Rare genetic variant makes some Inuit infants extremely vulnerable to viral infections and vaccines

Breaking new ground 19. may 2022 3 min Professor Trine Mogensen Written by Kristian Sjøgren

Researchers have identified a genetic variant among Inuit people that makes 1 in 1,500 infants extremely vulnerable to viral infections and live-attenuated viral vaccines. The genetic variant may potentially be so frequent among Inuit people that population screening at birth may be sensible to prevent children from dying from simple viral infections or from childhood vaccinations.

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Inuit people have a unique genetic variant that makes 1 in 1,500 children extremely susceptible to severe viral infections – to the extent that the live-attenuated vaccine for measles, mumps and rubella (MMR) can be fatal.

The research also shows that the genetic variant could potentially affect one in 1,500 children. According to the researchers, population screening at birth may be beneficial so that these children can get appropriate treatment and are not given the MMR vaccine as part of the childhood vaccination programme.

“We were surprised that such a potentially frequent and fatal genetic variant has been able to exist undetected among the Inuit for so long. One reason may be that the deaths of young children from a viral infection in small remote settlements have rarely been thoroughly investigated, and we have therefore not discovered that the cause could often be genetic. This may warrant further studies on how prevalent this genetic variant actually is among Inuit people. If it turns out to be as widespread as the indications suggest, we should consider screening for it,” explains Trine Mogensen, Professor, Department of Biomedicine, Aarhus University and Department of Infectious Diseases, Aarhus University Hospital.

The research has been published in the Journal of Experimental Medicine.

Sick child triggered major discovery

The research started by chance with a young child who was hospitalised at Rigshospitalet in Copenhagen with symptoms resembling severe meningitis or severe tuberculous meningitis following routine MMR vaccination.

The doctors performed genetic analysis and in collaboration with Trine Mogensen’s research group in Aarhus, which specialises in antiviral immunity, found a new genetic variant, that was disease-causing.

The researchers examined the boy’s blood and immune cells for signs of genetic variants linked to various types of immunodeficiency but found none.

“Several known genetic variants make people vulnerable to viral infections. These may provide poor antibody response or disable the immune system. But this boy, who was only 16 months old at the time of the investigation, had none of these,” says Trine Mogensen.

Genetic variant destroys protein on cell surface

The researchers did, however, find a previously unknown genetic variant in the IFNAR2 gene that causes a mutation of a surface protein on the body’s cells.

This surface protein is usually activated by interferon in connection with a viral infection. Interferon interacts with the surface protein and strengthens the cells’ defences against viruses that otherwise divide inside the cells and produce more viruses.

“This means that if the cells cannot be stimulated with interferon, there will be no antiviral response. This is far from ideal to ensure protection from viruses, which the boy was not,” explains Trine Mogensen.

Variant leads to extremely serious infections

The researchers then examined the boy’s cells in the laboratory, which were exposed to viruses such as herpes simplex virus, measles and mumps.

The researchers found that the cells had no defence against the viral infections. The viruses just kept dividing inside the cells until the cells ruptured.

“We found that the cells did not mobilise any defence and that an extremely severe viral infection occurred,” says Trine Mogensen.

More common than first thought

After discovering the genetic variant, the researchers from Denmark contacted researchers from Newcastle University in the United Kingdom.

The Newcastle researchers had been contacted by doctors in Alaska and Canada, where four Inuit children had become severely ill with influenza or COVID-19 after MMR vaccination.

The doctors examined the children’s DNA and discovered that, like the boy in Rigshospitalet, these children had the same genetic variant, which knocks out the surface receptor on the cells.

The boy was therefore not a one-off case.

The researchers then examined thousands of blood samples from both Greenland and other countries and found that the genetic mutation that predisposes to the poor immune response does not exist outside the Arctic but is present in up to one in every 1,500 Inuit people.

“We envision that many deaths in the Arctic have probably never been registered because the children were not even hospitalised before they died,” explains Trine Mogensen.

Screening for variant may be beneficial

Trine Mogensen believes that further studies are required to map the frequency of this variant among Inuit in the Arctic – which the researchers are initiating.

If, according to Trine Mogensen, the genetic variant is present among one in 1,500 infants, screening at birth through a heel-prick test might become standard.

Children with the variant must first be treated with antiviral medication, which can protect against severe chickenpox and herpes.

In addition, the live-attenuated MMR vaccine in the childhood vaccination programme must be replaced by other vaccines, such as the mRNA vaccines that were used to combat SARS-CoV-2.

It would also be sensible to vaccinate the children against influenza and COVID-19 – but with non-live attenuated vaccines.

“We have found five children with this variant, and three have died. That is how serious it is. But you can take many preventive measures by knowing about the variant, and the more you know about it, the easier the measures will be. Perhaps it will also be sensible to test siblings for similar variants, since this may be important for them to know later in life when they plan to have children,” adds Trine Mogensen.

Variant may have protected against other diseases

Several factors may account for the fact that such a deadly mutation has survived in the Inuit population.

The Inuit population is relatively small and has narrow genetic variation, and there has not been much genetic mixing in the small, isolated settlements in which people have lived for hundreds of years.

The genetic variant may therefore have become more concentrated in the population, but this may not be the full explanation.

“Genetic variants that are harmful often provide the person some other evolutionary advantage that means that they are not shed. This variant may provide protection against other diseases that were more prevalent in the Inuit population in the past – including tuberculosis. But so far this is only pure speculation,” concludes Trine Mogensen.

Life-threatening viral disease in a novel form of autosomal recessive IFNAR2 deficiency in the Arctic” has been published in the Journal of Experimental Medicine. The Novo Nordisk Foundation awarded a Tandem Programme grant to Trine Mogensen for the project Identification of Novel Primary Immunodeficiencies Conferring Susceptibility to Viral Infections (2015), a grant for the project Deciphering the Role of Host Genetics in the Pathogenesis and Susceptibility to Severe COVID-19 (2020) and a grant for the project Exploring the Role of Host Immunogenetics in Susceptibility to Severe COVID-19 to Identify Novel Targets for Disease Prevention and Treatment (2021).

Trine H. Mogensen obtained her medical degree from Aarhus University (AU) in 2002, a PhD degree in 2003, and a Doctor of Medical Sciences degree (DMSc...

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