versions of the questionnaire use both the same algorithm and scoring tariff to convert responses into health utilities.
One year is equivalent to 365 days therefore 1 QALY would be equivalent to 365 quality-adjusted life days (QALDs). The QALD has previously been used to report the impact of influenza on HRQoL , and for ease of interpretation we express loss of HRQoL in terms of QALDs below.
Individuals were sent an initial questionnaire requesting details of their illness and its impact on their HRQoL for both the worst day of infection and the day that the questionnaire was received using the EQ-5D-3L. Three weeks later they were sent a follow-up questionnaire to obtain a further HRQoL measurement at recovery. Individuals who did not return the first questionnaire were sent it a second time along with the follow-up questionnaire three weeks later. We assumed that a three week period was sufficient for typical symptoms of measles to subside , and we assumed that if individuals reported that they had recovered then they were no longer suffering a measles-related reduction in their HRQoL. The value of HRQoL reported by individuals who reported having recovered was treated as their baseline HRQoL for the purposes of calculating QALY loss.
To assess the impact of measles infection on HRQoL, patients must complete the EQ-5D-3L when healthy (at recovery) and for the worst day of infection. We assumed that the QALY loss associated with measles for each individual can be represented by a triangular shape, as shown in Figure 1. A more precise picture would be possible if patients completed the EQ-5D-3L more frequently during their infection. In absence of these data we assume that we can represent the QALY loss as a linear deterioration in HRQoL from a recovery reading to its level on the worst day of infection. As a comparison, we also estimated HRQoL directly using the VAS, with HRQoL given by VAS score divided by 100.
HRQoL is plotted against time the area of the black triangle represents the loss of HRQoL due to illness.
Notification of potential study participants was received by the specialist epidemiologist for measles at Public Health England in Colindale who excluded ineligible patients. Letters and questionnaires were sent using a database updated daily with new notifications of suspected measles cases. In the analysis that follows, we consider only those individuals with laboratory-confirmed measles.
All questionnaires sent to confirmed or suspected measles cases were anonymised. A questionnaire was linked to the appropriate follow-up questionnaire using the HP Zone ID, an anonymised ID data field used on Public Health England databases. Sensitive patient identifiers such as the distribution address were handled by Public Health England, whereas the returned and anonymous questionnaires were processed by researchers at the London School of Hygiene and Tropical Medicine, with no links or access to the original sensitive information. All medical records used in the analysis were also anonymised by Public Health England using the HP Zone ID.
In accordance with The Health Service (Control of Patient Information) Regulations 2002 No. 1438 Section 251 Regulation 3 , Public Health England may process confidential patient information with a view to monitoring and managing
- outbreaks of communicable disease
- incidents of exposure to communicable disease
- the delivery, efficacy and safety of immunisation programmes.
Data were analysed using Microsoft Excel 2007 and R (version 3.0.2) . Public Health England obtained hospitalisation records for individuals who received the questionnaire, so hospitalisation rates were compared between responders and non-responders to test for severity bias. HRQoL data were analysed only for those patients who completed all five dimensions of health on the EQ-5D-3L in addition to reporting the duration of their illness. We calculated the QALY-loss due to measles using the EQ-5D-3L and the VAS and compared the two systems. We examined the three age-specific EQ-5D-3L questionnaires and looked for differences in the QALYs lost due to measles infection. Reported 95% confidence intervals of the means are based on 1,000 bootstrap replications.
The EQ-5D-3L requires the respondent to complete all five dimensions of the classification system in order to calculate a health-state utility. Omitting the response to any of the dimensions means the remaining responses cannot be used for this purpose, therefore a missing-value regression analysis was conducted using the VAS score to estimate the EQ-5D-3L utility where patients had completed the VAS but not all five dimensions of health. When assessing the HRQoL in individuals with haemophilia Miners et al.  showed a correlation between EQ-5D-3L utility and the VAS scores (R = 0.67, p<0.0001).
Vaccination trains your body to defend itself
Vaccination is the best way to protect yourself against one of the most infectious diseases known to humankind. Unlike a naturally-caught measles infection, vaccination introduces your body to a form of the live virus that has been greatly weakened in a laboratory. This allows you to build immunity against the disease without getting sick, as well as avoiding the horrible complications that can accompany measles infection.
It means you avoid the immune suppression that leaves you vulnerable to other infections, too. Vaccination doesn’t only protect you against getting measles, but also prevents other infections from taking hold while you’re in a state of measles-induced immune system suppression.
A Brief History of Measles
According to the best evidence we have, measles makes its appearance somewhere between the 11th and 12th Centuries when the measles virus diverged (separated) from the rinderpest virus (a sort of measles of cattle that has been eradicated through vaccination). This probably happened when cattle herders spent just a little too much time with their cattle somewhere in the Middle East.
Before we go any further, you need to understand that measles is highly infectious. It’s, like, really infectious. One person can infect up to 18 other people, and the virus floats in the air for up to two (maybe four) hours where an infectious person has been. What’s worse, a person is infectious 3 to 5 days before the onset of the typical measles rash, and 1 to 2 days before the onset of fever. This means that a perfectly healthy-looking person can go around spreading measles and not even know they’re sick.
Because of this, measles likely spread as people with the disease came into contact with population centers, and then as trade occurred between those population centers. Soon enough, measles was found worldwide, with some of the first accounts of it in the Americas in the 1600s. That said, the descriptions of some of the plagues brought to the Americas by Columbus and subsequent invasions do resemble measles. It’s hard to pinpoint when the exact introduction of measles to the Americas was since the invaders and explorers brought smallpox, syphilis and other plagues with them.
As worldwide travel became more accessible to more and more people, measles spread far and wide and established itself in communities where there was a cohort of children large enough born each year for it to continue to spread. It wasn’t just the children that suffered, however. Measles in adults has always had more serious consequences. During the Civil War, about 20,000 cases were reported in Union Soldiers, with about 500 deaths.
By the time the 1900s rolled around, this translated into hundred of thousands of cases worldwide, with thousands of deaths. It was only when better medical treatment became more available in the mid-1900s in the United States that deaths in American children began to decline. Measles cases, however, did not decline until the arrival of a vaccine in 1963. From then on, cases and deaths declined to very low levels in the United States and everywhere the vaccine was licensed and administered. However, outbreaks would still occur, concentrated mostly in the unimmunized.
In 1978, the Centers for Disease Control and Prevention (CDC) targeted measles for elimination. The initiative was soon followed by the Pan American Health Organization (PAHO). It wouldn’t be until the year 2000 that the goal was achieved of eliminating measles from the United States, and it would not be until 2015 that the entire continent was declared to have eliminated measles.
Elimination doesn’t mean eradication, though. As we know, there continue to be measles outbreaks in the United States and elsewhere, albeit for different reasons. In Venezuela and Brazil, for example, there have been measles outbreaks due to the collapse of the public health infrastructure in Venezuela. The political instability there then drove people to emigrate to Brazil, bringing measles with them.
In Madagascar, off the eastern coast of Africa, the low vaccine supply has triggered an outbreak that has seen tens of thousands sick and hundreds dead. In Europe, a measles outbreak that started in Ukraine has spread to the rest of the continent. And in the Philippines, bad reporting on some adverse events over a vaccine against dengue fever scared parents away from vaccinating altogether, triggering an outbreak that has killed dozens of children from measles.
In New York City in 2018, a measles outbreak happened among Orthodox Jewish community members whose religious practice is to not immunize. Across the country, in Washington State, an outbreak is still going on (in early 2019) in a community where anti-vaccine sentiment runs high and misinformation about the Measles Mumps and Rubella (MMR) vaccine is widespread… Misinformation that really got going in 1998.
Back in 1998, a researcher in the UK published a since-retracted paper whose conclusion read: “We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described. Virological studies are underway that may help to resolve this issue.” Nevertheless, the principal investigator in the study held on to the idea that the MMR vaccine caused autism, saying, “Again, this was very contentious and you would not get consensus from all members of the group on this, but that is my feeling, that the, the risk of this particular syndrome developing is related to the combined vaccine, the MMR, rather than the single vaccines.”
The study has since been denounced as a fraud, with the paper retracted and the principal investigator being struck off the medical register in the UK. In essence, he cannot practice medicine anymore. However, based on his “feeling” that the MMR vaccine caused autism, millions of parents around the world have declined the MMR vaccine — and other vaccines — out of a fear of their children becoming autistic. (This, as the evidence points more and more toward autism being a normal variation in the anatomy and physiology of human brains and human development and heavily influenced on genetics.)
As you can see, we are dealing with a virus that can be easily eradicated with a well-coordinated approach from health agencies around the world. This is because the vaccine confers long-term immunity, and having the disease or getting vaccinated both mean that you’re immune for a long time. If we were to vaccinate absolutely everyone for whom the vaccine is recommended (children age 1 and then before they start elementary education), and we did this the world over, measles would join smallpox and rinderpest as a virus that is wiped off the face of the planet. (Polio will likely be the next one, instead.)
Instead of that, we are faced with more and more epidemics around the world, many of them fueled by bad information or health inequalities, or a combination of both. A disease that we could eradicate is instead killing thousands, and the fight against it is taking more than just immunizing. It’s taking educating and fighting the spectre of misinformation that is being spread at the speed of light through social media and the internet.
Will we still be writing about measles in present-day terms one hundred years from now? The odds are we will… Measles outbreaks are turning out to be caused as much by the human condition as by the virus’ characteristics themselves.
Measles Leaves the Immune System Vulnerable to Other Diseases
Oct 31, 2019
C hildren who survive measles are protected against future measles infections, but have such diminished immunity that they may be left vulnerable to other pathogens, according to a pair of research papers in Science and Science Immunology today (October 31). The studies, which examined blood from unvaccinated children, show that the virus decimates the body’s repertoire of pathogen-specific immunological weapons.
“These [papers] really advance our understanding of the impact of measles virus on the immune system and consequently the potential for increased susceptibility to other infectious diseases,” says epidemiologist William Moss of the Johns Hopkins Bloomberg School of Public Health who was not involved in either study. They suggest, he continues, “that we may have been underestimating the impact of the measles vaccine on global child mortality.”
“They are clearly very important papers, particularly at this time when there is, in some quarters, so much anti-vaccine sentiment,” says immunologist Dan Littman of New York University who also did not participate in the research. They provide “real evidence-based data to argue for the importance of vaccination,” he adds. “Not that us immunologists needed any convincing.”
After measles infection, the children lost 11–73 percent of their antibody repertoire, meaning their immunological memories of previously encountered pathogens would be impaired.
Generally speaking, the measles virus causes a short-lived illness characterized by fever, fatigue, and a distinctive rash. In some cases, however, the virus, which attacks immune cells, leads to serious complications and even death. Before the measles vaccine was available, almost every child experienced an infection with this highly contagious virus. Since the vaccine’s introduction in 1963, there has been a steadily diminishing number of measles cases worldwide and, as a result, tens of millions of lives have been saved.
Since 2018, this downward trend has reversed. Largely because of reduced numbers of vaccinations, there has been almost three times as many cases reported worldwide in 2019 as there were last year.
The reversal is particularly concerning because the vaccine is thought to protect children from more than just measles, says epidemiologist Michael Mina of the Harvard TH Chan School of Public Health who is a coauthor of the Science paper. In the 1960s and ‘70s, “every time the vaccine was rolled out in a new region, childhood mortality would plummet” beyond what could be explained by preventing measles alone, he says.
One theory behind the unexpectedly large drops in mortality was that the vaccine prompted a general boost to the immune system. Population studies of measles epidemics, however, revealed that in the months and even years following outbreaks, the numbers of deaths caused by other infectious agents also increased. This suggested that measles made sufferers susceptible to other deadly infections, and therefore that, by preventing measles, the vaccine also prevented such weakening of the immune system. While this epidemiological evidence was strong, says Mina, “we really needed some biological data to back it up.”
To that end, Mina and colleagues examined blood samples collected from 77 unvaccinated children—members of religious communities who choose to forgo vaccinations—before and after natural measles infections. The team also studied samples from a further five unvaccinated children who did not catch the virus as well as 59 age-matched, vaccinated controls.
The blood was analyzed using a tool called VirScan, which detects the presence of antibodies against thousands of epitopes representing more than 400 viral and bacterial human pathogens. The assay revealed that, after a measles infection, the diversity of a person’s antibodies dwindles.
“Some of these effects were drastic,” says Stephen Elledge, a geneticist at Harvard Medical School and coauthor of the Science paper. Indeed, the children lost between 11 percent and 73 percent of their antibody repertoire, meaning their immunological memories of previously encountered pathogens would be impaired. No such loss was seen in the unvaccinated children who did not suffer measles infection or the vaccinated controls. The researchers also observed a similar loss in antibody diversity in unvaccinated macaque monkeys infected with the measles virus.
In the Science Immunology paper, immunogeneticist Velislava Petrova of the Wellcome Sanger Institute and colleagues examined B cell receptor sequences in the same blood samples. B cell receptors are essentially non-secreted versions of antibodies that reside in B cell membranes. The team found that, as with the antibodies, there was a dramatic loss of prior antigen-specific B cell receptor sequences as a result of measles infection.
Petrova’s group also looked at the effect of infection with a measles-like virus in ferrets. They showed that resistance to the flu, provided by vaccination, was lost in some of the ferrets as a result of the measles-like infection.
“From two independent studies, we show a very similar general picture about how important it is to vaccinate against measles,” Velislava says.
Elledge agrees. People use seatbelts to prevent serious injuries in car accidents, he says, and these studies show that “measles is like an accident to your immune system.” The vaccine is “like a seatbelt,” he says, and people should “buckle up.”
M.J. Mina et al., “Measles virus infection diminishes preexisting antibodies that offer protection from other pathogens,” Science, 366:599–606, 2019.
V. N. Petrova et al., “Incomplete genetic reconstitution of B cell pools contributes to prolonged immunosuppression after measles,” Sci Immunol, 4:eaay6125, 2019.
How The Measles Virus Became A Master of Contagion
Here are two recent stories about viruses. They started out alike, and ended up very differently.
In October, a woman in Guinea died of Ebola, leaving behind two daughters, one of them two years old, the other five. A relative named Aminata Gueye Tamboura took the orphaned children back to her home in northwest Mali–a 700-mile journey. Tamboura didn’t know it then, but the younger girl, named Fanta Conde, was infected with Ebola as well. For three days, they traveled on buses and in taxis as Fanta grew ill, developing a scorching fever and a perpetual nosebleed. Soon after arriving in Mali, she died.
Yet Tamboura never became infected with Ebola. Nor did Fanta’s sister or her uncle, who also made the trip. Nor did anyone else who shared the buses and taxis with Fanta, or who encountered Fanta elsewhere on her doomed journey. After Fanta’s death, the entire country of Mali braced for a devastating outbreak. But the outbreak never came.
The other story began in December. Someone–we don’t know who–paid a visit to Disneyland in California. That person, who we’ll call Patient Zero, was infected with the measles virus. But Patient Zero probably didn’t realize that he or she was incubating it, because the obvious symptoms, such as a rash and a high fever, wouldn’t emerge for several days. Strolling around Disneyland, Patient Zero cast off the measles virus in all directions, infecting dozens of people. Those people later developed measles, and may have spread the virus to others. By the end of January, the Disneyland outbreak had reached 94 cases, and that number is certain to rise higher.
These two stories show just how different viruses can be. For all the fear that Ebola can inspire, it’s a pretty bad transmitter. Measles, on the other hand, is among the most contagious viruses on Earth. There’s no single secret to measles’s power of contagion. Its adaptations for spreading are sprinkled across its whole life cycle.
While the biology of measles has only come into focus in the past few years, physicians have long been aware of its contagiousness. In 1846, a Danish doctor named Peter Panum recorded the first detailed account of a measles outbreak during his stay on the Faroe Islands, located between Scotland and Iceland. The disease leaped from one village to another. Out of the blue, someone would develop a blotchy pink rash that would spread across the entire body. A fever would ignite. “The patients were bathed in perspiration,” Panum wrote, “and, when the bedding was raised or the shin exposed, vapors literally rose from them like clouds.”
Because the Faroe Islands were so remote, Panum had an easy time observing the disease spread from person to person. He developed an eerie power of prediction. If one person developed a rash from measles, Panum knew that everyone else in the patient’s house would get sick two weeks later.
Panum noticed other predictable patterns, too. On average, he estimated, every infected person infected seven to nine other people. Today, the estimate for the average number of infections spread from each sick person is higher–between 12 and 18. By comparison, the figure for Ebola is only about two.
What made Panum’s observations all the more impressive is that he made them without knowing what was causing the measles outbreak. Scientists would not come to understand the nature of viruses for another five decades. The measles virus itself would not be discovered till in 1954, over a century after Panum’s stay on the Faroe Islands.
For the past five decades, scientists have been studying the measles virus, and yet many details of its life cycle are only now coming to light. As a virus, it has to do three things in order to avoid extinction: it has to invade a new host, make copies of itself, and get those copies to another host. At every step of the way, scientists are finding, the measles virus cranks up its chances of successful spread.
People get infected with measles viruses by breathing them into their lungs. The lining of the lungs contains immune cells that destroy incoming invaders and kill off infected cells. The measles virus boldly attacks these very sentinels. It uses a molecular key to open a passage into the immune cells. Once inside, it starts making new viruses that infect other immune cells. The virus-laden cells then creep from the windpipe to the lymph nodes, which are crowded with still more immune cells. It’s like a walk in Disneyland, except inside a person’s body. From the lymph nodes, infected immune cells spread the virus throughout the body. If the virus manages to slip into the nervous system, it can cause permanent brain damage.
After several days of multiplying, the virus starts making preparations to leave its host. Some of the infected immune cells creep up into the nose. The interior lining of the nose is made up of sheets of epithelial cells. The immune cells nuzzle up to the epithelial cells. A protein on their surface, made by the viruses, fuses them to the epithelial cells, allowing the virus to cross over. Now the measles virus is another step closer to leaving its host and finding a new one.
Each infected epithelial cell start making huge numbers of new measles viruses, which it dumps out into the nasal cavity, where they can get exhaled. Meanwhile, the infection also damages the upper airway, causing infected cells to rip free and get coughed out of the body.
People sick with measles release clouds of virus-laden droplets. The big droplets fall quickly to the ground or other surfaces, where they can stay infectious for hours. The small droplets meanwhile rise into the air, where they are lofted by currents and can deliver measles to people far away.
The sheer number of viruses produced by each sick person, along with the adaptations the viruses have for penetrating deep into the airway, make them tremendously contagious. If someone gets sick with measles, up to ninety percent of people in the same home who aren’t already immune will get sick, too. And because infected people can transmit the virus for days before symptoms emerge, the virus can spread to many homes before anyone realizes an outbreak is underway.
The late-arriving symptoms of measles are the outward sign that people’s immune systems are starting to fight the virus. Much of the battle takes place between uninfected immune cells and infected ones. The fight decimates the immune system. Even after people have conquered a measles infection, it can take weeks for their immune system to get back to full strength.
In this fragile state, people become vulnerable to other diseases such as pneumonia. The danger posed by these infections depends on how much care patients can get. In industrialized countries, only a tenth of 1 percent of people who get measles die. In developing countries, the rate is 5 to 10 percent. In refugee camps, the figure can be as high as 25 percent.
While people cope with these post-infection troubles, the virus has moved on to its next hosts. The contagion of measles is part of a “one-and-done” strategy that the viruses have evolved. After people recover from measles infections, their immune systems will protect them for life. As a result, the virus needs to be highly contagious for its long-term survival.
This strategy also means that measles vaccines can be extremely effective. By teaching people’s immune systems what the measles virus looks like, vaccines provide protection for life.
All these features of the measles virus add up to a startling paradox. Despite being far more contagious than the Ebola virus, the measles virus is a far better candidate for complete eradication from the face of the Earth.
Ebola viruses mainly circulate between animals (scientists suspect bats are their normal host). Every few years, they get into humans and cause an outbreak. Bringing Ebola outbreaks to a halt doesn’t mean that the virus has become extinct. It just means that it has retreated back to its regular host.
Measles, on the other hand, only infects humans. If we could make our species measles-free, that would mean the virus had become extinct, never to return. And the life cycle of measles actually makes it possible to block its transmission from person to person. It’s very rare for infections to last more than a couple weeks, so that there isn’t the risk of people surreptitiously spreading the disease for years. People who do get sick won’t get sick again, taking them out of the pool of potential hosts. And we are fortunate to have a safe, effective way to break measles transmission: a vaccine.
While the eradication of measles is possible, that doesn’t mean it will be easy. It requires long-term commitment from the entire world. If a country immunizes less than 95 percent of its population, the virus can still spread efficiently from person to person.
Despite these challenge, the world has made giant advances against measles in the past few decades. Before the development of measles vaccines in the early 1960s, 7 to 8 million children died around the world every year. In 2014, that figure was down to 145,000 deaths. The World Health Organization estimates that between 2000 and 2013, measles vaccination prevented 15.6 million deaths. In the coming decade, new vaccination campaigns may drive down deaths from measles even more.
But the Disneyland outbreak demonstrates just how quickly the measles virus can undo years of public health efforts. By 2000, the United States had reduced measles to the point that it could no longer circulate on its own inside the country. A few cases cropped up each year, imported by people traveling from other countries where measles is still a problem. But in recent years measles cases have bounced back–helped by a growing number of unvaccinated people.
The rate of measles vaccination is slipping year after year. In Arizona charter schools, 9 percent of kindergarteners have been exempted from vaccination. People who don’t vaccinate their children tend to live close by each other, creating pockets of vulnerability where measles outbreaks can endure, as the virus finds one host after another. The vulnerable also include children who are either too young or too sick with other diseases to get a vaccine.
It’s possible that the Disneyland outbreak will mark a turning point–a recognition that vaccination is a social contract we make to each other, so that we don’t allow the virus to infect our fellow citizens. Perhaps we will someday even eradicate measles from the face of the Earth. That will unquestionably be a boon for humanity. But it’s also possible that it could open the way to a new disease.
That’s because the measles virus has cousins.
Measles belongs to a cluster of viruses called morbilliviruses. They infect a wide range of animals, from whales to wildebeest, from pandas to primates. It appears that morbilliviruses use the same strategy as measles–coming in through immune cells and going out through epithelial cells. And they’re also just as contagious. Some studies suggest that measles started out several thousand years ago as one of these wild morbilliviruses. According to one theory, after we domesticated cattle, a cow morbillivirus jumped into humans. As human populations grew dense, the new measles virus found a comfortable new home.
Scientists have documented virtually no cases of morbilliviruses spreading from animals to humans. Given the staggering contagiousness of morbilliviruses, that’s pretty amazing. It’s possible that our immunity to measles also protects us from other morbilliviruses. These animal viruses may sometimes make incursions into our species, but the conditions are so harsh that they never have time to adapt to our biology.
If that’s true, it’s possible that the eradication of measles would open up a new ecological niche that another animal morbillivirus could invade. This possibility doesn’t mean that we should stop fighting measles. Instead, we should broaden our efforts. Even as we eradicate measles, we should become better acquainted with related viruses and prepare for the possibility that they may become new threats. With the lessons we learn from eradicating measles, we can be ready to battle the next master of contagion.
For more information about viruses, see my book A Planet of Viruses.
Thanks to Paul Duprex of Boston University for images and fact-checking.
How measles wipes out the body's immune memory
Over the last decade, evidence has mounted that the measles vaccine protects in not one but two ways: Not only does it prevent the well-known acute illness with spots and fever that frequently sends children to the hospital, but it also appears to protect from other infections over the long term.
How does this work?
Some researchers have suggested that the vaccine gives a general boost to the immune system.
Others have hypothesized that the vaccine's extended protective effects stem from preventing measles infection itself. According to this theory, the virus can impair the body's immune memory, causing so-called immune amnesia. By protecting against measles infection, the vaccine prevents the body from losing or "forgetting" its immune memory and preserves its resistance to other infections.
Past research hinted at the effects of immune amnesia, showing that immune suppression following measles infection could last as long as two to three years.
However, many scientists still debate which hypothesis is correct. Among the critical questions are: If immune amnesia is real, how exactly does it happen, and how severe is it?
Now, a study from an international team of researchers led by investigators at Harvard Medical School, Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health provides much-needed answers.
Reporting Oct. 31 in Science, the researchers show that the measles virus wipes out 11 percent to 73 percent of the different antibodies that protect against viral and bacterial strains a person was previously immune to -- anything from influenza to herpesvirus to bacteria that cause pneumonia and skin infections.
So, if a person had 100 different antibodies against chicken pox before contracting measles, they might emerge from having measles with only 50, cutting their chicken pox protection in half. That protection could dip even lower if some of the antibodies lost are potent defenses known as neutralizing antibodies.
"Imagine that your immunity against pathogens is like carrying around a book of photographs of criminals, and someone punched a bunch of holes in it," said the study's first author, Michael Mina, a postdoctoral researcher in the laboratory of Stephen Elledge at Harvard Medical School and Brigham and Women's Hospital at the time of the study, now an assistant professor of epidemiology at the Harvard T.H. Chan School of Public Health.
"It would then be much harder to recognize that criminal if you saw them, especially if the holes are punched over important features for recognition, like the eyes or mouth," said Mina.
The study is the first to measure the immune damage caused by the virus and underscores the value of preventing measles infection through vaccination, the authors said.
"The threat measles poses to people is much greater than we previously imagined," said senior author Stephen Elledge, the Gregor Mendel Professor of Genetics and of Medicine in the Blavatnik Institute at Harvard Medical School and Brigham and Women's Hospital. "We now understand the mechanism is a prolonged danger due to erasure of the immune memory, demonstrating that the measles vaccine is of even greater benefit than we knew."
The discovery that measles depletes people's antibody repertoires, partially obliterating immune memory to most previously encountered pathogens, supports the immune amnesia hypothesis.
"This is the best evidence yet that immune amnesia exists and impacts our bona fide long-term immune memory," added Mina, who first discovered the epidemiological effects of measles on long-term childhood mortality in a 2015 paper.
The team's current work was published simultaneously with a paper by a separate team in Science Immunology that reached complementary conclusions by measuring changes in B cells caused by the measles virus. An accompanying editorial in Science Immunology, written by Duane Wesemann, Harvard Medical School assistant professor of medicine at Brigham and Women's Hospital, contextualizes that study.
Elledge, Mina and colleagues found that those who survive measles gradually regain their previous immunity to other viruses and bacteria as they get re-exposed to them. But because this process may take months to years, people remain vulnerable in the meantime to serious complications of those infections.
In light of this finding, the researchers say clinicians may want to consider strengthening the immunity of patients recovering from measles infection with a round of booster shots of all previous routine vaccines, such as hepatitis and polio.
"Revaccination following measles could help to mitigate long-term suffering that might stem from immune amnesia and the increased susceptibility to other infections," the authors said.
Two steps forward, one step back
One of the most contagious diseases known to humankind, measles killed an average of 2.6 million people each year before a vaccine was developed, according to the World Health Organization. Widespread vaccination has slashed the death toll.
However, lack of access to vaccination and refusal to get vaccinated means measles still infects more than 7 million people and kills more than 100,000 each year worldwide, reports the WHO -- and cases are on the rise, tripling in early 2019. About 20 percent of people in the U.S. who get infected with measles require hospitalization, according to the CDC, and some experience well-known long-term consequences, including brain damage and vision and hearing loss.
Previous epidemiological research into immune amnesia suggests that death rates attributed to measles could be even higher -- accounting for as much as 50 percent of all childhood mortality -- if researchers factored in deaths caused by infections resulting from measles' ravaging effects on immunity.
Answers in the blood
This new discovery was made possible thanks to VirScan, a tool Elledge and Tomasz Kula, a PhD student in the Elledge Lab, developed in 2015.
VirScan detects antiviral and antibacterial antibodies in the blood that result from current or past encounters with viruses and bacteria, giving an overall snapshot of the immune system.
Study co-author Rik de Swart had gathered blood samples from unvaccinated children during a 2013 measles outbreak in the Netherlands. For the new study, Elledge's group used VirScan to measure antibodies before and two months after infection in 77 children from de Swart's samples who'd contracted the disease. The researchers also compared the measurements to those of 115 uninfected children and adults.
When Kula examined an initial set of these samples, he found a striking drop in antibodies from other pathogens in the measles-infected children that "clearly suggested a direct effect on the immune system," the authors said.
The effect resembled what Mina had hypothesized could drive measles-induced immune amnesia.
"This proved to be the first definitive evidence that measles affects the levels of protective antibodies themselves, providing a mechanism supporting immune amnesia," said Elledge.
Then, in collaboration with Diane Griffin at Johns Hopkins Bloomberg School of Public Health, the team measured antibodies in four rhesus macaques -- monkeys closely related to humans -- before and five months after measles infection. This covered a much longer period post-infection than what was available in the Netherlands samples.
Similar to the findings in people, the macaques lost an average of 40 to 60 percent of their preexisting antibodies to the viruses and bacteria they had been previously exposed to.
Further tests revealed that severe measles infection reduced people's overall immunity more than mild infection. This could be particularly problematic for certain categories of children and adults, the researchers said.
The authors stress that the effects observed in the current study occurred in previously healthy children. Because measles is known to hit malnourished children much harder, the degree of immune amnesia and its effects could be even more severe in less healthy populations.
"The average kid might emerge from measles with a dent in their immune system and their body will be able to handle that," said Elledge. "But kids on the edge -- such as those with severe measles infection or immune deficiencies or those who are malnourished -- will be in serious trouble."
Inoculation with the MMR (measles, mumps, rubella) vaccine did not impair children's overall immunity, the researchers found. The results align with decades of research.
Ensuring widespread vaccination against measles would not only help prevent the 120,000 deaths that will be directly attributed to measles this year alone but could also avert potentially hundreds of thousands of additional deaths attributable to the lasting damage to the immune system, the authors said.
"This drives home the importance of understanding and preventing the long-term effects of measles, including stealth effects that have flown under the radar of doctors and parents," said Mina. "If your child gets the measles and then gets pneumonia two years later, you wouldn't necessarily tie the two together. The symptoms of measles itself may be only the tip of the iceberg."
Funding and authorship
Yumei Leng and Mamie Li of the Elledge Lab are co-authors of the study. Additional authors are affiliated with the University Medical Centre Rotterdam, University of Helsinki, Helsinki University Hospital, University of Colorado School of Medicine, Genentech, Johns Hopkins University School of Medicine and Duke University Medical Center.
This study was supported by the Value of Vaccination Research Network, Gates Foundation, National Institutes of Health (grants U24AI118633, R01DK032493, R21AI095981 and R01AI131228), European Union Seventh Framework Programme (grant 202063), Academy of Finland (grant 250114) and PREPARE Europe (EU FP7 grant 602525). Elledge is an investigator of the Howard Hughes Medical Institute.
New research underscores the importance of the measles vaccine
Credit: CC0 Public Domain
As vaccines for COVID-19 begin to be distributed across the globe this week, new research from Western University underscores the importance of vaccination against the measles virus, another pathogen that has caused numerous outbreaks in the recent past as well. Researchers have shown that the measles virus can infect and destroy innate-like T lymphocytes, potentially compromising the body's ability to fight other infections.
Mansour Haeryfar and his team at Western's Schulich School of Medicine & Dentistry have shown that the measles virus can kill an abundant type of white blood cells known as Mucosa-associated invariant T cells (MAIT cells), which are responsible for mounting broad defense against a range of infections.
"It was already well known that the measles virus causes immunosuppression by infecting our memory cells," said Haeryfar. "What we found through our work is that the measles virus also infects and kills MAIT cells. These immune cells are known to participate in innate immunity, which is the body's nonspecific defense against a wide range of bacteria, fungi and viruses."
When a microbe infects your body, your immune system launches an attack. After you recover, specific immune cells called 'memory cells' are able to remember that encounter so they can launch a quicker, more deadly attack next time.
This is what is known as immunological memory. These memory cells can also be generated through vaccination.
Now, imagine an event that hits the reset button on all your past immunity by wiping out these memory cells.
Past research has shown that's exactly what the measles virus does through a phenomenon known as 'immune amnesia.' Haeryfar says many deaths from measles are actually due to secondary infections because of this state of immunosuppression.
For the first time, Haeryfar and his team have shown that the measles virus also infects MAIT cells. The loss of these white blood cells likely contributes to immunosuppression caused by the measles virus and increases a person's susceptibility to other infections. Their findings were published in in The Journal of Infectious Diseases.
"Our findings suggest that the drastic loss of MAIT cells during measles infection contributes to a person's inability to properly control subsequent infections, revealing a new mechanism of measles-induced immunosuppression," said Patrick Rudak, Ph.D. Candidate in Haeryfar's lab at Schulich Medicine & Dentistry and first author on the study. "To our knowledge, our study is the first to demonstrate that MAIT cells can be killed by direct infection with a virus, uncovering a previously undescribed aspect of MAIT cell biology."
The team demonstrated that MAIT cells were noticeably more susceptible to a measles infection than conventional memory cells.
Using this work as a jumping-off point, Haeryfar has put forward a theory, published today in the journal PLOS Pathogens, which he calls 'Innate Immune Amnesia'. This theory explains how a shortage of MAIT cells may make measles patients so susceptible to unrelated infections.
"MAIT cells may be considered the missing link for measles immunosuppression at the interface between the innate and adaptive arms of immunity," he writes in the theoretical paper.
As the COVID-19 pandemic continues across the globe, never before has an entire population been so focused on how viruses infect our body and our immune response. In the wake of the pandemic, the researchers say this work provides yet another strong case for the importance of vaccination against viral diseases like the measles.
"Through the measles vaccination, you not only protect yourself and your community against this virus but also ensure continued immunity to a wide range of other microbes," said Haeryfar.
Patrick T Rudak et al. Measles Virus Infects and Programs MAIT Cells for Apoptosis, The Journal of Infectious Diseases (2020). DOI: 10.1093/infdis/jiaa407