Does your right or left arm make a difference when you get a booster shot? (Photo by Ed Us from Unsplash)
In a nutshell
- Same-arm booster shots trigger a stronger early immune response than shots given in the opposite arm, leading to higher levels of neutralizing antibodies within the first week after vaccination.
- Memory B cells and specialized immune cells cluster in lymph nodes near the original injection site, helping the body respond more quickly and effectively to a follow-up dose in that same location.
- This finding could improve protection during critical early periods of outbreaks, and may apply to other multi-dose vaccines beyond COVID-19, offering a simple way to enhance vaccine effectiveness without changing the formulation.
SYDNEY — Your arm has a memory, at least when it comes to vaccines. A new international study reveals that getting your COVID booster in the same arm as your first shot creates a significantly stronger immune response. This simple change in vaccination practice could improve early immune protection during the critical first week after boosting.
According to research published in Cell, this has to do with memory B cells, specialized immune cells that “remember” previous infections or vaccinations and spring into action when they encounter similar threats again. These cells appear to cluster in the lymph nodes draining from the injection site, creating a localized army ready to mount a faster defense when boosted in the same location.
In experiments with mice, scientists discovered that the draining lymph node (dLN) closest to the initial injection site harbors immune cells that respond much more vigorously to a booster shot than lymph nodes elsewhere in the body. Specifically, memory B cells in the dLN were more likely to re-enter structures called germinal centers, essentially immune boot camps where antibodies undergo further training to become more effective against a pathogen.
To translate this to humans, researchers conducted a clinical study with 30 SARS-CoV-2-naive healthy volunteers receiving the Pfizer-BioNTech vaccine. Twenty participants received their second dose in the same arm as their first, while ten received it in the opposite arm.
Participants who received both doses in the same arm showed significantly higher levels of neutralizing antibodies against COVID-19 variants during the critical early period after vaccination, days 5-7 following their second shot. These same-arm recipients also developed stronger neutralizing responses against numerous COVID variants, including Delta and multiple Omicron subvariants.
The researchers found that specialized immune cells called subcapsular sinus macrophages (SSMs) play a previously unrecognized role in determining the fate of memory B cells following vaccination.
It’s not just the memory B cells themselves that matter, but their relationship with these SSMs. When boosting occurs in the same arm, these cells work in concert to rapidly produce high-quality antibodies.
Next time you’re offered a choice of which arm to receive a vaccine booster, consider using the same arm as your initial dose. While the difference in immune response appears to wane after about 4-6 months, the early advantage could be crucial in rapidly building defenses just days after receiving vaccinations.
Dr Rama Dhenni)
Many healthcare providers alternate arms for injections simply to reduce soreness or let the previous injection site recover. However, based on this research, boosting vaccines in the same arm may now have a solid standing. This could especially be helpful in pandemic scenarios where rapid protection against emerging variants is critical.
And it’s not just COVID-19 vaccines. Other vaccines require multiple doses. By simply standardizing which arm receives both the primary and booster doses, we could enhance protection against numerous diseases without changing the vaccines themselves or requiring more shots.
While the long-term protection evens out regardless of which arm receives the booster, those critical early days after vaccination could mean the difference between infection and immunity during an outbreak. Next time you’re asked “which arm?”, your answer might matter more than you think.
Paper Summary
Methodology
Researchers used both mouse models and human participants to investigate how the location of vaccine boosting impacts immune response. In the mouse studies, they tracked B cell responses to hen-egg lysozyme (HEL) by adoptively transferring HEL-specific B cells and OT-II T cells into mice before primary immunization in one flank. They then compared responses when boosting either the same side (draining lymph node/dLN) or opposite side (non-draining lymph node/ndLN). For the human study, they recruited 30 SARS-CoV-2-naive healthy adults receiving the BNT162b2 mRNA vaccine. Twenty participants received both doses in the same arm, while ten received doses in opposite arms. The researchers collected blood samples at multiple timepoints (pre-boost, days 5-7, 4 weeks, and 4-6 months) and performed fine needle biopsies of lymph nodes on days 5-7 after the second dose in 18 participants to examine immune responses at the cellular level.
Results
In mice, memory B cells residing in lymph nodes draining from the original vaccination site were more likely to reenter germinal centers when boosted on the same side, while memory B cells in non-draining lymph nodes tended to differentiate into plasma cells. This translated to stronger recall responses with more effective antibody production, especially against low-affinity antigens. In the human participants, same-arm boosting generated higher neutralizing antibody levels against ancestral SARS-CoV-2, Delta, and multiple Omicron variants during the early period post-boost (days 5-7). Same-arm vaccination also showed greater germinal center participation and clonal expansion of SARS-CoV-2-specific B cells. Mathematical modeling predicted that these differences would translate to higher vaccine effectiveness during the critical first week after boosting, though differences waned by the 4-week and 4-6 month timepoints.
Limitations
The human study had a relatively small sample size (30 participants). The researchers acknowledge that the BNT162b2 mRNA vaccine generates persistent germinal centers that could influence results differently than in their mouse models using protein antigens. The study focused primarily on early immune responses, and long-term differences between same-arm and opposite-arm boosting were minimal. Additional studies with larger cohorts and different vaccine types would be needed to confirm the generalizability of these findings.
Funding/Disclosures
The project was supported by the Australian National Health and Medical Research Council (NHMRC) Ideas grants, NHMRC Senior Research Fellowship, and NHMRC Investigator grants. Multiple researchers received support from various Australian Government and institutional scholarships. The authors declared no competing interests.
Publication Information
The study titled “Macrophages direct location-dependent recall of B cell memory to vaccination” was published in Cell (Volume 188, 1-20, June 26, 2025) by researchers from the Garvan Institute of Medical Research, Kirby Institute, and other Australian institutions. The lead authors were Rama Dhenni and Alexandra Carey Hoppé, with Tri Giang Phan as lead contact.
