Which Arm Gets Vaccinated Could Matter More Than You Think

Scientists have found that receiving a COVID-19 booster shot in the same arm as the initial dose triggers a faster and more effective immune response, thanks to primed macrophages in nearby lymph nodes.

Scientists in Sydney have discovered that receiving a COVID-19 booster shot in the same arm as the initial vaccine dose can lead to a faster and more effective immune response. The findings, published in Cell and led by researchers from the Garvan Institute of Medical Research and the Kirby Institute at UNSW Sydney, offer valuable insights for optimizing future vaccination strategies.

The study revealed that when a vaccine is injected, immune cells known as macrophages become “primed” in nearby lymph nodes. These primed macrophages play a key role in directing memory B cells, critical components of the immune system, to respond more efficiently to a subsequent booster shot administered in the same location.

Tested in mice and confirmed in human participants, the research supports a targeted approach to vaccination that could significantly boost immune protection by simply choosing the same arm for follow-up doses.

“This is a fundamental discovery in how the immune system organises itself to respond better to external threats – nature has come up with this brilliant system and we’re just now beginning to understand it,” says Professor Tri Phan, Director of the Precision Immunology Program at Garvan and co-senior author.

Scientia Professor Anthony Kelleher, Director of the Kirby Institute and co-senior author says: “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.”

How vaccination site matters

Immunisation introduces a harmless version of a pathogen, known as a vaccine antigen, into the body, which is filtered through lymph nodes – immune ‘training camps’ that train the body to fight off the real pathogen. The researchers previously discovered that memory B cells, which are crucial for generating antibody responses when infections return, linger in the lymph node closest to the injection site.

Memory B cells (red) interacting with macrophages (white) inside a lymph node (blue). Credit: Dr Rama Dhenni

Using state-of-the-art intravital imaging at Garvan, the team discovered that 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 given in the same location, these ‘primed’ macrophages – already on alert – efficiently captured the antigen and activated the memory B cells to make high quality antibodies.

“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,” says Dr Rama Dhenni, the study’s co-first author, who undertook the research as part of his Scientia PhD program at Garvan.

Clinical study validates findings

To determine the relevance of the animal results to human vaccines, the team at the Kirby Institute conducted a clinical study with 30 volunteers receiving the Pfizer-BioNTech COVID-19 mRNA vaccine. Twenty participants received their booster dose in the same arm as their first dose, while 10 had their second shot in the opposite arm.

“Those who received both doses in the same arm produced neutralising antibodies against SARS-CoV-2 significantly faster – within the first week after the second dose,” says Ms Alexandra Carey-Hoppé, co-first author and PhD student from the Kirby Institute.

“These antibodies from the same arm group, were also more effective against variants like Delta and Omicron. By four weeks, both groups had similar antibody levels, but that early protection could be crucial during an outbreak,” says Dr Mee Ling Munier, co-senior author and Vaccine Immunogenomics group leader at the Kirby Institute.

“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.”

Looking ahead

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,” says Professor Phan.

Reference: “Macrophages direct location-dependent recall of B cell memory to vaccination” by Rama Dhenni, Alexandra Carey Hoppé, Arnold Reynaldi, Wunna Kyaw, Nathalie Tricia Handoko, Abigail K. Grootveld, Yuki Honda Keith, Nayan Deger Bhattacharyya, Holly I. Ahel, Aiden Josiah Telfser, Andrew N. McCorkindale, Seyhan Yazar, Christina H.T. Bui, James T. Smith, Weng Hua Khoo, Mollie Boyd, Solange Obeid, Brad Milner, Mitchell Starr, Fabienne Brilot, Vanessa Milogiannakis, Anouschka Akerman, Anupriya Aggarwal, Miles P. Davenport, Elissa K. Deenick, Christine L. Chaffer, Peter I. Croucher, Robert Brink, Leonard D. Goldstein, Deborah Cromer, Stuart G. Turville, Anthony D. Kelleher, Vanessa Venturi, C. Mee Ling Munier and Tri Giang Phan, 28 April 2025, Cell.
DOI: 10.1016/j.cell.2025.04.005

This research was supported by the Australian National Health and Medical Research Council.

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