Most vaccines protect by inducing immune responses without causing disease, using killed pathogens, protein subunits, or genetic instructions rather than virulent organisms. Live attenuated vaccines use weakened versions that typically don't cause illness in healthy individuals. They introduce antigens, distinctive molecules from a pathogen, or, in the case of mRNA vaccines, genetic instructions for making a pathogen protein, to stimulate the immune system.
Upon vaccination, these antigens are recognized as foreign by antigen-presenting cells (APCs) such as dendritic cells and macrophages, which engulf the antigens. The APCs then display antigen fragments on their surface via major histocompatibility complex (MHC) molecules, signaling the presence of a pathogen-derived antigen.
This alert activates helper T cells and primes B cells. A minority of vaccines, plain bacterial polysaccharides such as PPSV23, activate B cells in a T-independent fashion and produce mostly short-lived IgM with little memory.
T-dependent vaccines, including live attenuated, inactivated, viral vector, protein subunit, conjugate, or mRNA types, prime the adaptive immune system and establish lasting immunological memory, leaving long-lived T and B lymphocytes ready to neutralize the pathogen on future exposure.
B Cells Respond with Help from T Cells
B cells are the antibody-producing cells of the immune system. Each B cell has a unique B cell receptor (BCR) on its surface that can bind a specific antigen. When a vaccine antigen enters the body, any B cell with a matching BCR will bind to it.
The B cell then internalizes the antigen, processes it, and presents fragments on its own MHC molecules. Meanwhile, helper T cells activated by APCs recognize the same antigen on B cell MHC.
Upon contact, the T cell secretes cytokines (immune signaling molecules) and provides essential costimulation (e.g., CD40 ligand binding CD40 on B cells) to fully activate the B cell.
This T cell help is crucial. It triggers the B cell to proliferate (clonal expansion) and begin its transformation. In the first few days after vaccination, some activated B cells differentiate into antibody-secreting cells outside lymphoid follicles. These early plasma cells, often called plasmablasts, secrete antibodies, mostly IgM and, after early class switching, a small amount of low-affinity IgG, that provide immediate but low-affinity protection.
This rapid response is transient, providing early protection while the remaining activated B cells migrate into germinal centers for affinity maturation and memory formation.
Germinal Centers Refine Antibodies (Affinity Maturation and Class Switching)
The principal efficacy mechanism of many vaccines arises in germinal centers (GCs), specialized zones in lymph nodes and the spleen where B cells improve their antibodies. Inside each GC, activated B cells proliferate rapidly and undergo somatic hypermutation driven by activation-induced cytidine deaminase (AID) in the genes that encode the antigen-binding region of their antibody.
This mutagenesis creates B-cell clones with slight changes in their binding sites. Clones that bind the vaccine antigen with the highest affinity receive survival signals, whereas weaker binders undergo apoptosis. Through this selection, the average binding strength of the antibody pool rises, a process called affinity maturation.
With cytokine cues from follicular helper T cells, the same B cells activate class-switch recombination, replacing the IgM constant region with IgG, IgA, or other isotypes without changing specificity. Switching gives antibodies new effector properties, for example, IgG diffuses into tissues and engages complement and Fc receptors.
After several weeks of GC reactions, the result is a refined pool of B cells carrying high-affinity, class-switched B-cell receptors. These cells then differentiate into two long-term protective subsets: plasma cells and memory B cells.
Plasma Cells and Memory B Cells
Plasma cells continuously secrete antibodies. Some are short-lived and produce transient waves of antibody secretion for days or weeks after vaccination. Many GC-derived plasma cells become long-lived and migrate to survival niches in the bone marrow. These niches are rich in CXCL12, APRIL, BAFF, BCMA, and IL-6, which together support plasma-cell survival for years or decades. There, they can persist for years or decades, releasing high-affinity antibodies that maintain protective serum levels.
Memory B cells, in contrast, remain quiescent. They reside in secondary lymphoid organs and circulate throughout the body, each carrying a high-affinity receptor for the vaccine antigen. On re-exposure, memory B cells reactivate quickly; they proliferate and become new plasma cells, producing a rapid increase in antibodies within days, far faster than a naïve response. This mechanism underpins long-term immunological memory.
For example, vaccination against influenza seeds memory B cells specific for viral hemagglutinin. When the virus is later inhaled, those cells generate antibodies that block infection and limit disease severity.
Booster Shots Strengthen Long‑Term Immunity
Even highly efficacious vaccines often require booster doses to maintain and enhance immunity. Over time, serum antibody levels can decline, and some memory lymphocytes gradually decrease in number, so protection weakens.
A booster vaccine reexposes the immune system to the antigen after the initial response has matured. This repeated exposure prompts memory B cells to reactivate and proliferate. Many of these memory cells rapidly differentiate into plasma cells, causing a rapid increase in antibody titres within days, which is known as an anamnestic response.
Some memory B cells migrate into germinal centers again and undergo another round of hypermutation and selection. This secondary germinal-center reaction can refine antibody affinity and adjust the antibody-class distribution if necessary. Boosters expand the memory B-cell pool and elevate overall efficacy.
A study showed that an mRNA COVID-19 booster triggered rapid secretion of broadly neutralising antibodies and expanded antigen-specific memory B-cell clones that had re-entered germinal centers, improving antibody breadth against viral variants.
Regular boosters for certain vaccines (such as tetanus or COVID-19) renew immune memory before it fades, ensuring that both long-lived plasma cells and memory B cells remain in protective numbers. Intervals of at least 3–6 months between doses allow germinal centers to mature fully and maximise the quality of the booster response. By reinforcing immunological memory, booster shots sustain high protection levels over the long term.
Summary
Vaccines induce adaptive immune responses by presenting pathogen-derived antigens that trigger T-cell-dependent B-cell activation. Germinal-center reactions drive affinity maturation and select high-affinity clones for differentiation into long-term effector populations. The result is two-component humoral immunity: long-lived plasma cells maintain protective serum antibody titers, while memory B cells rapidly differentiate into antibody-secreting cells upon re-exposure, neutralizing pathogens before systemic infection occurs. Booster immunizations, administered at appropriate intervals, maintain protective immunological memory by expanding both plasma cell and memory B cell compartments.