Researchers headed by teams at the Garvan Institute of Medical Research and at the Kirby Institute at UNSW Sydney have discovered why receiving a vaccine booster in the same arm as the first vaccine dose can generate a more effective immune response more quickly. The researchers found that when a vaccine is administered, macrophage immune cells became ‘primed’ inside lymph nodes. These macrophages then direct the positioning of memory B cells (Bmems) to more effectively respond to the booster when given in the same arm.
The researchers say findings from their study in mice, which they validated in humans receiving a COVID vaccine, provide evidence to refine vaccination approaches and offer a promising new approach for enhancing vaccine effectiveness.
“This is a fundamental discovery in how the immune system organizes itself to respond better to external threats—nature has come up with this brilliant system and we’re just now beginning to understand it,” said Professor Tri Phan, MBBS, FRACP, FRCPA, PhD, Director of the Precision Immunology Program at Garvan. Scientia Professor Anthony Kelleher, MBBS, PhD, BSc, FRACP, FRCPA, FAAHMS, Director of the Kirby Institute, further commented, “A unique and elegant aspect of this study is the team’s ability to understand the rapid generation of effective vaccine responses. We did this by dissecting the complex biology in mice and then showed similar findings in humans. All this was done at the site of the generation of the vaccine response, the lymph node.”
Phan, and Kelleher are co-senior authors of the team’s published paper in Cell, titled “Macrophages direct location-dependent recall of B cell memory to vaccination.”
Immunization introduces a harmless version of a pathogen—the vaccine antigen—into the body. This is filtered through lymph nodes, which act as immune ‘training camps’ that train the body to fight off the real pathogen. “Vaccines protect from recurrent infection and disease by inducing the secretion of neutralizing antibodies by long-lived plasma cells (PCs) and by generating memory B cells (Bmems),” the authors noted. Phan and colleagues had previously discovered that the memory B cells, which are crucial for generating antibody responses when infections return, linger in the draining lymph node (dLN) closest to the injection site.
Using state-of-the-art intravital imaging at Garvan, the team discovered that, in mouse models, the memory B cells migrate to the outer layer of the local lymph node, where they interact closely with the macrophages that reside there. When a booster was then given in the same location, the primed subcapsular sinus macrophages (SSMs)—already on alert— efficiently captured the antigen and activated the memory B cells to make high quality antibodies. “… we tracked the migratory behavior and cell fate of Bmems in response to prime-boost vaccination with a model protein antigen,” the team explained. “Our data show that murine Bmems in the dLN reside in the subcapsular niche where they interact with SSMs, in contrast to ndLN [non-dLN] Bmems, which are located deeper in the follicle.”
The quality and quantity of the recall response to a second immunization was significantly higher when boosted in the dLN on the same side, compared with the ndLN on the other side. “These site-specific differences in the Bmem recall response were dependent on SSMs in the subcapsular niche,” the authors noted.
![Memory B cells (red) interacting with macrophages (white) inside a lymph node (blue). [Dr Rama Dhenni]](https://www.genengnews.com/wp-content/uploads/2025/04/low-res-15-300x219.jpeg "Memory B cells (red) interacting with macrophages (white) inside a lymph node (blue). [Dr Rama Dhenni]")
Memory B cells (red) interacting with macrophages (white) inside a lymph node (blue). [Dr Rama Dhenni]
Study co-first author Rama Dhenni, PhD, who undertook the research as part of his Scientia PhD program at Garvan, commented, “Macrophages are known to gobble up pathogens and clear away dead cells, but our research suggests the ones in the lymph nodes closest to the injection site also play a central role in orchestrating an effective vaccine response the next time around. So location does matter.”
To determine the relevance of the animal results to human vaccines, the team at the Kirby Institute also conducted a clinical study with 30 volunteers receiving the Pfizer-BioNTech COVID-19 mRNA vaccine. 20 participants received their booster dose in the same arm as their first dose, while 10 had their second shot in the opposite arm. The results of analyses, the authors reported, indicated that “boosting of vaccine responses in the same arm as the priming dose generates superior depth and breadth of recall responses in the first week.”
Their collective data, the authors stated, “… show that primed SSMs control the quantity and quality of the Bmem recall response in the dLN and provide a rationale for administering the second dose of prime-boost vaccines in the same arm.”
Added Alexandra Carey-Hoppé, co-first author and PhD student from the Kirby Institute, “Those who received both doses in the same arm produced neutralizing antibodies against SARS-CoV-2 significantly faster—within the first week after the second dose.”
“These antibodies from the same arm group, were also more effective against variants like Delta and Omicron,” added Mee Ling Munier, PhD, co-senior author and Vaccine Immunogenomics group leader at the Kirby Institute. “By four weeks, both groups had similar antibody levels, but that early protection could be crucial during an outbreak.”
Munier added, “If you’ve had your COVID jabs in different arms, don’t worry – our research shows that over time the difference in protection diminishes. But during a pandemic, those first weeks of protection could make an enormous difference at a population level. The same-arm strategy could help achieve herd immunity faster—particularly important for rapidly mutating viruses where speed of response matters.”
Beyond the potential to refine vaccination guidelines, the findings offer a promising avenue for enhancing the effectiveness of vaccines. “If we can understand how to replicate or enhance the interactions between memory B cells and these macrophages, we may be able to design next-generation vaccines that require fewer boosters,” Phan pointed out. In their paper the authors concluded “These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.” From their results, they “… identify SSMs and their cell-cell communication with Bmems as potential cellular and molecular targets to improve the depth and breadth of antibody responses and vaccine efficacy.”
The post “Location Does Matter.” Site of Second Vaccine Dose Shapes Immune Response appeared first on GEN - Genetic Engineering and Biotechnology News.
The researchers say findings from their study in mice, which they validated in humans receiving a COVID vaccine, provide evidence to refine vaccination approaches and offer a promising new approach for enhancing vaccine effectiveness.
“This is a fundamental discovery in how the immune system organizes itself to respond better to external threats—nature has come up with this brilliant system and we’re just now beginning to understand it,” said Professor Tri Phan, MBBS, FRACP, FRCPA, PhD, Director of the Precision Immunology Program at Garvan. Scientia Professor Anthony Kelleher, MBBS, PhD, BSc, FRACP, FRCPA, FAAHMS, Director of the Kirby Institute, further commented, “A unique and elegant aspect of this study is the team’s ability to understand the rapid generation of effective vaccine responses. We did this by dissecting the complex biology in mice and then showed similar findings in humans. All this was done at the site of the generation of the vaccine response, the lymph node.”
Phan, and Kelleher are co-senior authors of the team’s published paper in Cell, titled “Macrophages direct location-dependent recall of B cell memory to vaccination.”
Immunization introduces a harmless version of a pathogen—the vaccine antigen—into the body. This is filtered through lymph nodes, which act as immune ‘training camps’ that train the body to fight off the real pathogen. “Vaccines protect from recurrent infection and disease by inducing the secretion of neutralizing antibodies by long-lived plasma cells (PCs) and by generating memory B cells (Bmems),” the authors noted. Phan and colleagues had previously discovered that the memory B cells, which are crucial for generating antibody responses when infections return, linger in the draining lymph node (dLN) closest to the injection site.
Using state-of-the-art intravital imaging at Garvan, the team discovered that, in mouse models, the memory B cells migrate to the outer layer of the local lymph node, where they interact closely with the macrophages that reside there. When a booster was then given in the same location, the primed subcapsular sinus macrophages (SSMs)—already on alert— efficiently captured the antigen and activated the memory B cells to make high quality antibodies. “… we tracked the migratory behavior and cell fate of Bmems in response to prime-boost vaccination with a model protein antigen,” the team explained. “Our data show that murine Bmems in the dLN reside in the subcapsular niche where they interact with SSMs, in contrast to ndLN [non-dLN] Bmems, which are located deeper in the follicle.”
The quality and quantity of the recall response to a second immunization was significantly higher when boosted in the dLN on the same side, compared with the ndLN on the other side. “These site-specific differences in the Bmem recall response were dependent on SSMs in the subcapsular niche,” the authors noted.
Memory B cells (red) interacting with macrophages (white) inside a lymph node (blue). [Dr Rama Dhenni]
Study co-first author Rama Dhenni, PhD, who undertook the research as part of his Scientia PhD program at Garvan, commented, “Macrophages are known to gobble up pathogens and clear away dead cells, but our research suggests the ones in the lymph nodes closest to the injection site also play a central role in orchestrating an effective vaccine response the next time around. So location does matter.”
To determine the relevance of the animal results to human vaccines, the team at the Kirby Institute also conducted a clinical study with 30 volunteers receiving the Pfizer-BioNTech COVID-19 mRNA vaccine. 20 participants received their booster dose in the same arm as their first dose, while 10 had their second shot in the opposite arm. The results of analyses, the authors reported, indicated that “boosting of vaccine responses in the same arm as the priming dose generates superior depth and breadth of recall responses in the first week.”
Their collective data, the authors stated, “… show that primed SSMs control the quantity and quality of the Bmem recall response in the dLN and provide a rationale for administering the second dose of prime-boost vaccines in the same arm.”
Added Alexandra Carey-Hoppé, co-first author and PhD student from the Kirby Institute, “Those who received both doses in the same arm produced neutralizing antibodies against SARS-CoV-2 significantly faster—within the first week after the second dose.”
“These antibodies from the same arm group, were also more effective against variants like Delta and Omicron,” added Mee Ling Munier, PhD, co-senior author and Vaccine Immunogenomics group leader at the Kirby Institute. “By four weeks, both groups had similar antibody levels, but that early protection could be crucial during an outbreak.”
Munier added, “If you’ve had your COVID jabs in different arms, don’t worry – our research shows that over time the difference in protection diminishes. But during a pandemic, those first weeks of protection could make an enormous difference at a population level. The same-arm strategy could help achieve herd immunity faster—particularly important for rapidly mutating viruses where speed of response matters.”
Beyond the potential to refine vaccination guidelines, the findings offer a promising avenue for enhancing the effectiveness of vaccines. “If we can understand how to replicate or enhance the interactions between memory B cells and these macrophages, we may be able to design next-generation vaccines that require fewer boosters,” Phan pointed out. In their paper the authors concluded “These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.” From their results, they “… identify SSMs and their cell-cell communication with Bmems as potential cellular and molecular targets to improve the depth and breadth of antibody responses and vaccine efficacy.”
The post “Location Does Matter.” Site of Second Vaccine Dose Shapes Immune Response appeared first on GEN - Genetic Engineering and Biotechnology News.