Exploring the interplay between vaccines and immune system development in infants

Worldwide, the mortality rate for children under the age of five has been decreasing year over year, with rates dropping 59% between 1990 and 2021, according to UNICEF. Despite this, five million children under five years old died in 2021, with infectious diseases presenting as the leading cause. Immune system development plays a significant role in this, as an infant transitions from the passive immunity granted by their mother to long-term active immunity.  

This process is incompletely understood, particularly how the developing immune system responds to vaccinations. This determines how the body develops protection against different infections and how adults, in turn, respond to vaccines.

“Infants die from many infections that adults don’t die from. The best thing we can do for this is vaccinate,” said Octavio Ramilo, MD, St. Jude Department of Infectious Diseases chair. “We know this strategy works, but we still don’t understand very well how the vaccines work. We need to do fundamental research into this.” 

Pediatric vaccination study offers a unique perspective

Ramilo is a co-corresponding author on recent work that delves into pediatric immune responses to vaccination. This research was a shared venture with investigators from the Jackson Laboratory for Genomic Medicine and Weill Cornell Medicine.  Published in Nature Communications, the researchers took a systems-level approach to explore the immune response over time to a routine vaccination series occurring when infants were two months old. This brought to light the complex system of changes occurring within the developing immune system as it enters the immunity boot camp of infancy and learns to fight off infections.

Immune response to vaccination in infancy differs from that of an older child or adult simply because these vaccines are the first time the immune system has seen the associated antigens. This allowed the researchers to explore the response with the benefit of a true baseline. “We tried to define why the different immune cells respond and how,” Ramilo said. “The beauty for us who want to understand how the immune system develops is that even in an infant, we can study this in tremendous depth.” 

The researchers made both expected and unexpected observations by parsing out the contributions from all the different immune players, from monocytes to B cells to T cells, and all the associated responses. 

Single-cell transcriptomics singles out the differences in cells

To explore the immune cell response to vaccination, the researchers used both bulk analysis techniques and more detailed, single-cell transcriptomics. If bulk analysis is looking down from a plane and recognizing a cornfield, single-cell transcriptomics is comparing kernels on individual ears of corn. 

The study found that among the infants in the study, there was substantial heterogeneity in the antibody responses to the different components of the initial vaccination. Their immune systems responded very differently relative to each other, in contrast to what has been observed even in infants a few months older.

“The response in infants that are vaccinated at six months of age was not so heterogeneous, and it was much, much better,” said Ramilo. However, this variability in the infant immune response was not a huge surprise to Ramilo; infants routinely respond poorly to initial vaccination, requiring three or four doses to achieve effective protection.

Bulk analysis recognized the heterogeneity between the infants’ immune systems. Single-cell transcriptomics offered the chance to identify the cause.

“The first thing we checked was the antiviral response, called the interferon response,” explained Ramilo. “We were surprised to see that the interferon response is very prominent and affects all immune cells. It’s really amazing.” 

Interferon functions as the alarm for the cell, recognizing invading pathogens and mobilizing the immune system.

The infants appeared to have a higher baseline expression of interferon and related genes than adults. The exact reason for the elevated baseline and its universal presence in almost all immune cells is unclear. There was also a noted increase in genes associated with targeted memory response, a curious finding considering the naivety of the immune system. 

Given the centrality of interferon to both the innate and adaptive immune response, investigating these differences further may offer novel insights. These findings imply there is still much to understand regarding gene regulation in the developing immune system.

Cell spatial arrangement may address newborn vaccination shortcomings

In addition to gene expression differences, the researchers explored the spatial behavior of the immune cells. B cells, for example, are responsible for antibody production and tend to organize in a particular area of the lymph node called the germinal center. This allows optimal antibody production and distribution, leading to long-term memory and immunity. B cells that are out of place can still function but are more akin to short-term memory.  Organizing within the germinal center is necessary for long-term memory to form. “We saw there was a subgroup of B cells that don’t go to the germinal center,” Ramilo said. “It is possible that this is why the infant’s antibody response is not that great. Some of the B cells don’t follow the best pathway.”

While Ramilo and his collaborators demonstrated that exploring the developing infant immune system is not only possible but also possible to do with single-cell resolution, his main takeaway is a simple one. 

“It proves the importance of studying infants and shows that they are very different compared to adults,” he expressed. “It also demonstrates the ability we now have with new technologies to study this in depth.”

While much is still to be learned, a better understanding of immune system development has significant implications for vaccinations. By appreciating how immune cells in infants respond to immunization, scientists can optimize efficacy, offering children a better chance to combat infection early in life. 

“We have begun to uncover these mechanisms and can think about how to design more effective vaccines for infants. If we find that there’s some other pathway that we can stimulate, maybe we can develop a vaccine with those components that can be more effective. And in one dose, we could protect infants early on and optimize how the immune system develops to adulthood,” Ramilo concluded.