Mayo Clinic researchers mapped how the measles virus mutated and spread in the brain of a person who succumbed to a rare, lethal brain disease. New cases of this disease, which is a complication of the measles virus, may occur as measles re-emerges among the unvaccinated, say researchers.
Using the latest tools in genetic sequencing, researchers at Mayo Clinic reconstructed how a collective of viral genomes colonised a human brain.
The virus acquired distinct mutations that drove the spread of the virus from the frontal cortex outward.
The highly contagious measles virus infects the upper respiratory tract where it uses the trachea as a trampoline to launch and spread through droplets dispersed when an infected person coughs or sneezes.
Dr Cattaneo pioneered studies on how the measles virus spreads throughout the body. He first began to study the measles virus about 40 years ago and was fascinated by the rare, lethal brain disease called subacute sclerosing panencephalitis (SSPE), which occurs in about 1 in every 10 000 measles cases.
It can take about five to 10 years after the initial infection for the measles virus to mutate and spread throughout the brain.
Symptoms of this progressive neurological disease include memory loss, seizures and immobility.
Dr. Cattaneo studied SSPE for several years until the lethal disease nearly disappeared as more people were vaccinated against measles. But now, measles is resurging due to vaccine hesitancy and missed vaccinations.
During the COVID pandemic, millions of children missed receiving their measles vaccinations, which has resulted in an estimated 18% increase in measles cases and 43% increase in death from measles in 2021 compared to 2022 worldwide, according to a recent Centers for Disease Control and Prevention (CDC) report.
“We suspect SSPE cases will rise again as well. This is sad because this horrible disease can be prevented by vaccination. But now we are in the position to study SSPE with modern, genetic sequencing technology and learn more about it,” says Iris Yousaf, co-lead author of the study and a fifth-year Ph.D. candidate at Mayo Clinic Graduate School of Biomedical Sciences.
Dr Cattaneo and Yousaf had a unique research opportunity through a collaboration with the CDC. They studied the brain of a person who had contracted measles as a child and had succumbed to SSPE years later as an adult.
They investigated 15 specimens from different regions of the brain and conducted genetic sequencing on each region to piece together the puzzle of how the measles virus mutated and spread.
The researchers discovered that, after the measles virus entered the brain, its genome began to mutate in harmful ways over successive generations, creating a population of varied genomes.
“In this population, two specific genomes had a combination of characteristics that worked together to promote virus spread from the initial location of the infection – the frontal cortex of the brain – out to colonise the entire organ,” says Dr Cattaneo.
The next steps in this research are to understand how specific mutations favour virus spread in the brain. These studies will be done in cultivated brain cells brain organoids. This knowledge may help in creating effective antiviral drugs to combat virus spread in the brain. However, pharmacological intervention in advanced disease stages is challenging, and preventing SSPE through measles vaccination remains the best method.
While grandmothers today have a popular image of spoiling their grandchildren with treats, in premodern times they also acted as healthcare providers. To find out more, University of Turku researchers looked at historical data on childhood mortality from infectious diseases in the 18th and 19th century in Finland. The study, which is published in the journal Proceedings of the Royal Society B, found that grandmothers decreased all-cause and cause-specific mortality of children.
In historical and in several contemporary societies, children with living grandmothers are more likely to survive into adulthood, but the mechanism behind this effect remains poorly known.
As childhood infections have been a leading cause of death in children under the age of 5 years, the researchers aimed to investigate whether the effect of grandmothers on childhood survival was related to providing knowledge in childcare, particularly during critical times such as epidemics. One way for grandmothers to do so could be by encouraging vaccine uptake or earlier vaccination against childhood infections, as has been observed in some contemporary populations.
Researchers first studied the effects of grandmothers on children’s cause-specific mortality, using historical records of five causes of death: smallpox, measles, pulmonary infections, diarrhoeal deaths, and accidents. The large multigenerational dataset of pre-industrial Finnish families included 9705 individuals from 12 parishes across Finland, where the survival of individuals until the of age 15 years was monitored from 1761 to 1900. In the second part of the study, the researchers determined whether increased survival against the childhood infection smallpox was mediated by vaccination. To this end, they used 1594 vaccination records from two rural parishes and matched them to their individual family histories.
The results show that grandmothers decreased all-cause mortality, an effect which was mediated through improved survival from smallpox, pulmonary and diarrhoeal infections, but not from measles or accidents. However, the researchers found no evidence of increased or earlier vaccination between children with or without grandmothers.
“Our results show that the grandmother’s presence protected against some childhood infections, which could indicate that in historical Finnish society, the assistance provided by grandmothers in childcare was likely an important factor in ensuring the survival of children,” says study lead author, Doctoral Researcher Susanna Ukonaho.
Grandmothers in contemporary societies
Although grandmother care provided health benefits in many historical societies, these benefits may no longer be relevant in contemporary societies. The progress in healthcare during the 20th century especially in high-income countries likely decreased the role of grandmothers. However, some studies indicate that grandmothers improve childhood survival in several contemporary middle- and low-income countries.
“The type of benefits that grandmothers provide may vary depending on cultural contexts and individual circumstances. Even though in many societies grandmothers are no longer essential for childhood survival, their efforts in childcare remain valuable for the well-being of the whole family,” says Ukonaho.
In October last year, the National Institute for Communicable Diseases (NICD) alerted the public to a measles outbreak in Limpopo. Since then, four more provinces have reported outbreaks, and the number of positive cases in the country has climbed rapidly.
Last week’s measles report from the NICD indicated that between the first week of October 2022 and mid-week in the second week of January 2023, a total of 397 cases of measles were identified across the country. Of those, 382 cases were detected in five provinces – Limpopo 145, North West 125, Mpumalanga 79, Gauteng 18, and the Free State 15. These five provinces have all met the criteria for a measles outbreak (three or more cases in a district within a month).
The remaining 15 cases are spread around KwaZulu-Natal, Northern Cape, the Eastern Cape, and the Western Cape – none of which have so far met the criteria for an outbreak.
‘Biggest outbreak in 11 years’
Dr Kerrigan McCarthy, a pathologist from the Centre for Vaccines and Immunology at the NICD, tells Spotlight that this is the biggest outbreak in 11 years, surpassing the outbreak in 2017 when around 280 cases of measles were identified.
According to the NICD report, the total number of laboratory-confirmed measles cases and the total number of samples submitted for testing has decreased for the third consecutive week. However, McCarthy cautions that this apparent decline might actually be due to a decrease in the number of specimens sent to the NICD for testing, and not to the outbreak actually slowing down.
“The fact that we have seen a decrease in the number of positive cases could be attributed to the decrease in number of specimens that have been submitted, but there is a small possibility that it could represent a turnaround in the outbreak. However, a consensus amongst us in public health is that it is the former problem,” says McCarthy.
She adds that the true extent of this outbreak – and whether new cases have really declined or not – may only become clear in the next few weeks, as schools across the country resume activities.
While it isn’t possible to predict exactly where the outbreak is going, McCarthy says at the moment it is following a similar trend to the widespread measles outbreak that occurred just over a decade ago. “In 2009 to 2011 we had an outbreak of over 22 000 measles cases… and in fact, in that outbreak, we saw a similar pattern. The outbreak was declared in late 2009 and cases started increasing into December and then when the schools closed and December holidays happened, there was a lull in cases and then when the schools returned there was a massive increase in cases,” she says.
Fears of much larger outbreaks
In a Spotlight article published in July last year, Dr Haroon Saloojee, Professor and Head of the Division of Community Paediatrics at the University of the Witwatersrand, and other experts warned that low vaccination rates may lead to measles outbreaks of the type we are now seeing. Now they are concerned that things might get worse.
Saloojee agrees that it isn’t possible to predict exactly how this outbreak will behave. “There are obviously three possible outcomes,” he says, “An increase, levelling off, or decline. My fear and expectation [are] that the outbreak will continue to expand. There are more than a million unvaccinated children under five, and possibly about 2.5 million unvaccinated under 15 years.
“We should be greatly concerned. It is highly likely that the outbreak will extend beyond the five provinces and affect all provinces in the country,” he says.
He adds that children are protected from measles through vaccination and if 95% of children are vaccinated against measles, then this herd immunity will protect the 5% who are not vaccinated. But in South Africa, measles coverage is not at 95%.
“In South Africa, at best, about 80% of children are vaccinated [against measles]. The proportion is lower in some provinces. Thus, all children, but particularly unvaccinated children, are at risk of acquiring measles,” he says. “We haven’t had a serious problem [with] measles in South Africa for at least the last 20 years. But in other low- and middle-income countries, it is still one of the five major causes of child mortality.”
Mass measles immunisation campaign needed
Saloojee tells Spotlight the only way to curtail the outbreak at this point is through a national supplementary mass measles immunisation campaign.
“There is only one option at this stage, as we are facing a crisis. A national supplementary immunisation campaign is warranted, despite its high cost and resource demands,” he says. “Such activities have already commenced in the affected provinces and will be extended to other provinces if the outbreak continues to spread. The aim of the campaign is to boost measles vaccine coverage to the 95% mark in the short term, so that herd immunity can kick in.”
How did we get here?
While such an immunisation campaign should help mitigate the current spread of measles, the question remains how a widespread outbreak could occur in the first place given South Africa’s well-established childhood immunisation programme.
“The outbreak was entirely predictable and preventable,” says Saloojee. “We have had similar outbreaks [about] every five years since 2000. Paradoxically, COVID delayed this outbreak, which should have happened in 2020 because the isolation measures protected against measles spread too.”
“However, we cannot run away from the fact that too few children receive all their routine vaccinations, and there is little being done to systematically change this such as stopping vaccine stockouts, and clinics and hospitals reducing missed opportunities to vaccinate eligible children,” he says. “If nothing is done, we can count on another outbreak in 2028.”
Countries across the world are reporting measles outbreaks, according to the CDC, which is being attributed to a disruption in services like routine immunisation because of the COVID pandemic. However, according to Saloojee, South Africa’s outbreak cannot be attributed exclusively to the pandemic disrupting services, instead, it is also due to years of suboptimal measles vaccine coverage.
Spotlight previously reported in-depth on results from the 2019 Expanded Programme on Immunisation (EPI) National Coverage survey, which showed that only around 77% (76.8%) of the children surveyed had received all fourteen age-appropriate vaccines from birth to 18 months. This includes the two doses of the measles vaccine.
Dr Lesley Bamford, a child health specialist in youth and school health at the National Department of Health, provided Spotlight with a table showing measles vaccination coverage per province between 2017 and 2022.
Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health
According to the figures provided by Bamford, national coverage for the first dose of the measles vaccine has improved from 80% in 2017-2018 to 88% in 2021-2022. However, coverage for the second measles dose remained stuck in a narrow band from 77% to 80%, until 2021-2022, when it improved to 84% – still well below the 95% coverage required for herd immunity.
Expanded vaccination campaign
The NICD report shows the highest number of measles cases so far have been in the five to nine-year age group, which represents 40% of cases. 29% of cases were in the one to four age group and 17% in the 10 to 14-year age group. The remaining cases occurred in children younger than one year and those aged 15 and older.
According to McCarthy, based on the distribution of cases in these age groups, the NICD recommended to the National Department of Health that it extend its planned mass measles vaccination campaign to include children between six months and 15 years of age – which the Department has agreed to do.
Bamford tells Spotlight that a mass measles immunisation campaign had already been planned across all provinces for February 2023. But for the five provinces experiencing outbreaks, the timeline has since moved up. The four remaining provinces will still start their campaigns in February as planned.
“The target age group for that campaign has been extended. So, the initial plan was targeting children under 5 years of age and now in most provinces, it has been extended to include all children six months to 15 years of age,” she says.
Spokesperson for the National Department of Health, Foster Mohale confirms that all children between the ages of six months and 15 years, regardless of documentation, are eligible to receive their measles vaccination in the catch-up drive. “Most provinces have been vaccinating all children between 6 months and 15 years, with [or] without documents because diseases have no discrimination. So, we haven’t received any concern or report about non-vaccination of children without documentation,” he says.
Bamford adds that a measles incident management team has been established by the National Department of Health, which meets with the NICD and the provinces on a weekly basis.
She says Limpopo started its campaign in November, Mpumalanga and North West started in December, and Gauteng and the Free State started in January. The campaigns have so far been conducted mainly at primary healthcare clinics and outreach to ECD centres but now that the school year has resumed, children will also be vaccinated at schools.
Because the provinces all started at different times, there is no specific timeline for the vaccination campaign to be completed, according to Bamford, but the expectation from the National Department is that all provinces will wrap up their campaigns by mid-February when the HPV vaccination campaign kicks off.
“We know that measles coverage is suboptimal, and that is why we were planning to run a campaign, but of course, that is the single biggest reason why we are now experiencing these outbreaks,” she says. “The only way really to stop measles outbreaks is to improve immunisation coverage.”
Over the festive season, the South African measles outbreak has now extended to five provinces, including Gauteng as of epidemiological week (epiweek) 51, the National Institute for Communicable Diseases (NICD) has reported.
From samples collected in epiweek 40 (end 8 Oct 2022) to epiweek 51 (end 24 Dec 2022), a total of 297 cases of laboratory-confirmed measles cases have been reported in South Africa. From epiweek 40 to mid-week 51, 2022, a total of 285 laboratory-confirmed cases were reported from five provinces with declared measles outbreaks in Limpopo (128 cases), Mpumalanga (68), North West (69), Gauteng (13), and Free State (7). The NICD classifies a measles outbreak as three or more confirmed laboratory measles cases reported within 30 days of disease onset, within a district.
The number of cases continues to increase daily as blood and throat swabs are submitted to the NICD for measles serology and PCR testing.
The age of laboratory-confirmed cases across the five provinces ranges from two months to 42 years. Of these, 41% were ages 5–9, followed by 28% for ages 1–4 and 15% for ages 10–14 . Vaccination status of 84 cases (29%) was known, of whom 33 (39%) were vaccinated.
Data on hospital admission rates and measles mortality rates are not yet known. Whilst cases that are seen at hospitals may not necessarily be admitted, this figure gives us an indication of the severity of illness, as patients consulted tertiary care facilities. The number of admitted patients will be a subset of these cases.
Since 11 October 2022, the National Institute for Communicable Diseases (NICD) seven measles cases have been detected in Greater Sekhukhune District in Limpopo province within 30 days, as of 21 October.
Infected individuals ranged from 9 months to 24 years. One child was fully vaccinated for measles, with two measles doses given in 2019. One child was unvaccinated, and the other five measles cases had unknown vaccination history. One measles case was hospitalised while one other had a complication that led to pneumonia.
District and provincial health officials have started a public health response. This includes enhanced surveillance for measles, contact tracing, screening for suspected cases using a case definition followed by collection of blood and throat swabs for measles diagnostic testing, and reviewing medical records to pick up missed cases. Vaccinations are underway for those exposed to suspected or confirmed cases.
The measles immunisation coverage data for the Greater Sekhukhune district showed a decrease of 87% to 64% for measles dose 1 and 86% to 60% for measles dose 2 from 2017 to 2022. This is below the 95% coverage needed to achieve herd immunity. A survey is being done to validate the vaccination data provided to the province and investigate factors that might be contributing to the measles outbreak. Community awareness and health promotion by healthcare workers is continuing in the district to inform the public about the spread of measles and interventions to prevent disease. Measles vaccination has been initiated for children under 15 years to increase the measles immunity in the community and to prevent further spread of measles.
Clinicians should continue to be on the alert for measles cases, especially in Limpopo Province, as large measles outbreaks are occurring in sub-Saharan Africa, including in neighbouring countries.
Signs and Symptoms
Measles is a highly contagious disease caused by a virus of the paromyxovirus family. Patients with measles present with fever and a rash. The rash looks like small, red, flat spots over the body. The rash does not form blisters, nor is it itchy or painful. Other signs include cough, conjunctivitis and coryza. Complications of measles can include diarrhoea, dehydration, encephalitis, blindness and death. Other measles complications are pneumonia, scarring of the cornea (kerato-conjunctivitis), and rarely encephalitis. Complications are more serious in very young children (under 2 years) or who are malnourished.
Clinicians and caregivers should check children’s road-to-health booklets to ensure measles vaccinations are up to date. Suspected measles cases should be notified on the NMC system. Click here to access the Case Notification form
An increase in measles cases in January and February 2022 is a worrying sign of a heightened risk for the spread of vaccine-preventable diseases and could trigger larger outbreaks, particularly of measles affecting millions of children in 2022, warn WHO and UNICEF.
The agencies warn that pandemic-related disruptions, widening vaccine access inequality, and the under-resourcing of routine immunisation are leaving too many children open to measles and other vaccine-preventable diseases.
The risk for large outbreaks has increased as communities relax social distancing practices and other anti-COVID measures. Additionally, the displacement of millions of people due to conflicts and crises including in Ukraine, Ethiopia, Somalia and Afghanistan, is causing disruptions in immunisation services, a lack of clean water and sanitation, and overcrowding, all of which increase the risk of vaccine-preventable disease outbreaks.
Almost 17 338 measles cases were reported worldwide in January and February 2022, compared to 9665 during the first two months of 2021. Measles is highly contagious, so cases tend to show up quickly when vaccinations decline. The agencies are concerned that outbreaks of measles could also forewarn outbreaks of other diseases that do not spread as rapidly.
Apart from its direct, sometimes lethal, effect on the body, the measles virus also weakens the immune system rendering a child more vulnerable for months after to other infectious diseases like pneumonia and diarrhoea. Most cases occur in settings that have faced social and economic hardships due to COVID, conflict or other crises, and have chronically weak health system infrastructure and insecurity.
“Measles is more than a dangerous and potentially deadly disease. It is also an early indication that there are gaps in our global immunization coverage, gaps vulnerable children cannot afford,” said Catherine Russell, UNICEF Executive Director. “It is encouraging that people in many communities are beginning to feel protected enough from COVID to return to more social activities. But doing so in places where children are not receiving routine vaccination creates the perfect storm for the spread of a disease like measles.”
In 2020, 23 million children missed out on basic childhood vaccines through routine health services, the highest number since 2009 and 3.7 million more than in 2019.
Top 5 countries with reported measles cases in the last 12 months, until April 2022 1
Country
Reported Measles cases
Rate per million cases
First dose measles coverage (%), 20192
First dose measles coverage (%), 20203
Somalia
9068
554
46
46
Yemen
3629
119
67
68
Afghanistan
3628
91
64
66
Nigeria
12 341
58
54
54
Ethiopia
3039
26
60
58
As of April 2022, the agencies report 21 large and disruptive measles outbreaks around the world in the last 12 months. Most of the measles cases were reported in Africa and the East Mediterranean region. The figures are likely higher as the pandemic has disrupted surveillance systems globally, with potential underreporting.
Countries with the largest measles outbreaks since the past year include Somalia, Yemen, Nigeria, Afghanistan and Ethiopia. Insufficient measles vaccine coverage is the major reason for outbreaks, wherever they occur.
“The COVID pandemic has interrupted immunisation services, health systems have been overwhelmed, and we are now seeing a resurgence of deadly diseases including measles. For many other diseases, the impact of these disruptions to immunisation services will be felt for decades to come,” said Dr Tedros Adhanom Ghebreyesus, Director-General of the World Health Organization. “Now is the moment to get essential immunisation back on track and launch catch-up campaigns so that everybody can have access to these life-saving vaccines.”
As of 1 April 2022, 57 vaccine-preventable disease campaigns in 43 countries that were scheduled to take place since the start of the pandemic are still postponed, impacting 203 million people, most of whom are children. Of these, 19 are measles campaigns, which put 73 million children at risk of measles due to missed vaccinations. In Ukraine, the measles catch-up campaign of 2019 was interrupted due to the COVID pandemic and thereafter due to the war. Routine and catch-up campaigns are needed wherever access is possible to help make sure there are not repeated outbreaks as in 2017–2019, when there were over 115 000 cases of measles and 41 deaths in the country – this was the highest incidence in Europe.
Coverage at or above 95% with 2 doses of the safe and effective measles vaccine can protect children against measles. However, COVID pandemic related disruptions have delayed the introduction of the second dose of the measles vaccine in many countries.
Note that the data only includes vaccinations provided in the public sector, whilst the denominator includes all children in South Africa. Graph courtesy of Dr Lesley Bamford, National Department of Health
