Booster Shot Geography Rewrites Our Understanding of Immunity

One of the enduring strengths of vaccination is its ability to create long-lasting immune memory. Two key players maintain this memory: long-lived plasma cells, which continuously produce antibodies, and memory B cells, which stand ready to adapt to future infections. These B cells are vital for fighting viruses that frequently mutate, such as those responsible for respiratory infections, e.g., COVID-19

Plasma cells dedicated to producing antibodies are the immune system’s tireless workers. However, they are fixed on targeting the antigens they were created to recognize. Memory B cells are more flexible; when re-exposed to an antigen, they can rapidly generate new plasma cells for a quick antibody response or re-enter the germinal center within lymph nodes to refine their ability to recognize viral variants.

A Zillow on Lymph Nodes

Lymph nodes are bean-shaped, strategically placed immune waystations that filter the fluid surrounding our cells and coordinate immune responses. They're factories, training academies, and intelligence hubs. The outermost layer, the cortex, like a Star Wars cantina, gathers a diverse and sometimes shady set of antigens from viruses, bacteria, and even a rogue cancer cell alerting the node’s internal defenses, the macrophages and B cells.  When B cells recognize a foreign antigen, some set up shop deeper in the lymph node, in a structure called the germinal center, where the numbers rapidly expand and become more tightly targeted against the foreign antigen. Some B cells remain to become long-lived memory B cells. The rest become plasma cells, antibody factories that migrate into the medulla, the node’s innermost region, pumping out antibodies that flow into circulation, targeting and neutralizing the invading pathogens. 

The decision to differentiate into antibody-producing plasma cells or to undergo further refinement in germinal centers is central to the strength and breadth of the immune response. 

Location, Location, Location: The Importance of Immune Geography

Much of what we understood about memory B cells came from in vitro experiments, where cells were removed from their tissue homes and studied in isolation. However, a newer in vivo study in Cell observed B cells in their natural environment, revealing insights into how their anatomical niche influences memory B cell behavior.

In a series of experiments in mice, the researchers found that memory B cells in the lymph node nearest the site of the original immune challenge (the jab) clustered in the node’s outer capsule—the lymph node’s cantina, more formally the subcapsular niche. Memory B cells, positioned here, closely interact with the macrophages that trap and present antigens. In this anatomic home, B cells detect antigens more efficiently and receive signals that help them stay positioned, maintaining and enhancing immune readiness.  

Memory B cells in more distant lymph nodes tend to migrate into the node's medulla, honing their targeting – a tradeoff of future readiness to combat similar antigens for the efficient management of the problem at hand. This finding suggests that proximity to antigen entry points fundamentally shapes how memory B cells patrol and respond, turning location into a crucial factor in immune readiness.

The study also revealed that the location of a booster shot significantly influences the immune system response. When mice were given a booster in the same location as their original immunization, targeting the same draining lymph node, there was a stronger proliferation of memory B cells and production of high-affinity antibodies, especially when facing weaker or slightly altered versions of the original antigen. 

It appears that the macrophages, once exposed to an antigen, become better equipped to hold on to and present antigens to memory B cells during future encounters. The macrophages keep memory B cells close and shape how effectively these cells can jump back into action. The findings highlight an underappreciated feature of immune memory—spatial imprinting—and suggest that returning to the scene of the immunological crime may be the best strategy for a stronger, faster, and smarter defense.

Mice can be four-legged humans

These observations were not limited to animal models. In a parallel study involving healthy adult volunteers, researchers tracked immune responses to Pfizer’s COVID-19 vaccine. They found that individuals who received their second vaccine dose in the same arm as the first dose produced stronger early recall responses, including broadly neutralizing antibodies. In contrast, those who received their booster in the opposite arm had weaker early responses. It should be noted that these changes equalized by about one month after immunization.

Implications for Vaccine Strategy

I have written about “original antigenic sin,” immune imprinting, where the immune system, once exposed to an antigen (like a viral spike protein), tends to preferentially recall and respond to that original version in future encounters. It results in a more limited immune response to new viral variants. 

By delivering booster shots into the same arm (ipsilateral administration), the antigen is directed toward the same regional lymph node that “remembers” the original immunization.

Ipsilateral administration promotes a more pristine “immaculate antigenicity” by recruiting those local memory B cells finely tuned to the original immunogen, enhancing the immune response's breadth, especially for variants resulting from slight antigenic drift. 

This study suggests a simple yet potentially powerful modification to vaccination protocols: when administering a booster dose, using the same injection site as the original dose could optimize the immune system’s ability to recall and respond effectively. The research also underscores the importance of anatomical context in immune function—revealing that where memory cells reside can be just as important as their molecular characteristics.

Source: Macrophages direct location-dependent recall of B cell memory to vaccination Cell DOI: 10.1016/j.cell.2025.04.005