Cameroonian scientist Dr Wilfred Ndifon has proposed a solution to a 70-year old immunological mystery relating to the original antigenic sin. This complex problem has played havoc with efforts to fight infectious diseases, particularly in places such as Africa where people can suffer successive infections. Ndifon and Tolullah Oni are two of 12 Next Einstein Forum Fellows working to solve major challenges in health, education, big data and quantum theory using science, technology, engineering and mathematics.
What is the original antigenic sin?
The original antigenic sin was first reported about 70 years ago by American epidemiologist Thomas Francis Jr. But its underlying biological mechanisms are still poorly understood.
This much we know: the human body activates white blood cells to fight an infection. When a new infection comes along the white blood cells are activated again. But they are less effective at fighting the new agent. This makes the body much less able to fight the new disease. This is what Thomas Francis described as the original antigenic sin.
The length of time over which original antigenic sin can occur depends on how long the immune system’s memory of a previous infection lasts, which in turn depends on the infecting pathogen. For pathogens like flu viruses, the immune system’s memory can persist throughout an individual’s lifetime.
The same problem arises when a person is treated with a vaccine to fight pathogen A. When that person is infected by a related pathogen B, the vaccine focuses on pathogen A making it less effective.
Why does this matter?
The original antigenic sin makes fighting diseases really difficult. This is because it reduces the effectiveness of vaccines. This happens because vaccines preferentially reactivate previously activated white blood cells. So past infections increase the risk for more severe future infections and for reduced vaccine effectiveness.
This risk is particularly high in sub-Saharan Africa where infections tend to occur frequently. The risk is high in regions where infections occur frequently simply because you need sequential infections with related pathogens in order for original antigenic sin to manifest.
So, the more infections there are, the more likely it is that the body’s defences will be compromised by original antigenic sin. This is also pertinent in the Northern Hemisphere where there are frequent sequential infections by related variants of flu viruses. This creates an ideal environment for original antigenic sin to manifest.
It is also important in other parts of the world where flu is prevalent.
Scientists have documented many instances of the original antigenic sin in humans, mice, and other organisms.
It has been beautifully illustrated in mice that were infected either with only one variant of the flu virus or with that variant followed a month later by another related variant. While the mice infected with only one variant were able to completely control a subsequent infection with that variant, those that were sequentially infected had about 10 000 times more virus in their lungs as a result of original antigenic sin.
NEF Fellow Wilfred Ndifon on how he solved 70 year old immunological problem.
A practical example
Imagine for a minute that you have malaria.
The immune system contains specialised white blood cells that are responsible for protecting the body from pathogens which cause malaria.
When the immune system is exposed to the pathogen, the pathogen is chopped into pieces called antigens. Then it is loaded onto the surface of other white blood cells. The white blood cells then become activated. They are then able to get rid of the malaria.
A small number of these white blood cells remain after the pathogen has been eliminated. They stay behind to enable a swift response to any infection by the same pathogen.
After eliminating malaria, let’s imagine you are infected by a new variant of the pathogen. Normally the body should unleash the same process. But this is not always the case.
In some cases, the white blood cells do not recognise the new pathogen. Instead, they focus on the previous pathogen. An earlier theory suggested that this may result from competition among certain white blood cells called B cells. In immunology this is called the original antigenic sin.
My study introduced and confirmed an original theory using mathematics and experimental data. My theory explains why original antigenic sin occurs. It is also the first theory to explain how original antigenic sin can be alleviated by a substance that is added to a vaccine to better activate the immune system’s cells. What we call an adjuvant.
I show that both original antigenic sin and its alleviation by adjuvants arise from the activity of certain white blood cells called T regulatory cells.
T regulatory cells activated by previous pathogens weaken certain white blood cells’ ability to load new pathogens onto their surface. This in turn causes fewer white blood cells to become activated, thereby making it difficult for the body to fight new pathogens and leading to original antigenic sin.
But my theory predicts that adjuvants will reduce the inhibition of white blood cell activation that is caused by T regulatory cells, thereby alleviating original antigenic sin.
My discovery opens up additional possibilities for preventing the destructive health consequences of original antigenic sin. For example, it suggests how original antigenic sin can be prevented from reducing a vaccine’s effectiveness. This can be done by designing vaccines so that their components better latch onto the surface of certain white blood cells.
This will counter the effect of the T regulatory cells and make the immune system more effective at getting rid of the pathogens targeted by the vaccine.
Wilfred Ndifon, Research Chair with joint appointments at both the South African and the Ghanaian centres of the African Institute for Mathematical Sciences. He is also affiliated to the Department of Mathematical Sciences, Stellenbosch University and Tolullah Oni, Senior Lecturer at the School of Public Health and Family Medicine, University of Cape Town