Right arm or left arm for that vaccination? It doesn’t really matter, but scientists suggest that whichever one you offer up for your secondary booster shot might make a difference and affect your immediate immune response.
In fact, they still aren’t sure if it’s better to give that second shot to the same arm or a different one.
Currently, only a handful of studies have explored whether you should switch sides between a first and second jab, and those on Covid vaccines have produced mixed results.
After the pandemic, for instance, researchers in Germany found that giving multiple jabs to the same arm produced better immune responses two weeks later.
Then, a follow-up study from researchers in the US found the exact opposite. According to that randomised trial, switching arms between shots resulted in a four-fold increase in Covid-specific antibodies four weeks after the second jab.
Now there’s been a contradictory finding by researchers in Australia, whose experiments on both humans and mice and agree with the same-arm study.
The trial, led by Dr Rama Dhenni from the Garvan Institute of Medical Research and Alexandra Carey Hoppé from the University of New South Wales (UNSW), involved 30 healthy participants who had not yet had Covid-19.
All participants received two shots of the Pfizer vaccine, three weeks apart – 20 had both shots in the same arm, while 10 got the booster in the opposite arm to the first jab.
Those in the same-arm group showed a boosted immune response in the week after their second shot, according to blood and lymph node analysis.
“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,” said Carey-Hoppé.
“These antibodies from the same arm group were also more effective against variants like Delta and Omicron,” said immunologist Dr Mee Ling Munier from UNSW.
Still, the apparent immune boost from a same-arm vaccination was ultimately short-lived. Four weeks after the booster, those who received a jab in the same arm showed similar antibody levels to those who received a jab in the opposite arm.
This suggests that the strengthened immune response from same-arm vaccinations does not last longer than a month.
“If you've had your Covid jabs in different arms, don’t worry – our research shows that over time the difference in protection diminishes,” Munier said. “But during a pandemic, those first weeks of protection could make an enormous difference at a population level.”
Further research is needed, but Munier suspects that this same-arm vaccine strategy could help achieve herd immunity faster.
To explore why that might be, Munier and colleagues used mouse models. When mice were given a second vaccine to the same side of the body, it increased their immune response in that side’s lymph nodes.
Lymph nodes drain fluid from their respective sides of the body. When a vaccine is administered to one arm, it introduces the corresponding lymph node to a weakened pathogen (or its components).
Immune cells called macrophages, which guard the entry point to the lymph nodes, handcuff these invaders and take them to unique players called memory B cells (Bmems).
These long-lived cells memorise what the danger looks like for future reference, and they also enter a specialised factory within the lymph node to trigger the production of antibodies tailored to that specific invader.
In the mouse models, when a second vaccine was given to the same side of the body, the draining lymph node’s sentinel macrophages were already primed to respond to that threat.
This means they jumped to action faster, communicating with “large clusters of reactivated Bmems” to send 10 times as many Bmems into the antibody factory as the non-draining lymph node.
Similar to the mouse data, when 18 of the human participants had their lymph nodes biopsied with a fine needle, the researchers found those who received a same-arm jab had increased percentages of Bmems in these antibody factories.
While these results are intriguing and shed some much-needed light on how vaccines work to boost our immune systems, Dhenni and colleagues said further research is needed to make any practical recommendations.
The new findings may be more relevant to initial boosters given in quick succession, for instance, not necessarily seasonal vaccines that can be given months, if not years, apart, when immune responses on both sides of the body have time to balance out.
“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,” said immunologist Professor Tri Phan.
The study was published in Cell.
Study details
Macrophages direct location-dependent recall of B cell memory to vaccination
Rama Dhenni, Alexandra Carey Hoppé, Arnold Reynaldi et al.
Published in Cell on 28 April 2025
Highlights
• Memory B cells in the draining lymph node (dLN) re-enter germinal centres when boosted
• Recirculating Bmems in the non-dLN tend to differentiate into plasma cells when boosted
• Primed subcapsular sinus macrophages in the dLN promote resident Bmem GC re-entry
• Vaccine boosting in the same arm promotes GC re-entry and rapid secretion of antibodies
Summary
Vaccines generate long-lived plasma cells and memory B cells (Bmems) that may re-enter secondary germinal centres (GCs) to further mutate their B cell receptor upon boosting and re-exposure to antigen. We show in mouse models that lymph nodes draining the site of primary vaccination harbour a subset of Bmems that reside in the subcapsular niche, generate larger recall responses, and are more likely to re-enter GCs compared with circulating Bmems in non-draining lymph nodes. This location-dependent recall of Bmems into the GC in the draining lymph node was dependent on CD169+ subcapsular sinus macrophages (SSMs) in the subcapsular niche. In human participants, boosting of the BNT162b2 vaccine in the same arm generated more rapid secretion of broadly neutralizing antibodies, GC participation, and clonal expansion of SARS-CoV-2-specific B cells than boosting of the opposite arm. These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.
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