The unique defenses of the infant immune system

There are 140 million babies born each year. Infections are the leading cause of life-threatening illness and death among them. Vaccines have revolutionized the prevention of infections and significantly reduced child mortality; however, most vaccines cannot be administered until around 2 months of age and require multiple doses before full protection is achieved. Globally, approximately five million children still die each year before the age of 5, and infections within the first month of life account for a significant proportion of these fatalities.

Understanding how the immune system develops from the earliest stages of life, including during pregnancy, offers a critical opportunity to develop new strategies to prevent early-life infections and reduce child mortality. Scientists at St. Jude are studying the developing immune system in the first months of life to gain insight into how the immune system becomes fully capable of fighting pathogens and learn how to better protect infants from serious infections.

Exploring the infant immune system

Octavio Ramilo, MD, and Asunción Mejías, MD, PhD, MsCS, Department of Infectious Diseases, study how early-life infections, particularly viral respiratory and perinatal infections, shape immune development.

“Infections that occur within the early months of life can set the stage for long-term health outcomes, making it crucial to understand the early immune development to improve lifelong health,” explained Mejías. By examining how infants’ immune responses differ from those of older children and adults, Ramilo and Mejías are uncovering the mechanisms that drive disease outcomes and guide the development of vaccines and therapies that better protect infants during this vulnerable period.

“When we compare healthy infants, children, young adults and older adults, it’s clear that the infant immune system is completely different,” explained Ramilo. “This led us to study it more closely.”

How the infant immune system differs from adults

The infant immune system is not just an immature version of the adult system; it is fundamentally different. Infants must develop the basic tools needed to fight infections, something older children and adults have already done. An early study by Ramilo and Mejias showed that very young infants, particularly around 2 to 3 months old, are highly vulnerable to severe respiratory syncytial virus (RSV) due to impaired innate immune responses, especially reduced interferon production, a fundamental antiviral response. As infants pass 6 months, their immune system changes dramatically, enabling stronger responses, including interferon and antibody production.

“We discovered that infants’ immune systems are completely different before and after 6 months of age,” explained Mejías. “In the first few months of life, their immune defenses are still developing, leaving them highly vulnerable to infections.”

In a study published in Nature Communications of infants with SARS-CoV-2 (the virus that causes COVID-19), Ramilo and Mejías found that infants had different immune responses than older children and adults. While interferon, an antiviral signaling molecule, is typically produced by a narrower group of immune cells in adults, the researchers found that in infants it was activated across many cell types, including immune cells not normally associated with interferon production.

“At first, we knew that interferon gene expression levels were high in the blood, but we didn’t know which cells were expressing it,” said Ramilo. “To our surprise, we saw very high interferon gene expression in many immune cell types, including monocytes, which is similar to adults, but also in CD4⁺ T cells, CD8⁺ T cells, and B cells in infants — something we don’t see in adults.”

These findings highlight that infants fight infections such as RSV and SARS-CoV-2 in ways that are distinct from older children and adults, which helps explain why very young infants are particularly vulnerable to severe disease.

Tracking infant immunity from pregnancy and beyond

A major challenge in studying infant infections is that research has often focused only on children after they become ill. Ramilo and Mejías are shifting that approach by examining the immune development from pregnancy through birth and the first months of life, tracking how the immune system responds to infections and vaccines during this critical window.

In a recent study, they compared pregnant women who were naturally infected with SARS-CoV-2, those who were vaccinated against it, and those who experienced both. They found that vaccination proved more effective than natural infection at generating antibodies that crossed the placenta and protected the baby. Mothers who received the SARS-CoV-2 vaccine transferred higher concentrations of antibodies to their infants, and those antibodies lasted longer, providing extended protection after birth.

“Many infants are at risk of severe infection before they can receive vaccinations,” explained Ramilo. “Our research confirms that a promising strategy is to vaccinate mothers during pregnancy, which allows antibodies to cross the placenta and provide protection to the baby.”

To study these effects in greater depth, the team is establishing a birth cohort, a long-term study that follows mothers and their babies from pregnancy through early life. By studying both together, researchers can see how maternal immunity, early exposures, infections and vaccines shape an infant’s immune responses and overall health outcomes.

“To understand the infections affecting infants, we have to start with the mother,” explained Mejías. “Early illness can result from limited immune protection passed from mom, and factors like maternal stress can shape an infant’s immune and vaccine responses.”

The team has recruited a small cohort of infants, allowing them to study their immune cells on day one of life, a first-of-its-kind study. They will gain longitudinal, sequential data, which enables the team to track how an infant’s immune system develops over time. 

By studying immune development from pregnancy through early life, Ramilo and Mejías are uncovering how infants respond to infections in ways that are fundamentally different from older children and adults. Their research highlights critical windows of vulnerability and the protective role of maternal antibodies, offering insights that could inform more effective, targeted vaccination strategies and therapies. With longitudinal data from birth cohorts, the team aims to map how immunity evolves from day one and to ultimately reduce the burden of infectious diseases and their associated mortality in the most vulnerable population: infants.